Bladder Cancer
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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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Information for Patients and the Public
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Latest Research Publications
Molecular Biology of Bladder Cancer
Urinary System Cancers

Information Patients and the Public (16 links)


Information for Health Professionals / Researchers (8 links)

Latest Research Publications

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

El-Gamal EM, Gouida MS
Flow cytometric study of cell cycle and DNA ploidy in bilharzial bladder cancer.
Clin Lab. 2015; 61(3-4):211-8 [PubMed] Related Publications
BACKGROUND: Tumor grade and stage are currently the most important prognostic variables in bladder cancer but establishing additional criteria is still needed for effective treatment. In this study, we analyzed DNA ploidy and the cell cycle: gap one stage (GO/1), synthesis stage (S-phase%), and gap two stage (G2/M) in urine and blood cells of bilharzial bladder cancer patients.
METHODS: The cell cycle and DNA ploidy were investigated using a flow cytometric technique for 150 bilharzial bladder cancer patients and 60 healthy normal controls.
RESULTS: This study demonstrated that GO/1 levels were significantly decreased in urine and blood cells of bladder cancer patients compared to controls and these decreases were significant in urine cells compared to blood cells and at high grade and stage. In contrast, S-phase%, G2/M, coefficient variation (CV), and DNA index (DI) levels were increased in urine and blood cells of patients compared to those of controls. These levels were significantly increased in urine patients compared to their blood. Finally, the undetectable DNA aneuploidy in control cells was significantly increased in urine cells of patients compared to their blood cells at higher grade and stage.
CONCLUSIONS: Taken together, the cell cycle and DNA aneuploidy analysis especially in urine cells of bilharzial bladder cancer patients may help in diagnosis, prognosis, and clinical treatment and can be considered as an additional marker for bladder cancer.


Jordan EJ, Iyer G
Targeted therapy in advanced bladder cancer: what have we learned?
Urol Clin North Am. 2015; 42(2):253-62, ix [PubMed] Related Publications
Despite advances in the treatment of other genitourinary malignancies, no novel therapies have been approved by the US Food and Drug Administration for urothelial carcinoma (UC) in the last 20 years. To date, no clinical trials of targeted agents in UC have led to improvements in survival compared with cytotoxic therapy. This article outlines representative trials of targeted therapies in UC and discusses the significance of genetic preselection in trial design as a method to optimize responses to these agents, thus, hopefully expanding the armamentarium of treatment options against this lethal disease.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter


Johnson DC, Greene PS, Nielsen ME
Surgical advances in bladder cancer: at what cost?
Urol Clin North Am. 2015; 42(2):235-52, ix [PubMed] Related Publications
Bladder cancer is the most expensive cancer to treat from diagnosis to death. Frequent disease recurrence, intense follow-up, and expensive, invasive techniques for diagnosis and treatment drive these costs for non-muscle invasive bladder cancer. Fluorescence cystoscopy increases the detection of superficial bladder cancer and reduces costs by improving the quality of resection and reducing recurrences. Radical cystectomy with intestinal diversion is the mainstay of treatment of invasive disease; however it is associated with substantial cost and morbidity. Increased efforts to improve the surgical management of bladder cancer while reducing the cost of treatment are increasingly necessary.


Lucca I, de Martino M, Klatte T, Shariat SF
Novel biomarkers to predict response and prognosis in localized bladder cancer.
Urol Clin North Am. 2015; 42(2):225-33, ix [PubMed] Related Publications
This review summarizes recent developments in diagnostic and prognostic biomarkers for nonmuscle invasive bladder cancer (NMIBC). Although the number of new biomarkers increases continuously, none are included in practice guidelines. Most NMIBC biomarkers show a higher sensitivity than urinary cytology, but lower specificity. Some protein and chromosome markers have been approved for screening and follow-up of patients in combination with cystoscopy. The long interval required for validation, testing, and approval of the assays and the lack of standardization could explain present issues in biomarker research. To enhance the development of new biomarkers, a more structured approach is required.


Balar AV, Milowsky MI
Neoadjuvant therapy in muscle-invasive bladder cancer: a model for rational accelerated drug development.
Urol Clin North Am. 2015; 42(2):217-24, viii-ix [PubMed] Related Publications
Since the advent of cisplatin-based combination therapy in the management of muscle-invasive and advanced bladder cancer, there has been little progress in improving outcomes for patients. Novel therapies beyond cytotoxic chemotherapy are needed. The neoadjuvant paradigm lends to acquiring ample pretreatment and posttreatment tumor tissue as a standard of care, which enables comprehensive biomarker analyses to better understand mechanisms of both response and resistance, which will aid drug development. This article discusses the evolution of neoadjuvant therapy as standard treatment and the role it may serve toward the development of novel therapies.

