Kelly JD, Dudderidge TJ, Wollenschlaeger A, et al.
Bladder cancer diagnosis and identification of clinically significant disease by combined urinary detection of Mcm5 and nuclear matrix protein 22.
PLoS One. 2012; 7(7):e40305 [PubMed] Free Access to Full Article

BACKGROUND: Urinary biomarkers for bladder cancer detection are constrained by inadequate sensitivity or specificity. Here we evaluate the diagnostic accuracy of Mcm5, a novel cell cycle biomarker of aberrant growth, alone and in combination with NMP22.
METHODS: 1677 consecutive patients under investigation for urinary tract malignancy were recruited to a prospective blinded observational study. All patients underwent ultrasound, intravenous urography, cystoscopy, urine culture and cytologic analysis. An immunofluorometric assay was used to measure Mcm5 levels in urine cell sediments. NMP22 urinary levels were determined with the FDA-approved NMP22® Test Kit.
RESULTS: Genito-urinary tract cancers were identified in 210/1564 (13%) patients with an Mcm5 result and in 195/1396 (14%) patients with an NMP22 result. At the assay cut-point where sensitivity and specificity were equal, the Mcm5 test detected primary and recurrent bladder cancers with 69% sensitivity (95% confidence interval = 62-75%) and 93% negative predictive value (95% CI = 92-95%). The area under the receiver operating characteristic curve for Mcm5 was 0.75 (95% CI = 0.71-0.79) and 0.72 (95% CI = 0.67-0.77) for NMP22. Importantly, Mcm5 combined with NMP22 identified 95% (79/83; 95% CI = 88-99%) of potentially life threatening diagnoses (i.e. grade 3 or carcinoma in situ or stage ≥pT1) with high specificity (72%, 95% CI = 69-74%).
CONCLUSIONS: The Mcm5 immunoassay is a non-invasive test for identifying patients with urothelial cancers with similar accuracy to the FDA-approved NMP22 ELISA Test Kit. The combination of Mcm5 plus NMP22 improves the detection of UCC and identifies 95% of clinically significant disease. Trials of a commercially developed Mcm5 assay suitable for an end-user laboratory alongside NMP22 are required to assess their potential clinical utility in improving diagnostic and surveillance care pathways.

Department of Pathology and Cancer Institute, University College London, London

Wilkinson C, Chowdhury F, Scarsbrook A, Smith J
BCG-induced granulomatous prostatitis--an incidental finding on FDG PET-CT.
Clin Imaging. 2012 Jul-Aug; 36(4):413-5 [PubMed]

We present a case of granulomatous prostatitis that presented in a rare way as an incidentally discovered focus of increased FDG activity within the prostate on PET-CT in a patient who had previously undergone intravesical bacille Calmette-Guérin treatment for bladder cancer. FDG uptake is commonly discovered in organs distant from the region of primary interest on PET-CT and so it is important to be aware of the potential causes of this.

Department of Radiology, St James University Hospital, Leeds, LS9 7TF

Allen NE, Appleby PN, Key TJ, et al.
Macronutrient intake and risk of urothelial cell carcinoma in the European prospective investigation into cancer and nutrition.
Int J Cancer. 2013; 132(3):635-44 [PubMed]

Previous studies have suggested that dietary factors may be important in the development of bladder cancer. We examined macronutrient intake in relation to risk of urothelial cell carcinoma among 469,339 men and women in the European Prospective Investigation into Cancer and Nutrition. Associations were examined using Cox regression, stratified by sex, age at recruitment and centre and further adjusted for smoking status and duration, body mass index and total energy intake. After an average of 11.3 years of follow-up, 1,416 new cases of urothelial cell carcinoma were identified. After allowing for measurement error, a 3% increase in the consumption of energy intake from animal protein was associated with a 15% higher risk (95% confidence interval [CI]: 3-30%; p(trend) = 0.01) and a 2% increase in energy from plant protein intake was associated with a 23% lower risk (95% CI: 36-7%, p(trend) = 0.006). Dietary intake of fat, carbohydrate, fibre or calcium was not associated with risk. These findings suggest that animal and/or plant protein may affect the risk of urothelial cell carcinoma, and examination of these associations in other studies is needed.

Cancer Epidemiology Unit, University of Oxford, Oxford

Thomas F, Rosario DJ, Rubin N, et al.
The long-term outcome of treated high-risk nonmuscle-invasive bladder cancer: time to change treatment paradigm?
Cancer. 2012; 118(22):5525-34 [PubMed]

BACKGROUND: The treatment of high-risk nonmuscle-invasive bladder cancer (NMIBC) is difficult given its unpredictable natural history and patient comorbidities. Because current case series are mostly limited in size, the authors report the outcomes from a large, single-center series.
METHODS: The authors reviewed all patients with primary, high-risk NMIBC at their institution from 1994 to 2010. Outcomes were matched with clinicopathologic data. Patients who had muscle invasion within 6 months or had insufficient follow-up (<6 months) were excluded. Correlations were analyzed using multivariable Cox regression and log-rank analysis (2-sided; P < .05).
RESULTS: In total, 712 patients (median age, 73.7 years) were included. Progression to muscle invasion occurred in 110 patients (15.8%; 95% confidence interval [CI], 13%-18.3%) at a median of 17.2 months (interquartile range, 8.9-35.8 months), including 26.5% (95% CI, 22.2%-31.3%) of the 366 patients who had >5 years follow-up. Progression was associated with age (hazard ratio [HR], 1.04; P = .007), dysplastic urothelium (HR, 1.6; P = .003), urothelial cell carcinoma variants (HR, 3.2; P = .001), and recurrence (HR, 18.3; P < .001). Disease-specific mortality occurred in 134 patients (18.8%; 95% CI, 16.1%-21.9%) at a median of 28 months (interquartile range, 15-45 months), including 28.7% (95% CI, 24.5%-33.3%) of those who had 5 years of follow-up. Disease-specific mortality was associated with age (HR, 1.1; P < .001), stage (HR, 1.7; P = .003), dysplasia (HR, 1.3; P = .05), and progression (HR, 5.2; P < .001). Neither progression nor disease-specific mortality were associated with the receipt of bacillus Calmette-Guerin (P > .6).
CONCLUSIONS: Within a program of conservative treatment, progression of high-risk NMIBC was associated with a poor prognosis. Surveillance and bacillus Calmette-Guerin were ineffective in altering the natural history of this disease. The authors concluded that the time has come to rethink the paradigm of management of this disease.

