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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]

    PubMed Central search for free-access publications about Bladder Cancer
    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).

Viriyasiripong S
Laparoscopic Radical Cystoprostatectomy, Surgical Technique and Result: A Case Report.
J Med Assoc Thai. 2015; 98 Suppl 10:S154-7 [PubMed] Related Publications
OBJECTIVE: Laparoscopic radical cystoprostatectomy is a complicated operation. The objective of this study is to present our technique and results of laparoscopic radical cystoprostatectomy.
MATERIAL AND METHOD: A 72-year-old Thai male presented with gross hematuria. Cystoscope was performed. Large bladder tumor near right ureteric orifice was observed. Then, transurethral resection of bladder tumor was performed. His tumor pathology was muscle invasive high grade urothelial carcinoma with clinical staging T2N0M0. Laparoscopic radical cystoprostatectomy was then conducted with bilateral pelvic nodes dissection and ileal conduit.
RESULTS: Operation period was eight hours. Blood loss was 500 ml. In pathological results, tumor invaded bladder muscle into perivesical tissue. Tumor margin was free. Lymph nodes were positive for malignancy 5/7 for right side and 0/4 for left side. Pathological staging was T3aN1M0. After post-operative period, the patient was discharged from hospital uneventfully.
CONCLUSION: Laparoscopic radical cystoprostatectomy in Maha Chakri Sirindhorn Medical Center is minimal invasive, feasible and safe. However, a longer follow-up period regarding long-term cancer control as well as functional and technical aspects will be required.

Wang K, Tian Y, Xu H
Improved Noninvasive Bladder Cancer Diagnosis using Urine Sediments and Novel DNA Methylation Biomarker Panels.
Clin Lab. 2016; 62(3):327-36 [PubMed] Related Publications
BACKGROUND: Aberrant DNA methylation status early in carcinogenesis represents a potential indicator of tumor detection. We would like to establish a DNA methylation biomarker panel for bladder cancer detection in the research.
METHODS: Seven candidate genes with known cancer associations were selected for this study. The DNA methylation status of the candidate genes was analyzed by methylation-specific polymerase chain reaction assays to evaluate the relationship between bladder cancer and target gene methylation status in the urine sediments of participants.
RESULTS: 112 bladder cancer patients, 10 healthy volunteers, and 17 glandular cystitis patients were enrolled. There were significant differences in the methylation status of p14ARF, RUNX3, RARβ, DAPK, and HPP1 between the healthy control, glandular cystitis, and bladder cancer groups (p = 0.027, p < 0.001, p < 0.001, p = 0.030 and p = 0.003, respectively). A panel composed of all five genes with significant methylation differences yielded an area under the receiver-operating characteristic curve (AUC) of 0.936 and had 98.21% sensitivity and 88.89% specificity, while a panel using just two of these genes (RUNX3 and RARP) yielded an AUC of 0.918 with 96.64% sensitivity and 88.89% specificity. Another panel of two genes (p14ARF and HPP1) had 100% specificity, but an AUC of 0.688 and 37.50% sensitivity.
CONCLUSIONS: Using the urine of bladder cancer patients and healthy controls, we assessed several novel DNA methylation biomarker panels that demonstrated good bladder cancer detection capability. Based on the results of this study we recommend the RUNX3 and RARβ panel as the first choice for bladder cancer detection. In suspicious or difficult to diagnose cases, the p14ARF and HPP1 panel could be used as an additional diagnostic tool due to its high specificity.

Mirjalili SM, Hashemipour S, Salehi S, et al.
Thyroid metastasis of bladder transitional cell carcinoma.
Malays J Pathol. 2016; 38(1):65-70 [PubMed] Related Publications
The thyroid gland is a rare site for cancer metastasis. We report a 75-year-old man who was referred with a history of hematuria and generalized bone pain for the past few months. He had a past history of partial left lobe thyroidectomy for follicular adenoma. Subsequently he was referred for a thyroid mass and a subtotal thyroidectomy showed a poorly-differentiated carcinoma. On the latest admission, the patient underwent resection of a bladder tumour with malignant histology and an immunohistochemical profile of CK7+/CK20+/34 Beta E12+/CEA-/PSA-. Re-examination of thyroid sections with immunohistochemical stains revealed the malignant cells to be CK7+/CK20+/34 Beta E12+/CEA-/TTF1-. The findings were compatible with metastasis of the bladder transitional cell carcinoma to the thyroid gland.Scans revealed multiple liver and bone metastases. The patient died 2 months after the diagnosis.

Białecki J, Nowak-Misiak M, Rąpała K, et al.
Spinal tuberculosis with severe neurological symptoms as a complication of intravesical BCG therapy for carcinoma of the bladder.
Neurol Neurochir Pol. 2016; 50(2):131-8 [PubMed] Related Publications
INTRODUCTION: Non-invasive bladder cancer is effectively treated with intravesical BCG therapy. The administration of the BCG vaccine is to destroy the neoplastic lesion or prevent further recurrences. The activity of the vaccine involves boosting the immune system through the stimulation of the inflammation in the bladder. Adverse reactions after this immunotherapy are rare. The aim of the study was to present complications in the form of spinal tuberculosis and serious neurological symptoms that occurred during intravesical BCG immunotherapy for carcinoma of the bladder. The manuscript also describes a method for neurosurgical spinal cord decompression of the thoracic spine.
MATERIAL AND METHODS: In the first patient, aged 66, after intravesical BCG therapy for bladder carcinoma, back pain and spastic paralysis of the lower limbs were observed. The MRI and CT revealed destruction of the intervertebral disc and vertebral endplates Th11-Th12. Mycobacterium tuberculosis complex bacilli were cultured from the material obtained by puncture aspiration. In the second patient, aged 35 years, during intravesical BCG immunotherapy for carcinoma of the bladder, girdle thoracic spine pain was observed. The MRI and CT of the spine showed visible lesions characteristic of tuberculosis. Immobilization in a plaster corset and implementation of antituberculous treatment resulted in quick relief of the pain and healing of the tuberculosis focus in the spine.
CONCLUSION: The cases described in the work are the first documented reports in the Polish literature of spinal tuberculosis which occurred as a complication of intravesical administration of bacilli Calmette-Guérin. The diagnosis was based on the finding of BCG vaccine bacillus with molecular methods or PCR. Full antimycobacterial treatment was implemented.

