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 (16 links)

Information for Health Professionals / Researchers (8 links)

Latest Research Publications

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

Chen Y, Zhang L, Lu X, et al.
Sinomenine reverses multidrug resistance in bladder cancer cells via P-glycoprotein-dependent and independent manners.
Pharmazie. 2014; 69(1):48-54 [PubMed] Related Publications
P-Glycoprotein-mediated multidrug resistance is a frequent event during chemotherapy and a key obstacle for bladder cancer therapy. Search for strategies to reverse multidrug resistance is a promising approach to improve the management of bladder cancer. In the present study, we reported a novel P-glycoprotein-mediated multidrug resistant cell model 253J/DOX, which was generated from human bladder cancer 253J cell line. Furthermore, we found that the multidrug resistant phenotype of 253J/DOX cells could be overcome by sinomenine, an alkaloid derived from the stem of Sinomenium acutum. Mechanistically, the chemosensitive effect by sinomenine was mediated by down-regulating P-glycoprotein expression, as well as triggering apoptotic pathways. The chemosensitive effect of sinomenine may make it a prime candidate agent to target bladder cancer.

Related: Apoptosis

Bernardo C, Costa C, Amaro T, et al.
Patient-derived sialyl-Tn-positive invasive bladder cancer xenografts in nude mice: an exploratory model study.
Anticancer Res. 2014; 34(2):735-44 [PubMed] Related Publications
BACKGROUND: More than 70% of muscle invasive bladder cancers (MIBC) express the cell-surface antigen sialyl-Tn (sTn) that promotes motility and invasive potential of tumor cells. Effective drug testing models to optimize therapy against these tumors are warranted.
MATERIALS AND METHODS: Fragments of sTn-positive MIBC were subcutaneously engrafted into nude mice and expanded until the third passage. Histology and immunoexpression of tumor markers (p53, p63, Ki-67, CK20, sTn) were studied in order to evaluate tumor phenotype maintenance.
RESULTS: Tumor take rate was low in the first passage (1/9) but increased and became consistent, therefore suitable for drug testing, in the third passage (13/13). Histology and immunoexpression patterns were similar between primary tumors and xenografts. However, p53 and ki-67 levels increased with passages suggesting a selection of more proliferative clones. STn expression, even though decreased, was preserved in xenografts.
CONCLUSION: We describe the first patient-derived sTn-positive xenograft model to be used for drug testing and identification of prognostic biomarkers.

Halpenny D, Salati U, Torregiani WC, Browne R
Selective arterial embolization for control of haematuria secondary to advanced or recurrent transitional cell carcinoma of the bladder.
JBR-BTR. 2013 Sep-Oct; 96(5):282-5 [PubMed] Related Publications
AIM: Haematuria is a common symptom in patients with advanced transitional cell carcinoma of the bladder. We report our experience of selective pelvic embolization using gelfoam as an embolic agent to treat intractable haematuria in these patients.
METHODS: Three male patients aged 66-79 (mean 73.6 years) with inoperable or recurrent transitional cell carcinoma of the bladder underwent selective embolization to treat haematuria over a 9 month period. Initial pathological tumour stages were T2, T3, and T3a. Gelfoam was used as the embolic agent.
RESULTS: In all patients extensive vesical neovascularisation was identified without a single focus of active extravasation. Following embolization all patients experienced cessation of haematuria. Mean transfusion requirements were 8.6 units pre-embolization and 0.3 units post-embolization. At follow up of between 6-13 months (mean 10 months) no further episodes of bleeding had been reported. No patient experienced procedure-related complications.
CONCLUSION: Radiologically guided embolization is a safe and effective method for palliating haematuria in patients with transitional cell carcinoma. On the basis of our experience we would recommend gelfoam as the embolic agent of choice.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

Mertens LS, Mir MC, Scott AM, et al.
18F-fluorodeoxyglucose--positron emission tomography/computed tomography aids staging and predicts mortality in patients with muscle-invasive bladder cancer.
Urology. 2014; 83(2):393-8 [PubMed] Related Publications
OBJECTIVE: To investigate the association between extravesical (18)F-fluorodeoxyglucose (FDG) avid lesions on FDG-positron emission tomography/computed tomography (PET/CT) and mortality in patients with muscle-invasive bladder cancer.
METHODS: An international, bi-institutional cohort study of 211 patients with muscle-invasive bladder cancer who underwent staging CT and FDG-PET/CT imaging. On the basis of the presence of extravesical FDG-avid lesions suspicious for malignancy on PET/CT images, patients were divided into a PET/CT-positive and PET/CT-negative group. Data on staging and mortality were retrospectively analyzed from prospective databases. Kaplan-Meier analyses were performed to compare overall (OS) and disease-specific survival (DSS) between the groups. Multivariable Cox regression models were used to investigate the association between extravesical PET/CT lesions and mortality. Extravesical lesions suspicious for malignancy on conventional CT were included in the models.
RESULTS: Of the 211 patients, 98 (46.4%) had 1 or more extravesical lesions on PET/CT, 113 (53.5%) had a negative PET/CT. Conventional CT revealed extravesical lesions in 51 patients (24.4%). Median follow-up was 18 months. Patients with a positive PET/CT had a significantly shorter OS and DSS (median OS: 14 vs 50 months, P = .001; DSS: 16 vs 50 months, P <.001). In multivariable analysis, the presence of extravesical lesions on PET/CT was an independent prognostic indicator of mortality (OS: hazard ratio = 3.0, confidence interval 95% 1.7-5.1). This association was not statistically significant for conventional CT (hazard ratio = 1.6 (95% confidence interval 0.9-2.7).
CONCLUSION: On the basis of our results, the presence of extravesical FDG-avid lesions on PET/CT might be considered an independent indicator of mortality.