The Academic Urology Unit and Institute for Cancer Studies, University of Sheffield, Sheffield

Poludniowski GG, Evans PM, Webb S
Cone beam computed tomography number errors and consequences for radiotherapy planning: an investigation of correction methods.
Int J Radiat Oncol Biol Phys. 2012; 84(1):e109-14 [PubMed]

PURPOSE: The potential of keV cone beam computed tomography (CBCT) for guiding adaptive replanning is well-known. There are impediments to this, one being CBCT number accuracy. The purpose of this study was to investigate CBCT number correction methods and the affect of residual inaccuracies on dose deposition. Four different correction strategies were applied to the same patient data to compare performance and the sophistication of correction-method needed for acceptable dose errors.
METHODS AND MATERIALS: Planning CT and CBCT reconstructions were used for 12 patients (6 brain, 3 prostate, and 3 bladder cancer patients). All patients were treated using Elekta linear accelerators and XVI imaging systems. Two of the CBCT number correction methods investigated were based on an algorithm previously proposed by the authors but only previously applied to phantoms. Two further methods, based on an approach previously suggested in the research literature, were also examined. Dose calculations were performed using scans of a "worst" subset of patients using the Pinnacle³ version 9.0 treatment planning system and the patients' clinical plans.
RESULTS: All mean errors in CBCT number were <50 HU, and all correction methods performed well or adequately in dose calculations. The worst single dose discrepancy identified for any of the examined methods or patients was 3.0%. Mean errors in the doses to treatment volumes or organs at risk were negatively correlated with the mean error in CT number. That is, a mean CT number that was too large, averaged over the entire CBCT volume, implied an underdosing in a volume-of-interest and vice versa.
CONCLUSIONS: Results suggest that (1) the correction of CBCT numbers to within a mean error of 50 HU in the scan volume provides acceptable discrepancies in dose (<3%) and (2) this is achievable with even quite unsophisticated correction methods.

Joint Department of Physics, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey

James ND, Hussain SA, Hall E, et al.
Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer.
N Engl J Med. 2012; 366(16):1477-88 [PubMed]

BACKGROUND: Radiotherapy is an alternative to cystectomy in patients with muscle-invasive bladder cancer. In other disease sites, synchronous chemoradiotherapy has been associated with increased local control and improved survival, as compared with radiotherapy alone.
METHODS: In this multicenter, phase 3 trial, we randomly assigned 360 patients with muscle-invasive bladder cancer to undergo radiotherapy with or without synchronous chemotherapy. The regimen consisted of fluorouracil (500 mg per square meter of body-surface area per day) during fractions 1 to 5 and 16 to 20 of radiotherapy and mitomycin C (12 mg per square meter) on day 1. Patients were also randomly assigned to undergo either whole-bladder radiotherapy or modified-volume radiotherapy (in which the volume of bladder receiving full-dose radiotherapy was reduced) in a partial 2-by-2 factorial design (results not reported here). The primary end point was survival free of locoregional disease. Secondary end points included overall survival and toxic effects.
RESULTS: At 2 years, rates of locoregional disease-free survival were 67% (95% confidence interval [CI], 59 to 74) in the chemoradiotherapy group and 54% (95% CI, 46 to 62) in the radiotherapy group. With a median follow-up of 69.9 months, the hazard ratio in the chemoradiotherapy group was 0.68 (95% CI, 0.48 to 0.96; P=0.03). Five-year rates of overall survival were 48% (95% CI, 40 to 55) in the chemoradiotherapy group and 35% (95% CI, 28 to 43) in the radiotherapy group (hazard ratio, 0.82; 95% CI, 0.63 to 1.09; P=0.16). Grade 3 or 4 adverse events were slightly more common in the chemoradiotherapy group than in the radiotherapy group during treatment (36.0% vs. 27.5%, P=0.07) but not during follow-up (8.3% vs. 15.7%, P=0.07).
CONCLUSIONS: Synchronous chemotherapy with fluorouracil and mitomycin C combined with radiotherapy significantly improved locoregional control of bladder cancer, as compared with radiotherapy alone, with no significant increase in adverse events. (Funded by Cancer Research U.K.; BC2001 Current Controlled Trials number, ISRCTN68324339.).

University of Birmingham, School of Cancer Sciences, Edgbaston, Birmingham B15 2TT

Kelly JD, Hall E
Boxing bladder cancer with COX-2-specific inhibition.
Cancer Prev Res (Phila). 2011; 4(10):1534-5 [PubMed]

Preventing recurrence of non-muscle-invasive bladder cancer (NMIBC) is important for improving patient well-being and reducing the health economic burden of this disease. To date, no oral agent has shown sufficient benefit to be adopted in clinical practice, where current strategies rely on topical (intravesical) administration of chemotherapy and immunotherapy. In this issue of the journal (beginning on page 1580), Sabichi and colleagues report the first phase II randomized controlled trial of the COX-2 inhibitor celecoxib in bladder cancer. The trial set out to measure an overly ambitious effect size but nevertheless showed encouraging signs of celecoxib activity. It lends support to COX-2 inhibition in NMIBC, which is being tested in several subsequent trials, and to the need for conclusive evidence.