Han E, Jang SY, Kim G, et al.
Rosiglitazone Use and the Risk of Bladder Cancer in Patients With Type 2 Diabetes.
Medicine (Baltimore). 2016; 95(6):e2786 [PubMed] Free Access to Full Article Related Publications
Patients with diabetes have a higher incidence of bladder cancer; however, the association between thiazolidinedione use and bladder cancer risk has been controversial. We aimed to investigate whether pioglitazone or rosiglitazone use is associated with bladder cancer risk in patients with type 2 diabetes mellitus.This nationwide nested case-control study used data set obtained from the Korean National Health Insurance Service National Sample Cohort 2002 to 2013. Among the 47,738 patients with incident diabetes, 85 cases of newly diagnosed bladder cancer and 850 controls (1:10 matched by age, sex, index year, and diabetes diagnosis year) were recruited. Type 2 diabetes mellitus and bladder cancer were diagnosed using the International Statistical Classification of Diseases and Related Health Problems, 10th Revision code.More cases of bladder cancer were diagnosed in men (81.2%), and the stratified age peaked at 70 to 79 years old. Exclusive rosiglitazone use raised the incidence of bladder cancer (odds ratio [OR] = 3.07, 95% confidence interval [CI ] = 1.48-6.37). The risk of bladder cancer started to increase after less than 3 months use (OR = 3.30, 95% CI = 1.02-10.70) and peaked at 3 to 12 months of rosiglitazone use (OR = 4.48, 95% CI = 1.51-13.31). Patients were first exposed to exclusive rosiglitazone within 1 year (OR = 11.74, 95% CI = 2.46-56.12) and those who had consistently used it for 1 year (OR = 4.48 95% CI = 1.51-13.31), had higher risks of bladder cancer compared with nonthiazolidinedione users. Neither pioglitazone use nor exclusive pioglitazone use were associated with an increased incidence of bladder cancer.Rosiglitazone use is associated with an increased risk of incident bladder cancer independent of age and sex in patients with type 2 diabetes mellitus. The highest odds of bladder cancer in rosiglitazone users was seen in those with <1 year of exposure.

Zhou Q, Chang H, Yang L, et al.
Arteriovenous Malformation Masquerading as a Bladder Tumor. A Case Report.
Anal Quant Cytopathol Histpathol. 2015; 37(5):322-5 [PubMed] Related Publications
BACKGROUND: Arteriovenous malformation (AVM) of the urinary bladder is an extremely rare benign vascular lesion. The clinical significance of bladder AVM lies in its presentation with painless hematuria and a hyperemic sessile bladder wall mass.
CASE REPORT: A 47-year-old man presented with irritative symptoms and hematuria. Cystoscopically the lesion appeared as an erythematous, broad-based mass obscuring the right ureteral orifice. The patient underwent cystoprostatectomy for suspected mass lesion. Histologically the bladder tumor was composed of numerous malformed blood vessels of various calibers with myxoid degeneration. Immunohistochemically the bland endothelial cells lining in the vessels were reactive for markers of CD31 and CD34. Ki67 index was < 1%. The patient was free of disease 24 months after surgery.
CONCLUSION: Our findings broaden the morphologic spectrum of bladder arteriovenous malformation and emphasize its deceptive presentation.

Antonova O, Toncheva D, Grigorov E
Bladder cancer risk from the perspective of genetic polymorphisms in the carcinogen metabolizing enzymes.
J BUON. 2015 Nov-Dec; 20(6):1397-406 [PubMed] Related Publications
Urinary bladder cancer is a socially significant healthcare problem. A diverse array of aromatic and heterocyclic amines, derived from the chemical and transport industry, diet, and cigarette smoke are considered carcinogens for the bladder. To exert their carcinogenic effect and to initiate the carcinogenic response, the arylamines require a metabolic activation by the host enzymes to chemically reactive compounds. The aim of this article was to review the latest and basic research developments on the role of the polymorphisms in the carcinogen metabolizing enzymes N-acetyltransferase (NAT), Glutathione S-transferases (GST), and Soluble sulfotransferases (SULT), with emphasis on the susceptibility to urinary bladder cancer. A PubMed search was conducted to identify original and review articles containing information about these polymophic variants in different populations and according to their prevalence in bladder cancer patients. We noticed that some genotypes were found to be predisposing and some protective for bladder cancer development. The NAT2 slow genotype, together with GSTM1 null genotype facilitated the development of bladder cancer in almost all ethnic groups. The 213His allele of the SULT1A1 gene which is associated with lower enzyme activity and decreased mutagen activation was reported to protect from bladder cancer in almost all studies.

