The hypoxia-inducible genes VEGF and CA9 are differentially regulated in superficial vs invasive bladder cancer.

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 approximately 80 microm 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.

Radiation-induced haemorrhagic cystitis.

OBJECTIVES: In this article we review the literature concerning the frequency and management of severe haemorrhagic radiation-induced cystitis. METHODS: A Medline search was performed from 1966 to 1999 for articles in English. A total of 309 references were found. Abstracts and complete articles were reviewed. RESULTS: Severe haemorrhagic cystitis following radiotherapy remains a relatively rare event. However, the fact that it is relentlessly progressive and that treatment options are suboptimal makes it clinically important. The incidence of severe haematuria following pelvic irradiation is difficult to determine from the literature although most studies state an incidence of less than 5% which increases with time since irradiation. Methods of treatment include simple bladder irrigation, cystodiathermy, oral, parenteral and intravesical agent, hyperbaric oxygen therapy, hydrodistension, internal iliac embolisation, urinary diversion and cystectomy. No management strategy is 100% successful and a stepwise progression in treatment intensity is often required. CONCLUSION: The articles available on radiation-induced haemorrhagic cystitis are principally retrospective and involve small numbers of patients who have had several different treatment modalities. In the absence of randomised studies comparing treatments, it is impossible to set definitive rules about management but patients with this condition probably warrant early and aggressive treatment.

Angiogenesis, angiogenic factor expression and prognosis of bladder cancer.

Angiogenesis is the process by which tumours induce a blood supply from their surrounding tissues and it has been shown to be necessary for tumour growth. Evidence is accumulating for both the prognostic usefulness of measures of angiogenesis and its potential as a target for anticancer therapy. This review discusses the evidence concerning the association between angiogenesis and bladder cancer, focusing on the mechanisms behind the angiogenic process and the quantification of factors believed to be involved, relating these clinically to their prognostic use and to the antiangiogenic strategies so far described in vitro and in vivo.

Eukaryotic initiation factor-4E in superficial and muscle invasive bladder cancer and its correlation with vascular endothelial growth factor expression and tumour progression.

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 pTa and pT1) contrasting with low expression in muscle invasive tumours (stage > or = pT2). 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 (elF-4E), a factor implicated in the translational regulation of VEGF, was greater in tumours than normal bladder (P < 0.0001) and correlated with VEGE 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.

Vascular endothelial growth factor: an important angiogenic mediator in bladder cancer.

Angiogenesis is the growth of new blood vessels from existing ones and is critical for tumour development, invasion and metastasis. In bladder cancer the prognostic significance of mean vascular density, a surrogate for angiogenesis, has lead to study of the factors determining the angiogenic phenotype. The motivation for these studies has been the search for non-invasive prognostic or diagnostic markers for the disease and for new therapeutic strategies against bladder cancer recurrence and progression. Whilst a large number of factors are involved in the mediation of tumour angiogenesis, vascular endothelial growth factor (VEGF) is widely considered to be central to the process. This review highlights the information presently available regarding the role of VEGF in bladder cancer through observational studies of its expression in bladder tumours and within the urine. In addition the value of VEGF in determining the prognosis in bladder cancer and the future possibilities for anti-VEGF therapy are discussed.

Urinary vascular endothelial growth factor and its correlation with bladder cancer recurrence rates.

PURPOSE: Vascular endothelial growth factor (VEGF) is a principal growth factor mediating tumor angiogenesis. The high expression of VEGF within bladder tumors is associated with a poor prognosis. We quantified urinary VEGF and determined its potential as a prognostic marker in bladder cancer. MATERIALS AND METHODS: VEGF was measured by enzyme-linked immunosorbent assay in the urine of 261 patients, including 153 undergoing cystoscopic surveillance for bladder cancer and 108 with another advanced malignancy or a benign urological condition. The source of urinary VEGF was studied through its quantification in bladder tumors and normal bladders. RESULTS: Urinary VEGF was higher in patients undergoing cystoscopic surveillance for bladder cancer than in those with an advanced nonbladder malignancy (p <0.0001) or a benign urological condition (p = 0.004). The highest levels were noted in patients with bladder cancer compared to those with clear cystoscopy (p <0.0001). In 26 cases the correlation between VEGF protein levels in bladder cancer and urine (r = 0.67, p = 0.003) suggested that the tumor is a source of urinary VEGF. Increased VEGF protein in normal urothelium in 22 patients with bladder cancer compared to that in 7 cadaveric organ donors (p = 0.002) indicates that urinary VEGF may also be derived from nonmalignant urothelium. In 61 cases we established a correlation between urinary VEGF and stage T1 or less superficial bladder tumor recurrence rates (r = 0.45, p <0.0001). CONCLUSIONS: 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.