Related: Cisplatin Doxorubicin Methotrexate Vinblastine


Mitra AP, Lerner SP
Potential role for targeted therapy in muscle-invasive bladder cancer: lessons from the cancer genome atlas and beyond.
Urol Clin North Am. 2015; 42(2):201-15, viii [PubMed] Related Publications
The Cancer Genome Atlas project has identified and confirmed several important molecular alterations that form the basis for tumorigenesis and disease progression in muscle-invasive bladder cancer. Profiling studies also have reported on validated biomarker panels that predict prognosis and may be used to identify patients who require more aggressive therapy. This article describes the major molecular alterations in muscle-invasive urothelial carcinoma, and how several of these are being investigated as targets for novel therapeutics. It also highlights studies that identify biomarkers for platinum sensitivity, and efforts to integrate targeted therapeutics and companion theranostics for personalized treatment of muscle-invasive bladder cancer.


Cha EK, Donahue TF, Bochner BH
Radical transurethral resection alone, robotic or partial cystectomy, or extended lymphadenectomy: can we select patients with muscle invasion for less or more surgery?
Urol Clin North Am. 2015; 42(2):189-99, viii [PubMed] Related Publications
Improvements in the accuracy of clinical staging and refinements in patient selection may allow for improved outcomes of bladder-preservation strategies for muscle-invasive bladder cancer incorporating radical transurethral resection (TUR) and partial cystectomy (PC). Retrospective studies of patients treated with radical cystectomy and pelvic lymph node dissection have reported an association between greater extent of lymphadenectomy and improved clinical outcomes. However, there is no consensus regarding the optimal extent of lymphadenectomy, as there are currently no reports from prospective, randomized trials to address this issue in regards to cancer-specific and overall survival. Future advances in the understanding of the appropriate extent of lymphadenectomy requires well-designed prospective clinical trials that directly compare varying extents of surgery with their ability to provide local and distant disease control and disease-specific survival.


Sfakianos JP, Galsky MD
Neoadjuvant chemotherapy in the management of muscle-invasive bladder cancer: bridging the gap between evidence and practice.
Urol Clin North Am. 2015; 42(2):181-7, viii [PubMed] Related Publications
Although cisplatin-based chemotherapy followed by radical cystectomy is the standard treatment of muscle-invasive bladder cancer, population-based studies reveal that only a small fraction of patients actually receive such treatment. A comprehensive understanding of the reasons for this gap between efficacy and effectiveness is necessary to increase the likelihood of cure of all patients with muscle-invasive bladder cancer. These reasons include systems-, provider-, and patient-level barriers that are not amenable to a single solution. Tackling each barrier will ultimately be necessary to bridge the disconnect between what is achievable and what is actually achieved.

Related: Cisplatin Doxorubicin Methotrexate Vinblastine


Premo C, Apolo AB, Agarwal PK, Citrin DE
Trimodality therapy in bladder cancer: who, what, and when?
Urol Clin North Am. 2015; 42(2):169-80, vii [PubMed] Article available free on PMC after 01/05/2016 Related Publications
Radical cystectomy is a standard treatment of nonmetastatic, muscle-invasive bladder cancer. Treatment with trimodality therapy consisting of maximal transurethral resection of the bladder tumor followed by concurrent chemotherapy and radiation has emerged as a method to preserve the native bladder in highly motivated patients. Several factors can affect the likelihood of long-term bladder preservation after trimodality therapy and therefore should be taken into account when selecting patients. New radiation techniques such as intensity modulated radiation therapy and image-guided radiation therapy may decrease the toxicity of radiotherapy in this setting. Novel chemotherapy regimens may improve response rates and minimize toxicity.


Boehm BE, Svatek RS
Novel therapeutic approaches for recurrent nonmuscle invasive bladder cancer.
Urol Clin North Am. 2015; 42(2):159-68, vii [PubMed] Related Publications
This article summarizes strategies being investigated in patients with nonmuscle invasive bladder cancer. Progress has been made toward improving the delivery method of intravesical agents. Intravesical therapy is limited by the amount of time that the agent remains in contact with the bladder. Bladder cancer is considered to be responsive to immune therapy. Thus, many novel approaches are immune-based therapies and include cancer vaccines, use of Bacillus Calmette-Guérin (BCG) subcomponents, and checkpoint inhibitors. Finally, access to bladder mucosa via direct catheterization into the bladder via the urethra has enabled unique strategies for delivery of cancer therapy including viral- or plasmid-based gene therapy.


Zlatev DV, Altobelli E, Liao JC
Advances in imaging technologies in the evaluation of high-grade bladder cancer.
Urol Clin North Am. 2015; 42(2):147-57, vii [PubMed] Article available free on PMC after 01/05/2016 Related Publications
Bladder cancer ranges from a low-grade variant to high-grade disease. Assessment for treatment depends on white light cystoscopy, however because of its limitations there is a need for improved visualization of flat, multifocal, high-grade, and muscle-invasive lesions. Photodynamic diagnosis and narrow-band imaging provide additional contrast enhancement of bladder tumors and have been shown to improve detection rates. Confocal laser endomicroscopy and optical coherence tomography enable real-time, high-resolution, subsurface tissue characterization with spatial resolutions similar to histology. Molecular imaging offers the potential for the combination of optical imaging technologies with cancer-specific molecular agents to improve the specificity of disease detection.