Division of Surgery and Interventional Science, UCL Medical School, University College London

Stewart GD, Humphries KJ, Cutress ML, et al.
Long-term comparative outcomes of open versus laparoscopic nephroureterectomy for upper urinary tract urothelial-cell carcinoma after a median follow-up of 13 years*.
J Endourol. 2011; 25(8):1329-35 [PubMed]

BACKGROUND AND PURPOSE: Open nephroureterectomy (ONU) rather than laparoscopic nephroureterectomy (LNU) is still regarded as the standard of care for extirpative surgical management of upper urinary tract urothelial-cell carcinoma (UUT-UCC). The longest published follow-up of LNU is 7 years. We report outcomes for patients having surgery ≥10 years ago.
PATIENTS AND METHODS: Consecutive patients with UUT-UCC who were treated with ONU (n=39) or LNU (n=23) between April 1992 to September 2000 were included. Preoperative, tumor, operative and postoperative characteristics, recurrence, and outcomes were collated. Survival was estimated using the Kaplan-Meier method.
RESULTS: Median follow-up of censored patients was 163 months (13.6 y). Estimated mean overall survival (OS) was 111 months for ONU and 103 months for LNU. Mean progression free survival (PFS) was 175 months for ONU and 143 months for LNU. Probability of PFS at 10 years was 79% for ONU and 76% for LNU and was unchanged at 15 years. There was no significant difference between ONU and LNU in terms of OS (P=0.51, log-rank test), PFS (P=0.70) or cancer-specific survival (CSS; P=0.43). There were no prognostic differences between ONU and LNU after correcting for confounding variables. There was no increase in the probability of a bladder cancer recurrence from 10 to 15 years postoperation.
CONCLUSION: Long-term follow-up of patients who were operated on more than 10 years ago suggests that LNU has oncologic equivalence to ONU because there were no significant differences in OS, PFS, or CSS between ONU and LNU patients followed for a median of 13 years.

Edinburgh Urological Cancer Group, University of Edinburgh , Department of Urology, Western General Hospital, Edinburgh

Xue K, Pridgeon S, Gillibrand R, et al.
Clinical presentations of schistosoma hematobium: three case reports and review.
Can J Urol. 2011; 18(3):5757-62 [PubMed]

Urinary schistosomiasis is a prevalent parasitic infection in certain areas of Africa and the Middle East. It could present with common as well as unusual urological symptoms, which poses a considerable diagnostic challenge in countries where there is relative low incidence of the disease. We describe three unusual cases of urinary schistosomiasis identified in patients presenting to a London hospital. One patient was found to have schistosomiasis in the seminal vesicles following surgery for prostatic adenocarcinoma. Another was found to have schistosoma-related granulomatous inflammation within a urachal cyst. Thirdly a patient was found to have simultaneous occurrence of transitional cell carcinoma and schistosomiasis of the bladder. We review the literature on the presentations of the parasite and its association with malignancy. In conclusion, awareness of the disease prevalence, clinical and histopathological features will help to avoid missing the diagnosis.

Department of Urology, North Middlesex University Hospital, London

International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial.
J Clin Oncol. 2011; 29(16):2171-7 [PubMed] Free Access to Full Article

PURPOSE: This article presents the long-term results of the international multicenter randomized trial that investigated the use of neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) chemotherapy in patients with muscle-invasive urothelial cancer of the bladder treated by cystectomy and/or radiotherapy. Nine hundred seventy-six patients were recruited between 1989 and 1995, and median follow-up is now 8.0 years.
PATIENTS AND METHODS: This was a randomized phase III trial of either no neoadjuvant chemotherapy or three cycles of CMV.
RESULTS: The previously reported possible survival advantage of CMV is now statistically significant at the 5% level. Results show a statistically significant 16% reduction in the risk of death (hazard ratio, 0.84; 95% CI, 0.72 to 0.99; P = .037, corresponding to an increase in 10-year survival from 30% to 36%) after CMV.
CONCLUSION: We conclude that CMV chemotherapy improves outcome as first-line adjunctive treatment for invasive bladder cancer. Two large randomized trials (by the Medical Research Council/European Organisation for Research and Treatment of Cancer and Southwest Oncology Group) have confirmed a statistically significant and clinically relevant survival benefit, and neoadjuvant chemotherapy followed by definitive local therapy should be viewed as state of the art, as compared with cystectomy or radiotherapy alone, for deeply invasive bladder cancer.

Medical Research Council Clinical Trials Unit, London

Canetta E, Mazilu M, De Luca AC, et al.
Modulated Raman spectroscopy for enhanced identification of bladder tumor cells in urine samples.
J Biomed Opt. 2011; 16(3):037002 [PubMed]

Standard Raman spectroscopy (SRS) is a noninvasive technique that is used in the biomedical field to discriminate between normal and cancer cells. However, the presence of a strong fluorescence background detracts from the use of SRS in real-time clinical applications. Recently, we have reported a novel modulated Raman spectroscopy (MRS) technique to extract the Raman spectra from the background. In this paper, we present the first application of MRS to the identification of human urothelial cells (SV-HUC-1) and bladder cancer cells (MGH) in urine samples. These results are compared to those obtained by SRS. Classification using the principal component analysis clearly shows that MRS allows discrimination between Raman spectra of SV-HUC-1 and MGH cells with high sensitivity (98%) and specificity (95%). MRS is also used to distinguish between SV-HUC-1 and MGH cells after exposure to urine for up to 6 h. We observe a marked change in the MRS of SV-HUC-1 and MGH cells with time in urine, indicating that the conditions of sample collection will be important for the application of this methodology to clinical urine samples.

