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Biomedical subjects

D Cranston

Publications and source records attributed to D Cranston.

At least 19 recordsLinked to original sources
PubMed2003

Polymorphisms in tumour necrosis factor (TNF) are associated with risk of bladder cancer and grade of tumour at presentation.

The purpose of this study is to assess the role of tumour necrosis factor (TNF) polymorphisms in the risk of developing bladder cancer and effect on tumour stage, grade and progression. In all, seven single-nucleotide polymorphisms in TNF were studied in 196 bladder cancer patients and 208 controls using a PCR-SSP genotyping technique. It was seen that there was a significant association of two polymorphisms in TNF with bladder cancer: the TNF+488A allele was found in 28.1% of patients compared with 14.9% of controls (P=0.0012). In addition, TNF-859T was found in 26.0% of patients compared with 14.4% of the controls (P=0.0036). The two loci were in tight linkage disequilibrium, that is, almost all the individuals having TNF+488A also had TNF-859T. Patients with the TNF+488A or TNF-859T were more likely to present with a moderately differentiated tumour than those patients without the uncommon allele. In all, 16.7% of patients with TNF+488A and 29.9% of patients without TNF+488A presented with a G1 tumour (P=0.015). A total of 14% of patients with TNF-859T and 30.5% of patients without TNF-859T presented with a G1 tumour (P=0.0043). There was no significant effect on time to first recurrence, stage progression or grade progression. In conclusion, a significant association between TNF polymorphisms TNF+488A and TNF-859T and risk of bladder cancer was detected in this study. Both these polymorphisms were associated with grade of tumour at presentation although there was no significant effect on subsequent tumour behaviour.

Adult↗
PubMed2002

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.

Antigens, Neoplasm↗
PubMed2001

High incidence of lichen sclerosus in patients with squamous cell carcinoma of the penis.

BACKGROUND: There is a well-documented association between lichen sclerosus (LS) and vulval carcinoma in women; however, until recently, there have only been anecdotal reports of penile squamous cell carcinoma (SCC) occurring in men with LS. OBJECTIVE: The incidence of penile carcinoma occurring on a background of LS remains uncertain, and we wished to examine this possible association further. METHOD: To address this, all the cases (n = 20) of penile SCC held on our pathology database (4 years) were examined. Histology was reviewed, blind to the clinical picture, for evidence of LS, applying strict histological criteria. Subsequently, clinical notes were reviewed for history of LS before the SCC presented, and history of previous circumcision, treatments, node involvement, metastases and death. RESULTS: In eight cases, evidence of LS was found in the excision specimen. Seven of these had well-differentiated SCC. In the 12 cases with no evidence of LS, only three were well differentiated. With case note review, seven had a history of LS (four with histological LS), sometimes preceding the SCC by 10 years. These all had well-differentiated SCC. Ten of the 20 patients are dead, seven from metastatic disease. Four deaths occurred in the 'well-differentiated LS' group, but only one from penile SCC metastatic disease. CONCLUSIONS: There appears to be a definite association between SCC of the penis and the presence of LS, similar to that reported between LS and vulval SCC in women. Of the 20 patients with penile SCC studied, 11 had a clinical history and/or histological evidence of LS. However, clinical presentation of the LS or need for circumcision may precede the SCC by many years. As follow-up is impractical, counselling at the time of diagnosis is very important, and it is essential that medical practitioners are aware of this association so that the subsequent risk from SCC is reduced.

Adult↗
PubMed2001

Human bladder cancer invasion model using rat bladder in vitro and its use to test mechanisms and therapeutic inhibitors of invasion.

As well as being a passive support, the extracellular matrix also regulates key biological processes such as invasion, differentiation and angiogenesis. We have therefore developed an in vitro model of bladder cancer invasion using de-epithelialized rat bladder to allow for tumour cell-extracellular matrix interactions. Onto this we have seeded a panel of human bladder cancer cell lines (RT4, RT112, 253J and EJ28 (T24)) representing progression from well to poorly differentiated phenotypes and used as models of superficial to invasive bladder cancer. The better differentiated cell lines RT4 and RT112 reproducibly grew as stratified epithelium, whereas poorly differentiated EJ28 cells invaded across a broad front. Invasion was not simply related to proliferation rate, measured either as doubling time on plastic (non-invasive 253J and invasive EJ28 having the same doubling time) or by Ki-67 proliferation index within the model. We used the model to test the ability of 4 compounds that interfere with tumour cell-extracellular matrix interactions (suramin, N-acetylcysteine and the urokinase plasminogen activator pathway antagonists A5 compound and monoclonal antibody Mab 3936) to inhibit invasion. At non-toxic concentrations, all significantly inhibited invasion (P< 0.05), although to varying degrees, suramin and A5 almost completely and N-acetylcysteine the least. In conclusion, this model shows the urokinase system is important for bladder invasion and can be used to investigate other mechanisms of bladder cancer invasion and also for the testing of intravesical drugs.