Aluwini S, van Rooij PH, Kirkels WJ, et al.
Bladder function preservation with brachytherapy, external beam radiation therapy, and limited surgery in bladder cancer patients: long-term results.
Int J Radiat Oncol Biol Phys. 2014; 88(3):611-7 [PubMed] Related Publications
PURPOSE: To report long-term results of a bladder preservation strategy for muscle-invasive bladder cancer (MIBC) using external beam radiation therapy and brachytherapy/interstitial radiation therapy (IRT).
METHODS AND MATERIALS: Between May 1989 and October 2011, 192 selected patients with MIBC were treated with a combined regimen of preoperative external beam radiation therapy and subsequent surgical exploration with or without partial cystectomy and insertion of source carrier tubes for afterloading IRT using low dose rate and pulsed dose rate. Data for oncologic and functional outcomes were prospectively collected. The primary endpoints were local recurrence-free survival (LRFS), bladder function preservation survival, and salvage cystectomy-free survival. The endpoints were constructed according to the Kaplan-Meier method.
RESULTS: The mean follow-up period was 105.5 months. The LRFS rate was 80% and 73% at 5 and 10 years, respectively. Salvage cystectomy-free survival at 5 and 10 years was 93% and 85%. The 5- and 10-year overall survival rates were 65% and 46%, whereas cancer-specific survival at 5 and 10 years was 75% and 67%. The distant metastases-free survival rate was 76% and 69% at 5 and 10 years. Multivariate analysis revealed no independent predictors of LRFS. Radiation Therapy Oncology Group grade ≥3 late bladder and rectum toxicity were recorded in 11 patients (5.7%) and 2 patients (1%), respectively.
CONCLUSIONS: A multimodality bladder-sparing regimen using IRT offers excellent long-term oncologic outcome in selected patients with MIBC. The late toxicity rate is low, and the majority of patients preserve their functional bladder.

Related: Brachytherapy

Goldsmith B, Baumann BC, He J, et al.
Occult pelvic lymph node involvement in bladder cancer: implications for definitive radiation.
Int J Radiat Oncol Biol Phys. 2014; 88(3):603-10 [PubMed] Related Publications
PURPOSE: To inform radiation treatment planning for clinically staged, node-negative bladder cancer patients by identifying clinical factors associated with the presence and location of occult pathologic pelvic lymph nodes.
METHODS AND MATERIALS: The records of patients with clinically staged T1-T4N0 urothelial carcinoma of the bladder undergoing radical cystectomy and pelvic lymphadenectomy at a single institution were reviewed. Logistic regression was used to evaluate associations between preoperative clinical variables and occult pathologic pelvic or common iliac lymph nodes. Percentages of patient with involved lymph node regions entirely encompassed within whole bladder (perivesicular nodal region), small pelvic (perivesicular, obturator, internal iliac, and external iliac nodal regions), and extended pelvic clinical target volume (CTV) (small pelvic CTV plus common iliac regions) were calculated.
RESULTS: Among 315 eligible patients, 81 (26%) were found to have involved pelvic lymph nodes at the time of surgery, with 38 (12%) having involved common iliac lymph nodes. Risk of occult pathologically involved lymph nodes did not vary with clinical T stage. On multivariate analysis, the presence of lymphovascular invasion (LVI) on preoperative biopsy was significantly associated with occult pelvic nodal involvement (odds ratio 3.740, 95% confidence interval 1.865-7.499, P<.001) and marginally associated with occult common iliac nodal involvement (odds ratio 2.307, 95% confidence interval 0.978-5.441, P=.056). The percentages of patients with involved lymph node regions entirely encompassed by whole bladder, small pelvic, and extended pelvic CTVs varied with clinical risk factors, ranging from 85.4%, 95.1%, and 100% in non-muscle-invasive patients to 44.7%, 71.1%, and 94.8% in patients with muscle-invasive disease and biopsy LVI.
CONCLUSIONS: Occult pelvic lymph node rates are substantial for all clinical subgroups, especially patients with LVI on biopsy. Extended coverage of pelvic lymph nodes up to the level of the common iliac nodes may be warranted in subsets of patients.

Turgeon GA, Souhami L, Cury FL, et al.
Hypofractionated intensity modulated radiation therapy in combined modality treatment for bladder preservation in elderly patients with invasive bladder cancer.
Int J Radiat Oncol Biol Phys. 2014; 88(2):326-31 [PubMed] Related Publications
PURPOSE/OBJECTIVE(S): To review our experience with bladder-preserving trimodality treatment (TMT) using hypofractionated intensity modulated radiation therapy (IMRT) for the treatment of elderly patients with muscle-invasive bladder cancer.
METHODS AND MATERIALS: Retrospective study of elderly patients treated with TMT using hypofractionated IMRT (50 Gy in 20 fractions) with concomitant weekly radiosensitizing chemotherapy. Eligibility criteria were as follows: age ≥70 years, a proven diagnosis of muscle-invasive transitional cell bladder carcinoma, stage T2-T3N0M0 disease, and receipt of TMT with curative intent. Response rate was assessed by cystoscopic evaluation and bladder biopsy.
RESULTS: 24 patients with a median age of 79 years were eligible. A complete response was confirmed in 83% of the patients. Of the remaining patients, 1 of them underwent salvage cystectomy, and no disease was found in the bladder on histopathologic assessment. After a median follow-up time of 28 months, of the patients with a complete response, 2 patients had muscle-invasive recurrence, 1 experienced locoregional failure, and 3 experienced distant metastasis. The overall and cancer-specific survival rates at 3 years were 61% and 71%, respectively. Of the surviving patients, 75% have a disease-free and functioning bladder. All patients completed hypofractionated IMRT, and 19 patients tolerated all 4 cycles of chemotherapy. Acute grade 3 gastrointestinal or genitourinary toxicities occurred in only 4% of the patients, and acute grade 3 or 4 hematologic toxicities, liver toxicities, or both were experienced by 17% of the cohort. No patient experienced grade 4 gastrointestinal or genitourinary toxicity.
CONCLUSIONS: Hypofractionated IMRT with concurrent radiosensitizing chemotherapy appears to be an effective and well-tolerated curative treatment strategy in the elderly population and should be considered for patients who are not candidates for cystectomy or who wish to avoid cystectomy.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter Cisplatin Gemcitabine