University of St Andrews, SUPA-School of Physics and Astronomy, North Haugh, St Andrews

Naish JH, McGrath DM, Bains LJ, et al.
Comparison of dynamic contrast-enhanced MRI and dynamic contrast-enhanced CT biomarkers in bladder cancer.
Magn Reson Med. 2011; 66(1):219-26 [PubMed]

Dynamic contrast-enhanced MRI (DCE-MRI) is frequently used to provide response biomarkers in clinical trials of novel cancer therapeutics but assessment of their physiological accuracy is difficult. DCE-CT provides an independent probe of similar pharmacokinetic processes and may be modeled in the same way as DCE-MRI to provide purportedly equivalent physiological parameters. In this study, DCE-MRI and DCE-CT were directly compared in subjects with primary bladder cancer to assess the degree to which the model parameters report modeled physiology rather than artefacts of the measurement technique and to determine the interchangeability of the techniques in a clinical trial setting. The biomarker K(trans) obtained by fitting an extended version of the Kety model voxelwise to both DCE-MRI and DCE-CT data was in excellent agreement (mean across subjects was 0.085 ± 0.030 min(-1) for DCE-MRI and 0.087 ± 0.033 min(-1) for DCE-CT, intermodality coefficient of variation 9%). The parameter v(p) derived from DCE-CT was significantly greater than that derived from DCE-MRI (0.018 ± 0.006 compared to 0.009 ± 0.008, P = 0.0007) and v(e) was in reasonable agreement only for low values. The study provides evidence that the biomarker K(trans) is a robust parameter indicative of the underlying physiology and relatively independent of the method of measurement.

Imaging Science and Biomedical Engineering, School of Cancer and Enabling Sciences, University of Manchester, Manchester

Mowatt G, N'Dow J, Vale L, et al.
Photodynamic diagnosis of bladder cancer compared with white light cystoscopy: Systematic review and meta-analysis.
Int J Technol Assess Health Care. 2011; 27(1):3-10 [PubMed]

OBJECTIVES: The aim of this study was to assess the test performance and clinical effectiveness of photodynamic diagnosis (PDD) compared with white light cystoscopy (WLC) in people suspected of new or recurrent bladder cancer.
METHODS: A systematic review was conducted of randomized controlled trials (RCTs), nonrandomized comparative studies, or diagnostic cross-sectional studies comparing PDD with WLC. Fifteen electronic databases and Web sites were searched (last searches April 2008). For clinical effectiveness, only RCTs were considered.
RESULTS: Twenty-seven studies (2,949 participants) assessed test performance. PDD had higher sensitivity than WLC (92 percent, 95 percent confidence interval [CI], 80-100 percent versus 71 percent, 95 percent CI, 49-93 percent) but lower specificity (57 percent, 95 percent CI, 36-79 percent versus 72 percent, 95 percent CI, 47-96 percent). For detecting higher risk tumors, median range sensitivity of PDD (89 percent [6-100 percent]) was higher than WLC (56 percent [0-100 percent]) whereas for lower risk tumors it was broadly similar (92 percent [20-95 percent] versus 95 percent [8-100 percent]). Four RCTs (709 participants) using 5-aminolaevulinic acid (5-ALA) as the photosensitising agent reported clinical effectiveness. Using PDD at transurethral resection of bladder tumor (TURBT) resulted in fewer residual tumors at check cystoscopy (relative risk [RR], 0.37, 95 percent CI, 0.20-0.69) and longer recurrence-free survival (RR, 1.37, 95 percent CI, 1.18-1.59), compared with WLC.
CONCLUSIONS: PDD detects more bladder tumors than WLC, including more high-risk tumors. Based on four RCTs reporting clinical effectiveness, 5-aminolaevulinic acid-mediated PDD at TURBT facilitates a more complete resection and prolongs recurrence-free survival.

Health Services Research Unit, University of Aberdeen, Foresterhill, AB25 2ZD Aberdeen

Choudhury A, Swindell R, Logue JP, et al.
Phase II study of conformal hypofractionated radiotherapy with concurrent gemcitabine in muscle-invasive bladder cancer.
J Clin Oncol. 2011; 29(6):733-8 [PubMed]

PURPOSE: The aim of this prospective, phase II trial was to determine the response of muscle-invasive bladder cancer (MIBC) to concurrent chemoradiotherapy of weekly gemcitabine with 4 weeks of radiotherapy (RT; GemX).
PATIENTS AND METHODS: Fifty patients with transitional cell carcinoma, stage T2-3, N0, M0 after transurethral resection and magnetic resonance imaging, were recruited. Gemcitabine was given intravenously at 100 mg/m(2) on days 1, 8, 15, and 22 of a 28-day RT schedule that delivered 52.5 Gy in 20 fractions. Chemotherapy was stopped for Radiation Therapy Oncology Group (RTOG) grade 3 bladder or bowel toxicity. The primary end points were tumor response, toxicity, and survival.
RESULTS: All patients completed RT; 46 tolerated all four cycles of gemcitabine. Two patients stopped after two cycles, and two stopped after three cycles, because of bowel toxicity. Forty-seven patients had a post-treatment cystoscopy; 44 (88%) achieved a complete endoscopic response. At a median follow-up of 36 months (range, 15 to 62 months), 36 patients were alive, and 32 of these had a functional and intact bladder. Fourteen patients died; seven died as a result of metastatic MIBC, five died as a result of intercurrent disease, and two died as a result of treatment-associated deaths. Four patients underwent cystectomy; three because of recurrent disease and one because of toxicity. One patient required a bowel resection for late toxicity. By using Kaplan-Meier analyses, 3-year cancer-specific survival was 82%, and overall survival was 75%.
CONCLUSION: Concurrent gemcitabine-based chemoradiotherapy (ie, GemX) produces a high response rate in MIBC and has durable local control and acceptable toxicity, which allows patients to preserve their own bladder. This treatment modality warrants additional investigation in a phase III setting.

The Christie NHS Foundation Trust, Wilmslow Rd, Manchester, M20 4BX United Kingdom.