Kilari D, Iczkowski KA, Pandya C, et al.
Copper Transporter-CTR1 Expression and Pathological Outcomes in Platinum-treated Muscle-invasive Bladder Cancer Patients.
Anticancer Res. 2016; 36(2):495-501 [PubMed] Related Publications
BACKGROUND/AIM: Platinum (Pt)-based neoadjuvant chemotherapy (NAC) is the standard-of-care for muscle-invasive bladder cancer (MIBC). However, the survival benefit with NAC is driven by patients with pathological response at cystectomy. Non-responders are subject to adverse effects of Pt, with delay in definitive treatment. Copper transporter receptor 1 (CTR1) plays an important role in Pt uptake and the level of expression may influence Pt sensitivity. We hypothesized that tumor CTR1 expression correlated with pathological outcome.
PATIENTS AND METHODS: We identified matched paraffin-embedded tissues from pre-NAC transurethral bladder tumor resection (TURBT) and post-NAC radical cystectomy (RC) specimens in 47 patients with MIBC who received Pt-based NAC. Tumor and adjacent normal tissues were stained with CTR1 antibody. CTR1 expression was determined through immunohistochemistry by two pathologists blinded to the outcome (0=undetectable; 1+=barely detectable; 2+=moderate; and 3+=intense staining). Pathological response was defined as either down-staging to non-MIBC (≤pT1N0M0) or complete pathological response (pT0). Pathological outcome was compared between the CTR1 expression groups.
RESULTS: Forty-three percent of TURBT and 41% of RC specimens expressed a CTR1 score of 3+. Forty-four percent of patients had a pathological response to NAC, and 17% had pT0 disease at cystectomy. In both pre-NAC TURBT and post-NAC RC specimens, a CTR1 expression score of 3+ correlated with pathological response (p=0.0076 and p=0.023, respectively).
CONCLUSION: This is the first study to demonstrate a correlation between CTR1 tumor expression and pathological outcome in Pt-treated MIBC. These findings suggest that CTR1 expression may be a biomarker for Pt sensitivity.

Shen Z, Xie L, Chen T, et al.
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.
Medicine (Baltimore). 2016; 95(5):e2625 [PubMed] Free Access to Full Article Related Publications
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.

Di Lorenzo G, Pagliuca M, Perillo T, et al.
Complete Response and Fatigue Improvement With the Combined Use of Cyclophosphamide and Quercetin in a Patient With Metastatic Bladder Cancer: A Case Report.
Medicine (Baltimore). 2016; 95(5):e2598 [PubMed] Free Access to Full Article Related Publications
Bladder cancer is a major cause of cancer-related mortality, with an estimated 74,000 new cases and 16,000 deaths in the United States in 2015. In patients with metastatic disease, vinflunine and taxanes are the most widely used chemotherapy agents in the second-line setting after failure of platinum-based treatment. Cyclophosphamide has been used in combination with paclitaxel in urothelial carcinoma of the bladder, but there are no data about the effectiveness of cyclophosphamide administered as a single agent.We here describe the first case of an advanced bladder cancer patient suffering from grade 2 fatigue.He benefited from administration of third-line single-agent metronomic oral cyclophosphamide plus oral doses of quercetin. A complete, prolonged radiologic response according to the RECIST criteria 1.1 was achieved with minimal toxicity and an improvement in fatigue.Further studies are required to assess the potential benefits associated with the combined use of cyclophosphamide plus quercetin in advanced bladder cancer patients.

Carvalho DR
Improving Access to Adjuvant Intravesical Therapy for Non-Muscle Invasive Bladder Cancer in a Community Hospital.
Urol Nurs. 2015 Nov-Dec; 35(6):287-91 [PubMed] Related Publications
Relative to the high incidence of bladder cancer in Connecticut, an analysis of practice patterns in treatment of early stage bladder cancer was undertaken in a 275-bed community hospital, to determine if the practice patterns mirrored National Comprehensive Cancer Network guidelines. A nurse-led performance improvement project followed. Subsequently change in bladder cancer recurrence rates related to change in practice patterns was assessed.

Cui J, Wang W, Chen S, et al.
Combination of Intravesical Chemotherapy and Bacillus Calmette-Guerin Versus Bacillus Calmette-Guerin Monotherapy in Intermediate- and High-risk Nonmuscle Invasive Bladder Cancer: A Systematic Review and Meta-analysis.
Medicine (Baltimore). 2016; 95(3):e2572 [PubMed] Related Publications
Urothelial carcinoma of the bladder has become a major cause of morbidity, mortality, and health-related costs. There is still no standard instillation therapy against bladder cancer. A meta-analysis was conducted to evaluate the efficacy and toxicity of adding chemotherapy to Bacillus Calmette-Guerin (BCG) in intermediate- and high-risk nonmuscle invasive bladder cancer (NMIBC).All randomized controlled trials (RCTs) that evaluated the efficacy of combination therapy and BCG monotherapy for intermediate- and high-risk NMIBC were comprehensively searched. Relevant databases, including PubMed, Embase, Cochrane Central Register of Controlled trials databases, and American Society of Clinical Oncology (http://www.asco.org/ASCO), the clinical trial registration website (ClinicalTrials.gov), and relevant trials from the references of selected studies were searched from initial state up to June 6, 2015. Random-effects model was used to estimate hazard ratios (HRs) statistics. All statistical analyses were performed by STATA (version 13.0, College Station, TX).Seven studies, including 1373 patients with intermediate- and high-risk NMIBC, were identified. For disease-free survival, the pooled HRs from all studies was 0.69 (95% confidence interval [CI], 0.48-1.00; P = 0.048). The disease-free survival benefit was more apparent among patients with intermediate-risk NMIBC (P = 0.002) or Ta/T1 with/without carcinoma in situ (P < 0.01). In subgroup analysis, a significant reduction in recurrence was found in studies that explored the influence of a perioperative single dose instillation compared with delayed BCG monotherapy (HR = 0.60; 95% CI, 0.38-0.92; P = 0.021). No significant difference was found for progression-free survival (HR = 0.78; 95% CI, 0.43-1.44; P = 0.435).Patients with intermediate- and high-risk NMIBC who underwent combination therapy achieved lower rates of recurrence than those who underwent BCG therapy alone. No difference in progression-free survival was found between the 2 different therapy schedules. Better efficacy for a perioperative single dose instillation compared with delayed BCG monotherapy was found in this meta-analysis.

