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.

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...

This study assesses the role of posttransplant HLA antibody monitoring in the surveillance of pancreas transplant recipients. Four hundred thirty‐three pancreas transplants were performed at the Oxford Transplant Centre 2006–2011 (317 simultaneous pancreas kidney [SPK] and 116 isolated pancreas [IP]). HLA antibody monitoring was performed at 0, 6 and 12 months and annually and during clinical events. There was no association between pancreas graft failure and recipient or donor characteristics. Posttransplant antibody status, available for 354 (81.8%) of recipients, demonstrated that 141 (39.8%) developed de novo HLA antibodies, of which 52 (36.9%) were de novo donor‐specific HLA antibodies (DSA) (34 SPK, 18 IP). The development of antibodies to donor HLA, but not to nondonor HLA, was significantly associated with poorer graft outcomes, with 1‐ and 3‐year graft survival inferior in SPK recipients (85.2% vs. 93.5%; 71.8% vs. 90.3%, respectively; log‐rank p = 0.002), and particularly in IP recipients (50.0% vs. 82.9%; 16.7 vs. 79.4%, respectively; log‐rank p = 0.001). In a multivariate analysis, development of de novo DSA emerged as a strong independent predictor of pancreas graft failure (hazard ratio 4.66, p < 0.001). This is the largest study to examine de novo HLA antibodies following pancreas transplantation and clearly defines a high‐risk group in need of specific intervention.

Our study demonstrates that VEGF is high in the urine of patients with bladder cancer and it correlates with tumor recurrence rates. VEGF is implicated in the pathogenesis of bladder cancer recurrence. Its quantification may provide a valuable noninvasive marker for the early detection of bladder tumor recurrence as well as a therapy target.