Aydin O, Yacinkaya S, Eren E, et al.
Diminished arylesterase enzyme activity and total thiol levels in bladder cancer patients.
Clin Lab. 2013; 59(11-12):1231-7 [PubMed] Related Publications
BACKGROUND: It is difficult to think of a disease in the etiology of which free radicals would not be involved. The human body has a number of endogenous free-radical scavenging systems to avoid harm that can lead to any disease including cancer. This study aims to measure the total anti-oxidative status (TAS), in particular the activities of HDL-associated anti-oxidative enzymes paraoxonase (PON1), arylesterase (ARE), and total thiol levels (Ttl) in bladder cancer (BC) patients for the first time in literature.
METHODS: Forty two male patients (mean age, 66.6 +/- 12.7 years) with BC who had presented at the Urology Outpatient Clinic were prospectively included in the study. Forty age- and gender-matched healthy control subjects (mean age 65 +/- 7.4 years) were also enrolled for comparison. Analysis of PON1, ARE activities, measurement of TAS, and Ttl of serum were carried out using colorimetric measurement methods. Statistical analyses were performed using the MedCalc statistical software program.
RESULTS: ARE enzyme activity and Ttl levels were significantly lower in patients with BC compared to controls (p = 0.03; p = 0.02, respectively), whereas PON1 enzyme activity and TAS did not show significant differences. Ttl levels were lower in patients with a high grade cancer compared to those with a low grade cancer (p = 0.03).
CONCLUSIONS: Anti-oxidant measurements might be essential in routine clinical use, not only as cancer disease markers but also as major actors in the management of anti-oxidant remedies in the very near future. Our findings showed that determination of ARE enzyme activity and Ttl levels were more precise than PON1 enzyme activity or TAS measurements, particularly in BC patients. When composing a marker panel, it should be kept in mind that determination of anti-oxidant levels based merely on TAS or PON1 activity may be deceptive and must include ARE enzyme activity and/or Ttl measurements. However, long-term clinical studies are needed to clarify the pathophysiological role of serum anti-oxidative levels and HDL-associated PON1 activity in BC patients.

Li G, Liu Y, Yin H, et al.
E-cadherin gene promoter hypermethylation may contribute to the risk of bladder cancer among Asian populations.
Gene. 2014; 534(1):48-53 [PubMed] Related Publications
There are increasing scientific evidences suggesting that E-cadherin gene promoter hypermethylation may contribute to the development and progression of bladder cancer, but existing studies have yielded inconclusive results. This meta-analysis aims to assess the role of E-cadherin promoter hypermethylation in bladder carcinogenesis. We conducted an extensive literature search for relevant studies on PubMed, Embase, Web of Science, Cochrane Library, and CBM databases from their inception through May 1st, 2013. This meta-analysis was performed using the STATA 12.0 software. Crude risk ratio (RR) with 95% confidence interval (CI) was calculated. Ten clinical studies were included in this meta-analysis with a total of 620 bladder cancer samples,199 normal adjacent samples and 131 normal urothelium tissue. Our meta-analysis revealed that the methylation frequencies in bladder cancer tissues were obviously higher than those in normal control tissues (RR = 2.02, 95%CI: 1.00–4.12, P = 0.050). Subgroup analysis by ethnicity indicated that higher methylation frequencies were observed in bladder cancer tissues among Asian populations (RR = 2.35, 95%CI: 1.11–4.95, P = 0.025), but not among Caucasian populations (RR = 1.62, 95%CI: 0.48–5.53, P = 0.439). Univariate and multivariate meta-regression analyses showed that ethnicity may be the major source of heterogeneity (Pb0.05).No publication bias was detected in this meta-analysis (P=0.358). The present meta-analysis indicates that E-cadherin gene promoter hypermethylation may contribute to increased risk of bladder cancer among Asian populations.

Jwa E, Kim YS, Ahn H, et al.
Adjuvant radiotherapy for stage III/IV urothelial carcinoma of the upper tract.
Anticancer Res. 2014; 34(1):333-8 [PubMed] Related Publications
AIM: In order to define the role of adjuvant radiotherapy (RT), the clinical outcomes of patients with stage III/IV urothelial carcinoma of the upper urinary tract (UTUC) were reviewed.
PATIENTS AND METHODS: Clinical data from a total of 127 patients who underwent radical nephroureterectomy with bladder cuff were analyzed. While 36 patients underwent adjuvant RT following surgery, 91 were treated with surgery-alone. Differences in risk-adjusted treatment outcomes between the two groups were assessed using a multivariable Cox proportional-hazards model and inverse probability of treatment weighting with propensity score for balancing covariates including use of chemotherapy between the two groups was estimated.
RESULTS: With a median follow-up of 38.3 months, 3-year actuarial locoregional recurrence-free survival rates were 89% vs. 61% in the RT vs. non-RT groups, respectively (p=0.01). Three-year bladder recurrence-free survival rates were 73% and 52% in favor of the RT group (p=0.02). After adjustment for differences in covariates, the risks of locoregional, bladder, and disease recurrence were found significantly lower in the RT group.
CONCLUSION: Adjuvant RT may be beneficial in terms of locoregional and bladder control in patients with stage III/IV UTUC. Further prospective studied are needed to verify these findings.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