Whyard T, Waltzer WC, Waltzer D, Romanov V
Metabolic alterations in bladder cancer: applications for cancer imaging.
Exp Cell Res. 2016; 341(1):77-83 [PubMed] Related Publications
Treatment planning, outcome and prognosis are strongly related to the adequate tumor staging for bladder cancer (BC). Unfortunately, a large discrepancy exists between the preoperative clinical and final pathologic staging. Therefore, an advanced imaging-based technique is crucial for adequate staging. Although Magnetic Resonance Imaging (MRI) is currently the best in vivo imaging technique for BC staging because of its excellent soft-tissue contrast and absence of ionizing radiation it lacks cancer-specificity. Tumor-specific positron emission tomography (PET), which is based on the Warburg effect (preferential uptake of glucose by cancer cells), exploits the radioactively-labeled glucose analogs, i.e., FDG. Although FDG-PET is highly cancer specific, it lacks resolution and contrast quality comparable with MRI. Chemical Exchange Saturation Transfer (CEST) MRI enables the detection of low concentrations of metabolites containing protons. BC is an attractive target for glucose CEST MRI because, in addition to the typical systemic administration, glucose might also be directly applied into the bladder to reduce toxicity-related complications. As a first stage of the development of a contrast-specific BC imaging technique we have studied glucose uptake by bladder epithelial cells and have observed that glucose is, indeed, consumed by BC cells with higher intensity than by non-transformed urothelial cells. This effect might be partly explained by increased expression of glucose transporters GLUT1 and GLUT3 in transformed cells as compared to normal urothelium. We also detected higher lactate production by BC cells which is another cancer-specific manifestation of the Warburg effect. In addition, we have observed other metabolic alterations in BC cells as compared to non-transformed cells: in particular, increased pyruvate synthesis. When glucose was substituted by glutamine in culture media, preferential uptake of glutamine by BC cells was observed. The preferential uptake of glucose by BC cells gives an opportunity to develop NMR based imaging procedures where glucose or its derivatives can serve as a contrasting agent. In addition, metabolic alterations observed in BC cells could provide the basis for development of new anti-cancer therapeutics.

Du C, Gao Y, Xu S, et al.
KLF5 promotes cell migration by up-regulating FYN in bladder cancer cells.
FEBS Lett. 2016; 590(3):408-18 [PubMed] Related Publications
Krüppel-like factor 5 (KLF5) promotes cell proliferation of bladder cancer. However, whether KLF5 regulates other cell processes in bladder cancer is not clear. We found that KLF5 increases cell migration and lamellipodia formation, expression of FYN and phosphorylation of FAK in bladder cancer cells. In addition, KLF5 promotes transcription of FYN through binding to its promoter. FYN overexpression rescues cell migration and lamellipodia formation reduced by KLF5 knockdown. Furthermore, the KLF5/FYN/p-FAK axis is necessary for lysophosphatidic acid (LPA) to promote cell migration. Our findings indicate that both KLF5 and FYN are important in the regulation of cell migration in bladder cancer cells. We propose the KLF5/FYN/p-FAK axis as a potential therapeutic target in bladder cancer.

Zhou J, Dai W, Song J
miR-1182 inhibits growth and mediates the chemosensitivity of bladder cancer by targeting hTERT.
Biochem Biophys Res Commun. 2016; 470(2):445-52 [PubMed] Related Publications
microRNAs (miRNAs) have been demonstrated to contribute to tumor progression and metastasis and proposed to be key regulators of diverse biological processes. In this study, we report that miR-1182 is deregulated in bladder cancer tissues and cell lines. To characterize the role of miR-1182 in bladder cancer cells, we performed functional assays. The overexpression of miR-1182 significantly inhibits bladder cancer cell proliferation, colony formation, and invasion. Moreover, its up-regulation induced cell cycle arrest and apoptosis and mediated chemosensitivity to cisplatin in bladder cancer. Furthermore, a luciferase reporter assay and a rescue experiment indicated that miR-1182 directly targets hTERT by binding its 3'UTR. In conclusion, these results demonstrate that miR-1182 acts as a tumor suppressor and may be a potential biomarker for bladder cancer diagnosis and treatment.

Ribal MJ, Mengual L, Lozano JJ, et al.
Gene expression test for the non-invasive diagnosis of bladder cancer: A prospective, blinded, international and multicenter validation study.
Eur J Cancer. 2016; 54:131-8 [PubMed] Related Publications
OBJECTIVE: This study aimed to validate, in a prospective, blinded, international and multicenter cohort, our previously reported four non-invasive tests for bladder cancer (BC) diagnosis based on the gene expression patterns of urine.
METHODS: Consecutive voided urine samples from BC patients and controls were prospectively collected in five European centres (n=789). Finally, 525 samples were successfully analysed. Gene expression values were quantified using TaqMan Arrays and previously reported diagnostic algorithms were applied to gene expression data. Results from the most accurate gene signature for BC diagnosis were associated with clinical parameters using analysis of variance test.
RESULTS: High diagnostic accuracy for the four gene signatures was found in the independent validation set (area under curve [AUC]=0.903-0.918), with the signature composed of two genes (GS_D2) having the best performance (sensitivity: 81.48%; specificity: 91.26%; AUC: 0.918). The diagnostic accuracy of GS_D2 was not affected by the number of tumours (p=0.58) but was statistically associated with tumour size (p=0.008). Also, GS_D2 diagnostic accuracy increases with increasing BC tumour risk. We found no differences in the performance of the GS_D2 test among the populations and centres in detecting tumours (p=0.7) and controls (p=0.2).
CONCLUSIONS: Our GS_D2 test is non-invasive, non-observer dependent and non-labour-intensive, and has demonstrated diagnostic accuracy in an independent, international and multicenter study, equal or superior to the current gold standard (cystoscopy combined with cytology). Additionally, it has higher sensitivity than cytology while maintaining its specificity. Consequently, it meets the requirements for consideration as a molecular test applicable to clinical practice in the management of BC.

