Tumor development is angiogenesis dependent, and vascular endothe 11*1 growth factor (VEGF) is a key growth factor in this process. We demonstrate that high expression of VEGF mRNA in 55 superficIal blad der cancers was associated with earlier recurrence (P = 0.001; hazard ratio, 3.09) and progression to a more invasive phenotype (P = 0.02; hazard ratio, 533). VEGF mRNA expression correlated with protein although in cases without high p53 protein expression, high VEGF mRNA also predicts a poor prognosis. The relationship between VEGF and early twnor recurrence suggests that seeding via angiogenesis may be a major mechanism in the pathogenesis of recurrence. These studies indicate that VEGF can predict the behavior of superfidal bladder tumors and is a therapeutic target for intravesical therapy.

Regulation by hypoxia may underlie the expression of vascular endothelial growth factor in bladder cancer. We have compared the distribution of vascular endothelial growth factor mRNA with a hypoxia marker, carbonic anhydrase 9 (CA IX). vascular endothelial growth factor mRNA was analysed by in situ hybridisation and CA IX by immunochemistry in 22 cases of bladder cancer. The relationship of microvessels to the distribution of CA IX was determined. In a separate series of 49 superficial tumours, CA IX immunostaining was compared with clinico-pathological outcome. In superficial and invasive disease there was overlap in the expression of vascular endothelial growth factor and CA IX, CA IX being more widespread. Both were expressed predominantly on the luminal surface, and surrounding areas of necrosis (invasive tumours). Expression of both factors was greater in superficial disease. Expression was absent within ∼80 μm of microvessels. Unlike vascular endothelial growth factor, CA IX did not predict outcome in superficial disease. Differential responses to reoxygenation provide one explanation: vascular endothelial growth factor mRNA declined rapidly, while CA IX expression was sustained for >72 h. Expression of vascular endothelial growth factor mRNA in bladder tumours is consistent with hypoxic regulation and suggests differential regulation in superficial vs invasive disease. The expression of CA IX on the luminal surface justifies investigation of its utility as a therapeutic target/prognostic indicator. British Journal of Cancer (2002) 86 , 1276–1282. DOI: 10.1038/sj/bjc/6600215 www.bjcancer.com © 2002 Cancer Research UK

What ' s known on the subject? and What does the study add?Haematuria clinics with same day imaging and fl exible cystoscopy are an effi cient way for investigating patients with haematuria. The principal role of haematuria clinics with reference to bladder cancer is to determine which patients are ' normal ' and may be discharged, and which patients are abnormal and should undergo rigid cystoscopy. It is well recognised that CT urography offers a thorough evaluation of the upper urinary tract for stones, renal masses and urothelial neoplasms but the role of CT urography for diagnosing bladder cancer is less certain. The aim of the present study was to evaluate the diagnostic accuracy of CT urography in patients with visible haematuria aged > 40 years and to determine if CT urography has a role for diagnosing bladder cancer.This study shows that the optimum diagnostic strategy for investigating patients with visible haematuria aged > 40 years with infection excluded is a combined strategy using CT urography and fl exible cystoscopy. Patients positive for bladder cancer on CT urography should be referred directly for rigid cystoscopy and so avoid fl exible cystoscopy. The number of fl exible cystoscopies required therefore may be reduced by 17%. The present study also shows that the diagnostic accuracy of voided urine cytology is too low to justify its continuing use in a haematuria clinic using CT urography and fl exible cystoscopy. OBJECTIVES• To evaluate and compare the diagnostic accuracy of computed tomography (CT) urography with fl exible cystoscopy and voided urine cytology for diagnosing bladder cancer.• To evaluate diagnostic strategies using CT urography as: (i) an additional test or (ii) a replacement test or (iii) a triage test for diagnosing bladder cancer in patients referred to a hospital haematuria rapid diagnosis clinic. PATIENTS AND METHODS• The clinical cohort consisted of a consecutive series of 778 patients referred to a hospital haematuria rapid diagnosis clinic from 1 March 2004 to 17 December 2007. Criteria for referral were at least one episode of macroscopic haematuria, age > 40 years and urinary tract infection excluded. Of the 778 patients, there were 747 with technically adequate CT urography and fl exible cystoscopy examinations for analysis.• On the same day, patients underwent examination by a clinical nurse specialist followed by voided urine cytology, CT urography and fl exible cystoscopy. Voided urine cytology was scored using a 5-point system. CT urography was reported immediately by a uroradiologist and fl exible cystoscopy performed by a urologist. Both examinations were scored using a 3-point system: 1, normal; 2, equivocal; and 3, positive for bladder cancer.• The reference standard consisted of review of the hospital imaging and histopathology databases in December 2009 for all patients and reports from the medical notes for those referred for rigid cystoscopy. Follow-up was for 21 -66 months. RESULTS• The prevalence of bladder cancer in the clinical cohort was 20% (156/77...

