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
Information for Health Professionals / Researchers
Latest Research Publications
Molecular Biology of Bladder Cancer
Urinary System Cancers

Information Patients and the Public (14 links)


Information for Health Professionals / Researchers (8 links)

Latest Research Publications

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

Large MC, Cohn JA, Steinberg GD
Optimal risk-adapted surveillance strategies for NMIBC, including upper tract imaging.
Urol Clin North Am. 2013; 40(2):305-15 [PubMed]
Non-muscle invasive bladder cancer (NMIBC) represents approximately 70% of all incident cases of bladder cancer. The financial burden of NMIBC continues to increase, underscoring the importance of efficient, evidence-based management of this disease. Consensus guidelines differ on risk definition and in management recommendations. This article reviews the incidence and financial impact of NMIBC and details the recommendations for diagnosis, treatment, and surveillance made by the American Urological Association, International Consultation on Bladder Cancer-European Association of Urology, and National Comprehensive Cancer Network. Established and developing adjunctive laboratory and imaging tests directed at diagnosis and management of NMIBC are also discussed.


Ritch CR, Clark PE, Morgan TM
Restaging transurethral resection for non-muscle invasive bladder cancer: who, why, when, and how?
Urol Clin North Am. 2013; 40(2):295-304 [PubMed]
The rate of clinical understaging in non-muscle invasive bladder cancer (NMIBC) after an initial transurethral resection (TUR) is significant, particularly for high-grade disease, and this has a major impact on prognosis. A repeat TUR, 2 to 6 weeks following the initial resection, is recommended in appropriately selected cases to avoid diagnostic inaccuracy and improve treatment allocation. This article summarizes the rationale and indications for performing a repeat TUR in NMIBC and also provides information regarding patient selection and technique.


Sanfrancesco J, Jones JS, Hansel DE
Diagnostically challenging cases: what are atypia and dysplasia?
Urol Clin North Am. 2013; 40(2):281-93 [PubMed]
This article addresses the spectrum of atypia and dysplasia within the bladder epithelium and the diagnostic categories developed to further classify challenging lesions. In addition, the effects of inflammation, specific therapies, and instrumentation on the bladder mucosa as well as the associated difficulty in achieving the appropriate diagnosis are also discussed.


Gillespie JA, O'Donnell MA
New imaging techniques for non-muscle invasive bladder cancer: ready for primetime.
Urol Clin North Am. 2013; 40(2):271-9 [PubMed]
Treatment of non-muscle invasive bladder cancer (NMBIC) requires direct visual appreciation of the tumor. Transurethral resection that is dependent solely on white light cystoscopy (WLC) often fails to accurately stage or completely resect NMIBC. These deficiencies of WLC are significant contributors to the high rates of recurrence and eventual progression to muscle invasive disease. This article looks at technologies that are being used in adjunct to WLC to augment the urologist's ability to identify, stage, and treat NMIBC.


James AC, Gore JL
The costs of non-muscle invasive bladder cancer.
Urol Clin North Am. 2013; 40(2):261-9 [PubMed]
Bladder cancer is a common diagnosis, affecting 70,000 Americans each year. Because the diagnosis, management, and long-term follow-up of non-muscle invasive bladder cancer requires advanced imaging and invasive testing, economic evaluations have shown bladder cancer to be the costliest cancer to treat in the US on a per capita basis. Adjunctive tests for surveillance have not obviated the need for cystoscopy and cytology. Indirect costs to patients include loss of work, decreased productivity, and diminished quality of life associated with diagnosis, treatment, and surveillance. Improved value may be achieved with better compliance with evidence-based practices for non-muscle invasive bladder cancer care.


Ingimarsson JP, Seigne JD
The conundrum of prostatic urethral involvement.
Urol Clin North Am. 2013; 40(2):249-59 [PubMed]
The presence and depth of urothelial cancer involvement in the prostatic urethra can significantly affect the management of a patient with non-muscle invasive bladder cancer. This article presents an overview of the incidence, diagnosis, management, and follow-up of urothelial cancer.


Daneshmand S
Determining the role of cystectomy for high-grade T1 urothelial carcinoma.
Urol Clin North Am. 2013; 40(2):233-47 [PubMed]
High-grade T1 (HGT1) urothelial carcinoma is an invasive disease with high predisposition for recurrence and progression. The optimal treatment of HGT1 disease remains controversial. Clinical HGT1 disease represents a heterogeneous group of patients with variable clinical behavior. Radical cystectomy for HGT1 disease is associated with excellent survival and offers the best opportunity for cure; however, it has a potential cost of decrease in quality of life. This article summarizes features associated with increased risk of progression and provides a framework for optimal treatment strategy with a focus on the role of radical cystectomy for HGT1 disease.