Ayari C, Besançon M, Bergeron A, et al.
Poly(I:C) potentiates Bacillus Calmette-Guérin immunotherapy for bladder cancer.
Cancer Immunol Immunother. 2016; 65(2):223-34 [PubMed] Related Publications
Non-specific immunotherapy consisting of intravesical instillation of Bacillus Calmette-Guérin (BCG) is currently the best available treatment to prevent non-muscle-invasive bladder tumor recurrence and progression. This treatment however is suboptimal, and more effective immunotherapeutic approaches are needed. Toll-like receptors (TLRs) play a major role in the activation of the immune system in response to pathogens and danger signals but also in anti-tumor responses. We previously showed that human urothelial cells express functional TLRs and respond to TLR2 and TLR3 agonists. In this study, we analyzed the potential of polyinosinic:polycytidylic acid [poly(I:C)], a TLR3 agonist, to replace or complement BCG in the treatment of non-muscle-invasive bladder cancer. We observed that poly(I:C) had an anti-proliferative, cytotoxic, and apoptotic effect in vitro on two low-grade human bladder cancer cell lines, MGH-U3 and RT4. In MGH-U3 cells, poly(I:C) induced growth arrest at the G1-S transition. Poly(I:C) also increased the immunogenicity of MGH-U3 and RT4 cells, inducing the secretion of MHC class I molecules and of pro-inflammatory cytokines. By comparison, poly(I:C) had less in vitro impact on two high-grade human bladder cancer cell lines, 5637 and T24, and on MBT-2 murine high-grade bladder cancer cells. The latter can be used as an immunocompetent model of bladder cancer. The combination poly(I:C)/BCG was much more effective in reducing MBT-2 tumor growth in mice than either treatment alone. It completely cured 29% of mice and also induced an immunological memory response. In conclusion, our study suggests that adding poly(I:C) to BCG may enhance the therapeutic effect of BCG.

Li Q, Bagrodia A, Cha EK, Coleman JA
Prognostic Genetic Signatures in Upper Tract Urothelial Carcinoma.
Curr Urol Rep. 2016; 17(2):12 [PubMed] Free Access to Full Article Related Publications
Urothelial carcinoma is a highly heterogeneous disease that can arise throughout the entire urothelial lining from the renal pelvis to the proximal urethra. Upper tract urothelial carcinoma (UTUC) is rare, and while it shares many similarities with urothelial carcinoma of bladder (UCB), there are also significant differences between UTUC and UCB regarding clinical management and outcomes. No major advances have been made recently in the development of new systemic therapies for urothelial carcinoma, partly due to the lack of understanding of underlying molecular pathogenetic mechanisms. In the past decade, the emergence of next-generation sequencing has greatly enabled genomic characterization of tumor samples. Researchers are currently exploring a personalized approach to augment traditional clinical decision-making based on genetic alterations. In the present review, we summarize current genomic advances in UTUC and discuss the potential implications of these developments for developing prognostic and predictive biomarkers.

Syed IS, Pedram A, Farhat WA
Role of Sonic Hedgehog (Shh) Signaling in Bladder Cancer Stemness and Tumorigenesis.
Curr Urol Rep. 2016; 17(2):11 [PubMed] Related Publications
Sonic hedgehog (Shh) signaling pathway has emerged as a critical component of bladder development, cancer initiation, and progression. While the role of Shh signaling in bladder development is well documented, its role in bladder cancer progression is uncertain. Additionally, epithelial-to-mesenchymal transition (EMT) has been identified to promote bladder cancer progression in the initial stages and also contribute to drug resistance in the later stage and ultimately metastasis. We speculate that epithelial-to-mesenchymal transitions (EMT) and Shh fuel the carcinogenesis process. This review presents the most recent studies focusing on the role of Shh signaling in bladder cancer progression.

Donahue TF, Cha EK, Bochner BH
Rationale and Early Experience with Prophylactic Placement of Mesh to Prevent Parastomal Hernia Formation after Ileal Conduit Urinary Diversion and Cystectomy for Bladder Cancer.
Curr Urol Rep. 2016; 17(2):9 [PubMed] Free Access to Full Article Related Publications
Parastomal hernias (PH) represent a clinically significant problem for many patients after radical cystectomy and ileal conduit diversion. The prevalence may be as high as 60% and in some series, up to 30% of patients require surgical intervention due to the complications of pain, poor fit of an ostomy appliance, leakage, urinary obstruction, and bowel obstruction or strangulation. Due to the potential morbidity associated with PH repair, there have been efforts to prevent PH development at the time of the index surgery. Four randomized trials of prophylactic mesh placement at the time of colostomy and ileostomy stoma formation have demonstrated significant reductions in PH rates with acceptably low complication rates. In this review, we describe the clinical and radiographic definitions of PH, the clinical impact and risk factors behind its development, and the rationale behind prophylactic mesh placement for patients undergoing ileal conduit urinary diversion. Additionally, we report our experience with prophylactic mesh placed at radical cystectomy at our institution.