Tadin T, Sotosek S, Rahelić D, Fuckar Z
Diagnostic accuracy of ultrasound T-staging of the urinary bladder cancer in comparison with histology in elderly patients.
Coll Antropol. 2014; 38(4):1123-6 [PubMed] Related Publications
Urinary bladder cancer (UBC) is dominantly the cancer of the elderly occurring primarily in the 6h, 7!h and 81h decade of life. The aim of this study was to evaluate diagnostic accuracy of ultrasound T-staging (UTS) of UBC in dhe group of elderly patients. In 152 elderly patients referred to transabdominal ultrasound examination in two different facilities (76 each) due to various symptoms (primarily painless gross or microscopic haematuria) UBC was diagnosed. Initial UTS at the moment of detection was performed and compared with final histological T-staging (HTS). A high level of conformity between UTS and HTS was detected. In a total of 152 patients with UBC there were 115 (75.66%) patients with complete match between the UTS and HTS, 24 (15.79%) patients with minimal variation within one stage, and 13 (8.55%) patients with one stage difference between the UTS and HTS. The best result was established for the stage T1, where the accuracy was 94.5%. In other stages the accuracy was between 84.9% and 91.8%. The Youden's index for all the stages was over 0.6. UTS has a high diagnostic accuracy, especially for stages T1 and T2. It is extremely useful tool in differentiating the superficial UBC from the muscle-invasive one, being of significant importance in planning the further treatment of elderly patients and having important role in choosing appropriate surgical approach.


Wen J, Li HZ, Ji ZG, Jin J
Effects of sunitinib malate on growth of human bladder transitional cell line T24 in vitro.
Chin Med Sci J. 2015; 30(1):51-5 [PubMed] Related Publications
OBJECTIVE: To investigate the growth-inhibitory effect of sunitinib malate on human bladder transitional cell carcinoma (TCC) in vitro.
METHODS: Human bladder TCC cell line T24 was cultured and exposed to graded concentrations of sunitinib malate for 72 hours in vitro to determine the sensitivities to drug. Cell viability was measured by MTT assay. Cell apoptotic morphology was observed by fluorescence microscope following DAPI staining. Band expressions of Fas, Fas ligand, poly (ADP-ribose) polymerase (PARP) and β-actin were analyzed by Western blot. Wound healing process of T24 cells exposed to sunitinib malate was assayed.
RESULTS: Sunitinib malate exerted a concentration-dependent and time-dependent inhibitory effect on the T24 cell lines. Fluorescence microscopy showed that small vacuoles appeared in the nuclei of T24 cells and the vacuoles were bigger with higher drug concentrations. The expressions of Fas ligand and PARP in T24 cells treated with sunitinib malate exhibited a concentration-dependent increase. Moreover sunitinib malate suppressed the wound healing process in a concentration-dependent manner.
CONCLUSION: Sunitinib malate exerted marked inhibitory activity against bladder cancer cell line T24.

Related: TNFRSF6 gene Apoptosis Transitional Cell Cancer of the Renal Pelvis and Ureter Sunitinib (Sutent)


Palleschi G, Pastore AL, Ripoli A, et al.
Videourodynamic evaluation of intracorporeally reconstructed orthotopic U-shaped ileal neobladders.
Urology. 2015; 85(4):883-9 [PubMed] Related Publications
OBJECTIVE: To study the functional outcomes of 30 patients who had previously undergone laparoscopic radical cystectomy with intracorporeal orthotopic ileal neobladder reconstruction using videourodynamic (VUDM) assessment 180 days postoperatively.
METHODS: Between November 2010 and December 2013, 30 male patients had undergone laparoscopic radical cystectomy with bilateral standard pelvic lymphadenectomy and pure laparoscopic orthotopic ileal U-shaped neobladder diversion. The demographic data were as follows: median age, 67 years (range, 62-79); body mass index, 22.3 kg/m(2) (range, 16-26.1 kg/m(2)); and mean American Society of Anesthesiologists score 2.2 (range, 1-3). Functional outcomes were assessed performing a standard VUDM study combined with perineal floor electromyography 180 days postoperatively.
RESULTS: VUDM evaluations showed good functional outcomes of the reservoirs. Mean maximal neobladder capacity was 287 mL (range, 210-335 mL). Residual peristaltic activity was observed in all the individuals evaluated; however, only 9 of 30 individuals (30%) displayed severe peristaltic activity. Six of these 9 individuals (66.6%) experienced urinary leakage during these contractions. Mean postvoid residual volume was 44 mL (range, 0-105 mL), and peak flow rate was 13.9 mL/s (range, 9.7-29.2 mL/s). The Valsalva maneuver was positive in 5 of 30 subjects (17%). Bladder morphology assessed during contrast cystography showed the desired U-shape in all cases. Ureteral reflux was observed in 7 of 30 individuals (23.3%).
CONCLUSION: Based on VUDM, our study shows that U-shaped ileal neobladders achieved by a totally laparoscopic approach obtained good functional outcomes. These findings support the evidence that a minimally invasive approach does not impose technical limitations that negatively impact the surgical results.