Ahn JJ, McKiernan JM
New agents for bacillus Calmette-Guérin-refractory bladder cancer.
Urol Clin North Am. 2013; 40(2):219-32 [PubMed]
Bacillus Calmette-Guérin has been established as the primary treatment of high-risk non-muscle invasive bladder cancer. If patients do not respond or later recur, the most reliable treatment option is cystectomy. For those who are unwilling or unable to undergo this significant procedure, there is a multitude of alternative intravesical therapies. This article provides an overview of treatment options for patients with non-muscle invasive bladder cancer who have failed intravesical bacillus Calmette-Guérin therapy. It includes information on recent and ongoing trials and serves as a guide for clinicians regarding available therapies and a reference for researchers in this field.


Shah JB, Kamat AM
Strategies for optimizing bacillus Calmette-Guérin.
Urol Clin North Am. 2013; 40(2):211-8 [PubMed]
For treating patients with superficial bladder cancer and a moderate-to-high risk of tumor recurrence or progression, intravesical BCG has been the key development of the last generation. However, BCG has also brought with it a novel set of challenges. An understanding of when, to whom, and how BCG should be given is critical if optimal outcomes are to be achieved. This article the authors reviews the role that BCG has played in the management of bladder cancer over the last several decades and discusses specific approaches to optimize BCG. It focuses on selection and technical strategies.


Griffin JG, Holzbeierlein J
Side effects of perioperative intravesical treatment and treatment strategies for these side effects.
Urol Clin North Am. 2013; 40(2):197-210 [PubMed]
Perioperative intravesical chemotherapy has a well-established role in the treatment of non-muscle invasive bladder cancer. There are multiple agents that can be used in this fashion with varying properties. Although chemical cystitis is the most common side effect and is usually self-limiting, significant toxicity can occur with intravesical chemotherapy. It is imperative that the urologist is aware of the acute and delayed side effects of intravesical chemotherapy and how to manage potential complications. Both local and systemic toxicities are discussed, as well as strategies to minimize and manage them.


Johnson DC, Pruthi RS, Woods ME
Perioperative chemotherapy: when to use it, what to use, and why.
Urol Clin North Am. 2013; 40(2):183-95 [PubMed]
This article provides an overview of intravesical chemotherapy agents used for non-muscle invasive bladder cancer; summarizes the evidence on single-dose perioperative administration, induction therapy, and maintenance therapy; and briefly discusses ongoing research.


O'Neil BB, Lowrance WT
Office-based Bladder Tumor Fulguration and Surveillance: Indications and Techniques.
Urol Clin North Am. 2013; 40(2):175-82 [PubMed]
This article summarizes the current literature on office-based management of low-grade, noninvasive bladder cancer. Discussion includes differences in recurrence and progression rates between neoplasm grades and stages, role of visual grading for diagnosis, cost advantages of treatment outside the operating room, and a step-by-step description of office-based procedures.


Tomasini JM, Konety BR
Urinary markers/cytology: what and when should a urologist use.
Urol Clin North Am. 2013; 40(2):165-73 [PubMed]
As of 2012, bladder cancer is the fourth most common cancer afflicting men and ninth most common cancer in women. Nearly 80% of all bladder cancer diagnoses are non-muscle invasive at presentation, most of whom will develop recurrent disease within 5 years of initial diagnosis. Urinary tumor markers provide a noninvasive method for both screening and surveillance of bladder cancer. This article reviews the current Food and Drug Administration-approved urinary biomarkers for detection of non-muscle invasive bladder cancer.


Lammers RJ, Sylvester RJ, Lee CT, Witjes JA
NMIBC risk calculators: how useful are they for the practicing urologist and how can their clinical utility be improved?
Urol Clin North Am. 2013; 40(2):155-64 [PubMed]
The natural history of non-muscle invasive bladder cancer (NMIBC) in individual patients can be unpredictable. Although there are known clinical and molecular factors associated with tumor recurrence and progression, it is challenging to reconcile these data during a typical patient encounter within a busy clinic. The authors discuss the European Organization for Research and Treatment of Cancer's risk tables along with other models for predicting prognosis in patients with NMIBC. The authors also describe their advantages and disadvantages and the barriers to using these risk models in daily clinical practice and provide a future perspective on prognostic models.