Han Y, Liu Y, Zhang H, et al.
Hsa-miR-125b suppresses bladder cancer development by down-regulating oncogene SIRT7 and oncogenic long non-coding RNA MALAT1.
FEBS Lett. 2013; 587(23):3875-82 [PubMed] Related Publications
MicroRNAs mainly inhibit coding genes and long non-coding RNA expression. Here, we report that hsa-miR-125b and oncogene SIRT7/oncogenic long non-coding RNA MALAT1 were inversely expressed in bladder cancer. Hsa-miR-125b mimic down-regulated, whereas hsa-miR-125b inhibitor up-regulated the expression of SIRT7 and MALAT1. Binding sites were confirmed between hsa-miR-125b and SIRT7/MALAT1. Up-regulation of hsa-miR-125b or down-regulation of SIRT7 inhibited proliferation, motility and increased apoptosis. The effects of up-regulation of hsa-miR-125b were similar to that of silencing MALAT1 in bladder cancer as we had previously described. These data suggest that hsa-miR-125b suppresses bladder cancer development via inhibiting SIRT7 and MALAT1.

Related: Apoptosis MALAT1

Malkhasyan K, Deshpande HA, Adeniran AJ, et al.
The use of serum hCG as a marker of tumor progression and of the response of metastatic urothelial cancer to systemic chemotherapy.
Oncology (Williston Park). 2013; 27(10):1028, 1030 [PubMed] Related Publications
This case confirms the observation that urothelial carcinomas can secrete beta-hCG, and that beta-hCG can potentially be used as a marker of a patient's clinical response to treatment. Prospective studies are clearly warranted by these observations.

Sharp VJ, Barnes KT, Erickson BA
Assessment of asymptomatic microscopic hematuria in adults.
Am Fam Physician. 2013; 88(11):747-54 [PubMed] Related Publications
Although routine screening for bladder cancer is not recommended, microscopic hematuria is often incidentally discovered by primary care physicians. The American Urological Association has published an updated guideline for the management of asymptomatic microscopic hematuria, which is defined as the presence of three or more red blood cells per high-power field visible in a properly collected urine specimen without evidence of infection. The most common causes of microscopic hematuria are urinary tract infection, benign prostatic hyperplasia, and urinary calculi. However, up to 5% of patients with asymptomatic microscopic hematuria are found to have a urinary tract malignancy. The risk of urologic malignancy is increased in men, persons older than 35 years, and persons with a history of smoking. Microscopic hematuria in the setting of urinary tract infection should resolve after appropriate antibiotic treatment; persistence of hematuria warrants a diagnostic workup. Dysmorphic red blood cells, cellular casts, proteinuria, elevated creatinine levels, or hypertension in the presence of microscopic hematuria should prompt concurrent nephrologic and urologic referral. The upper urinary tract is best evaluated with multiphasic computed tomography urography, which identifies hydronephrosis, urinary calculi, and renal and ureteral lesions. The lower urinary tract is best evaluated with cystoscopy for urethral stricture disease, benign prostatic hyperplasia, and bladder masses. Voided urine cytology is no longer recommended as part of the routine evaluation of asymptomatic microscopic hematuria, unless there are risk factors for malignancy.

Sirintrapun SJ, Ward M, Woo J, Cimic A
High-stage urachal adenocarcinoma can be associated with microsatellite instability and KRAS mutations.
Hum Pathol. 2014; 45(2):327-30 [PubMed] Related Publications
Urachal adenocarcinoma (UAC) is a rare tumor of the urinary bladder, which can show intestinal, mucinous, and signet ring cell histology. The morphology is similar to that of colorectal adenocarcinoma (CAC). Microsatellite instability (MSI), KRAS, and BRAF have been more extensively studied in CAC. What is not known is whether UAC in its morphologic similarity to CAC could show immunohistochemical features of MSI along with KRAS- and BRAF-activating mutations. A retrospective review of institutional archives for UAC cases found 7 cases, all of which were high stage. Most (6/7) of our UAC cases showed evidence of MSI or mutations of KRAS. No cases showed a BRAF mutation at codon 600. Of the cases that demonstrated MSI, 1 showed mutS homolog 2 and mutS homolog 6 loss, and 2 showed PMS2 (postmeiotic segregation increased 2) loss. Of the remaining 4 cases, 3 showed KRAS mutations at codon 12. Our UAC series showed mutual exclusivity of MSI and KRAS mutations. Furthermore, our UAC cases with KRAS mutations showed markedly better overall survival (mean, 101.7 versus 6.5 months; P = .035). Thus, our study justifies ancillary testing for MSI and KRAS in UAC, particularly when there is high-stage and mucinous histology, but a larger multi-institutional accruement of UAC cases is necessary to further validate our novel findings.

Jensen BT, de Blok W, Kiesbye B, Kristensen SA
Validation of the urostomy education scale: the European experience.
Urol Nurs. 2013 Sep-Oct; 33(5):219-29 [PubMed] Related Publications
Bladder cancer is the fourth most common cancer among European males. Once diagnosed with muscle invasive bladder cancer, a radical cystectomy is the first line treatment, which results in a urostomy. The placement of a urostomy and the care required impacts the patient's life. Previous research validated the Urostomy Education Scale as the first standardized tool capable of documenting the patients' level of stoma self-care skills and useful to guide patient education interventions. A Danish-Dutch Fellowship was established to support and provide further evidence of applicability of the Urostomy Education Scale.

