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Bladder Cancer

Bladder cancer is a disease in which malignant cells arise in the bladder. Symptoms can include blood in the urine, pain during urination, increased frequency of passing urine, or feeling the need to urinate but with nothing coming out. The bulk of bladder cancers are histlogically classed as transitional cell carcinomas which arise in the uroepithelium (lining of the bladder). Other types include squamous cell carcinomas, and adenocarcinomas. Treatment will depend on how far the tumour has invaded the surrounding tissues, and if it has spread to other parts of the body. World-wide about 260,000 people are diagnosed with bladder cancer each year.

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Molecular Biology of Bladder Cancer
Urinary System Cancers

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  • PubMed search for publications about Bladder Cancer - Limit search to: [Reviews]

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    MeSH term: Urinary Bladder Neoplasms
    International US National Library of Medicine
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Patel S, Hafez O, Sexton WJ, Edwards DA
Perioperative Management of a Patient With an Intrathecal Drug Delivery Device Infusing Ziconotide: A Case Report.
A A Case Rep. 2017; 8(4):78-80 [PubMed] Related Publications
Intrathecal ziconotide is used for the treatment of chronic pain and is delivered by an implanted drug delivery device. Anesthesiologists should be familiar with the perioperative management of the pump as well as the potential adverse events related to continued ziconotide infusion during general anesthesia. A case is presented demonstrating the perioperative management of an intrathecal drug delivery device infusing ziconotide in a patient presenting for radical cystectomy with pelvic lymphadenectomy and ileal conduit diversion.

Liu Y, Bui MM, Xu B
Urothelial Carcinoma With Squamous Differentiation Is Associated With High Tumor Stage and Pelvic Lymph-Node Metastasis.
Cancer Control. 2017; 24(1):78-82 [PubMed] Related Publications
BACKGROUND: Squamous differentiation occurs in up to 20% of urothelial carcinoma cases and is thought to be an unfavorable prognostic factor.
METHODS: Data from urothelial carcinoma in patients treated with cystectomy from 2002 to 2014 at Roswell Park Cancer Institute were retrospectively reviewed. A 2-tier system was adopted for stage analysis. T1 and T2 disease were grouped in organ-confined and low-stage categories, whereas T3 and T4 disease were grouped in high-stage categories. The extent of squamous differentiation was semi-quantified as focal (≤20%) or extensive (> 20%).
RESULTS: Squamous differentiation occurred in 19.3% (47 of 244) of cases. Urothelial carcinoma with squamous differentiation presented with a significantly higher rate of high-stage disease compared with pure urothelial carcinoma (72.3% vs 43.1%; P < .01). The nodal metastatic rate in urothelial carcinoma with extensive squamous differentiation was significantly higher than that seen in pure urothelial carcinoma (46.2% vs 27.0%; P = .04).
CONCLUSIONS: Urothelial carcinoma with squamous differentiation is associated with advanced tumor stage. In addition, urothelial carcinoma with extensive squamous differentiation presented with a significantly higher rate of nodal metastasis. These findings can be the contributing factors for the unfavorable clinical outcomes seen in patients with urothelial carcinoma and squamous differentiation.

Nakamura T, Noma Y, Sakurai Y, Harashima H
Modifying Cationic Liposomes with Cholesteryl-PEG Prevents Their Aggregation in Human Urine and Enhances Cellular Uptake by Bladder Cancer Cells.
Biol Pharm Bull. 2017; 40(2):234-237 [PubMed] Related Publications
Intravesical drug delivery by cationic liposomes (Cat-LPs) represents a potent nanotechnology for enhancing therapeutic effects against bladder disorders. However, preventing the aggregation of Cat-LPs in urine poses a significant barrier. We report on an examination of the effect of modifying liposomes with polyethylene glycol (PEG) lipids to prevent Cat-LPs from aggregating in human urine. Although Cat-LPs underwent significant aggregation in human urine, introducing 5 mol% of PEG2k lipid or 2 mol% of PEG5k lipid completely inhibited the aggregation of the Cat-LPs. When 2 mol% of PEG2k lipids were introduced, the lipid structures of 1,2-distearoly-sn-glycero-3-phosphoethanolamine (DSPE) and 1,2-distearoyl-sn-glycerol (DSG) greatly prevented aggregation compared with cholesterol. By contrast, when Cat-LPs, after incubation in urine, were exposed to bladder cancer cells, only introducing cholesteryl-PEG into the Cat-LPs showed a significant enhancement in cellular uptake. These results offer the potential for incorporating cholesteryl-PEG into Cat-LPs for achieving both stability in urine and effective cellular uptake.

Hadami K, Ameziane El Hassani R, Ameur A, et al.
Association between GPX1 Pro189Leu polymorphism and the occurrence of bladder cancer in Morocco.
Cell Mol Biol (Noisy-le-grand). 2016; 62(14):38-43 [PubMed] Related Publications
Worldwide, Bladder cancer is the most frequent male malignancy. It is the third most common male malignancy in Morocco. The risk factors for developing bladder cancer are multiples including dietary conditions, environmental exposure and oxidative stress. GPX1 gene encoding for the human cellular antioxidant enzyme glutathione peroxidase1 is a key factor in the cell detoxification process. GPX1 Pro198Leu polymorphism is associated with a decrease of enzyme activity and may contribute to bladder cancer susceptibility. The present case-control study was planned to assess the presence of GPX1 Pro198Leu polymorphism in Moroccan population to determine whether it is associated with the risk of developing bladder cancer in Moroccan patients. A total of 32 patients with bladder cancer and 40 healthy controls were enrolled. Genotyping of the GPX1 Pro198Leu polymorphism was carried out by PCR amplification and DNA sequencing. Pro198Leu polymorphism was observed in both bladder cancer patients and healthy controls. No significant association between the polymorphism and bladder cancer occurrence was found (Pro/Leu vs. Pro/Pro: p=0.425; Leu vs. Pro: p=0.435). For the analysis of Pro198Leu polymorphism and progression of bladder cancer, no association was observed neither for stages (Pro/Leu vs. Pro/Pro: p=0.500; Leu vs. Pro: p=0.500) nor grades (Pro/Leu vs. Pro/Pro: p=0.415; Leu vs. Pro: p=0.427). Our results clearly showed no significant association between Pro198Leu polymorphism and risk of bladder cancer in our population, suggesting that the effect of this polymorphism on bladder cancer development might be a result of a combination with other genetic alterations and/or non-genetic variables such as diet and lifestyle factors.