Muto G, Collura D, Simone G, et al.
Stapled orthotopic ileal neobladder after radical cystectomy for bladder cancer: Functional results and complications over a 20-year period.
Eur J Surg Oncol. 2016; 42(3):412-8 [PubMed] Related Publications
AIMS: To present the long term-results and complications of a large series of stapled ileal orthotopic neobladders.
MATERIALS AND METHODS: From 1992 to 2012 we performed 606 radical cystectomies with stapled orthotopic neobladder substitution in male patients. The median patient age was 65 years (interquartile range [IQR]: 58-71).
RESULTS: Median operative time was 205 min (IQR: 180-225). The overall survival rates at 5, 10, 15, and 20 yr were 68% (336 of 494), 55% (207 of 376), 38% (98 of 259), and 23% (14 of 62), respectively, and the disease specific survival rates were 75% (371 of 494), 59% (222 of 376), 50% (130 of 259), and 35% (22 of 62), respectively. After a median follow-up of 81 months (IQR: 30-144), a total of 147 early (less than 90 days) complications (38 diversion related, 109 diversion unrelated) occurred in 144 patients (24%); 163 late complications (141 diversion related, 22 diversion unrelated) affected 141 patients (23%). At 60 months, daytime and nighttime continence was complete in 96% and 72% of cases, respectively. Urodynamic studies showed that maximum capacity, residual volume, maximum flow rate, pressure at maximum capacity, and maximum outlet closure pressure were not statistically different at 12 and 60 months postoperatively.
CONCLUSIONS: The use of a stapler when performing orthotopic neobladders significantly reduces the operating time, and offers good functional results with acceptable complication rates. Our results could encourage the use of a stapler when performing an ileal neobladder during laparoscopic and robotic radical cystectomies.

Arikan O, Yýldýrým A, Ýsbilen B, et al.
Clinical significance of serum and urinary HER2/neu protein levels in primary non-muscle invasive bladder cancer.
Int Braz J Urol. 2015 Nov-Dec; 41(6):1080-7 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: We aimed to compare serum and urinary HER2/neu levels between healthy control group and patients with non-muscle invasive bladder cancer. Additionally, we evaluated relationship of HER2/neu levels with tumor stage, grade, recurrence and progression.
MATERIALS AND METHODS: Fourty-four patients with primary non-muscle invasive bladder tumors (Group 2) and 40 healthy control group (Group 1) were included the study. Blood and urinary samples were collected from all patients and HER2/neu levels were measured by ELISA method. Blood and urinary HER2/neu levels and additionally, ratio of urinary HER2/neu levels to urinary creatinine levels were recorded. Demographic data and tumor characteristics were recorded.
RESULTS: Mean serum HER2/neu levels were similar between two groups and statistically significant difference wasn't observed. Urinary HER2/neu levels were significantly higher in group 2 than group 1. Ratio of urinary HER2/neu to urinary creatinine was significantly higher in group 2 than group 1, (p=0,021). Serum and urinary HER2/ neu levels were not associated with tumor stage, grade, recurrence and progression while ratio of urinary HER2/neu to urinary creatinin levels were significantly higher in high-grade tumors. HER2/neu, the sensitivity of the test was found to be 20.5%, and the specificity was 97.5%, also for the urinary HER2/neu/urinary creatinine ratio, the sensitivity and specificity of the test were found to be 31.8% and 87.5%, respectively.
CONCLUSIONS: Urinary HER2/neu and ratio of urinary creatinine urine were significantly higher in patients with bladder cancer compared to healthy subjects. Large series and controlled studies are needed for use as a tumor marker.

Wang W, Chen H, Liu Z, et al.
Regulator of cullins-1 expression knockdown suppresses the malignant progression of muscle-invasive transitional cell carcinoma by regulating mTOR/DEPTOR pathway.
Br J Cancer. 2016; 114(3):305-13 [PubMed] Article available free on PMC after 02/02/2017 Related Publications
BACKGROUND: Regulator of cullins-1 (ROC1) is a key subunit in the cullin-RING ligase (CRL) protein complex. Our previous study indicated that ROC1 was essential for bladder cancer cell survival and that ROC1 knockdown inhibited CRL activity, triggering G2 phase arrest and senescence. However, the role of ROC1 in the malignant progression of bladder cancer remained unknown.
METHODS: ROC1 expression in cancer cells was knocked down by siRNA silencing. The effects of ROC1 silencing were evaluated by in vitro assays for cell migration and by an in vivo mouse metastasis model. Epithelial-mesenchymal transition (EMT) induction was evaluated by immunofluorescence staining and western blotting of EMT-associated proteins. ROC1 expression in human tumours was further evaluated by immunohistochemical analysis.
RESULTS: ROC1 knockdown suppresses bladder cancer cell migration by inhibiting EMT. ROC1 knockdown inhibited EMT by inhibiting mammalian target of rapamycin (mTOR) activity via the accumulation of the mTOR-inhibitory protein DEPTOR, a CRL substrate. DEPTOR knockdown partially rescued ROC1 knockdown-inhibited EMT and the ROC1-induced inhibition of cancer cell migration. Furthermore, in vivo studies using a nude mouse metastasis model confirmed the in vitro data. Finally, tissue microarray analysis of clinical bladder cancer specimens indicated a positive correlation between ROC1 expression and EMT.
CONCLUSIONS: ROC1 has an important role in the malignant progression of bladder cancer via the mTOR/DEPTOR pathway. ROC1 may serve as a novel therapeutic target for the treatment of muscle-invasive transitional cell carcinoma.