Lee YC, Wu WJ, Li WM, et al.
Prognostic value of p53 protein overexpression in upper tract urothelial carcinomas in Taiwan.
Anticancer Res. 2013; 33(3):1091-8 [PubMed]
BACKGROUND: p53 plays an important role in maintaining genomic stability and regulating the cell cycle. However, the accumulation of p53 protein has been reported to be involved in the carcinogenesis, progression, and metastasis of many types of human cancer. This study evaluates the clinical significance of p53 expression in upper tract urothelial carcinoma.
PATIENTS AND METHODS: One-hundred and twelve cases of upper tract urothelial carcinoma were included in this study. p53 expression was evaluated by immunohistochemistry and the association of p53 expression with clinicopathological variables was analyzed.
RESULTS: p53 expression was significantly correlated with patients who were undergoing hemodialysis (p=0.005) and had increased serum creatinine levels (p=0.001). High p53 expression was associated with poor progression-free (p=0.025) and cancer-specific survival (p=0.021), Cox regression analysis also revealed that p53 was an independent predictor of poor progression-free (hazard ratio=3.74, p=0.025) and cancer-specific (hazard ratio=5.87, p=0.030) survival.
CONCLUSION: Our findings indicate that p53 expression is a potential biomarker for predicting patient survival. Further study is necessary to investigate the role of p53 in the carcinogenesis of upper tract urothelial carcinoma.


Hauser S, Kogej M, Fechner G, et al.
Serum DNA hypermethylation in patients with bladder cancer: results of a prospective multicenter study.
Anticancer Res. 2013; 33(3):779-84 [PubMed]
BACKGROUND: Cell-free serum DNA levels are increased in patients with cancer, and at least partially, these DNA fragments are derived from cancer cells. A few reports indicated that methylated serum DNA in patients with bladder cancer (BCA) is a useful non-invasive biomarker. The purpose of this prospective multicenter study was to validate earlier studies.
MATERIALS AND METHODS: In total, 227 consecutive participants (non-muscle invasive BCA, n=75; muscle-invasive BCA, n=20; transurethral bladder resection (TURB) without BCA, n=48; benign disease, n=31; healthy individuals, n=53), were recruited for this study. Cell-free serum DNA was isolated and digested with methylation-sensitive restriction-enzymes (Bsh1236I, HpaII and HinP1I) to quantify the amount of methylated (TIMP3, APC, RARB, TIG1, GSTP1, p14, p16, PTGS2 and RASSF1A) DNA fragments.
RESULTS: The amount of methylated DNA was usually small (<10%), and the methylation frequencies varied for different genes (e.g. frequent: TIMP3; moderate: APC, RARB, TIG1; infrequent: p16, PTGS2, p14, RASSF1A, GSTP1). Methylation levels at each gene site and the number of methylated genes were increased in BCA compared to healthy individuals, but were similar in BCA and patients with non-malignant disease. The number of methylated genes allowed for discrimination (62% sensitivity, 89% specificity) of BCA patients from healthy individuals. DNA hypermethylation was not correlated with advanced stage or grade in patients with BCA.
CONCLUSION: The detection of hypermethylated DNA in serum allows for discrimination of patients with BCA and healthy individuals, but there is no difference between patients with BCA and those with non-malignant disease, thereby limiting its value as a non-invasive biomarker.


Zhuo W, Zhang L, Cai L, et al.
XRCC1 Arg399Gln polymorphism and bladder cancer risk: updated meta-analyses based on 5767 cases and 6919 controls.
Exp Biol Med (Maywood). 2013; 238(1):66-76 [PubMed]
Previous reports implicate XRCC1 Arg399Gln polymorphism as a possible risk factor for several cancers. Published meta-analyses have been conducted on the association of XRCC1 Arg399Gln polymorphism with susceptibility to bladder cancer, and have generated conflicting results. The present study aimed to derive a more precise estimation of the relationship. Updated meta-analyses assessing the association of XRCC1 Arg399Gln polymorphism with bladder cancer were conducted and subgroup analyses on ethnicity, smoking status and source of controls were further performed. Eligible studies were identified for the period up to May 2012. A total of 19 case-control studies comprising 5767 cases and 6919 controls were lastly selected for analysis. The overall data failed to indicate significant associations between XRCC1 Arg399Gln polymorphism and bladder cancer risk (Gln/Gln versus Arg/Arg: odds ratio (OR) = 0.97; 95% CI = 0.85-1.10; dominant model: OR = 1.02; 95% CI = 0.94-1.09; recessive model: OR = 0.95; 95% CI = 0.84-1.07). In subgroup analyses stratified by ethnicity, smoking status and source of controls, respectively, similar results were obtained. In conclusion, the results of the present study suggest that XRCC1 Arg399Gln polymorphism might not modify the susceptibility to bladder cancer. Further large and well-designed studies are needed to confirm this conclusion.