Raman SP, Fishman EK
Upper and Lower Tract Urothelial Imaging Using Computed Tomography Urography.
Radiol Clin North Am. 2017; 55(2):225-241 [PubMed] Related Publications
Computed tomography (CT) urography is the best noninvasive method of evaluating the upper urinary tract for urothelial malignancies. However, the utility of CT urography is heavily contingent on the use of proper image acquisition protocols. This article focuses on the appropriate protocols for optimizing CT urography acquisitions, including contrast administration and the timing of imaging acquisitions, as well as the use of ancillary techniques to increase collecting system distention. In addition, imaging findings are discussed that should raise concern for urothelial carcinoma at each of the 3 segments of the urinary tract: the intrarenal collecting systems, ureters, and bladder.

Solinas C, Chanzá NM, Awada A, Scartozzi M
The immune infiltrate in prostate, bladder and testicular tumors: An old friend for new challenges.
Cancer Treat Rev. 2017; 53:138-145 [PubMed] Related Publications
In genito-urinary tumors immunotherapy has been administered for a long time: Calmette-Guèrin Bacillus as adjuvant treatment in high risk patients with non muscle invasive urothelial bladder cancer and interleukin-2 and interferon-α in metastatic kidney cancer. The vaccine Sipuleucel-T has been approved by United States Food and Drug Administration for the treatment of castration resistant prostate cancer patients with asymptomatic or minimally symptomatic disease, given the 22% reduction of mortality risk in this group. Recently immunotherapeutic agents targeting inhibitory immune checkpoint molecules lead to improved outcomes and lasting anti-tumor effects in a variety of hematological and solid malignancies, including urogenital tumors. The benefit from these treatments has been observed only in a proportion of subjects, raising a need in optimizing patients' selection for immune checkpoint blockade. The composition and activity of a pre-existing immune infiltrate may aid in identifying ideal candidates to immunotherapy, with possible implications for the clinical management of neoplastic diseases from earlier to later stages.

Su X, Fang D, Li X, et al.
The Influence of Tumor Size on Oncologic Outcomes for Patients with Upper Tract Urothelial Carcinoma after Radical Nephroureterectomy.
Biomed Res Int. 2016; 2016:4368943 [PubMed] Free Access to Full Article Related Publications
Previous studies have reached diverse conclusions about the influence of tumor size on the oncologic outcomes in patients with upper tract urothelial carcinoma (UTUC). In this study, we retrospectively analyzed the records of 687 patients and evaluated how tumor size affected the prognosis of patients with UTUC after surgery. Clinicopathologic characteristics and oncological outcomes were compared according to tumor size (≤3 cm versus >3 cm). During a median follow-up period of 65 months (range 3-144 months), 225 patients (32.8%) died from UTUC and 228 patients (33.2%) experienced intravesical recurrence (IVR). Patients with a larger tumor size tended to have a significantly higher percentage of being male (p = 0.011), tobacco consumption (p = 0.036), lack of preoperative ureteroscopy history (p = 0.003), renal pelvic location (p < 0.001), tumor necrosis (p = 0.003), advanced tumor stage (p < 0.001), higher tumor grade (p = 0.003), and lymph node metastasis (p = 0.018). Univariate analysis revealed that a tumor size >3 cm was significantly associated with worse cancer-specific survival (p = 0.002) and IVR (p = 0.011). However, the influence was not statistically significant after controlling for other factors in the multivariate analysis (hazard ratio [HR] 1.124, p = 0.414 and HR 1.196, p = 0.219). In conclusion, UTUC patients with a larger tumor present aggressive biological characteristics and tend to have a worse prognosis.

Wang CT, Chen TM, Mei CT, et al.
The Functional Haplotypes of CHRM3 Modulate mRNA Expression and Associate with Bladder Cancer among a Chinese Han Population in Kaohsiung City.
Biomed Res Int. 2016; 2016:4052846 [PubMed] Free Access to Full Article Related Publications
Bladder cancer is one of the major cancer types and both environmental factors and genetic background play important roles in its pathology. Kaohsiung is a high industrialized city in Taiwan, and here we focused on this region to evaluate the genetic effects on bladder cancer. Muscarinic acetylcholine receptor M3 (CHRM3) was reported as a key receptor in different cancer types. CHRM3 is located at 1q42-43 which was reported to associate with bladder cancer. Our study attempted to delineate whether genetic variants of CHRM3 contribute to bladder cancer in Chinese Han population in south Taiwan. Five selected SNPs (rs2165870, rs10802789, rs685550, rs7520974, and rs3738435) were genotyped for 30 bladder cancer patients and 60 control individuals and genetic association studies were performed. Five haplotypes (GTTAT, ATTGT, GCTAC, ACTAC, and ACCAC) were found significantly associated with low CHRM3 mRNA level and contributed to increased susceptibility of bladder cancer in Kaohsiung city after rigid 10000 consecutive permutation tests. To our knowledge, this is the first genetic association study that reveals the genetic contribution of CHRM3 gene in bladder cancer etiology.