Dudziec E, Miah S, Choudhry HM, et al.
Hypermethylation of CpG islands and shores around specific microRNAs and mirtrons is associated with the phenotype and presence of bladder cancer.
Clin Cancer Res. 2011; 17(6):1287-96 [PubMed]

PURPOSE: To analyze the role and translational potential for hypermethylation of CpG islands and shores in the regulation of small RNAs within urothelial cell carcinoma (UCC). To examine microRNAs (miR) and mirtrons, a new class of RNA located within gene introns and processed in a Drosha-independent manner. Experimental design: The methylation status of 865 small RNAs was evaluated in normal and malignant cell lines by using 5-azacytidine and microarrays. Bisulfite sequencing was used for CpG regions around selected RNAs. Prognostic and diagnostic associations for epigenetically regulated RNAs were examined by using material from 359 patients, including 216 tumors and 121 urinary samples (68 cases and 53 controls). Functional analyses examined the effect of silencing susceptible RNAs in normal urothelial cells.
RESULTS: Exonic/UTR-located miRs and mirtons are most susceptible to epigenetic regulation. We identified 4 mirtrons and 16 miRs with CpG hypermethylation across 35 regions in normal and malignant urothelium. For several miRs, hypermethylation was more frequent and dense in CpG shores than islands (e.g., miRs-9/149/210/212/328/503/1224/1227/1229), and was associated with tumor grade, stage, and prognosis (e.g., miR-1224 multivariate analysis OR = 2.5; 95% CI, 1.3-5.0; P = 0.006). The urinary expression of epigenetically silenced RNAs (miRs-152/328/1224) was associated with the presence of UCC (concordance index, 0.86; 95% CI, 0.80-0.93; ANOVA P < 0.016).
CONCLUSIONS: Hypermethylation of mirtrons and miRs is common in UCC. Mirtrons appear particularly susceptible to epigenetic regulation. Aberrant hypermethylation of small RNAs is associated with the presence and behavior of UCC, suggesting potential roles as diagnostic and prognostic biomarkers.

The Institute for Cancer Studies and The Academic Urology Unit, University of Sheffield, Sheffield

Hoskin PJ, Rojas AM, Bentzen SM, Saunders MI
Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma.
J Clin Oncol. 2010; 28(33):4912-8 [PubMed]

PURPOSE: Phase II clinical studies suggest that hypoxic modification with carbogen and nicotinamide (CON) may increase the efficacy of radiotherapy (RT).
PATIENTS AND METHODS: Three hundred thirty-three patients with locally advanced bladder carcinoma were randomly assigned to RT alone versus RT with CON. A schedule of either 55 Gy in 20 fractions in 4 weeks or 64 Gy in 32 fractions in 6.5 weeks was used. The primary end point was cystoscopic control at 6 months (CC(6m)) and secondary end points were overall survival (OS), local relapse-free survival (RFS), urinary and rectal morbidity.
RESULTS: CC(6m) was 81% for RT + CON and 76% for RT alone (P = .3); however, just more than half of patients underwent cystoscopy at that time. Three-year estimates of OS were 59% and 46% (P = .04) and 3-year estimates of RFS were 54% and 43% (P = .06) for RT + CON versus RT alone. Risk of death was 14% lower with RT + CON (P = .04). In multivariate comparison, RT + CON significantly reduced the risk of relapse (P = .05) and death (P = .03). There was no evidence that differences in late urinary or GI morbidity between treatment groups or between fractionation schedules were significant.
CONCLUSION: RT + CON produced a small nonsignificant improvement in CC(6m). Differences in OS, risk of death, and local relapse were significantly in favor of RT + CON. Late morbidity was similar in both trial arms. Results indicate a benefit of adding CON to radical RT.

Cancer Centre, Mount Vernon Hospital, Northwood, Middlesex

Choudhury A, Nelson LD, Teo MT, et al.
MRE11 expression is predictive of cause-specific survival following radical radiotherapy for muscle-invasive bladder cancer.
Cancer Res. 2010; 70(18):7017-26 [PubMed] Free Access to Full Article

Radical radiotherapy and surgery achieve similar cure rates in muscle-invasive bladder cancer, but the choice of which treatment would be most beneficial cannot currently be predicted for individual patients. The primary aim of this study was to assess whether expression of any of a panel of DNA damage signaling proteins in tumor samples taken before irradiation could be used as a predictive marker of radiotherapy response, or rather was prognostic. Protein expression of MRE11, RAD50, NBS1, ATM, and H2AX was studied by immunohistochemistry in pretreatment tumor specimens from two cohorts of bladder cancer patients (validation cohort prospectively acquired) treated with radical radiotherapy and one cohort of cystectomy patients. In the radiotherapy test cohort (n = 86), low tumor MRE11 expression was associated with worse cancer-specific survival compared with high expression [43.1% versus 68.7% 3-year cause-specific survival (CSS), P = 0.012] by Kaplan-Meier analysis. This was confirmed in the radiotherapy validation cohort (n = 93; 43.0% versus 71.2%, P = 0.020). However, in the cystectomy cohort (n = 88), MRE11 expression was not associated with cancer-specific survival, commensurate with MRE11 being a predictive marker. High MRE11 expression in the combined radiotherapy cohort had a significantly better cancer-specific survival compared with the high-expression cystectomy cohort (69.9% versus 53.8% 3-year CSS, P = 0.021). In this validated immunohistochemistry study, MRE11 protein expression was shown and confirmed as a predictive factor associated with survival following bladder cancer radiotherapy, justifying its inclusion in subsequent trial designs. MRE11 expression may ultimately allow patient selection for radiotherapy or cystectomy, thus improving overall cure rates.

Sections of Experimental Oncology and Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, Cancer Research UK Genome Variation Laboratory Service, Leeds

Punwani S
Diffusion weighted imaging of female pelvic cancers: concepts and clinical applications.
Eur J Radiol. 2011; 78(1):21-9 [PubMed]

Early applications of diffusion weighted magnetic resonance imaging (DWI) were limited to neuroimaging, concentrating either on stroke or brain tumours. With recent advances in MRI hardware and software DWI is now increasingly being investigated for cancer assessment throughout the body. Clinical applications of DWI relating to female pelvic cancers have largely concentrated on detection, localisation and staging of disease. More recently investigators have started to evaluate the ability of DWI for determining tumour histology and even predicting the outcome of chemoradiation treatment. This article reviews the physical concepts of MR diffusion weighting, illustrates the biophysical basis of diffusion contrast and reports the clinical applications of DWI for cervical, endometrial, ovarian, rectal and bladder tumours.