Lopez-Beltran A, Montironi R, Vidal A, et al.
Urothelial dysplasia of the bladder: diagnostic features and clinical significance.
Anal Quant Cytol Histol. 2013; 35(3):121-9 [PubMed] Related Publications
The 2004 World Health Organization classification system for urothelial neoplasia identifies urothelial dysplasia (low-grade intraurothelial neoplasia) as a premalignant lesion of the urothelium. Although diagnostic criteria of urothelial dysplasia have been improved in recent years, there is a frequent lack of interobserver reproducibility. Follow-up studies suggest that dysplasia is a marker for urothelial instability and disease progression in up to 19% of patients, thus supporting an active clinical follow-up in these patients. The main differential diagnosis of urothelial dysplasia includes flat urothelial lesions with atypia, mainly flat (simple) urothelial hyperplasia, reactive urothelial atypia, urothelial atypia of unknown significance, and urothelial carcinoma in situ (high-grade intraurothelial neoplasia). In most cases, morphologic features alone suffice for diagnosis. Some cases may require a panel of immunohistochemical antibodies consisting of cytokeratin 20, p53 and CD44 for diagnosis. We present pathologic features and clinical significance of urothelial dysplasia with emphasis on differential diagnosis from common flat urothelial lesions with atypia.

Related: TP53 Urinary System Cancers

Kouloulias V, Mosa E, Tolia M, et al.
Evaluation of efficacy and toxicity in two different hypofractionated 3D-conformal external beam radiotherapy schedules in localised muscle invasive bladder cancer.
J BUON. 2013 Oct-Dec; 18(4):942-8 [PubMed] Related Publications
PURPOSE: To evaluate the efficacy as well as acute and late toxicity of two different accelerated hypofractionated 3D-conformal radiotherapy (Hypo-3DCRT) schedules in patients with bladder cancer.
METHODS: Between February 2006 and June 2011, 50 elderly patients with cT1-2N0 bladder carcinoma were treated with Hypo-3DCRT. Mean age was 75 years. All patients were medically inoperable, with poor performance status, who couldn't tolerate either cystectomy or radical external beam irradiation on a daily basis. A dose of 36 Gy in 6 weekly fractions (arm A, N=39) or 39.96 Gy of 3.33 Gy twice daily, once a week, for 6 weeks (arm B, N=11) were prescribed. The primary study endpoints were the evaluation of acute/late gastrointestinal (GI) toxicity according to the EORTC/RTOG scale together with the visual analogue bladder-related pain score (VAS).
RESULTS: The GI acute toxicities were: grade 1: arm A 24/39 (61.5%), arm B 9/11 (81.8%); grade 2: arm A 14/39 (35.9%), arm B 1/11 (9.1%); grade 3: arm A 1/39 (9.1%) (x(2), p=0.29). Only grade 1 late GI toxicity was seen and was significantly higher in arm A: arm A 17/39 (43.6%) and arm B 1/11 (9.1%) (x(2), p=0.037). The reduction of VAS score was similar in both arms (p=0.065). The median relapse free survival (RFS) was 15 and 16 months for arm A and B, respectively (log rank, p=0.71).
CONCLUSIONS: Beyond the non-randomized design of the trial, the Hypo-3DCRT schedules used appear to be an acceptable alternative to the traditional longer radiotherapy (RT) schedules for elderly patients unfit for daily irradiation.

Netto GJ
Molecular genetics and genomics progress in urothelial bladder cancer.
Semin Diagn Pathol. 2013; 30(4):313-20 [PubMed] Related Publications
The clinical management of solid tumor patients has recently undergone a paradigm shift as the result of the accelerated advances in cancer genetics and genomics. Molecular diagnostics is now an integral part of routine clinical management in lung, colon, and breast cancer patients. In a disappointing contrast, molecular biomarkers remain largely excluded from current management algorithms of urologic malignancies. The need for new treatment alternatives and validated prognostic molecular biomarkers that can help clinicians identify patients in need of early aggressive management is pressing. Identifying robust predictive biomarkers that can stratify response to newly introduced targeted therapeutics is another crucially needed development. The following is a brief discussion of some promising candidate biomarkers that may soon become a part of clinical management of bladder cancers.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

Turati F, Pelucchi C, Galeone C, et al.
Personal hair dye use and bladder cancer: a meta-analysis.
Ann Epidemiol. 2014; 24(2):151-9 [PubMed] Related Publications
Despite considerable research, the issue of hair dyes and bladder cancer is still open to discussion. In January 2013, we searched in PubMed/EMBASE to identify observational studies investigating the association between personal use of hair dyes and bladder cancer incidence/mortality. Pooled relative risks (RRs) and corresponding 95% confidence intervals (CIs) were calculated using random-effects models. Fifteen case-control and two cohort studies were available for meta-analysis (8504 cases/deaths, 14,102 controls, and 617,937 persons at risk). Compared with no use, the pooled RR of bladder cancer for personal use of any type of hair dyes was 0.93 (95% CI, 0.82-1.05), with moderate heterogeneity among studies (I(2) = 34.1%, P = .07). Similar RRs were found for females (RR = 0.95) and males (RR = 0.81). Based on seven studies, the pooled RR for personal use of permanent hair dyes was 0.92 (95% CI, 0.77-1.09). Compared with no use, no association was observed for the highest categories of duration of use and lifetime frequency of use of both any type of dyes and permanent dyes. The pooled RR from four studies reporting results for use of dark-colored dyes was 1.29 (95% CI, 0.98-1.71). This meta-analysis allows to definitively exclude any appreciable excess risk of bladder cancer among personal hair dye users.

Olsen DL, Anderson SR
Metastatic plasmacytoid urothelial carcinoma: a case report and review of the literature.
Acta Cytol. 2014; 58(1):108-12 [PubMed] Related Publications
Plasmacytoid urothelial carcinoma is a rare form of invasive urothelial carcinoma first described in 1991 by Sahin et al. [Acta Cytol 1991;35:277-280]. Since this original publication, over 70 cases of plasmacytoid urothelial carcinoma have been described. A small number of cytologic descriptions have been published, including cases involving cerebrospinal fluid cytology, bladder washings and urine cytology. To our knowledge, we describe the first fine needle aspiration of metastatic plasmacytoid urothelial carcinoma in a 75-year-old man who presented with a pathologic fracture of the L4 vertebral body. One of the diagnostic pitfalls in the cytologic evaluation of this rare malignancy is the positive staining with CD138. While CD138 is a marker for plasma cell differentiation, it is also positive in plasmacytoid urothelial carcinoma. In addition to recognizing the cytomorphologic details, a full immunohistochemical panel is helpful in properly characterizing this entity. A brief discussion of long-term prognosis and treatment benefit is provided.