Haddad AQ, Singla N, Gupta N, et al.
Association of distance to treatment facility on quality and survival outcomes after radical cystectomy for bladder cancer.
Urology. 2015; 85(4):876-82 [PubMed] Related Publications
OBJECTIVE: To examine the association of travel distance on quality and survival outcome measures for bladder cancer patients undergoing radical cystectomy for urothelial carcinoma.
METHODS: Four hundred eight patients who underwent radical cystectomy for bladder cancer at a single institution from 2007 to 2013 were included. Multivariate logistic regression was used to determine the association of distance from treatment facility with 90-day mortality and quality-of-care endpoints including neoadjuvant chemotherapy use and time to cystectomy. Survival was assessed by multivariate Cox regression.
RESULTS: Fifty-seven percent of patients lived within 50 miles of the treatment facility. There was no difference in time to cystectomy or the utilization of neoadjuvant chemotherapy between patients in different distance groups. On multivariate analysis, distance to treatment facility was the only predictor of 90-day mortality (odds ratio, 11.20; 95% confidence interval, 2.27-55.43; P = .003, for patients traveling >150 vs <50 miles). Although there was no difference in recurrence and cancer-specific survival between distance groups, greater distance was associated with worse overall survival on multivariate analysis (hazard ratio, 1.59; 95% confidence interval, 0.99-2.56; P = .05, for patients traveling >150 vs <50 miles).
CONCLUSION: Distance to treatment facility did not impact quality measures including time to cystectomy or use of neoadjuvant chemotherapy, and there was no difference in cancer-specific mortality between distance groups. There was a detrimental association of increased travel distance with 90-day mortality, which could reflect disparities in access to care after cystectomy.


Calamaro P, Ravetti JL, Toncini C
Paraganglioma of the urinary bladder: a challenging diagnosis in transurethral resection specimens: a case report.
Anal Quant Cytopathol Histpathol. 2014; 36(5):290-4 [PubMed] Related Publications
BACKGROUND: Urinary bladder paraganglioma is a rare neoplasm that originates from embryonic rests of chromaffin cells in the sympathetic plexus of the detrusor muscle, and which occasionally can be observed in transurethral resection specimens. Artifactual changes due to the procedure may frequently simulate an advanced urothelial carcinoma.
CASE: A 65-year-old woman presented with episodic macroscopic hematuria. No symptoms of hyperadrenergic stimulation were referred. Cystoscopic examination revealed a protruding mass on the left side of the bladder. Transurethral resection (TUR) was performed, and histological examination revealed a tissue organized in solid nests delineated by delicate fibrovascular septa. There were artifactual changes that consisted of cautery effect and absence of orientation of the fragments. The tumor infiltrated the muscle layer and part of the muscularis mucosae of the bladder. No necrosis or mitoses were observed. On immunohistochemical staining, the tumor cells were negative for epithelial membrane antigen, cytokeratin 7, and carcinoembryonic antigen and positive for chromogranin A, NSE, and PGP9.5. Immunohistochemistry for S-100 highlighted sustentacular cells.
CONCLUSION: It is essential to consider the diagnosis of urinary bladder paraganglioma on TUR specimens in order to avoid inappropriate treatment.

Related: Pheochromocytoma and Paraganglioma


Almeida M, Canas-Marques R, Lopez-Beltran A, et al.
Small cell carcinoma of the bladder associated with schistosomiasis: a case report.
Anal Quant Cytopathol Histpathol. 2014; 36(6):339-44 [PubMed] Related Publications
BACKGROUND: Smoking and occupational exposure to bladder cancer carcinogens are the major risk factors for bladder cancer development in industrialized countries, where urothelial carcinoma is the most common histologic type, accounting for >90% of cases. In Africa and the Middle East, with highly prevalent chronic infection by Schistosoma haematobium (S. haematobium), urinary bladder squamous cell carcinoma is the most prevalent histologic type of bladder cancer, followed by transitional cell carcinoma. Small cell carcinoma accounts for <1% of all primary bladder malignancies. It has the same demographic and clinical features as conventional urothelial carcinoma, and to our knowledge there is no data regarding its association with S. haematobium infection.
CASE: We report on the clinicopathological characteristics of a 62-year-old, African man who presented with gross hematuria and advanced disease, resulting in a diagnosis of small cell carcinoma of the bladder associated with S. haematobium infection. He was treated with neoadjuvant chemotherapy followed by cystoprostatectomy, and remains alive after 19 months of follow-up.
CONCLUSION: We cannot rule out the possibility that a parasitic infection played a major role in the pathogenesis of small cell bladder carcinoma in this particular case.