Patel R, Bock M, Polotti CF, Elsamra S
Pharmacokinetic drug evaluation of atezolizumab for the treatment of locally advanced or metastatic urothelial carcinoma.
Expert Opin Drug Metab Toxicol. 2017; 13(2):225-232 [PubMed] Related Publications
INTRODUCTION: Muscle invasive bladder cancer (MIBC) is difficult to manage for patients who progress during or after initial chemotherapy regimens. Current regimens offer low response rates with high toxicities. The advent of immune checkpoint inhibitors may represent a new opportunity for effective management of these patients. Areas covered: Atezolizumab is an engineered humanized monoclonal immunoglobulin G1 antibody that binds selectively to PD-L1 and prevents its interaction with PD-1 and B7-1. It is administered intravenously and is given every 3 weeks as long as there is no evidence of tumor progression. Phase I trials confirmed antitumor activity of atezolizumab in patients with advanced or metastatic urothelial carcinoma. Phase II trials showed an improved response rate and a longer durable response than current conventional therapy. Phase III trials are currently underway with an estimated accrual end date of 2017. Expert opinion: MIBC is a high-risk disease, and after progression on current chemotherapy regimens, second-line treatments leave much to be desired. Emerging evidence of efficacy and safety and a recent accelerated approval by the FDA presents atezolizumab as a promising treatment option. Current clinical challenges include the details of disease progression and determining where immune checkpoint inhibition will reside in the treatment algorithm.

Chen A, Liu A, Liu J, et al.
Application of dual-energy spectral CT imaging in differential diagnosis of bladder cancer and benign prostate hyperplasia.
Medicine (Baltimore). 2016; 95(52):e5705 [PubMed] Free Access to Full Article Related Publications
The aim of this study was to explore the clinical value of dual-energy spectral CT imaging in the differential diagnosis between bladder cancer and benign prostate hyperplasia (BPH).We retrospectively analyzed images of 118 patients who received pelvic dual-energy spectral CT imaging. These patients were later confirmed to have bladder cancer in 61 patients and BPH in 57 patients. CT values of the 2 lesion types from 40 to 140 keV were measured from the monochromatic spectral CT image to generate spectral HU curves. The slope of the spectral curve and the lesion effective atomic number were calculated. The measured parameters were analyzed with independent-sample Mann-Whitney U test.There was a statistically significant difference in CT value between the 2 groups from 40 to 90 keV, with the biggest difference at 40 keV (median and interquartile range: 83.3 HU and 22.9 HU vs 60.6 HU and 16.7 HU, Z = 5.932, P < 0.001). The slope of the spectral HU curve for bladder cancer was markedly higher than that of BPH (median and interquartile range: 0.48 and 0.23 vs 0.26 and 0.22, Z = 5.162, P < 0.001); the difference in effective atomic number (median and interquartile range: 7.99 and 0.21 vs 7.80 and 0.20, Z = 5.233, P < 0.001) was also statistically significant.Dual-energy spectral CT imaging provides high sensitivity and specificity for differentiating bladder cancer from benign prostate hyperplasia.

Sun X, Deng Q, Liang Z, et al.
Cigarette smoke extract induces epithelial-mesenchymal transition of human bladder cancer T24 cells through activation of ERK1/2 pathway.
Biomed Pharmacother. 2017; 86:457-465 [PubMed] Related Publications
Bladder cancer is a common genitourinary malignant disease worldwide. Abundant evidence has shown that cigarette smoke (CS) is a crucial risk factor for bladder cancer. Nevertheless, the mechanism underlying the relationship between cigarette smoking and bladder cancer remains unclear. In the present study, we investigated the effects of cigarette smoke extract (CSE) on mitogen-activated protein kinase (MAPK) pathway activation and EMT alterations in human bladder cancer T24 cells, and the preventive effect of extracellular regulated protein kinases 1 and 2 (ERK1/2) inhibitor U0126 was further examined. Our results illustrated that CSE exposure induced morphological change of human bladder cancer T24 cells, enhanced migratory and invasive capacities, reduced epithelial marker expression and elevated mesenchymal marker expression. Meanwhile, exposure of T24 cells to CSE resulted in activation of ERK1/2 pathway as well as activator protein 1 (AP-1) proteins. Interestingly, treatment with ERK1/2 inhibitor U0126 effectively abrogated CSE-triggered EMT and ERK1/2/AP-1 activation. These findings provide novel insight into the molecular mechanisms of CS-associated bladder cancer and may open up new avenues in the search for potential target of bladder cancer intervention.

Manig L, Käsmann L, Janssen S, Rades D
Predicting Survival After Irradiation of Metastases from Transitional Carcinoma of the Bladder.
Anticancer Res. 2016; 36(12):6663-6665 [PubMed] Related Publications
AIM: For patients with metastatic bladder cancer, radiotherapy is a good option to control symptoms and improve outcomes. Potential prognostic factors for survival including the radiation dose were investigated.
PATIENTS AND METHODS: Ten factors were evaluated in 63 patients for association with survival after irradiation namely age, gender, performance status, initial T-category, initial N-category, metastases at initial diagnosis, number of metastases, metastatic sites, radiation dose and time from diagnosis of metastases to irradiation.
RESULTS: On univariate analysis, survival was negatively associated with Karnofsky performance score (KPS) ≤70 (p=0.033), initial N-category ≥1 (p=0.026) and radiation doses given as equivalent dose in 2-Gy fractions (EQD2) <20 Gy. Doses >30 Gy were slightly superior to 20-30 Gy. On multivariate analysis, EQD2 (p=0.015) maintained its significance; a trend was found for N-category (p=0.063) and KPS (p=0.073).
CONCLUSION: Predictors for survival after irradiation of metastases from bladder cancer were identified. Radiation doses ≥20 Gy should be used.