Pouessel D, Chevret S, Rolland F, et al.
Standard or accelerated methotrexate, vinblastine, doxorubicin and cisplatin as neoadjuvant chemotherapy for locally advanced urothelial bladder cancer: Does dose intensity matter?
Eur J Cancer. 2016; 54:69-74 [PubMed] Related Publications
BACKGROUND: There is continuing controversy regarding the optimal regimen for neoadjuvant chemotherapy (NAC) in bladder cancer.
PATIENTS AND METHODS: We performed a retrospective analysis of 241 consecutive bladder cancer patients who received a combination of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) using a standard (52 patients) or an accelerated schedule (189 patients) as NAC before radical cystectomy in 17 centres of the French GEnito-urinary TUmour Group from March 2004-May 2013.
RESULTS: The median age was 62 years. As expected, the median number of cycles, the median total dose of cisplatin and the median cisplatin dose intensity were higher in patients treated with the accelerated regimen. Conversely, the median duration of chemotherapy was shorter. Regarding toxicity, grade III/IV neutropenia, grade III thrombocytopenia and grade III anaemia as well were more frequently observed in patients treated with the standard regimen. Among 211 (88%) patients who proceeded to cystectomy, 75 (35%) patients achieved an ypT0 pN0 status (no pathologic residual tumour cells) with no significant difference according to the MVAC schedule. Three-year overall survival rates were 66.5% (95% confidence interval [CI], 56-79) and 72% (95% CI, 59.5-88) in the standard and accelerated cohorts, respectively. In the multivariate analysis, two independent prognostic parameters were retained: the ypT0 stage and the ypN0 stage. Heterogeneity test did not show any interaction with NAC regimens.
CONCLUSION: Similar pathological response and survival rates were observed whatever the chemotherapy regimen used. Haematological toxicity was greater in patients who received standard MVAC.

Zhang J, Wang S, Han F, et al.
MicroRNA-542-3p suppresses cellular proliferation of bladder cancer cells through post-transcriptionally regulating survivin.
Gene. 2016; 579(2):146-52 [PubMed] Related Publications
AIM: To investigate the clinical significance of microRNA-542-3p (miR-542-3p) and its target gene survivin in human bladder cancer, and to determine their functions in malignant phenotypes of this disease.
METHODS: Expression levels of miR-542-3p and survivin mRNA in bladder cancer and adjacent normal tissues were detected by quantitative RT-PCR. Cell proliferation and cell cycle were assessed by cell viability assay, flow cytometry and colony formation assay based on two human bladder cancer cell lines.
RESULTS: MiR-542-3p expression was downregulated, while survivin mRNA expression was upregulated in bladder cancer tissues, compared to adjacent normal tissues (both P<0.001). Importantly, the expression level of miR-542-3p in bladder cancer tissues was negatively correlated with that of survivin mRNA. MiR-542-3p-low and/or survivin-high expression were all significantly associated with tumor stage (all P<0.05) and tumor recurrence (all P<0.05) of patients with bladder cancer. Moreover, the enforced expression of miR-542-3p remarkably inhibited cell proliferation by inducing G1 phase arrest in both T24 and J82 cells, and decreased the expression level of survivin protein. In contrast, the knock-down of miR-542-3p dramatically promoted the proliferation of bladder cancer cells by accelerating the progression of cell cycle and increased the expression level of survivin protein.
CONCLUSION: MiR-542-3p and its target gene survivin may play crucial roles in the aggressive progression of human bladder cancer. More interestingly, miR-542-3p may function as a tumor suppressor and inhibit the proliferation of bladder cancer cells, implying that miR-542-3p-survivin signal axis might be a novel therapeutic target of this disease.

Jiang F, Ma S, Xue Y, et al.
LDH-A promotes malignant progression via activation of epithelial-to-mesenchymal transition and conferring stemness in muscle-invasive bladder cancer.
Biochem Biophys Res Commun. 2016; 469(4):985-92 [PubMed] Related Publications
Lactate dehydrogenase-A(LDH-A) is an important rate-limiting enzyme in the Warburg effect. Survival analysis indicated poor clinical outcomes in MIBC with high LDH-A expression. The results of in vitro experiment indicated that LDH-A promotes MIBC cells proliferation, invasion and migration. The positive relationship between LDH-A expression and CSC/EMT markers was confirmed both in invasive bladder cell line and in 136 MIBC specimens. Thus, we conclude that LDH-A may be a promising target for MIBC.

Wang J, Manucha V
Villous Adenoma of the Urinary Bladder: A Brief Review of the Literature.
Arch Pathol Lab Med. 2016; 140(1):91-3 [PubMed] Related Publications
Villous adenoma is a rare neoplasm in the urinary tract. It usually occurs in patients older than 50 years with a male predominance. The affected patients typically present with hematuria, irritative voiding symptoms, and mucosuria. The malignant potential of this entity has not been established, but some of the case series studies on bladder villous adenoma do suggest a possible association with malignant tumors. Findings on ultrasonography, computed tomographic scanning, magnetic resonance imaging, or on cystoscopic examination are nonspecific. Therefore, villous adenoma of the bladder is primarily a histologic diagnosis. This review will highlight the current theories on its pathogenesis and discuss its main histologic and immunohistochemical features to aid the diagnosis.