Buchner A, May M, Burger M, et al.
Prediction of outcome in patients with urothelial carcinoma of the bladder following radical cystectomy using artificial neural networks.
Eur J Surg Oncol. 2013; 39(4):372-9 [PubMed]
AIM: The outcome of patients with urothelial carcinoma of the bladder (UCB) after radical cystectomy (RC) shows remarkable variability. We evaluated the ability of artificial neural networks (ANN) to perform risk stratification in UCB patients based on common parameters available at the time of RC.
METHODS: Data from 2111 UCB patients that underwent RC in eight centers were analysed; the median follow-up was 30 months (IQR: 12-60). Age, gender, tumour stage and grade (TURB/RC), carcinoma in situ (TURB/RC), lymph node status, and lymphovascular invasion were used as input data for the ANN. Endpoints were tumour recurrence, cancer-specific mortality (CSM) and all-cause death (ACD). Additionally, the predictive accuracies (PA) of the ANNs were compared with the PA of Cox proportional hazards regression models.
RESULTS: The recurrence-, CSM-, and ACD- rates after 5 years were 36%, 33%, and 46%, respectively. The best ANN had 74%, 76% and 69% accuracy for tumour recurrence, CSM and ACD, respectively. Lymph node status was one of the most important factors for the network's decision. The PA of the ANNs for recurrence, CSM and ACD were improved by 1.6% (p = 0.247), 4.7% (p < 0.001) and 3.5% (p = 0.007), respectively, in comparison to the Cox models.
CONCLUSIONS: ANN predicted tumour recurrence, CSM, and ACD in UCB patients after RC with reasonable accuracy. In this study, ANN significantly outperformed the Cox models regarding prediction of CSM and ACD using the same patients and variables. ANNs are a promising approach for individual risk stratification and may optimize individual treatment planning.


Ito A, Shintaku I, Satoh M, et al.
Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial.
J Clin Oncol. 2013; 31(11):1422-7 [PubMed]
PURPOSE: We evaluated the efficacy of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma (UUT-UC).
PATIENTS AND METHODS: From December 2005 to November 2008, 77 patients clinically diagnosed with UUT-UC from 11 institutions participating in the Tohoku Urological Evidence-Based Medicine Study Group were preoperatively enrolled in this study. Patients were randomly assigned to receive or not receive a single instillation of THP (30 mg in 30 mL of saline) into the bladder within 48 hours after nephroureterectomy. Cystoscopy and urinary cytology were repeated every 3 months for 2 years or until the occurrence of first bladder recurrence.
RESULTS: Seventy-two patients were evaluable for efficacy analysis, 21 of whom had a subsequent bladder recurrence. Significantly fewer patients who received THP had a recurrence compared with the control group (16.9% at 1 year and 16.9% at 2 years in the THP group v 31.8% at 1 year and 42.2% at 2 years in the control group; log-rank P = .025). No remarkable adverse events were observed in the THP-treated group. Based on multivariate analysis, THP instillation (hazard rate [HR], 0.26; 95% CI, 0.07 to 0.91; P = .035) and open surgery (HR, 0.28; 95% CI, 0.09 to 0.84; P = .024) were independently predictive of a reduced incidence of bladder recurrence.
CONCLUSION: In this prospective randomized phase II study, a single intravesical instillation of THP seemed to reduce bladder recurrence after nephroureterectomy. A phase III, large-scale, multicenter study is needed to confirm these observations.