Hancock BM, McGuire KL, Tsuji S, et al.
A Single Intravesical Instillation of VAX014 Inhibits Orthotopic Superficial Bladder Tumor Implantation to Increase Survival.
Anticancer Res. 2016; 36(12):6243-6248 [PubMed] Related Publications
BACKGROUND/AIM: VAX014 minicells (VAX014) have been previously characterized as an integrin-specific oncolytic biotherapeutic agent. The present study was designed to evaluate the potential of VAX014 as an immediate post-operative intravesical adjuvant therapy in the treatment of non-muscle invasive bladder cancer (NMIBC).
MATERIALS AND METHODS: The ability of VAX014 to kill a panel of dissociated urothelial carcinoma cell lines was tested in vitro. In vivo experiments were conducted using a single intravesical dose of VAX014 in the anti-implantation variation of the MB49 syngeneic orthotopic bladder cancer model with tumor implantation and overall survival rates serving as study endpoints.
RESULTS: VAX014 rapidly killed dissociated urothelial carcinoma cells, while single dose in vivo pharmacology studies demonstrated the dose-dependent ability of VAX014 to prevent tumor implantation and development, ultimately resulting in a significant survival advantage compared to controls.
CONCLUSION: These results suggest that VAX014 holds potential as an immediate post-operative adjuvant therapy in NMIBC.

Lázaro M, Gallardo E, Doménech M, et al.
SEOM Clinical Guideline for treatment of muscle-invasive and metastatic urothelial bladder cancer (2016).
Clin Transl Oncol. 2016; 18(12):1197-1205 [PubMed] Free Access to Full Article Related Publications
The goal of this article is to provide recommendations for the diagnosis and treatment of muscle-invasive and metastatic bladder cancer. The diagnosis of muscle-invasive bladder cancer is made by pathologic evaluation after transurethral resection. Recently, a molecular classification has been proposed. Staging of muscle-invasive bladder cancer must be done by computed tomography scans of the chest, abdomen and pelvis and classified on the basis of UICC system. Radical cystectomy and lymph node dissection are the treatment of choice. In muscle-invasive bladder cancer, neoadjuvant chemotherapy should be recommended in patients with good performance status and no renal function impairment. Although there is insufficient evidence for use of adjuvant chemotherapy, its use must be considered when neoadjuvant therapy had not been administered in high-risk patients. Multimodality bladder-preserving treatment in localized disease is an alternative in selected and compliant patients for whom cystectomy is not considered for clinical or personal reasons. In metastatic disease, the first-line treatment for patients must be based on cisplatin-containing combination. Vinflunine is the only drug approved for use in second line in Europe. Recently, immunotherapy treatment has demonstrated activity in this setting.

Zhang N, Jiang G, Liu X, et al.
Prediction of Bacillus Calmette-Guerin Response in Patients with Bladder Cancer after Transurethral Resection of Bladder Tumor by Using Genetic Variation Based on Genomic Studies.
Biomed Res Int. 2016; 2016:9859021 [PubMed] Free Access to Full Article Related Publications
Purpose. We aimed to comprehensively review contemporary literature on genetic and epigenetic biomarkers associated with the prediction of Bacillus Calmette-Guerin (BCG) response after the transurethral resection of a bladder tumor and to discuss the application of these biomarkers in precision cancer care for bladder cancer. Method. We performed a systematic review of published literatures in the databases PubMed and Embase by using the following key words: bladder cancer, BCG, gene, and methylation. Studies associated with cell lines, animal models, and muscle invasive bladder cancer were excluded. Results. The genetic variations associated with BCG response can be classified into three categories: germline variations, somatic variations, and epigenetic alterations. Genes related to BCG response were mainly involved in single-nucleotide polymorphisms, copy number variations, and gene methylations. Conclusions. Although these gene alterations are currently the most promising predictive markers of BCG response, most studies about bladder cancer DNA biomarkers are related to germline variations in candidate genes, and the results are not consistent. Only one study is related to somatic variation, and further evaluation in large-scale validation studies should be conducted to assess the potential clinical application of these findings. In addition, other biomarkers based on different "-omics" technologies should be considered in future studies.

Strojan Fležar M, Srebotnik-Kirbiš I, Gutnik H
Use of vimentin immunocytochemical staining for evaluation of atypical cells in voided urine samples.
Diagn Cytopathol. 2017; 45(2):85-90 [PubMed] Related Publications
BACKGROUND: Cytomorphology of exfoliated atypical reactive/repair renal tubular cells (RRTC) can resemble atypical urothelial cells thus suggesting a differential diagnostic question of urothelial neoplasia in urinary cytology. Vimentin expression has been shown in RRTC and used for differentiation from atypical urothelial cells.
METHODS: The institutional computer database was searched for urinary cytology cases with vimentin immunocytochemical staining (2008-2012). Original cytopathological diagnoses based on cytomorphology and the results of vimentin immunostaining were compared to follow-up data, including histopathological diagnosis, subsequent urinary cytopathology reports, and clinical findings.
RESULTS: Of the 42 cases with vimentin immunocytochemical staining, 33 were positive and 9 negative. Consequently, significant renal disease was found in 9/33 (27%) of vimentin positive cases and nehrolithiasis in 4/33 (12%) of vimentin positive and 1/9 (11%) of vimentin negative cases. Erythrocyturia of undetermined origin was diagnosed in nine cases (seven vimentin positive and two negative). Urinary cytology follow-up was negative in three vimentin positive cases. Urothelial carcinoma was found in 3/9 (30%) of vimentin negative cases. Thirteen patients were lost to follow-up.
CONCLUSIONS: Vimentin immunocytochemical staining could be used as an ancillary method for evaluation of atypical cells in urinary specimens in selected cases with RRTC exhibiting cytological atypia. Unnecessary diagnostic procedures for evaluation of urothelial carcinoma could be avoided in vimentin positive cases and further diagnostic work-up for evaluation of a significant renal disease could be suggested in vimentin positive cases. Diagn. Cytopathol. 2017;45:85-90. © 2016 Wiley Periodicals, Inc.