Related: SDC1

Jarow JP, Lerner SP, Kluetz PG, et al.
Clinical trial design for the development of new therapies for nonmuscle-invasive bladder cancer: report of a Food and Drug Administration and American Urological Association public workshop.
Urology. 2014; 83(2):262-4 [PubMed] Related Publications
OBJECTIVE: To summarize the discussion at a public workshop, cosponsored by the U.S. Food and Drug Administration (FDA) and the American Urological Association, reviewing potential trial designs for the development of new therapies for non-muscle-invasive bladder cancer (NMIBC). There have been only 3 drug approvals for NMIBC in the last 30 years, and product development for this disease has been stymied by difficulties in trial design and patient accrual.
METHODS: A workshop evaluating potential trial design for the development of therapies for NMIBC was held in San Diego, CA, in May 2013. Invited experts representing all stakeholders, including urology, medical oncology, radiation oncology, industry, and patient advocates, discussed development of products for all risk strata of NMIBC.
RESULTS: The panel responded to specific questions from the FDA, discussing eligibility criteria, efficacy endpoints, and trial design for patients with a mix of high-grade papillary disease and carcinoma in situ, Bacillus Calmette-Guerin (BCG)-refractory disease, and intermediate-risk disease. Panel members also addressed the magnitude of response that would be clinically meaningful for various disease strata and trial design options for perioperative intravesical chemotherapy instillation at the time of resection of bladder tumors.
CONCLUSION: Expert commentary provided by panel members will inform a planned FDA guidance on pathways for drug and biologic development for NMIBC and will be discussed at meetings of the FDA's Oncologic Drugs Advisory Committee. FDA intends to develop a set of principles that can be used to promote the development of new products for this disease.

Related: USA

Lee RK, Abol-Enein H, Artibani W, et al.
Urinary diversion after radical cystectomy for bladder cancer: options, patient selection, and outcomes.
BJU Int. 2014; 113(1):11-23 [PubMed] Related Publications
CONTEXT: The urinary reconstructive options available after radical cystectomy (RC) for bladder cancer are discussed, as are the criteria for selection of the most appropriate diversion, and the outcomes and complications associated with different diversion options.
OBJECTIVE: To critically review the peer-reviewed literature on the function and oncological outcomes, complications, and factors influencing choice of procedure with urinary diversion after RC for bladder carcinoma.
EVIDENCE ACQUISITION: A Medline search was conducted to identify original articles, review articles, and editorials on urinary diversion in patients treated with RC. Searches were limited to the English language. Keywords included: 'bladder cancer', 'cystectomy', 'diversion', 'neobladder', and 'conduit'. The articles with the highest level of evidence were selected and reviewed, with the consensus of all of the authors of this paper.
EVIDENCE SYNTHESIS: Both continent and incontinent diversions are available for urinary reconstruction after RC. In appropriately selected patients, an orthotopic neobladder permits the elimination of an external stoma and preservation of body image without compromising cancer control. However, the patient must be fully educated and committed to the labour-intensive rehabilitation process. He must also be able to perform self-catheterisation if necessary. When involvement of the urinary outflow tract by tumour prevents the use of an orthotopic neobladder, a continent cutaneous reservoir may still offer the opportunity for continence albeit one that requires obligate self-catheterisation. For patients who are not candidates for continent diversion, the ileal loop remains an acceptable and reliable option.
CONCLUSIONS: Both continent and incontinent diversions are available for urinary reconstruction after RC. Orthotopic neobladders optimally preserve body image, while continent cutaneous diversions represent a reasonable alternative. Ileal conduits represent the fastest, easiest, least complication-prone, and most commonly performed urinary diversion.

Izumi K, Itai S, Takahashi Y, et al.
Factors predictive of oncological outcome after nephroureterectomy: comparison between laparoscopic and open procedures.
Anticancer Res. 2013; 33(12):5501-6 [PubMed] Related Publications
BACKGROUND: Although laparoscopic radical nephroureterectomy is the standard treatment for localized upper urinary tract urothelial carcinoma, open radical nephroureterectomy has been reported to have a different rate of intravesical recurrence.
PATIENTS AND METHODS: Intravesical recurrence-free, progression-free, and overall survival rates among patients undergoing open and laparoscopic radical nephroureterectomy from 2002 to 2013 were analyzed.
RESULTS: Although no single factor predicted intravesical recurrence-free survival, a past history of bladder cancer or grade 3 was related to poorer intravesical recurrence-free survival rate in patients treated with laparoscopic radical nephroureterectomy. Moreover, the novel proposed risk classification based on our data clearly showed better progression-free survival and overall survival, as well as intravesical recurrence-free survival, in patients treated with laparoscopic radical nephroureterectomy.
CONCLUSION: The findings reported here may help urologists predict oncological outcomes and to plan follow-up schedules after laparoscopic radical nephroureterectomy.