Department of Academic Radiology, 2nd Floor Podium, University College London Hospital, 235 Euston Road, London NW1 2BU

Clarke LL, Kennedy CT, Hollingworth P
Palmar fasciitis and polyarthritis syndrome associated with transitional cell carcinoma of the bladder.
J Am Acad Dermatol. 2011; 64(6):1159-63 [PubMed]

Palmar fasciitis and polyarthritis syndrome is a rare, disabling, paraneoplastic condition of unknown pathogenesis. There is no known effective treatment, although the condition may be halted by control of the cancer. Previously reported cases have mostly been in patients with advanced ovarian malignancies. We present the case of a 69-year-old woman with this condition in association with bladder carcinoma, together with a review of the literature and discussion of possible therapeutic options.

University Hospitals Bristol NHS Foundation Trust, Bristol

Owen HC, Giedl J, Wild PJ, et al.
Low frequency of epigenetic events in urothelial tumors in young patients.
J Urol. 2010; 184(2):459-63 [PubMed]

PURPOSE: Bladder urothelial cell carcinoma is uncommon in young patients. We recently reported a series of tumors in patients younger than 20 years at diagnosis and performed exhaustive genetic screening for molecular alterations. Few events typical of bladder urothelial cell carcinoma were detected. Since many carcinogenic events occur at the epigenetic rather than the genetic level, we analyzed the same tumors for alterations in DNA hypermethylation. We compared our findings with those in tumors in older patients with similar pathological profiles.
MATERIALS AND METHODS: We analyzed 76 bladder urothelial cell carcinomas from 3 groups stratified by age at diagnosis, including less than 19, 20 to 45 and greater than 46 years (median 78), and matched for low grade and nonmuscle invasive stage. We used quantified methyl specific polymerase chain reaction to investigate promoter methylation for 8 tumor suppressor genes implicated in urothelial carcinogenesis.
RESULTS: Tumors in the youngest age group had the lowest incidence of global hypermethylation compared to the other tumors with a methyl index of 37.5% vs 62.5% and 50%, respectively (ANOVA p = 0.009). When individual loci were analyzed, younger patients had a significantly lower rate and concentration of methylation at APC, Bcl2, MGMT and E-cadherin promoters than in the older groups (p <0.05). Few differences were present between the 2 older cohorts but the APC and MGMT methylation concentration increased with age.
CONCLUSIONS: Urothelial tumors in patients younger than 19 years have a low rate of epigenetic alteration. Tumors in patients older than 20 years have epigenetic profiles similar to those of tumors in patients within the typical bladder urothelial cell carcinoma age range.

Academic Urology Unit and Institute for Cancer Studies, University of Sheffield, Sheffield

Bryan RT, Tselepis C
Cadherin switching and bladder cancer.
J Urol. 2010; 184(2):423-31 [PubMed]

PURPOSE: Progression to or presentation with muscle invasive disease represents the critical clinical step in bladder cancer, necessitating more aggressive therapy and carrying a significantly worse survival rate. Bladder tumors typically show decreased expression of the cell-cell adhesion molecule E-cadherin as grade and stage progress, accompanied by increased expression of N-cadherin or P-cadherin in muscle invasive tumors. This phenomenon has been described as cadherin switching and may represent the key step in invasion. We introduce some of the concepts of cadherin mediated cell adhesion and biology, and describe cadherin switching in detail for bladder cancer.
MATERIALS AND METHODS: We performed a PubMed search for articles summarizing important concepts in cadherin biology and presenting primary evidence of cadherin expression in bladder cancer.
RESULTS: Cadherin switching promotes a more malignant and invasive phenotype of bladder cancer in patients and laboratory based experimental systems. Bladder cancer is novel in that a switch to N-cadherin and P-cadherin expression occurs, although the precise timing and nature of this process remain unknown. Similarly the associated signaling pathways remain to be fully elucidated.
CONCLUSIONS: Cadherin switching is an important process late in the molecular pathogenesis of bladder cancer, and it may hold some of the answers to the development of muscle invasive and metastatic disease. Thus, the cadherin cell adhesion molecules represent strong candidate biological and molecular targets for preventing disease progression, and further investigation is warranted.

School of Cancer Sciences, University of Birmingham, Birmingham

Punwani S
Contrast enhanced MR imaging of female pelvic cancers: established methods and emerging applications.
Eur J Radiol. 2011; 78(1):2-11 [PubMed]

Contrast enhanced magnetic resonance imaging of female pelvic cancers has been established for over 20 years. Conventional contrast enhanced imaging involves acquiring a set of pre-contrast T1 weighted images, followed by intravenous injection of an gadolinium based contrast agent and subsequent acquisition of a second set of contrast enhanced images. Developments in MR hardware and pulse sequences over the last 10 years have made dynamic contrast enhanced (DCE) protocols possible. DCE-MRI entails imaging of the same volume repeatedly prior to, during and following contrast injection. There have also been developments in image analysis methods and tools to reflect the increased data acquired. Qualitative analysis of contrast enhanced imaging (whether a single set or temporal series) by radiologists remains the mainstay for clinical reporting. Semi-quantitative assessment of signal intensity versus time curves and full pharmacokinetic modelling methods have emerged for evaluation of DCE-MRI data. DCE-MRI has found an established role in the detection, localisation and staging of female pelvic malignancies. Emerging applications of DCE-MRI include assessment of tumour grade, histology prior to and following treatment and prediction of individual and final treatment outcome. This article reviews the biophysical basis of contrast enhancement, the technical aspects of performance and analysis of DCE-MRI studies, and the established and emerging clinical utility of DCE-MRI in female pelvic malignancies.