Hermans TJ, Fransen van de Putte EE, Horenblas S, et al.
Perioperative treatment and radical cystectomy for bladder cancer--a population based trend analysis of 10,338 patients in the Netherlands.
Eur J Cancer. 2016; 54:18-26 [PubMed] Related Publications
BACKGROUND: In Europe, population-based data concerning perioperative treatment (PT) and radical cystectomy (RC) are lacking. We assessed temporal trends in PT (neoadjuvant chemotherapy [NAC], neoadjuvant radiotherapy [NAR], adjuvant chemotherapy [AC], adjuvant radiotherapy [AR]) and RC in the Netherlands and identified patients' and hospital characteristics associated with PT.
METHODS: This nationwide, retrospective, population-based study included cTa/is, T1-4, N0-3, M0-1 bladder cancer patients from the Netherlands Cancer Registry who underwent RC with curative intent between 1995 and 2013. PT-administration over time was compared with chi-square tests. Multivariable logistic regression analyses were performed to identify characteristics associated with PT usage. The sub-groups cT2-4N0M0 and cT2-4, N0 or NX, M0 or MX were separately analysed.
RESULTS: In total, 10,338 patients met inclusion criteria. Eighty-six percent did not receive PT, 7.0% received NAC (or induction chemotherapy [IC]), 3.2% NAR, 1.8% AC, and 2.1% AR. NAC usage increased from 0.6% in 1995 to 21% in 2013 (p < 0.001), application of NAR decreased from 15% to 0.4% (p < 0.001). Usage of AC and AR in 2013 was <1.5%. Comparable temporal trends were found in 6032 patients staged cT2-4N0M0. Multivariable logistic regression analysis revealed that younger age, ≥ cT3, ≥ cN1 and treatment in academic/teaching hospitals were associated with NAC or IC (all p < 0.05).
CONCLUSIONS: The increase in NAC administration in the Netherlands reflects a slow but steady adoption of evidence-based guidelines over the last two decades. Considerable variability in patients' and hospital characteristics in the likelihood of receiving NAC exists. Conversely, NAR, AR and AC are hardly administered anymore.

Mitin T, George A, Zietman AL, et al.
Long-Term Outcomes Among Patients Who Achieve Complete or Near-Complete Responses After the Induction Phase of Bladder-Preserving Combined-Modality Therapy for Muscle-Invasive Bladder Cancer: A Pooled Analysis of NRG Oncology/RTOG 9906 and 0233.
Int J Radiat Oncol Biol Phys. 2016; 94(1):67-74 [PubMed] Article available free on PMC after 01/01/2017 Related Publications
PURPOSE: To investigate the differences in outcomes among patients with muscle-invasive bladder cancer on NRG Oncology Radiation Therapy Oncology Group protocols 9906 and 0233 who achieved complete response and near-complete response after induction chemoradiation and then completed bladder-preserving therapy with chemoradiation therapy (chemo-RT) to full dose (60-64 Gy).
PATIENTS AND METHODS: A pooled analysis was performed on 119 eligible patients with muscle-invasive bladder cancer enrolled on NRG Oncology Radiation Therapy Oncology Group trials 9906 and 0233, who were classified as having a complete (T0) or near-complete (Ta or Tis) response after induction chemo-RT and completed consolidation with a total RT dose of at least 60 Gy. Bladder recurrence, salvage cystectomy rates, and disease-specific survival were estimated by the cumulative incidence method and bladder-intact and overall survivals by the Kaplan-Meier method.
RESULTS: Among the 119 eligible patients, 101 (85%) achieved T0, and 18 (15%) achieved Ta or Tis after induction chemo-RT and proceeded to consolidation. After a median follow-up of 5.9 years, 36 of 101 T0 patients (36%) versus 5 of 18 Ta or Tis patients (28%) experienced bladder recurrence (P=.52). Thirteen patients among complete responders eventually required late salvage cystectomy for tumor recurrence, compared with 1 patient among near-complete responders (P=.63). Disease-specific, bladder-intact, and overall survivals were not significantly different between T0 and Ta/Tis cases.
CONCLUSIONS: The bladder recurrence and salvage cystectomy rates of the complete and the near-complete responders were similar. Therefore it is reasonable to recommend that patients with Ta or Tis after induction chemo-RT continue with bladder-sparing therapy with consolidation chemo-RT to full dose (60-64 Gy).

Santos F, Dragomir A, Zakaria AS, et al.
Predictors of costs associated with radical cystectomy for bladder cancer: A population-based retrospective cohort study in the province of Quebec, Canada.
J Surg Oncol. 2016; 113(2):223-8 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: There is paucity of studies on the predictors of bladder cancer (BC) management costs. We aimed to determine predictors of costs associated with radical cystectomy (RC) for BC.
METHODS: We conducted a retrospective analysis in a cohort of 2,759 patients who underwent RC for BC between 2000 and 2009. We analyzed predictors of pre-surgery, RC, post-surgery, and total costs. The following variables were considered as potential predictors: age, gender, hospital/surgeon case load, academic hospital, and geo-administrative region. Multivariate linear regression was used to determine predictors.
RESULTS: Predictors of pre-surgery costs were: age (β = 808.64, P < 0.0001) and having surgery in an academic hospital (β = 511.42, P = 0.003). Increased RC costs were associated with age (β = 196.73, P = 0.0006), hospital/surgeon annual load (β = 484.45 and β = 254.21, P < 0.0001, respectively). Having surgery in academic hospitals and geographic region were significant predictors of low RC costs (β = -1085.82 and β = -449.31, P < 0.0001, respectively). Increasing age and the presence of post-operative complications were predictors of high post-operative costs (β = 623.48, β = 5781.44, P = 0.01, respectively), while hospital load was associated with low post-surgery costs (β = -949.79, P < 0.0001).
CONCLUSION: Patients' age and surgery performed by high-volume health providers were predictive factors of high RC costs. Low RC costs were associated with surgeries performed in academic hospitals.

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