Pudasaini S, Subedi N, Prasad KB, et al.
Cystoscopic bladder biopsies: a histopathological study.
Nepal Med Coll J. 2014; 16(1):9-12 [PubMed] Related Publications
Urothelial carcinoma is the most common tumor of the bladder and is a major cause of morbidity and mortality. Cystitis constitutes an important source of clinical signs and symptoms. In this study 31 cystoscopic biopsies subjected for histopathological examination were taken. The study was conducted in the department of Pathology of Nepal Medial College Teaching Hospital over a period of two years (October 2012 to September 2014). The mean age of the patient undergoing cystoscopic biopsy was 61.3 years, most of the patients being elderly male. 51.6% cases were clinically malignant. The most common histopathological diagnoses were cystitis (29%) and non invasive papillary urothelial carcinoma, low grade (29%). 58% are neoplastic lesions. 51.6% of the case was malignant lesions on histopathology. Among the malignant lesion of urinary bladder 93.7% were urothelial tumor and 6.3% were glandular neoplasm (adenocarcinoma, signet ring cell). There was no detrusor muscle in 33.3% cases of urothelial tumor to assess the muscle invasion. 26.7% cases of urothelial tumor shows muscle invasion. Histopathological study of cystoscopic biopsy helps in early detection of tumor and its management.


Claxton LD
The history, genotoxicity, and carcinogenicity of carbon-based fuels and their emissions. Part 3: diesel and gasoline.
Mutat Res Rev Mutat Res. 2015 Jan-Mar; 763:30-85 [PubMed] Related Publications
Within this review the genotoxicity of diesel and gasoline fuels and emissions is placed in an historical context. New technologies have changed the composition of transportation methods considerably, reducing emissions of many of the components of health concern. The similarity of modern diesel and gasoline fuels and emissions to other carbonaceous fuels and emissions is striking. Recently an International Agency for Research on Cancer (IARC) Working Group concluded that there was sufficient evidence in humans for the carcinogenicity of diesel exhaust (Group 1). In addition, the Working Group found that diesel exhaust has "a positive association (limited evidence) with an increased risk of bladder cancer." Like most other carbonaceous fuel emissions, diesel and gasoline exhausts contain toxic levels of respirable particles (PM <2.5μm) and polycyclic aromatic hydrocarbons. However, the level of toxic components in exhausts from diesel and gasoline emissions has declined in certain regions over time because of changes in engine design, the development of better aftertreatment devices (e.g., catalysts), increased fuel economy, changes in the fuels and additives used, and greater regulation. Additional research and better exposure assessments are needed so that decision makers and the public can decide to what extent diesel and gasoline engines should be replaced.


Antonova O, Yossifova L, Staneva R, et al.
Changes in the gene expression profile of the bladder cancer cell lines after treatment with Helix lucorum and Rapana venosa hemocyanin.
J BUON. 2015 Jan-Feb; 20(1):180-7 [PubMed] Related Publications
PURPOSE: The purpose of this study was to elucidate the mechanism of action of the Helix lucorum hemocyanin (HlH), b-HlH-h, and RvH2-g hemocyanins as potential agents against bladder cancer.
METHODS: We evaluated the viability of 647-V, T-24, and CAL-29 bladder cancer cell lines after treatment with the tested hemocyanins. The cell viability was measured at 72 hrs with MTT and WST-1 assays. Acridine orange/propidium iodide double staining was used to discriminate between apoptotic and necrotic cells. Gene expression profiling of the 168 genes from human inflammatory cytokines and signal transduction pathways were performed on the tumor cells before and after hemocyanins' treatment.
RESULTS: The results showed decreased survival of cancer cells in the presence of HlH and two functional units: b-HlH-h and RvH2-g. Acridine orange/propidium iodide double staining revealed that the decreased viability was due to apoptosis. The gene expression data showed upregulation of genes involved in the apoptosis as well as of the immune system activation, and downregulation of the CCL2, CCL17, CCL21, CXCL1, and ABCF1 genes.
CONCLUSIONS: The present study is the first to report gene expression in human cells under the influence of hemocyanins. The mechanism of antitumor activity of the HlH, b-HlH-h, and RvH2-g hemocyanins includes induction of apoptosis. In addition to the antiproliferative effect, downregulation of the genes with metastatic potential was observed. Together with the already known immunogenic effect, these findings support further studies on hemocyanins as potential therapeutic agents against bladder cancer.

Related: Apoptosis


Beane Freeman LE, Karagas MR, Baris D, et al.
Is the inverse association between selenium and bladder cancer due to confounding by smoking?
Am J Epidemiol. 2015; 181(7):488-95 [PubMed] Related Publications
Selenium has been linked to a reduced risk of bladder cancer in some studies. Smoking, a well-established risk factor for bladder cancer, has been associated with lower selenium levels in the body. We investigated the selenium-bladder cancer association in subjects from Maine, New Hampshire, and Vermont in the New England Bladder Cancer Case-Control Study. At interview (2001-2005), participants provided information on a variety of factors, including a comprehensive smoking history, and submitted toenail samples, from which we measured selenium levels. We estimated odds ratios and 95% confidence intervals among 1,058 cases and 1,271 controls using logistic regression. After controlling for smoking, we saw no evidence of an association between selenium levels and bladder cancer (for fourth quartile vs. first quartile, odds ratio (OR) = 0.98, 95% confidence interval (CI): 0.77, 1.25). When results were restricted to regular smokers, there appeared to be an inverse association (OR = 0.76, 95% CI: 0.58, 0.99); however, when pack-years of smoking were considered, this association was attenuated (OR = 0.91, 95% CI: 0.68, 1.20), indicating potential confounding by smoking. Despite some reports of an inverse association between selenium and bladder cancer overall, our results, combined with an in-depth evaluation of other studies, suggested that confounding from smoking intensity or duration could explain this association. Our study highlights the need to carefully evaluate the confounding association of smoking in the selenium-bladder cancer association.