Chang WS, Tsai CW, Ji HX, et al.
Associations of cyclooxygenase 2 polymorphic genotypes with bladder cancer risk in Taiwan.
Anticancer Res. 2013; 33(12):5401-5 [PubMed] Related Publications
AIM: Bladder cancer is the sixth most common cancer worldwide and its incidence is particularly high in southwestern Taiwan. However, the genetic contribution to its etiology is not well-understood. The aim of this study is to evaluate the association of cyclooxygenase 2 (Cox-2) polymorphic genotypes with Taiwan bladder cancer patients.
MATERIALS AND METHODS: Six polymorphic variants of Cox-2 were analyzed regarding their association with bladder cancer risk, and three hundred and seventy-five patients with bladder cancer and same amount of age- and gender-matched healthy controls recruited were genotyped by the PCR-RFLP method.
RESULTS: Among the six polymorphic sites examined, only the Cox-2 promoter G-765C (rs20417) genotypes were positively associated with bladder cancer risk (p=0.0102). Individuals with the Cox-2 -765GC genotypes were associated with higher prostate cancer risk than those with -765GG.
CONCLUSION: Our findings provide evidence that the C allele of Cox-2 promoter G-765C may be associated with the overexpression of COX-2 during bladder cancer development and may be a useful marker for the early detection of bladder cancer.

Related: PTGS2

Kopparapu PK, Boorjian SA, Robinson BD, et al.
Expression of cyclin d1 and its association with disease characteristics in bladder cancer.
Anticancer Res. 2013; 33(12):5235-42 [PubMed] Related Publications
AIM: Invasive urothelial carcinoma of the bladder (UCB) is characterized by alterations in cell-cycle regulatory pathways. Defects in the expression of cyclin D1, a key cell-cycle regulator, have been implicated in progression of various types of cancer. In the present study, we investigated whether cyclin D1 expression is associated with clinicopathological parameters and whether it has any potential prognostic value in determining risk of UCB recurrence.
PATIENTS AND METHODS: Tissue microarrays containing bladder cancer specimens (n=212) and adjacent normal bladder tissues (n=131) were immunostained using an antibody against cyclin D1. The association between cyclin D1 and clinicopathological parameters including stage, lymph node metastasis, and disease-free survival, were evaluated. Cyclin D1 mRNA expression data from human normal bladder (n=14) and cancer specimens (n=28) were extracted from the public Oncomine database.
RESULTS: Cyclin D1 mRNA and protein expression were significantly higher in UCB compared to adjacent non-malignant bladder tissue (for mRNA p=0.003, for protein p=0.001). Cyclin D1 protein expression was significantly higher in non-invasive tumors than in muscle-invasive UCB (p=0.016). Among patients with muscle-invasive UCB, increased cyclin D1 expression in tumor cells significantly correlated with lymph node metastasis (p<0.001), and there was a trend of cyclin D1 together with lymph node positivity to be associated with disease recurrence (p=0.678). Loss of nuclear cyclin D1 expression in tumor cells was likewise significantly associated with the presence of lymph node metastasis (p<0.001).
CONCLUSION: Altered expression of cyclin D1 is associated with lymph node metastasis and risk of UCB recurrence. Cyclin D1 expression may therefore have clinical value as a prognostic marker and potential therapeutic target.

Wang H, Cai Z, Yang F, et al.
Enhanced antitumor efficacy of integrin-targeted oncolytic adenovirus AxdAdB3-F/RGD on bladder cancer.
Urology. 2014; 83(2):508.e13-9 [PubMed] Related Publications
OBJECTIVE: To evaluate the therapeutic efficacy of AxdAdB-3 with Arg-Gly-Asp (RGD)-fiber modification (AxdAdB3-F/RGD), which enables integrin-dependent infection in bladder cancers.
METHODS: Flow cytometric analysis was applied to evaluated adenovirus-mediated gene transduction into various cells. The cytopathic effects of AxdAdB3-F/RGD were evaluated in bladder cancer cell lines and a normal bladder mucosa-derived cell line (HCV29) with AxCAZ3-F/RGD (control) or AxdAdB-3. The efficacy of bladder instillation therapy with AxdAdB3-F/RGD for orthotopic bladder cancer was investigated in nude mice.
RESULTS: Expression of coxsackievirus adenovirus receptor (CAR) and integrins (αvβ3 and αvβ5) vary in different bladder cancer cell lines. The susceptibility of various cell lines to adenovirus was associated with the expression of CAR. AxdAdB-3 was more cytopathic in CAR-positive bladder cancer cells than in CAR-negative cells, whereas AxdAdB3-F/RGD caused effective oncolysis in both CAR-positive and CAR-negative bladder cancer cells. AxdAdB3-F/RGD was not cytotoxic to HCV29 cells. Direct instillation of AxdAdB3-F/RGD into the bladder of the orthotopic model, established by CAR-deficient human bladder cancer cells, inhibited tumor growth and led to significantly elongated survival.
CONCLUSION: E1A and E1B double-restricted oncolytic adenovirus with RGD fiber modification has enhanced infectivity and oncolytic effects to CAR-deficient bladder cancers, suggesting the therapeutic potential of AxdAdB3-F/RGD for bladder cancers.

Nishioka K, Shimizu S, Shinohara N, et al.
Prospective phase II study of image-guided local boost using a real-time tumor-tracking radiotherapy (RTRT) system for locally advanced bladder cancer.
Jpn J Clin Oncol. 2014; 44(1):28-35 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The real-time tumor-tracking radiotherapy system with fiducial markers has the advantage that it can be used to verify the localization of the markers during radiation delivery in real-time. We conducted a prospective Phase II study of image-guided local-boost radiotherapy for locally advanced bladder cancer using a real-time tumor-tracking radiotherapy system for positioning, and here we report the results regarding the safety and efficacy of the technique.
METHODS: Twenty patients with a T2-T4N0M0 urothelial carcinoma of the bladder who were clinically inoperable or refused surgery were enrolled. Transurethral tumor resection and 40 Gy irradiation to the whole bladder was followed by the transurethral endoscopic implantation of gold markers in the bladder wall around the primary tumor. A boost of 25 Gy in 10 fractions was made to the primary tumor while maintaining the displacement from the planned position at less than ±2 mm during radiation delivery using a real-time tumor-tracking radiotherapy system. The toxicity, local control and survival were evaluated.
RESULTS: Among the 20 patients, 14 were treated with concurrent chemoradiotherapy. The median follow-up period was 55.5 months. Urethral and bowel late toxicity (Grade 3) were each observed in one patient. The local-control rate, overall survival and cause-specific survival with the native bladder after 5 years were 64, 61 and 65%.
CONCLUSIONS: Image-guided local-boost radiotherapy using a real-time tumor-tracking radiotherapy system can be safely accomplished, and the clinical outcome is encouraging. A larger prospective multi-institutional study is warranted for more precise evaluations of the technological efficacy and patients' quality of life.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter Nedaplatin