Courtade-Saïdi M, Aziza J, d'Aure D, et al.
Immunocytochemical staining for p53 and Ki-67 helps to characterise urothelial cells in urine cytology.
Cytopathology. 2016; 27(6):456-464 [PubMed] Related Publications
OBJECTIVE: The presence of atypical cells in urine cytology is unsatisfactory for both cytologists and clinicians. The objective of this study was to test whether p53 and Ki-67 immunostaining could improve urothelial carcinoma (UC) detection on urinary cytology.
METHODS: A total of 196 urine samples were analysed, 142 from the bladder, 41 from the upper tract and 13 from ileal bladder replacement. Cytology results were expressed as normal (N) (n = 81), atypia cannot exclude low-grade UC (ALG) (n = 25), suspicious for high-grade UC (SHG) (n = 39) and high-grade UC (HG) (n = 51). Actual diagnoses were confirmed by histopathological analysis, cystoscopic examination or follow-up for at least 1 year. Immunocytochemistry performed on CytoSpin(™) slides allowed the determination of the percentage of positive cells with p53 and Ki-67.
RESULTS: The median percentage values [first to third quartile] of p53 and Ki-67 were 0 [0-5] and 0 [0-1] for N cytology, 5 [0-40] and 2 [1-10] for ALG, 10 [0-30] and 6 [3-25] for SHG, and 30 [10-80] and 20 [10-30] for HG, respectively. Statistically higher values were observed for both tests (P < 0.001) in positive cytologies (ALG, SHG and HG). The optimal cut-offs were 5% for p53 and 3% for Ki-67. The sensitivity and specificity for the detection of all UC were 86.4% and 76.7% for cytology alone, 81.3% and 93.2% for cytology and p53, 75.7% and 88% for cytology and Ki-67, and 68.9% and 97.5% for cytology, p53 and Ki-67, respectively.
CONCLUSION: Using p53 and/or Ki-67 in addition to cytology increases the specificity without penalising the sensitivity.

Manley KV, Hubbard R, Swallow D, et al.
Risk factors for development of primary bladder squamous cell carcinoma.
Ann R Coll Surg Engl. 2017; 99(2):155-160 [PubMed] Related Publications
INTRODUCTION The aim of this study was to investigate the prevalence of risk factors for primary squamous cell carcinoma (SCC) of the bladder. MATERIALS A total of 90 cases of primary SCC of the bladder were identified through multicentre analysis. Patient demographics, stage and grade of cancer at presentation, management and outcomes were recorded. The presence of known risk factors (catheter use, neuropathic bladder, smoking history, recurrent urinary tract infection and bladder stones) was also documented. RESULTS Over half of the patients had at least one identifiable risk factor for the development of primary bladder SCC: 13.9% of patients had a history of catheter use (clean intermittent self-catheterisation [CISC] in 11.1%), 10.0% of patients had a neuropathic bladder, 27.8% were smokers or ex-smokers and 20.0% had a documented history of recurrent urinary tract infection. Statistical analysis of the results showed no association between risk factors and grade of tumour at presentation. CONCLUSIONS These data further support the association between primary bladder SCC and several of the well documented risk factors for its development. Chronic use of CISC may confer a greater risk for development of SCC than thought previously. Further evidence of the role of CISC in primary SCC is required to justify routine screening and to determine exactly when surveillance of the bladder should begin for this group of patients.

Tokas T, Avgeris M, Alamanis C, et al.
Downregulated KLK13 expression in bladder cancer highlights tumor aggressiveness and unfavorable patients' prognosis.
J Cancer Res Clin Oncol. 2017; 143(3):521-532 [PubMed] Related Publications
PURPOSE: Despite recent research advantages on the molecular and subcellular background, bladder cancer (BlCa) remains a clinically neglected malignancy. This is strongly reflected by the generic approach of disease diagnosis and management. Additionally, patients' prognosis became a rather demanding task due to the great disease heterogeneity. Here, we aimed to evaluate, for the first time, the clinical value of KLK13 in BlCa.
METHODS: A total of 279 bladder specimens (137 tumors, 107 adjacent normal tissues and 35 healthy samples) were included. Total RNA was extracted, reverse transcribed, and KLK13 expression was assessed by quantitative real-time PCR.
RESULTS: KLK13 expression is significantly increased in bladder tumors compared to normal adjacent epithelium. However, reduced KLK13 expression is correlated with disease aggressiveness, including higher tumor stage and grade, and high-risk TaT1 tumors according to the EORTC stratification. Moreover, Kaplan-Meier and Cox regression analysis highlighted the prognostic value of the reduced KLK13 expression for the prediction of TaT1 patients' recurrence and shorter disease-free survival following TURBT. Finally, the combination of KLK13 expression with EORTC-risk stratification results to an improved prediction of TaT1 patients' outcome.
CONCLUSION: This first clinical study of KLK13 in BlCa reveals its deregulated expression in bladder tumors and highlights KLK13 as a promising marker for improving TaT1 patients' prognosis following treatment.