Sávio AL, da Silva GN, Salvadori DM
Inhibition of bladder cancer cell proliferation by allyl isothiocyanate (mustard essential oil).
Mutat Res. 2015; 771:29-35 [PubMed] Related Publications
Natural compounds hold great promise for combating antibiotic resistance, the failure to control some diseases, the emergence of new diseases and the toxicity of some contemporary medical products. Allyl isothiocyanate (AITC), which is abundant in cruciferous vegetables and mustard seeds and is commonly referred to as mustard essential oil, exhibits promising antineoplastic activity against bladder cancer, although its mechanism of action is not fully understood. Therefore, the aim of this study was to investigate the effects of AITC activity on bladder cancer cell lines carrying a wild type (wt; RT4) or mutated (T24) TP53 gene. Morphological changes, cell cycle kinetics and CDK1, SMAD4, BAX, BCL2, ANLN and S100P gene expression were evaluated. In both cell lines, treatment with AITC inhibited cell proliferation (at 62.5, 72.5, 82.5 and 92.5μM AITC) and induced morphological changes, including scattered and elongated cells and cellular debris. Gene expression profiles revealed increased S100P and BAX and decreased BCL2 expression in RT4 cells following AITC treatment. T24 cells displayed increased BCL2, BAX and ANLN and decreased S100P expression. No changes in SMAD4 and CDK1 expression were observed in either cell line. In conclusion, AITC inhibits cell proliferation independent of TP53 status. However, the mechanism of action of AITC differed in the two cell lines; in RT4 cells, it mainly acted via the classical BAX/BCL2 pathway, while in T24 cells, AITC modulated the activities of ANLN (related to cytokinesis) and S100P. These data confirm the role of AITC as a potential antiproliferative compound that modulates gene expression according to the tumor cell TP53 genotype.


Pellucchi F, Freschi M, Moschini M, et al.
Oncological predictive value of the 2004 World Health Organisation grading classification in primary T1 non-muscle-invasive bladder cancer. A step forward or back?
BJU Int. 2015; 115(2):267-73 [PubMed] Related Publications
OBJECTIVE: To compare the clinical reliability of the 1973 and 2004 World Health Organisation (WHO) classification systems in pT1 bladder cancer.
PATIENTS AND METHODS: We retrospectively evaluated 291 consecutive patients who had pT1 high grade bladder cancer between 2004 and 2011. All tumours were simultaneously evaluated by a single uro-pathologist as high grade and G2 or G3. All patients underwent a second transurethral resection (TUR) and those confirmed with non-muscle-invasive bladder cancer at second TUR received bacille Calmette-Guérin. Follow-up included urine cytology and cystoscopy 3 months after second TUR and then every 6 months for 5 years. Univariate and multivariate analysis to determine recurrence-free survival (RFS) and progression-free survival (PFS) rates were performed using the Kaplan–Meier method with the log-rank test.
RESULTS: G2 tumours were found in 124 (46.6%) and G3 in 142 (53.4%) patients. The mean (median; range) follow-up period was 31.1 (19; 1–93) months. The 5-year RFS rate was 39.1% for the overall high grade population, and 49.1 and 31.8% for G2 and G3 subgroups, respectively. The 5-year PFS was 82% for the overall high grade population and 89 and 73% for G2 and G3 subgroups, respectively. RFS (P < 0.002) and PFS (P < 0.001) rates were significantly different between the G2 and G3 subgroups. In multivariate analysis, only the grade assessed according to the 1973 WHO significantly correlated with both RFS (P = 0.003) and PFS (P < 0.001).
CONCLUSION: The results suggest that the 1973 WHO classification system has higher prognostic reliability for patients with T1 disease. If confirmed, these findings should be carefully taken into account when making treatment decisions for patients with T1 bladder cancer.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter


Dal Moro F, Bovo A, Crestani A, et al.
Effect of hypertension on outcomes of high-risk patients after BCG-treated bladder cancer: a single-institution long follow-up cohort study.
Medicine (Baltimore). 2015; 94(9):e589 [PubMed] Related Publications
Immunotherapy with Bacillus Calmette-Guérin (BCG) is the most efficacious treatment for high-risk bladder cancer (BC) (Ta/T1 or carcinoma in situ) to reduce the risk of recurrence. Our aim was to evaluate whether hypertension and diabetes influence the outcome of patients with noninvasive BC treated with BCG instillations.In order to collect homogeneous data, we considered as "hypertensive" only those patients who had previous diagnosed hypertension and a history of taking medical therapy with antihypertensive drugs (AHT), and as "diabetic" only those prescribed oral antidiabetics or insulin (ADT).We analyzed 343 high-risk BC patients undergoing BCG (1995-2010) with a median follow-up of 116 months (range 48-238). The distribution of various kinds of AHT and antidiabetic drugs was homogeneous, with no significant differences (p > 0.05).In both univariate and multivariate analyses, the only statistically significant parameter prognostic for recurrence after BCG treatment was AHT. Recurrence-free survival curves showed a significant correlation with AHT (p = 0.0168, hazards ratio [HR] 1.45, 95% confidence interval [CI] 1.0692-1.9619); there was no correlation (p = 0.9040) with ADT (HR 0.9750, 95% CI 0.6457-1.4721). After stratification of AHT and ADT according to drug(s) prescribed, there were no significant differences in the BC recurrence rate (p > 0.05).In this study with a very long-term follow-up, hypertension alone (evaluated by AHT) revealed the increased risk of BC recurrence after BCG treatment.Several hypotheses have been formulated to support these findings, but further prospective studies are needed to both evaluate the real influence of hypertension and identify a possible prognostic factor to be used in selecting poor-prognosis BC patients as early candidates for surgical treatment.


Faraj SF, Munari E, Guner G, et al.
Assessment of tumoral PD-L1 expression and intratumoral CD8+ T cells in urothelial carcinoma.
Urology. 2015; 85(3):703.e1-6 [PubMed] Related Publications
OBJECTIVE: To evaluate programmed death ligand 1 (PD-L1) expression in urothelial carcinoma of the bladder in relationship with tumor-infiltrating CD8+ T cells.
MATERIALS AND METHODS: Tissue microarrays were prepared from 56 cystectomy specimens performed at our hospital (1994-2002). PD-L1 immunoexpression was assessed using the murine antihuman PD-L1 monoclonal antibody 5H1. Extent of membranous PD-L1 expression was assigned in each spot. Spots showing ≥5% expression were considered positive. Average PD-L1 expression per tumor was also calculated (5% positivity cutoff). "High CD8 density" was defined as the presence of ≥60 CD8+ intraepithelial lymphocytes per high power field in a given spot. A tumor was considered high density if ≥50% of its spots were of high density.
RESULTS: PD-L1 expression was positive in approximately 20% of tumors. None of the benign urothelium spots expressed PD-L1. High CD8 density was observed in approximately 20% of cases. CD8 density did not correlate with PD-L1 expression. Overall survival (OS) and disease-specific survival (DSS) rates were 14% and 28%, respectively (median follow-up, 31.5 months). PD-L1 expression was associated with age at cystectomy (P = .01). Remaining clinicopathologic parameters were not associated with PD-L1 expression or CD8 density. High CD8 density was associated with favorable OS (P = .02) and DSS (P = .02). The same was true when CD8 density was adjusted for demographic and clinicopathologic parameters. There was no correlation between PD-L1 expression and outcome.
CONCLUSION: High intratumoral CD8+ T cell density is associated with better OS and DSS in invasive urothelial carcinoma of the bladder. We found no correlation between PD-L1 expression and outcome.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter


Kaleva AI, Hone RW, Szakacs SM, et al.
Tongue metastasis from a poorly differentiated urothelial carcinoma of the bladder.
Ann R Coll Surg Engl. 2015; 97(2):e30-1 [PubMed] Related Publications
Chemotherapy may cause oral ulceration but a thorough investigation of symptoms and signs is important to determine the underlying diagnosis accurately. We describe a case of a patient with a poorly differentiated urothelial carcinoma of the bladder developing a tongue metastasis. This is a challenging diagnosis to make given the rarity of the presentation but it illustrates the need to evaluate any new symptoms fully.


Borah S, Xi L, Zaug AJ, et al.
Cancer. TERT promoter mutations and telomerase reactivation in urothelial cancer.
Science. 2015; 347(6225):1006-10 [PubMed] Related Publications
Reactivation of telomerase, the chromosome end-replicating enzyme, drives human cell immortality and cancer. Point mutations in the telomerase reverse transcriptase (TERT) gene promoter occur at high frequency in multiple cancers, including urothelial cancer (UC), but their effect on telomerase function has been unclear. In a study of 23 human UC cell lines, we show that these promoter mutations correlate with higher levels of TERT messenger RNA (mRNA), TERT protein, telomerase enzymatic activity, and telomere length. Although previous studies found no relation between TERT promoter mutations and UC patient outcome, we find that elevated TERT mRNA expression strongly correlates with reduced disease-specific survival in two independent UC patient cohorts (n = 35; n = 87). These results suggest that high telomerase activity may be a better marker of aggressive UC tumors than TERT promoter mutations alone.