Wu J, Liu J, Jia R, Song H
Nur77 inhibits androgen-induced bladder cancer growth.
Cancer Invest. 2013; 31(10):654-60 [PubMed] Related Publications
Currently, bladder cancer ranks as the second most common genitourinary malignancy which is exacting significant morbidity and mortality worldwide. Although there are abundant epidemiological and basic studies which strongly suggest the role of androgen hormone in bladder cancer, the underlying mechanism is not fully understood. In the current study, we sought to identify a new competitive inhibitor for androgen receptor in bladder cancer cells. Our results showed that Nur77 hyperexpression inhibits UM-UC-3 cell growth and cell cycle progression while Nur77 knockdown exerts the opposite effect. In our cell culture model, we also demonstrated that Nur77 competitively inhibits androgen-dependent transcription activity and more specifically, Nur77 competes with androgen receptor for binding to src-1, a well-known coactivator for steroids. More importantly, we also showed that a small molecule agonist for Nur77, Cytosporone B, significantly inhibits androgen-dependent bladder cancer cell growth in two different cell lines. These data provide a good proof-of-principle that Nur77 signaling machinery could be a new target for growth control of androgen-dependent bladder cancer cells.

Related: Signal Transduction

Melak D, Ferreccio C, Kalman D, et al.
Arsenic methylation and lung and bladder cancer in a case-control study in northern Chile.
Toxicol Appl Pharmacol. 2014; 274(2):225-31 [PubMed] Related Publications
In humans, ingested inorganic arsenic is metabolized to monomethylarsenic (MMA) then to dimethylarsenic (DMA), although this process is not complete in most people. The trivalent form of MMA is highly toxic in vitro and previous studies have identified associations between the proportion of urinary arsenic as MMA (%MMA) and several arsenic-related diseases. To date, however, relatively little is known about its role in lung cancer, the most common cause of arsenic-related death, or about its impacts on people drinking water with lower arsenic concentrations (e.g., <200μg/L). In this study, urinary arsenic metabolites were measured in 94 lung and 117 bladder cancer cases and 347 population-based controls from areas in northern Chile with a wide range of drinking water arsenic concentrations. Lung cancer odds ratios adjusted for age, sex, and smoking by increasing tertiles of %MMA were 1.00, 1.91 (95% confidence interval (CI), 0.99-3.67), and 3.26 (1.76-6.04) (p-trend <0.001). Corresponding odds ratios for bladder cancer were 1.00, 1.81 (1.06-3.11), and 2.02 (1.15-3.54) (p-trend <0.001). In analyses confined to subjects only with arsenic water concentrations <200μg/L (median=60μg/L), lung and bladder cancer odds ratios for subjects in the upper tertile of %MMA compared to subjects in the lower two tertiles were 2.48 (1.08-5.68) and 2.37 (1.01-5.57), respectively. Overall, these findings provide evidence that inter-individual differences in arsenic metabolism may be an important risk factor for arsenic-related lung cancer, and may play a role in cancer risks among people exposed to relatively low arsenic water concentrations.

Related: Lung Cancer

Xylinas E, Green DA, Otto B, et al.
Robotic-assisted radical cystectomy with extracorporeal urinary diversion for urothelial carcinoma of the bladder: analysis of complications and oncologic outcomes in 175 patients with a median follow-up of 3 years.
Urology. 2013; 82(6):1323-9 [PubMed] Related Publications
OBJECTIVE: To report oncologic outcomes and complications after robotic-assisted radical cystectomy (RARC).
MATERIALS AND METHODS: From March 2004 to August 2011, 175 consecutive patients underwent RARC with extracorporeal urinary diversion at our institution by a single surgeon. The study design was prospective. Perioperative parameters and postoperative complications were prospectively collected using the modified Clavien system. Recurrence-free survival and cancer-specific survival curves were generated using the Kaplan-Meier method.
RESULTS: A total of 145 men and 30 women with a median age of 73 years and a median body mass index of 27 kg/m(2) underwent RARC. Four patients (2.3%) required conversion to open surgery because of difficulty to progress. One hundred nine patients (62%) underwent a transcutaneous ileal conduit, 40 patients (23%) an orthotopic neobladder, and 26 (15%) a continent cutaneous conduit. The median operating time was 360 minutes (interquartile range [IQR]: 300-420). The median estimated blood loss was 400 mL (IQR: 250-612), with a transfusion rate of 17.0%. The median postoperative length of stay was 7.0 days (IQR: 5.2-10). Early (<30 days) and late surgery-related complications (30-90 days) occurred in 74 (42%) and 59 (34%) patients, respectively. The perioperative mortality rate was 2.8%. The positive soft tissue surgical margins rate was 5%. The median number of lymph nodes removed was 19 (IQR: 12-28). The median follow-up was 37 months (IQR: 21.5-53.5). Actuarial recurrence-free survival and cancer-specific survival at 2, 3, and 5 years after RARC were 67%, 63%, 63% and 73%, 68%, 66%, respectively.
CONCLUSION: RARC achieved mid-term oncologic efficacy. Moreover, the complication rates were comparable with open radical cystectomy series.

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