Granados R, Duarte JA, Corrales T, et al.
Applying the Paris System for Reporting Urine Cytology Increases the Rate of Atypical Urothelial Cells in Benign Cases: A Need for Patient Management Recommendations.
Acta Cytol. 2017; 61(1):71-76 [PubMed] Related Publications
The Paris System (TPS) for reporting urinary cytology attempts to unify the terminology in this field.
OBJECTIVES: To analyze the impact of adopting TPS by measuring nomenclature agreement and cytohistological correlation.
MATERIALS AND METHODS: Voided urine liquid-based cytology samples corresponding to 149 biopsy-proven cases (76 high-grade carcinomas, 40 low-grade carcinomas, and 33 benign lesions), were reclassified by the same pathologist using TPS. Diagnostic agreement and sensitivity for both nomenclature systems was measured.
RESULTS: When using TPS, the rate of atypical samples increased 8 times (from 3 to 24.2%) in benign cases, 10 times (from 2.5 to 25%) in low-grade carcinomas, and 2.4 times (from 6.6 to 15.8%) in high-grade carcinomas. The false-positive rate (abnormal cytology in negative or low-grade carcinoma cases) increased from 11 to 34.2%. Sensitivity was higher (63 vs. 49%) with TPS at the expense of a lower specificity (73 vs. 91%). The agreement between both nomenclatures was moderate for negative and high-grade carcinoma cases (k = 0.42 and 0.56, respectively) and weak for low-grade tumors (k = 0.35).
CONCLUSIONS: Adopting TPS for reporting urine cytology results in a considerable increase in atypical diagnoses, improving sensitivity but lowering specificity. Appropriate management recommendations for patients with an atypical cytological diagnosis are required.

Li X, Liu S
Suppression of HBXIP Reduces Cell Proliferation, Migration and Invasion In Vitro, and Tumorigenesis In Vivo in Human Urothelial Carcinoma of the Bladder.
Cancer Biother Radiopharm. 2016; 31(9):311-316 [PubMed] Related Publications
Hepatitis B X-interacting protein (HBXIP) has been found overexpressed in several types of human cancer, however, the status of HBXIP expression in urothelial carcinoma of the bladder (UCB) has not been explored. In this study, the authors used real-time polymerase chain reaction and Western blot to test the expression of HBXIP in UCB and adjacent tissues. The expression of HBXIP was significantly increased in UCB tissues. In addition, they showed that suppression of HBXIP induced cell cycle arrest and increased cell apoptosis in T24 cells. Also, suppression of HBXIP also decreased T24 and PC3 cell proliferation, migration, and invasion. More importantly, the authors found that inhibition of HBXIP reduced the tumorigenesis in vivo, suggesting that HBXIP plays an important role in UCB progression. These data for the first time showed that HBXIP acts as an oncoprotein in UCB, suggesting that HBXIP may become a potential novel therapeutic target for the treatment of UCB.

Wu YP, Lin TT, Chen SH, et al.
Comparison of the efficacy and feasibility of en bloc transurethral resection of bladder tumor versus conventional transurethral resection of bladder tumor: A meta-analysis.
Medicine (Baltimore). 2016; 95(45):e5372 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The aim of this meta-analysis was to compare the feasibility of en bloc transurethral resection of bladder tumor (ETURBT) versus conventional transurethral resection of bladder tumor (CTURBT).
METHODS: Relevant trials were identified in a literature search of MEDLINE, EMBASE, Cochrane Library, Web of Science, and Google Scholar using appropriate search terms. All comparative studies reporting participant demographics, tumor characteristics, study characteristics, and outcome data were included.
RESULTS: Seven trials with 886 participants were included, 438 underwent ETURBT and 448 underwent CTURBT. There was no significant difference in operation time between 2 groups (P = 0.38). The hospitalization time (HT) and catheterization time (CT) were shorter in ETURBT group (mean difference[MD] -1.22, 95% confidence interval [CI] -1.63 to -0.80, P < 0.01; MD -0.61, 95% CI -1.11 to -0.11, P < 0.01). There was significant difference in 24-month recurrence rate (24-month RR) (odds ratio [OR] 0.66, 95% CI 0.47-0.92, P = 0.02). The rate of complication with respect to bladder perforation (P = 0.004), bladder irritation (P < 0.01), and obturator nerve reflex (P < 0.01) was lower in ETURBT. The postoperative adjuvant intravesical chemotherapy was evaluated by subgroup analysis, and 24-month RR in CTURBT is higher than that in ETURBT in mitomycin intravesical irrigation group (P = 0.02).
CONCLUSION: The first meta-analysis indicates that ETURBT might prove to be preferable alternative to CTURBT management of nonmuscle invasive bladder carcinoma. ETURBT is associated with shorter HT and CT, less complication rate, and lower recurrence-free rate. Moreover, it can provide high-qualified specimen for the pathologic diagnosis. Well designed randomized controlled trials are needed to make results comparable.