Acetylcysteine↗
PubMed2001

Haematuria: a long-term problem after prostatectomy.

OBJECTIVE: The causes of 'late' haematuria (2 years or more) following endoscopic and open prostatectomy were studied. METHODS: Between 1994 and 1996, more than 400 patients were evaluated for haematuria. Ninety patients with post-prostatectomy haematuria were investigated with upper tract imaging and cystoscopic examination. Amongst these 90 patients, 30 presented with haematuria within 2 years of surgery. These patients were excluded from the study as they had normal investigations. RESULTS: Of these 60 patients, 24 (43%) had demonstrable causes of haematuria in their urinary tract. Six of them had urinary tract malignancy. CONCLUSIONS: There is a substantial likelihood of finding a cause for haematuria in patients who had prostatectomy even though they had full-scale urological investigations before. There is a need, therefore, to carry out necessary screening investigations in such patients.

Aged↗
PubMed2001

Relation of vascular endothelial growth factor production to expression and regulation of hypoxia-inducible factor-1 alpha and hypoxia-inducible factor-2 alpha in human bladder tumors and cell lines.

Hypoxia is an important regulator of vascular endothelial growth factor (VEGF) expression, and VEGF is associated with poor prognosis in bladder cancer. To investigate further the mechanisms of VEGF regulation, we examined VEGF expression by mRNA and protein analysis in four human bladder cancer cell lines, showing a progression from well to poorly differentiated phenotypes under varying conditions of confluence and hypoxia (0.1% O(2)) and with chemical mimics of hypoxia. Hypoxia significantly increased VEGF protein expression in all cell lines, although this effect was dependent on the degree of confluence. The superficial bladder cancer cell line RT4 lost hypoxia inducibility at confluence, whereas inducibility was maintained in the invasive cell lines 253J and EJ28. This pattern of VEGF expression in the invasive cell lines correlated with the expression of the transcription factor hypoxia inducible factor-1 alpha (HIF-1 alpha) and with hypoxia-inducible factor-2 alpha (HIF-2 alpha) and in RT4 correlated with a marked reduction in HIF-1 alpha inducibility at confluence. Using the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor LY 294002, we show that this VEGF hypoxia-inducible pathway regulated by HIF-1 alpha is distinct from a PI 3-kinase-dependent pathway, which regulates basal amounts of VEGF, but does not affect inducibility. Both HIF-1 alpha and HIF-2 alpha protein and mRNA were up-regulated in primary human bladder tumors (n = 12) compared with normal bladder specimens (n = 4), with significant intertumor variation. These results suggest that components of the hypoxia response pathway, including HIF-1 alpha and HIF-2 alpha, are important cofactors in the regulation of VEGF in bladder cancer and are therapeutic targets in this disease.

Basic Helix-Loop-Helix Proteins↗
PubMed2000

A double-blind randomized controlled trial and economic evaluation of transurethral resection vs contact laser vaporization for benign prostatic enlargement: a 3-year follow-up.

OBJECTIVE: To evaluate the effect of contact laser prostate surgery in the treatment of benign prostatic hyperplasia. PATIENTS AND METHODS: A prospective double-blind randomized controlled trial of transurethral resection of the prostate (TURP) and contact laser prostatectomy was conducted, with an economic evaluation of both procedures. The primary outcome measure was the change in the American Urologic Association symptom score, with secondary outcome measures being the peak urinary flow rate, treatment-related complications, re-operation rate and health service costs. RESULTS: The perioperative blood loss and transfusion requirements were statistically significantly lower for laser prostatectomy than for TURP. There was no clinically significant difference between TURP and contact laser prostatectomy in the mean change in symptom scores and flow rates. There were distinct perioperative advantages in favour of the contact laser treatment, but some disadvantages in terms of re-catheterization and re-operation rates. CONCLUSIONS: Contact laser prostatectomy is a valid treatment for benign prostatic hypertrophy. The performance of contact laser prostatectomy as day-case surgery would have cost advantages to the National Health Service.