Zhong M, Gersbach E, Rohan SM, Yang XJ
Primary adenocarcinoma of the urinary bladder: differential diagnosis and clinical relevance.
Arch Pathol Lab Med. 2013; 137(3):371-81 [PubMed]
CONTEXT: Glandular lesions of the urinary bladder include a broad spectrum of entities ranging from completely benign glandular lesions to primary and secondary malignancies. Common benign bladder lesions that exhibit glandular differentiation include cystitis cystica, cystitis glandularis, von Brunn nests, nephrogenic adenoma, intestinal metaplasia, urachal remnant, endometriosis, and prostatic-type polyp. The World Health Organization defines primary adenocarcinoma of the bladder as an epithelial malignancy with pure glandular differentiation without evidence of typical urothelial carcinoma. Malignant lesions that should be included in the differential diagnosis of a primary adenocarcinoma of the bladder include noninvasive and invasive urothelial carcinoma with glandular differentiation and secondary malignancies involving the bladder by direct extension or metastasis. The recognition and distinction of these different entities may be a challenge for pathologists, but they are of great clinical importance.
OBJECTIVE: To review features of primary bladder adenocarcinoma as well as those entities that need to be differentiated from primary bladder adenocarcinoma, with emphasis on clinical findings, pathologic characteristics, and immunoprofiles.
DATA SOURCES: Selected original articles published in the PubMed service of the US National Library of Medicine.
CONCLUSIONS: The accurate diagnosis of adenocarcinoma of the urinary bladder is important and challenging. It has to prompt an extensive clinical workup to rule out other glandular lesions in the urinary bladder, especially the possibility of secondary involvement of the bladder by an adenocarcinoma from a different site.


Takaoka E, Matsui Y, Inoue T, et al.
Risk factors for intravesical recurrence in patients with high-grade T1 bladder cancer in the second TUR era.
Jpn J Clin Oncol. 2013; 43(4):404-9 [PubMed]
OBJECTIVE: We aimed to elucidate risk factors for intravesical recurrence of high-grade T1 bladder cancer in the second transurethral resection era.
METHODS: The analysis included 73 patients with high-grade T1 bladder cancer on initial transurethral resection. The median follow-up period was 49.2 months. Recurrence-free survival, progression-free survival and risk factors related to the presence of residual tumors or recurrence-free survival were statistically analyzed.
RESULTS: The pathological findings for second transurethral resection were pT0 36 (49%), pTis/a 21 (29%), pT1 13 (18%) and pT2 3 (4%), respectively. The risk factor for residual tumors at second transurethral resection was the presence of concomitant carcinoma in situ at the initial transurethral resection (P < 0.01). The bladder was preserved in all 57 patients with pT0/is/a tumors on second transurethral resection, and 43 patients (75%) received intravesical BCG therapy. Of these patients, 3-year recurrence-free survival and 3-year progression-free survival rates were 81 and 96%, respectively. In addition, the presence of pTis/a residual tumors on second transurethral resection had a significant impact on the recurrence. Five of the 13 patients with pT1 on second transurethral resection were immediately treated by radical cystectomy or radiation therapy combined with chemotherapy, and two (25%) of the eight who were treated by intravesical BCG therapy had progression including distant metastasis.
CONCLUSIONS: High recurrence-free survival and progression-free survival were achieved by a second transurethral resection and intravesical BCG therapy in the patients with pT0/is/a on the second transurethral resection. In this group, the residual tumors at second transurethral resection are risk factors for intravesical recurrence.


Montanari E, de la Rosette J, Longo F, et al.
Narrow-band imaging (NBI) and white light (WLI) transurethral resection of the bladder in the treatment of non-muscle-invasive bladder cancer.
Arch Ital Urol Androl. 2012; 84(4):179-83 [PubMed]
OBJECTIVE: Narrow-band imaging (NBI) is an optical image enhancement technology Summary that narrows the bandwidth of the light output from the endoscopy system to 415 nm and 540 nm. The aim of the present study is to evaluate the feasibility of NBI transurethral resection of the bladder (TURB NBI) compared to in White Light (TURB WLI) (Feasibility study) and the recurrence rate at the 1-year follow-up in patients treated for non-muscle-invasive bladder cancer (NMIBC) (recurrence study).
METHODS: A total of 92 patients with a suspicion of primary or recurrent bladder cancer were prospectively enrolled in our study. Forty-five were consecutively enrolled to undergo WLI TURB and 47 consecutively to undergo NBI TURB. All patients underwent routine follow-up with flexible WLI cystoscopy every 3 months during the first year and every 6 months during the second year, supplemented by urine examination, urine culture, and bladder washout cytology.
RESULTS: Type I-II complications were reported in 12 patients in the NBI group (25%) and in 10 patients in the WLI group (22%). Patients with High Grade NMIBC who underwent a second look WLI TURB had residual disease in 33% of NBI group and in 43% of WLI group.The recurrence rate at one year follow-up was 35% in NBI group and 50% in WLI group. No statistic significance can be issued for the clinical differences observed.
CONCLUSIONS: TURB performed entirely by the NBI technique is feasible and safe. It guarantees a complete and rapid resection of good quality from a pathological point of view. Moreover, the technique is relatively inexpensive with respect to other methods proposed to enhance the detection rate, for which data on operative endoscopy are lacking. In our clinical experience, even if not statistically significant, NBI TURB reduces at one year follow up the recurrence rate of bladder NMI tumours when compared to WLI TURB (35% vs. 50%). Other larger, randomized, prospective trials with longer follow-up periods are required to confirm our outcomes.