Liu J, Li D, Cao L, et al.
Elevated preoperative plasma fibrinogen level is an independent predictor of malignancy and advanced stage disease in patients with bladder urothelial tumors.
Int J Surg. 2016; 36(Pt A):249-254 [PubMed] Related Publications
PURPOSE: To investigate the association between preoperative plasma fibrinogen levels and clinicopathological features in patients with bladder urothelial tumors.
METHODS: In this retrospective single-center study, we evaluated preoperative plasma fibrinogen levels in 503 patients newly diagnosed with bladder urothelial tumors between January 2009 and October 2014. All patients received surgical intervention as the primary treatment method. Associations between preoperative plasma fibrinogen levels and clinicopathological parameters were analyzed. Univariate and multivariate logistic regression analyses were performed to identify independent associations.
RESULTS: The mean preoperative fibrinogen level in patients with bladder urothelial carcinoma (BUC) was significantly higher than that in patients with papilloma or papillary urothelial neoplasm of low malignant potential (PUNLMP) (P = 0.004). Additionally, patients with BUC with advanced-stage disease showed elevated plasma fibrinogen levels compared to patients with early-stage disease (high-grade BUC vs. low-grade BUC: P = 0.002; muscle-invasive BUC vs. non-muscle-invasive BUC: P = 0.010). In a multivariate regression model, a plasma fibrinogen level >3.04 g/L was identified to be independently associated with the presence of BUC (hazard ratio [HR] = 1.653, P = 0.047), high-grade BUC (HR = 1.869, P = 0.004), and muscle-invasive BUC (HR = 1.870, P = 0.044).
CONCLUSIONS: Elevated preoperative plasma fibrinogen level is an independent predictor of malignancy as well as advanced-stage carcinoma in patients with bladder urothelial tumors, suggesting that plasma fibrinogen may be a promising diagnostic and prognostic biomarker for bladder tumors.

Tagliabue L, Russo G, Lucignani G
18F-FDG PET/CT in Bladder Cancer.
Clin Nucl Med. 2016; 41(12):e522-e524 [PubMed] Related Publications
Urinary clearance of F-FDG and variability in bladder wall FDG uptake may hamper the interpretation and limit the use of FDG-PET/CT for imaging bladder tumors. Nevertheless, careful combined evaluation of both CT and FDG-PET images of the urinary tract can provide useful findings. We present 2 cases of bladder cancer detected by FDG-PET/CT. These cases suggest that FDG uptake can be indicative of malignancy in bladder cancer when viewed in conjunction with CT scans and that whole-body FDG-PET/CT scans should always be reviewed with particular attention to the urinary tract because abnormalities suggestive of bladder cancer can be found unexpectedly.

Ohtake S, Kawahara T, Kasahara R, et al.
Pretreatment Neutrophil-to-Lymphocyte Ratio Can Predict the Prognosis in Bladder Cancer Patients Who Receive Gemcitabine and Nedaplatin Therapy.
Biomed Res Int. 2016; 2016:9846823 [PubMed] Free Access to Full Article Related Publications
Introduction and Objectives. Neutrophil-to-lymphocyte ratio (NLR) has been suggested to be a simple marker of the systemic inflammatory response in critical care patients. We previously assessed the utility of NLR as a biomarker to predict tumor recurrence and cancer death in bladder cancer patients who underwent radical cystectomy. In this study, we evaluated the prognostic impact of NLR in bladder cancer patients who received gemcitabine and nedaplatin (GN) chemotherapy. Methods. A total of 23 patients who received GN chemotherapy for advanced bladder cancer were enrolled in this study. The cut-off point of NLR according to the sensitivity and specificity levels was derived from the area under receiver operator characteristics (AUROC) curve plotted for disease progression or overall mortality. Results. The NLR cut-off point was determined as 4.14 for both tumor progression and overall mortality. Median progression-free survival (PFS)/overall survival (OS) in the higher NLR group (NLR ≥ 4.14) and lower NLR group (NLR < 4.14) were 194/468 days versus 73/237 days, respectively. Kaplan-Meier analysis showed that higher NLR significantly correlated with poorer PFS (p = 0.011) and OS (p = 0.045). Conclusions. NLR may serve as a new biomarker to predict responses to GN-based chemotherapy in advanced bladder cancer patients and/or their prognosis.

Chen YJ, Wang HF, Liang M, et al.
Upregulation of miR-3658 in bladder cancer and tumor progression.
Genet Mol Res. 2016; 15(4) [PubMed] Related Publications
Despite increasing advances in surgical techniques and adjuvant chemotherapies, bladder cancer remains the ninth leading cause of male malignancy-associated deaths worldwide. Several microRNAs (miRNAs) have been identified to be closely associated with the progression and prognosis of, and response to treatments in various human cancers. However, few studies have investigated the role of miR-3658 in bladder cancer. In this study, we examined the expression of miR-3658 in 96 pairs of bladder cancer tissues and adjacent non-tumor tissues via quantitative reverse-transcription polymerase chain reaction. Results showed that expression of miR-3658 was up-regulated in the bladder cancer tissues as compared with that in the corresponding control tissues (4.15 ± 2.78 vs 2.17 ± 1.14; P < 0.0001). Furthermore, higher miR-3658 expression was significantly associated with lymph node invasion, distant metastasis, histological grade, TNM stage, and tumor recurrence in bladder cancer (all P < 0.0001). miR-3658 expression was not associated with other clinicopathological variables such as age, gender, tumor size, and number (all P > 0.05). Our study revealed that miR-3658 overexpression is involved in tumor progression of bladder cancer, indicating that the miRNA possesses prognostic values.