Department of Academic Radiology, 2nd Floor Podium, University College London Hospital, 235 Euston Road, London NW1 2BU

Welton JL, Khanna S, Giles PJ, et al.
Proteomics analysis of bladder cancer exosomes.
Mol Cell Proteomics. 2010; 9(6):1324-38 [PubMed] Free Access to Full Article

Exosomes are nanometer-sized vesicles, secreted by various cell types, present in biological fluids that are particularly rich in membrane proteins. Ex vivo analysis of exosomes may provide biomarker discovery platforms and form non-invasive tools for disease diagnosis and monitoring. These vesicles have never before been studied in the context of bladder cancer, a major malignancy of the urological tract. We present the first proteomics analysis of bladder cancer cell exosomes. Using ultracentrifugation on a sucrose cushion, exosomes were highly purified from cultured HT1376 bladder cancer cells and verified as low in contaminants by Western blotting and flow cytometry of exosome-coated beads. Solubilization in a buffer containing SDS and DTT was essential for achieving proteomics analysis using an LC-MALDI-TOF/TOF MS approach. We report 353 high quality identifications with 72 proteins not previously identified by other human exosome proteomics studies. Overrepresentation analysis to compare this data set with previous exosome proteomics studies (using the ExoCarta database) revealed that the proteome was consistent with that of various exosomes with particular overlap with exosomes of carcinoma origin. Interrogating the Gene Ontology database highlighted a strong association of this proteome with carcinoma of bladder and other sites. The data also highlighted how homology among human leukocyte antigen haplotypes may confound MASCOT designation of major histocompatability complex Class I nomenclature, requiring data from PCR-based human leukocyte antigen haplotyping to clarify anomalous identifications. Validation of 18 MS protein identifications (including basigin, galectin-3, trophoblast glycoprotein (5T4), and others) was performed by a combination of Western blotting, flotation on linear sucrose gradients, and flow cytometry, confirming their exosomal expression. Some were confirmed positive on urinary exosomes from a bladder cancer patient. In summary, the exosome proteomics data set presented is of unrivaled quality. The data will aid in the development of urine exosome-based clinical tools for monitoring disease and will inform follow-up studies into varied aspects of exosome manufacture and function.

Section of Oncology and Palliative Medicine, Department of Pharmacology, Oncology and Radiology, School of Medicine, Cardiff University, Velindre Cancer Centre, Whitchurch, Cardiff CF14 2TL

Kiltie AE
Common predisposition alleles for moderately common cancers: bladder cancer.
Curr Opin Genet Dev. 2010; 20(3):218-24 [PubMed]

Bladder cancer is the 5th commonest cancer and two major risk factors are smoking and occupational chemical exposure. There is also evidence of a genetic component to its aetiology. Candidate gene studies have mostly focused on genes involved in adduct metabolism and DNA repair, including a recent consortium-based meta-analysis. Recently, two genome-wide association studies in bladder cancer have been published and a third is awaited with interest. These first two studies have identified three SNPs of genome-wide significance, two located within the 8q24 'gene desert'. These SNPs are positioned near or within loci of genes potentially implicated in cancer predisposition, namely MYC, TP63 and PSCA, although the functional significance of this is as yet unclear.

Gray Institute for Radiation Oncology and Biology, Old Road Campus Research Building, Headington, Oxford

Colebatch AN, Mounce KE
Mycobacterium bovis discitis as a complication of intravesical Bacillus Calmette-Guérin therapy.
J Clin Rheumatol. 2010; 16(2):74-5 [PubMed]

We report a culture-proven case of Mycobacterium bovis discitis in a 67-year-old man who had received intravesical Bacillus Calmette-Guérin for bladder cancer 5 years previously. He presented with severe low back pain, and imaging revealed features of discitis and paraspinal abscesses. On aspiration of the abnormal tissue, culture confirmed infection with M. bovis. Quadruple antituberculous therapy was commenced at this stage, with a subsequent good clinical response. Hematogenous spread of M. bovis is a rare, often delayed, complication of intravesical BCG therapy, but early appropriate treatment can result in a good prognosis.

Department of Rheumatology, Christchurch Hospital, Christchurch

Venyo AK, Herring D, Greenwood H, Maloney DJ
The expression of beta human chorionic gonadotrophin (β-HCG) in human urothelial carcinoma.
Pan Afr Med J. 2010; 7:20 [PubMed] Free Access to Full Article

INTRODUCTION: Studies regarding the immuno-histological expression and relevance of Beta-Human Chorionic Gonadotrophin (=-HCG) in urothelial carcinoma are few. There is also no clear cut way of predicting exactly which superficial urothelial carcinomas would subsequently recur or progress and which muscle-invasive urothelial tumours would progress. The objective of the study was to study the immunohistological expression of =-HCG in urothelial carcinoma with regards to grade, category and outcome following treatment
METHODS: The expression of =-HCG in urothelial carcinomas of 86 patients was studied with regards to grade, stage and outcome using an immunohistological (ABC) method and formalin fixed/paraffin embedded tumours.
RESULTS: Of the 86 tumours (55 superficial and 31 muscle-invasive) studied 45, 16 and 26 were graded as G1, G2, and G3 respectively. Thirteen of the 55 superficial tumours were positively stained for β=-HCG and 42 negatively stained. Twenty of the 31 muscle-invasive tumours studied were positively stained for β=-HCG and 11 were negative. Of the 13 β=-HCG positive superficial tumours only one did not recur at follow up and 12 subsequently recurred, of the 42 β=-HCG negative superficial tumours 19 did not recur and 23 recurred. Only one of twenty patients with β=-HCG positive muscle-invasive tumours survived; 6 of 11 patients with β=-HCG negative muscle-invasive tumours survived. The results indicate that positive staining of the tumours was more commonly associated with tumours of higher grade, higher stage and inferior outcome.
CONCLUSION: The Immunohistological expression of β=-HCG would likely predict superficial tumours that would recur and muscle-invasive tumours with inferior outcome.