Drug-induced bladder and urinary disorders. Incidence, prevention and management.

The bladder is vulnerable to the adverse effects of drugs because of its complex control and the frequent excretion of drug metabolites in the urine. Incontinence results when bladder pressure exceeds sphincter resistance. Stress incontinence because of sphincter weakness occurs with antipsychotics and alpha-blockers, especially in women. Urge incontinence and irritative symptoms may be caused by drugs. Anticholinergics, anaesthetics and analgesics cause urinary retention because of failure of bladder contraction. They are more likely to cause retention in men because of prostatic enlargement. Cyclophosphamide and tiaprofenic acid can cause chemical cystitis, and should be withdrawn if a patient develops irritative symptoms or haematuria. Cyclophosphamide may also induce bladder tumours. Adverse effects of cyclophosphamide can be reduced with prophylactic administration of mesna and adequate hydration. Mitomycin, doxorubicin or bacillus Calmette-Guerin (BCG) instilled locally to treat bladder tumours can cause cystitis, contracture and calcification. Their administration should be limited to 1 hour per week for a maximum of 8 weeks. Retroperitoneal fibrosis and urine discolouration may be caused by drugs. Ureteric calculi may result from any drug causing nephrolithiasis.

Vascular endothelial growth factor is a predictor of relapse and stage progression in superficial bladder cancer.

Tumor development is angiogenesis dependent, and vascular endothelial growth factor (VEGF) is a key growth factor in this process. We demonstrate that high expression of VEGF mRNA in 55 superficial bladder 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, 5.33). VEGF mRNA expression correlated with protein levels in superficial tumors (r = 0.59, P = 0.003) and normal bladder (r = 0.65, P < 0.05), although the ratio of VEGF protein to mRNA was elevated in tumors compared to normal bladder (P = 0.004), suggesting posttranscriptional regulation. In this study, VEGF is implicated as a major downstream mediator of the effects of the p53 tumor suppressor gene by the association between high p53 protein (determined immunochemically) and high VEGF protein and mRNA expression (P < 0.02), although in cases without high p53 protein expression, high VEGF mRNA also predicts a poor prognosis. The relationship between VEGF and early tumor 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 superficial bladder tumors and is a therapeutic target for intravesical therapy.

Bilateral ureteric obstruction secondary to the prolonged use of tiaprofenic acid.

There is increasing awareness that the long-term use of the non-steroidal anti-inflammatory agent tiaprofenic acid (Surgam) is associated with a severe form of cystitis. The condition is usually reversible with complete resolution of symptoms on stopping the drug. We present a case of tiaprofenic acid-induced cystitis resulting in bilateral hydronephrosis suggesting ureteric obstruction. The previous reported cases are reviewed and the risks of delay in withdrawal of the drug and of permanent ureteric damage are discussed.

Is day case surgery in urology associated with high admission rates?

The nature of the procedures and patients in urological day surgery may lead to high admission rates. A retrospective audit was performed over 8 years (1988 to 1996) to determine admission rates in a urological day surgical unit and examine reasons for and methods of decreasing admissions. The overall admission rate was 9.3%. Higher rates were associated with cystoscopic procedures, with 46% of admissions after bladder tumour cystosurveillance and a further 18% after urethroscopic surgery for urethral strictures. There was a surgical indication for admission in 72% of cases, with an anaesthetic indication in 17%. The study demonstrates that admission rates accompanying urological day surgery are higher than the 3% proposed by The Royal College of Surgeons of England. Achieving a rate of 3% may require restrictive patient selection that will deprive some patients the benefits associated with urological day surgical care.

Symptomatic urethral hair ball and diverticulum complicating island flap urethroplasty.

A 29-year-old man underwent a one-stage island flap urethroplasty, using perineal skin, to treat a urethral stricture. Four years following surgery he represented with symptoms from a urethral diverticulum containing a hair ball. This was at the site of the previous urethroplasty and was treated by excision.

Bladder cancer angiogenesis, its role in recurrence, stage progression and as a therapeutic target.

In this article we review the role of angiogenesis in bladder tumor development and its putative role in determining tumor progression and recurrence. The potential value of antiangiogenic therapy in the disease is also discussed.

Malignant transformation in a fatal case of giant cell tumour of the sacrum.

Most giant cell tumours can be treated by local surgery and only rarely are they life threatening. We report a case of a giant cell tumour of the sacrum causing irresectable and fatal small bowel obstruction following malignant transformation of the tumour. The role of radiotherapy in this transformation is discussed.