Ali-El-Dein B, Mosbah A, Osman Y, et al.
Preservation of the internal genital organs during radical cystectomy in selected women with bladder cancer: a report on 15 cases with long term follow-up.
Eur J Surg Oncol. 2013; 39(4):358-64 [PubMed]
PURPOSE: To prospectively present the technique, functional and oncological outcome of internal genitalia sparing cystectomy for bladder cancer in 15 selected women.
PATIENTS AND METHODS: Between January 1995 and December 2010, 305 women underwent orthotopic neobladder after radical cystectomy. Of these, 15 cases with a mean age of 42 years underwent genitalia sparing. Inclusion criteria included stage (T2b N0 Mo or less, as assessed preoperatively, unifocal tumors away from the trigone, sexually active young women and internal genitalia free of tumor. Cystectomy with preservation of the uterus, vagina and ovaries and Hautmann neobladder were performed. Oncological, functional, urodynamic and sexual outcome using Female Sexual Function Index (FSFI) were evaluated.
RESULTS: Definitive histopathology showed advanced stage not recognized preoperatively in 2 patients, who developed local recurrence and bony metastasis after 3-4 months. A third patient developed bony metastasis after 15 months. No recurrence developed in the retained genital organs. The remaining 12 patients remained free of disease with a mean follow-up of 70 months. Among women eligible for functional evaluation, daytime and nighttime continence were achieved in 13/13 (100%) and 12/13 (92)%, respectively. Chronic urinary retention was not noted. The urodynamic parameters were comparable to those in other patients without genital preservation. Sexual function (FSFI) was better in these patients than in others without genital preservation.
CONCLUSIONS: Genital sparing cystectomy for bladder cancer is feasible in selected women. It provides a good functional outcome, better sexual function and the potential for fertility preservation. So far, the oncological outcome is favorable.


Jaiswal PK, Singh V, Srivastava P, Mittal RD
Association of IL-12, IL-18 variants and serum IL-18 with bladder cancer susceptibility in North Indian population.
Gene. 2013; 519(1):128-34 [PubMed]
IL-12 and IL-18 are immunomodulatory cytokines that play important roles in host immune response against cancers. Variation in DNA sequence in gene promoter may lead to altered IL-18 production and/or activity, and hence can modulate an individual's susceptibility to BC. To test this hypothesis, we investigated the relationship of IL-18 gene promoter -137 G/C and -607C/A polymorphisms and IL12 (-16974) A/C with the risk of BC in North Indian population. Polymorphisms in IL-18 and IL-12 genes were analyzed in 200 BC patients and 200 age, ethnicity and sex-matched controls, using restriction fragment length polymorphism-polymerase chain reaction (PCR-RFLP) and amplification refractory mutation specific-polymerase chain reaction (ARMS) method. The concentrations of IL-18 in serum were determined by ELISA. Significant association was observed with IL18 (-137) G/C heterozygous genotype (GC) with 1.96 folds risk of BC as well at C allele carrier and variant C allele having 2 fold and 1.6 fold risk for BC respectively. IL18 (-607) C/A, heterozygous CA genotype also showed a high risk (OR=1.59) for BC. While IL12 (-16974) A/C heterozygote genotype and C allele carrier demonstrated reduced risk of BC. Hetero genotype of IL18 (-137) G/C was associated with risk of recurrence (HR=2.35) in superficial BC patients receiving BCG treatment thus showing least survival. The distributions of IL-18 gene haplotypes were not significantly different between patients and controls. Serum IL-18 levels were significantly higher in BC patients than in the healthy subjects (p=0.025). Serum IL-18 levels was also significantly associated with IL18 (-137) G/C in heterozygous genotype (GC) (p=0.048). Our results suggest that IL-18 gene polymorphism contributes to bladder cancer risk whereas IL-12 is protective. A relation between IL18 (-137) G/C in heterozygous genotype with elevated IL-18 serum level and bladder cancer risk has been registered in the present study.