Aged↗
PubMed2000

Elevated serum vascular endothelial growth factor in patients with hormone-escaped prostate cancer.

OBJECTIVE: To investigate the role of serum vascular endothelial growth factor (VEGF) in the assessment of patients with prostate cancer. Patients, subjects and methods Serum from 78 men was assayed for VEGF using a commercially available enzyme-linked immunosorbent assay kit. Forty-eight patients had a histopathological diagnosis of prostate cancer (16 local disease, 32 metastatic), nine had benign prostatic hyperplasia (BPH) and 21 were healthy controls. RESULTS: The mean serum VEGF level was significantly higher in patients with hormone-escaped prostate cancer than in all other groups (P </= 0. 02). There were no significant differences in serum VEGF levels among the other groups. In 18 patients with serial measurements there was no significant difference in serum VEGF level during either response to or escape from hormonal therapy. CONCLUSIONS: The significantly higher serum VEGF level in patients with hormone-escaped prostate cancer suggests a role in the pathogenesis of advanced disease. However, the lack of significant differences among the other groups and the failure to indicate either response to or escape from hormonal therapy suggests that serum VEGF in this setting is of limited use.

Aged↗
PubMed2000

Angiogenesis and lymphangiogenesis in stage 1 germ cell tumours of the testis.

OBJECTIVE: To determine whether angiogenesis can be used as an additional prognostic indicator in patients with stage 1 germ cell tumours of the testis. PATIENTS AND METHODS: Paraffin sections were assessed immunohistochemically from 51 patients with clinical stage 1 germ cell tumours of the testis (28 seminoma, 23 teratoma) treated by orchidectomy and surveillance only. Sections were analysed for microvascular density (MVD), and expression of the angiogenic factors vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP). In addition, in the seminoma cases the presence of mRNA for the lymphangiogenic factor VEGF-C was examined by in situ hybridization, and its corresponding receptor VEGFR-3 by immunohistochemistry. RESULTS: Teratoma specimens had a significantly higher mean (range) MVD (85, 26-163; P < 0.01) than both seminoma (37, 16-91) and four normal specimens (26, 18-30). Teratoma specimens also had significantly higher VEGF expression than both seminoma and normal specimens (P < 0.01). Despite these differences between groups, and indeed individual tumours, there was no significant correlation between MVD and VEGF, or between either MVD or VEGF and relapse-free survival. TP expression was significantly greater in tumours than in normal specimens (P < 0.02) but with very little inter-tumour variation. VEGF-C mRNA and VEGFR-3 protein were detected in a third to a half of cases, with expression mostly around endothelial vessels. CONCLUSIONS: The marked differences between normal testis and tumours implicate angiogenesis in the biology of germ cell tumours of the testis. In addition, the detection of factors involved in lymphangiogenesis in some seminomas, tumours which initially metastasize primarily to lymph nodes, indicate that although not prognostic in this study, further studies are warranted in both these areas in the search for further prognostic indicators and therapeutic targets.

Adult↗
PubMed1999

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.

Adult↗
PubMed1998

The place of the high dependency unit in a modern New Zealand hospital.

AIM: To describe the concept of, and the benefits which come from having, a high dependency unit (HDU), based on the 24 years experience of Waikato Hospital. DESCRIPTION: The HDU (9 beds/1600 patients per year) is part of the Critical Care Unit which also contains an adult intensive care unit (ICU) (11 beds/1000 patients per year), and a paediatric ICU/HDU (3 beds/250 patients per year). The regular care in the HDU is given by the specialist teams, aided by input from the ICU team. Over three years, 4390 patients were admitted having an average stay of 34 hours (61% < 24 hours). Forty eight percent of patients were over 60 years of age. The main sources of admissions were the theatre (66%), emergency department (18%), ICU (14%) and wards (11%). The main destinations were the wards (92%) and ICU (4%), with a mortality of 0.6%. The reasons for admission, specialist teams and post-operative diagnoses are described. Clinicians value the area highly, and have used it extensively. The average cost was $NZ800 per day. CONCLUSIONS: Large hospitals in New Zealand should be planning an HDU to allow adequate care for those patients too complicated for the ward but not needing the ICU. Smaller hospitals can usefully combine the functions of ICU and HDU within one area.

Adult↗