Related: TERT


Li W, Kidiyoor A, Hu Y, et al.
Evaluation of transforming growth factor-β1 suppress Pokemon/epithelial-mesenchymal transition expression in human bladder cancer cells.
Tumour Biol. 2015; 36(2):1155-62 [PubMed] Related Publications
Transforming growth factor-β1 (TGF-β1) plays a dual role in apoptosis and in proapoptotic responses in the support of survival in a variety of cells. The aim of this study was to determine the function of TGF-β1 in bladder cancer cells and the relationship with POK erythroid myeloid ontogenic factor (Pokemon). TGF-β1 and its receptors mediate several tumorigenic cascades that regulate cell proliferation, migration, and survival of bladder cancer cells. Bladder cancer cells T24 were treated with different levels of TGF-β1. Levels of Pokemon, E-cadherin, Snail, MMP2, MMP9, Twist, VEGF, and β-catenin messenger RNA (mRNA) and protein were examined by real-time quantitative fluorescent PCR and Western blot analysis, respectively. The effects of TGF-β1 on epithelial-mesenchymal transition of T24 cells were evaluated with wound-healing assay, proliferation of T24 was evaluated with reference to growth curves with MTT assay, and cell invasive ability was investigated by Transwell assay. Data show that Pokemon was inhibited by TGF-β1 treatment; the gene and protein of E-cadherin and β-catenin expression level showed decreased markedly after TGF-β1 treatment (P < 0.05). While the bladder cancer cell after TGF-β1 treatment showed a significantly reduced wound-closing efficiency at 6, 12, and 24 h, mechanistic analyses demonstrated that different levels of TGF-β1 promotes tumor cell growth, migration, and invasion in bladder cancer cells (P < 0.01, P < 0.05, respectively). In summary, our findings suggest that TGF-β1 may inhibit the expression of Pokemon, β-catenin, and E-cadherin. The high expression of TGF-β1 leads to an increase in the phenotype and apical-base polarity of epithelial cells. These changes of cells may result in the recurrence and progression of bladder cancer at last. Related mechanism is worthy of further investigation.

Related: Apoptosis TGFB1 CTNNB1 gene


Bryan RT, Regan HL, Pirrie SJ, et al.
Protein shedding in urothelial bladder cancer: prognostic implications of soluble urinary EGFR and EpCAM.
Br J Cancer. 2015; 112(6):1052-8 [PubMed] Article available free on PMC after 17/03/2016 Related Publications
BACKGROUND: Better biomarkers must be found to develop clinically useful urine tests for bladder cancer. Proteomics can be used to identify the proteins released by cancer cell lines and generate candidate markers for developing such tests.
METHODS: We used shotgun proteomics to identify proteins released into culture media by eight bladder cancer cell lines. These data were compared with protein expression data from the Human Protein Atlas. Epidermal growth factor receptor (EGFR) was identified as a candidate biomarker and measured by ELISA in urine from 60 noncancer control subjects and from 436 patients with bladder cancer and long-term clinical follow-up.
RESULTS: Bladder cancer cell lines shed soluble EGFR ectodomain. Soluble EGFR is also detectable in urine and is highly elevated in some patients with high-grade bladder cancer. Urinary EGFR is an independent indicator of poor bladder cancer-specific survival with a hazard ratio of 2.89 (95% CI 1.81-4.62, P<0.001). In multivariable models including both urinary EGFR and EpCAM, both biomarkers are predictive of bladder cancer-specific survival and have prognostic value over and above that provided by standard clinical observations.
CONCLUSIONS: Measuring urinary EGFR and EpCAM may represent a simple and useful approach for fast-tracking the investigation and treatment of patients with the most aggressive bladder cancers.

Related: EPCAM EGFR


Jia Z, Ai X, Sun F, et al.
Identification of new hub genes associated with bladder carcinoma via bioinformatics analysis.
Tumori. 2015 Jan-Feb; 101(1):117-22 [PubMed] Related Publications
AIMS AND BACKGROUND: Bladder carcinoma (BC) is one of the most common malignant cancers worldwide. Several genes related to the mechanism of BC have been studied in recent years, but the current understanding of BC is still rather limited. This study aimed to find new differentially expressed genes (DEGs) associated with the occurrence and development of BC.
METHODS: In this work, we downloaded gene expression data from Gene Expression Omnibus under accession number GSE27448, which included 10 GeneChips from urinary BC tissues and 5 from normal tissues. DEGs were identified by the LIMMA package in R. Then the protein-protein interactions (PPIs) networks were analyzed with the database of Search Tool for the Retrieval of Interacting Genes, and gene ontology (GO) was applied to explore the underlying function of the DEGs using the Database for Annotation, Visualization and Integrated Discovery.
RESULTS: A total of 2,068 DEGs were found between BC and normal tissues. These genes were involved in 49 functional clusters. The top 10 highest degree nodes, such as POLR2F/2H (DNA directed RNA polymerase II polypeptide F/polypeptide H) and RPS14/15 (ribosomal protein S14/S15), were proven to be hub nodes in the PPIs network. ITGA7 (integrin, alpha 7), GRB14 (growth factor receptor-bound protein 14), CDC20 (cell division cycle 20) and PSMB1 (proteasome subunit, beta type, 1) were significant DEGs identified in the functional clusters.
CONCLUSIONS: Genes such as POLR2F/2H, RPS14/15, ITGA7, GRB14, CDC20 and PSMB1 were forecast to play important roles in the occurrence and progression of BC.


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