Summary Vascular endothelial growth factor (VEGF) is an important factor mediating tumour angiogenesis. VEGF mRNA is differentially expressed in bladder cancer with high expression in superficial tumours (stage pT a and pT 1 ) contrasting with low expression in muscle invasive tumours (stage ≥ pT 2 ). To investigate mechanisms regulating VEGF expression in bladder cancer, VEGF mRNA and protein were measured in normal bladder (n = 12) and primary bladder cancers (n = 57). VEGF protein levels correlated with mRNA expression in normal bladder (r = 0.68, P = 0.02) and bladder cancer (r = 0.46, P = 0.0007). Whilst VEGF mRNA expression was threefold higher in superficial compared to muscle invasive bladder cancers (P = 0.0001) there was no difference in VEGF protein (P = 0.81). Accordingly, the median protein:mRNA ratios increased more than 15-fold with increasing tumour stage (P < 0.0001) suggesting translational regulation. Expression of the eukaryotic initiation factor-4E (eIF-4E), a factor implicated in the translational regulation of VEGF, was greater in tumours than normal bladder (P < 0.0001) and correlated with VEGF protein:mRNA ratios (n = 43, r = 0.54, P = 0.0004) pointing to its role in the regulation of VEGF. In superficial tumours (n = 37) high expression of eIF-4E was associated with a poor prognosis and reduced stage progression-free survival (P = 0.04, Cox proportional hazards model). The study demonstrates that eIF-4E may be involved in translational regulation of VEGF in bladder cancer and might have a role as a prognostic factor in bladder cancer. © 2000 Cancer Research Campaign Keywords: angiogenesis; VEGF; eIF-4E; bladder cancer 161British Journal of Cancer (2000) 82(1), 161-166 © 2000 Cancer Research Campaign Article no. bjoc.1999 Received 25 January 1999 Revised 30 June 1999 Accepted 5 July 1999Correspondence to: AL Harris, Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DU, UK at The Churchill Hospital, Oxford, UK. Twelve specimens of macroscopically normal bladder were obtained from patients undergoing surgery for bladder cancer (n = 5) or from cadaveric organ donors at the time of donor nephroureterectomy (n = 7). All specimens were snap-frozen in liquid nitrogen at the time of resection. RNA and protein preparationRNA was prepared according to the method of Chomczynski and Saachi (Chomczynski and Saachi, 1987). All RNA samples were run on a 1% agarose gel (under RNAase-free conditions) and the concentrations measured spectrophotometrically prior to ribonuclease protection analysis.Tumour protein cytosolic and membrane fractions were prepared as previously described (Sacks et al, 1993). Briefly, tumours, frozen in liquid nitrogen, were morselized (cooled with liquid nitrogen) prior to homogenization, using a Dounce homogenizer, in 4 ml of HEPES-EDTA buffer containing proteinase inhibitors. This homogenate was centrifuged at 3000 g for 10 min (+4°C) and the supernatant further centrifuged at 100 000 g for 45 min (+2°C). The pellet was resuspended in 1 ml Tris-buffered sali...

scored for the presence and absence of UUT urothelial tumour by two radiologists, retrospectively and independently, and while unaware of the demographic and clinical information. The reference standards were the histopathology and clinical follow-up. RESULTS MDCTU CONCLUSIONThis study validates quantitatively the use of MDCTU for diagnosing UUT urothelial tumour.

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RESULTSThe prevalence of bladder tumours was 24%; when CTU was compared with the histopathological findings, there was one false-positive and three false-negative diagnoses, indicating a sensitivity of 0.93 and a specificity of 0.99, with a 0.98 positive and 0.97 negative predictive value for detecting bladder cancer. A review of the three falsenegative cases showed that one was missed on original CTU reporting, the second had the appearance of prostate cancer on CTU and the third was a squamous metaplasia. CONCLUSIONSCTU is an accurate method of detecting bladder tumours in the present patients, and is reliable and accurate for assessing the bladder. Our results support the use of CTU as a first-line screening tool for this high-risk group, the use of which will obviate the need for flexible cystoscopy in patients with a negative CTU and allow those with an obvious tumour to be referred directly for rigid cystoscopy and resection. The remaining patients should be referred for flexible cystoscopy. Such a pathway would accelerate patient assessment by using fewer tests and provide a true 'one-stop' clinic, allowing a comprehensive evaluation with a single test for the upper and lower urinary tract. KEYWORDS macroscopic haematuria, haematuria, bladder cancer, cystoscopy, virtual cystoscopy, CT urography OBJECTIVETo evaluate the use of computed tomography urography (CTU) for diagnosing bladder tumours in patients with macroscopic haematuria and aged > 40 years. PATIENTS AND METHODSIn all, 200 consecutive patients attending a fast-track haematuria clinic were assessed using 'same-day' CTU and flexible cystoscopy. Patients were aged > 40 years and had macroscopic haematuria with no urine infection. CTU studies were reported by one uroradiologist and scored on a 3-point scale to quantify the probability of bladder cancer. All flexible cystoscopies were performed by the same cystoscopist with no knowledge of the findings of CTU, and scored using a 3-point scale. Cystoscopy, pathological findings and CTU were then compared.

OBJECTIVE To analyse bladder cancer biopsies and investigate the pattern of expression of the type 1 insulin‐like growth factor receptor (IGF1R), a receptor tyrosine kinase that mediates tumour cell proliferation, motility and protection from apoptosis. MATERIALS AND METHODS Formalin‐fixed specimens of bladder cancer (40 whole‐mount, 80 cores on a tumour microarray) and normal bladder (15 samples) were stained immunohistochemically for the IGF1R. The IGF1R expression was also measured by quantitative reverse transcription‐polymerase chain reaction (Q‐RT‐PCR) on RNA extracted from fresh frozen bladder cancers (61) and benign bladder (12). RESULTS Of the 15 samples of normal bladder, 14 showed negligible (1+) or light (2+) IGF1R immunostaining. By contrast moderate (3+) or heavy (4+) staining for IGF1R was detected in 89 (74%) of the 120 samples of malignant urothelium. Q‐RT‐PCR showed significantly higher levels of steady‐state IGF1R mRNA in tumours (all cases, Ta–T4) than in normal bladder (P < 0.05), indicating up‐regulation at the transcriptional level. This difference was particularly evident when comparing normal urothelium with superficial (Ta–T1) or invasive (T2–4) tumours; only the latter showed significant IGF1R over‐expression at the RNA level (P < 0.05 vs normal bladder). CONCLUSION The IGF1R is up‐regulated in bladder cancer compared with non‐malignant bladder, and might contribute to a propensity for invasion.