Department of Urology, North Manchester General Hospital, Delaunays Road, Crumpsall, Manchester

Ramani VA, Maddineni SB, Grey BR, Clarke NW
Differential complication rates following radical cystectomy in the irradiated and nonirradiated pelvis.
Eur Urol. 2010; 57(6):1058-63 [PubMed]

BACKGROUND: Reports suggest that cystectomy following pelvic irradiation is associated with a higher morbidity and mortality than in primary cases. However, such reports are from an era when postcystectomy complication rates were higher than are currently reported.
OBJECTIVE: This study evaluates perioperative complications and mortality in primary radical and postradiation salvage cystectomy.
DESIGN, SETTING, AND PARTICIPANTS: Patients treated with cystectomy for bladder cancer or advanced pelvic malignancies involving the bladder were studied.
MEASUREMENTS: Perioperative complications and mortality were analysed for 426 primary and 420 salvage cystectomies performed at a single institution between 1970 and 2005.
RESULTS AND LIMITATIONS: The 30- and 60-d mortality in the 2000-2005 cohort were 0% and 1.2%, respectively, in the primary group and 1.4% and 4.3%, respectively, in the salvage cystectomy group. Thirty-day mortality between 1970 and 2005 was not statistically significant in the primary and salvage groups (4.2% and 7.1%, respectively).
CONCLUSIONS: This large series from a high-volume centre demonstrates no difference in perioperative mortality in primary or postradiation salvage radical cystectomy. Similarly, there was no significant difference in the incidence of most of the surgical or medical complications in either group, although the stomal stenosis rate was higher postradiation.

The Christie Hospital NHS Foundation Trust, Manchester

Hemelt M, Hu Z, Zhong Z, et al.
Fluid intake and the risk of bladder cancer: results from the South and East China case-control study on bladder cancer.
Int J Cancer. 2010; 127(3):638-45 [PubMed]

Although several studies have assessed the association between total fluid intake, specific drinks and bladder cancer, no firm conclusions can yet be drawn. Four hundred thirty two bladder cancer cases and 392 frequency matched hospital-based controls recruited in the South and East of China between October 2005 and June 2008 were interviewed on their intake of 6 nonalcoholic and 3 alcoholic drinks. Age, sex, smoking and hospital-adjusted odds ratios (OR) and 95 percent confidence intervals (95% CI) were calculated for all drinks and for total fluid intake using logistic regression. For 381 cases (81.9% men) and 371 controls (76.3% men), total fluid intake could be calculated. In men, an increase in total fluid intake was associated with a significantly decreased bladder cancer risk (OR 0.93, 95% CI: 0.88-0.99, per cup fluid consumed). Neither green nor black tea consumption was associated with bladder cancer. Daily consumption of milk significantly reduced the risk of bladder cancer by a half (OR 0.49, 95% CI: 0.32-0.76), which strengthens earlier suggestions that milk is probably associated with a decreased bladder cancer risk. Consumption of wine (OR 0.49, 95% CI: 0.34-0.70) and liquor/spirits (OR 0.65, 95% CI: 0.47-0.92) were associated with a significantly reduced risk. Consumption of water, fruit juice and beer appeared not associated with bladder cancer. There is no clear indication that the risks observed in this Chinese population are substantially different from those observed in Caucasian populations.

Unit of Genetic Epidemiology, Department of Public Health, Epidemiology and Biostatistics, University of Birmingham, Birmingham

Catto JW, Abbod MF, Wild PJ, et al.
The application of artificial intelligence to microarray data: identification of a novel gene signature to identify bladder cancer progression.
Eur Urol. 2010; 57(3):398-406 [PubMed]

BACKGROUND: New methods for identifying bladder cancer (BCa) progression are required. Gene expression microarrays can reveal insights into disease biology and identify novel biomarkers. However, these experiments produce large datasets that are difficult to interpret.
OBJECTIVE: To develop a novel method of microarray analysis combining two forms of artificial intelligence (AI): neurofuzzy modelling (NFM) and artificial neural networks (ANN) and validate it in a BCa cohort.
DESIGN, SETTING, AND PARTICIPANTS: We used AI and statistical analyses to identify progression-related genes in a microarray dataset (n=66 tumours, n=2800 genes). The AI-selected genes were then investigated in a second cohort (n=262 tumours) using immunohistochemistry.
MEASUREMENTS: We compared the accuracy of AI and statistical approaches to identify tumour progression.
RESULTS AND LIMITATIONS: AI identified 11 progression-associated genes (odds ratio [OR]: 0.70; 95% confidence interval [CI], 0.56-0.87; p=0.0004), and these were more discriminate than genes chosen using statistical analyses (OR: 1.24; 95% CI, 0.96-1.60; p=0.09). The expression of six AI-selected genes (LIG3, FAS, KRT18, ICAM1, DSG2, and BRCA2) was determined using commercial antibodies and successfully identified tumour progression (concordance index: 0.66; log-rank test: p=0.01). AI-selected genes were more discriminate than pathologic criteria at determining progression (Cox multivariate analysis: p=0.01). Limitations include the use of statistical correlation to identify 200 genes for AI analysis and that we did not compare regression identified genes with immunohistochemistry.
CONCLUSIONS: AI and statistical analyses use different techniques of inference to determine gene-phenotype associations and identify distinct prognostic gene signatures that are equally valid. We have identified a prognostic gene signature whose members reflect a variety of carcinogenic pathways that could identify progression in non-muscle-invasive BCa.

Academic Urology Unit, University of Sheffield, Sheffield

Hawtin K, Kent A, Collins C, Blunt D
Metastatic bladder cancer presenting as duodenal obstruction.
Ann Acad Med Singapore. 2009; 38(10):914-2 [PubMed]

INTRODUCTION: Bladder cancer is a common malignancy but presentation with metastatic disease is rare. This is the fi rst reported case of duodenal obstruction as a presentation of metastatic bladder cancer.
CLINICAL PICTURE: A middle-aged woman presented with nausea, vomiting, weight loss and intermittent haematuria. Radiology and histology confirmed metastatic bladder cancer to the retroperitoneum encasing the duodenum and causing obstruction.
TREATMENT: Insertion of a duodenal stent relieved the obstruction and palliative chemoradiotherapy was initiated.
OUTCOME: The patient died 15 months after diagnosis.
CONCLUSIONS: Clinicians and radiologists should be aware of atypical presentations of common malignancies.

Department of Radiology, Imperial College NHS Trust, Charing Cross Hospital, London