Zhou M, Wang S, Hu L, et al.
miR-199a-5p suppresses human bladder cancer cell metastasis by targeting CCR7.
BMC Urol. 2016; 16(1):64 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: C-C chemokine receptor type 7 (CCR7) overexpression correlated with lymphatic metastasis and poor prognosis is a major obstacle to bladder cancer treatment. Recent studies have revealed that miR-199a-5p was significantly abnormal expressed in several solid tumors and functioned as oncogene or tumor suppressor. This study was aimed to further investigate the effects of miR-199a-5p on the cell metastasis mediated by CCR7 in bladder cancer.
METHODS: Quantitative Real Time PCR (qRT-PCR) was firstly performed to identified the expression of miR-199a-5p and CCR7 in human bladder cancer samples and cell lines. Following that, the effects of miR-199a-5p on cell migratory and invasive activities were assessed by wound healing and Matrigel invasion assays, respectively. Finally, luciferase reporter assay and western blot were employed to investigate whether CCR7 could directly interact with miR-199a-5p.
RESULTS: miR-199a-5p downregulation and CCR7 upregulation were firstly observed in bladder cancer samples and cell lines. In addition, both miR-199a-5p downregulation and CCR7 upregulation were significantly involved in bladder cancer clinicopathological features. Moreover, overexpression of miR-199a-5p could inhibit baldder cancer cell migration and invasion. miR-199a-5p was confirmed to be able to target the 3' untranslated region (UTR) of CCR7 and regulate the expression of CCR7, Matrix metalloproteinases 9 (MMP-9) and Epithelial-Mesenchymal Transition (EMT)-related proteins.
CONCLUSION: Our findings added newer insights into the multifaceted role played by miR-199a-5p/CCR7 in bladder cancer, prompting for the first time this miRNA/chemokine axis that regulates cell metastasis. The results strongly supported miR-199a-5p as a potential therapeutic agent and diagnostic marker of bladder cancer.

Anzivino E, Zingaropoli MA, Iannetta M, et al.
Archetype and Rearranged Non-coding Control Regions in Urothelial Bladder Carcinoma of Immunocompetent Individuals.
Cancer Genomics Proteomics. 2016 11-12; 13(6):499-509 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Polyomaviruses (PyVs) are potential transforming viruses. Despite their involvement in human tumours still being debated, there is evidence to suggest a role for PyVs in bladder carcinoma (BC). Therefore, a possible association between PyVs and BC was investigated.
MATERIALS AND METHODS: Urine, blood and fresh bladder tissue specimens were collected from 29 patients with BC. PyV prevalence, non-coding control region (NCCR) organization and genotypic analysis were assessed.
RESULTS: Data showed a significant prevalence of John Cunningham (JC) PyV in BC tissues and in urine with respect to BKPyV, while simian virus 40 was not revealed. A BKPyV rearranged NCCR sequence was isolated, whereas a JCPyV archetypal structure was consistently retained. A prevalence of European genotypes was observed.
CONCLUSION: Our data would suggest a JCPyV involvement in cancer progression and a BKPyV association with BC pathogenesis in immunocompetent patients. However, further work is necessary to better understand the exact role of PyVs in urothelial carcinogenesis.

Abdel-Gawad M, Elsobky E, Shalaby MM, et al.
Quantitative Evaluation of Heavy Metals and Trace Elements in the Urinary Bladder: Comparison Between Cancerous, Adjacent Non-cancerous and Normal Cadaveric Tissue.
Biol Trace Elem Res. 2016; 174(2):280-286 [PubMed] Related Publications
The role of heavy metals and trace elements (HMTE) in the development of some cancers has been previously reported. Bladder carcinoma is a frequent malignancy of the urinary tract. The most common risk factors for bladder cancer are exposure to industrial carcinogens, cigarette smoking, gender, and possibly diet. The aim of this study was to evaluate HTME concentrations in the cancerous and adjacent non-cancerous tissues and compare them with those of normal cadaveric bladder. This prospective study included 102 paired samples of full-thickness cancer and adjacent non-cancerous bladder tissues of radical cystectomy (RC) specimens that were histologically proven as invasive bladder cancer (MIBC). We used 17 matched controls of non-malignant bladder tissue samples from cadavers. All samples were processed and evaluated for the concentration of 22 HMTE by using Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES). Outcome analysis was made by the Mann-Whitney U, chi-square, Kruskal-Wallis, and Wilcoxon signed ranks tests. When compared with cadaveric control or cancerous, the adjacent non-cancerous tissue had higher levels of six elements (arsenic, lead, selenium, strontium, zinc, and aluminum), and when compared with the control alone, it had a higher concentration of calcium, cadmium, chromium, potassium, magnesium, and nickel. The cancerous tissue had a higher concentration of cadmium, lead, chromium, calcium, potassium, phosphorous, magnesium, nickel, selenium, strontium, and zinc than cadaveric control. Boron level was higher in cadaveric control than cancerous and adjacent non-cancerous tissue. Cadmium level was higher in cancerous tissue with node-positive than node-negative cases. The high concentrations of cadmium, lead, chromium, nickel, and zinc, in the cancerous together with arsenic in the adjacent non-cancerous tissues of RC specimens suggest a pathogenic role of these elements in BC. However, further work-up is needed to support this conclusion by the application of these HMTE on BC cell lines.

Iwamoto H, Izumi K, Shimura Y, et al.
Metastasectomy Improves Survival in Patients with Metastatic Urothelial Carcinoma.
Anticancer Res. 2016; 36(10):5557-5561 [PubMed] Related Publications
Metastatic urothelial carcinoma is one of the most fatal urological malignancies. Cisplatin-based systemic chemotherapy is the standard treatment for metastatic urothelial carcinoma, and there is little evidence to support metastasectomy. The aims of the study were to evaluate the efficacy of metastasectomy and to investigate the prognoses of the patients. The study included 436 patients with urothelial carcinoma who were treated at our hospital. Of these, we included and retrospectively analyzed 29 patients who received curative treatment for the primary tumor and had been treated for metastases. Seven of these patients underwent metastasectomy. In a multivariate analysis, a serum C-reactive protein level before treatment for metastasis of <1 mg/dl and metastasectomy were independent significant predictors of both better progression-free survival and better overall survival. Metastasectomy may be considered a potential treatment for patients with metastases from urothelial carcinoma.

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