Luo M, Li Z, Wang W, et al.
Upregulated H19 contributes to bladder cancer cell proliferation by regulating ID2 expression.
FEBS J. 2013; 280(7):1709-16 [PubMed]
Long noncoding RNAs have been shown to have important regulatory roles in cancer biology, and long noncoding RNA 19 (H19) is essential for human tumor growth. However, little is known about how abnormal expression of H19 contributes to bladder cancer cell proliferation. In this study, we first evaluated the expression of H19 in bladder cancer tissues by real-time PCR, and defined the biological functions. We found that H19 expression levels were remarkably increased in bladder cancer tissues as compared with adjacent normal control tissue, and forced expression of H19 promoted bladder cancer cell proliferation in vitro. Inhibitor of DNA binding/differentiation 2 (ID2) expression levels were upregulated in bladder cancer tissues and in bladder cancer cells. A significant positive correlation was observed between H19 levels and ID2 levels in vivo. We further demonstrated that overexpression of H19 resulted in a significant increase in the expression of ID2, whereas H19 knockdown decreased ID2 expression in vitro. Gain-of-function and loss-of-function studies demonstrated that upregulated H19 increased bladder cancer cell proliferation by increasing ID2 expression. In conclusion, upregulated H19 increases bladder cancer growth by regulating ID2 expression, and thus may be helpful in the development of effective treatment strategies for bladder cancer.


Compérat E, Jacquet SF, Varinot J, et al.
Different subtypes of carcinoma in situ of the bladder do not have a different prognosis.
Virchows Arch. 2013; 462(3):343-8 [PubMed]
Urothelial carcinoma in situ (CIS) is a high-grade lesion with different subtypes (large cell pleomorphic (LCP), large cell nonpleomorphic (LC), small cell and clinging (CL)). We explored the frequency of different subtypes in primary CIS and compared different patterns with outcome. We explored whether subtyping of CIS leads to a change in therapy and/or follow-up and should be formally reported. We included 39 patients with a primary CIS and divided them into two groups: one with LPC/LG and one with CL elements. Other subtypes did not exist or occurred only as a mixture. Patient age ranged from 36 to 80 years (mean, 63 years). Twenty had a primary CIS with one single subtype. LCP was predominant with 16 (41 %) cases; the second most important subtype was the CL with four (10 %) cases. Mean follow-up was 26.4 months, (range, 4-100 months). Thirteen patients developed a ≥ pT2 carcinoma. When progression of the different subtypes was examined, no statistical significance was found between mixed forms (p = 0.9437) nor between pure forms (p = 0.744 and p = 0.5955, respectively). Pathologists need not include different subtypes of primary CIS in their report as there is no difference in patient outcomes. It is important to recognize all different subtypes as CIS for best patient treatment.


Lah K, Desai D, Hadway P, et al.
Primary vesical clear cell adenocarcinoma arising in endometriosis: a rare case of mullerian origin.
Anticancer Res. 2013; 33(2):615-7 [PubMed]
Clear cell adenocarcinoma arising out of endometriosis of the urinary bladder is a rare entity. The published literature has a dearth of information about this entity and its histogenesis. In the present case review we present a 59-year-old patient who was treated with robotic anterior pelvic exenteration and ileal conduit. The initial biopsy of bladder tumour purported a high-grade urothelial carcinoma, however the final specimen revealed a clear cell adenocarcinoma arising in endometriosis without any urothelial cancer. Early case reports refer to these lesions as mesonephric or mesonephroid adenocarcinomas but the current WHO nomenclature classifies them under non-urothelial epithelial neoplasms as clear cell adenocarcinomas. Here, we review the literature and discuss their origins.


Cheng D, Liang B, Li Y
Clinical value of vascular endothelial growth factor and endostatin in urine for diagnosis of bladder cancer.
Tumori. 2012; 98(6):762-7 [PubMed]
AIMS AND BACKGROUND: The aim of the study was to determine whether urinary VEGF and endostatin predict the presence of bladder cancer, and whether these noninvasive biomarkers provide clinically useful information in the bladder cancer patient as well.
METHODS AND STUDY DESIGN: Voided urine samples were collected from 239 patients (109 bladder cancers, 81 urological disorders, 49 healthy controls). The urine levels of VEGF and endostatin were determined with the sandwich enzyme immunoassay technique.
RESULTS: Urine levels of VEGF and endostatin were higher in patients with bladder cancer than those in patients with urological disorders and healthy controls (P <0.01). The difference between patients with urological disorder and healthy controls was significant only for VEGF (P <0.01). Urine level of VEGF was related to the tumor grade, and urine level of endostatin was related to tumor stage, tumor size and tumor number (P <0.05). The optimal cutoffs for VEGF and endostatin were calculated by the ROC curves as 860 pg/ml for VEGF, and 350 pg/ml for endostatin. The five-year survival rate was 60.0% in patients with low level of endostatin (<350 pg/ml) and 7.69% in patients with high level of endostatin (≥350 pg/ml) in the bladder cancer group. Patients with a high level of endostatin had a shorter survival time, whereas patients with a low level of endostatin had a longer survival time (P <0.05).
CONCLUSIONS: Urine levels of VEGF and endostatin may be a clinically useful aid in the diagnosis of bladder cancer, and endostatin but not VEGF is a supplementary prognostic marker for predicting tumor progression.


Peiris AN, Bailey BA, Manning T
Relationship of vitamin D monitoring and status to bladder cancer survival in veterans.
South Med J. 2013; 106(2):126-30 [PubMed]
OBJECTIVES: Veterans of the armed forces, like most population groups, have a high prevalence of vitamin D deficiency, which may be associated with adverse outcomes in several types of cancer. Ultraviolet irradiation is inversely linked with the risk of bladder cancer, presumably through enhanced vitamin D synthesis. We hypothesized that variations in vitamin D status and monitoring predict adverse outcomes in bladder cancer among veterans.
METHODS: A retrospective analysis of data in the Veterans Integrated Service Network-9 (southeastern United States) was performed for patients diagnosed between October 1, 1999 and February 29, 2008. Age, tobacco exposure, body mass index, and latitude and seasonality of sampling were included as variables in addition to serum vitamin 25(OH)D levels.
RESULTS: Monitoring of vitamin D and vitamin D levels and status were closely linked to survival in bladder cancer. Both the chances of survival and longevity improved with enhanced vitamin D status and monitoring. Veterans with bladder cancer had better outcomes if the initial vitamin D level was higher and had more monitoring of the vitamin. Initial vitamin D levels were more strongly related to outcomes than follow-up levels. The link between vitamin D and outcomes remained after adjusting for background variables such as age, body mass index, latitude, seasonality, and tobacco exposure.
CONCLUSIONS: Findings suggest that adequate vitamin D levels early in the course of the disease provide the best opportunity to improve outcomes. Ensuring that veterans with bladder cancer have adequate vitamin D reserves with appropriate monitoring may play a role in improving outcomes in bladder cancer.


Redelman-Sidi G, Iyer G, Solit DB, Glickman MS
Oncogenic activation of Pak1-dependent pathway of macropinocytosis determines BCG entry into bladder cancer cells.
Cancer Res. 2013; 73(3):1156-67 [PubMed]
Bacille Calmette-Guerin (BCG) is an attenuated strain of Mycobacterium bovis that is used widely as a vaccine for tuberculosis and is used as an effective treatment for superficial bladder carcinoma. Despite being the most successful cancer biotherapy, its mechanism of action and response determinants remain obscure. Here, we establish a model system to analyze BCG interaction with bladder cancer cells, using it to show that these cells vary dramatically in their susceptibility to BCG infection. Unexpectedly, the uptake of BCG by bladder cancer cells occurs by macropinocytosis rather than phagocytosis. BCG entry into bladder cancer cells relied upon Rac1, Cdc42, and their effector kinase Pak1. The difference in susceptibility between BCG-permissive and -resistant bladder cancer cells was due to oncogenic activation of signaling pathways that activate macropinocytosis, with phosphoinositide 3-kinase inhibitor activation stimulating BCG uptake independently of Akt. Similarly, activated Ras strongly activated Pak1-dependent uptake of BCG. These results reveal that oncogenic activation of macropinocytosis determines BCG uptake by bladder cancer cells, implying that tumor responsiveness to BCG may be governed by the specific mutations present in the treated cancer cell.


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