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J K Mellon

Publications and source records attributed to J K Mellon.

At least 19 recordsLinked to original sources
PubMed2006

Epidermal growth factor receptor status predicts local response to radical radiotherapy in muscle-invasive bladder cancer.

AIMS: Epidermal growth factor receptor (EGFR) is expressed by over 70% of muscle-invasive bladder tumours and is associated with diminished overall survival. In model tumour systems, ionising radiation has been shown to activate EGFR, leading to cellular proliferation and is therefore a possible mechanism of underlying radioresistance. We carried out an immunohistochemical study relating the clinical outcome of patients receiving radical radiotherapy for muscle-invasive bladder cancer to tumour EGFR status. MATERIALS AND METHODS: Archived paraffin-embedded tumours from 110 consecutive patients receiving radical radiotherapy for muscle-invasive bladder cancer between 1991 and 1997 were immunohistochemically stained for EGFR. Data were collected concerning the tumour stage and grade, the presence of ureteric obstruction, the response to radiotherapy at 3 months, local recurrence rates, metastatic spread and survival. Multivariate analysis of potential independent prognostic factors of impaired bladder cancer-specific survival was carried out using Cox's regression. RESULTS: Of 110 tumours, 79 (72%) stained positively for EGFR. Of 87 patients undergoing the 3-month check cystoscopy, 60 (69%) had a positive response to radiotherapy. A positive response to radiotherapy correlated significantly with a negative EGFR status (chi(2) test, P = 0.05). Kaplan-Meier survival analysis revealed a trend towards improved bladder cancer-specific survival in EGFR-negative patients (Log-rank, P = 0.10). A lack of response to radiotherapy at 3 months, local recurrence, metastatic spread and the presence of ureteric obstruction were all independent prognostic factors for diminished bladder cancer-specific survival (Cox's regression: P = 0.009, P = 0.001, P = 0.04 and P = 0.005, respectively). CONCLUSIONS: EGFR status predicts the local response to radiotherapy but does not provide prognostic utility in relation to overall or bladder cancer-specific survival. As EGFR status seems to be linked to the initial response to radiotherapy, its inhibition may be a means of enhancing the radio-responsiveness of these poor prognosis tumours. Colquhoun, A. J.

Aged↗
PubMed2006

Management of the gastrointestinal tract at the time of cystectomy.

Radical cystectomy impacts on the gastro-intestinal tract in several ways. Clearly there is the need for bowel mobilisation, resection and anastamosis in order to create a urinary diversion, and the use of bowel preparation or antibiotics are controversial topics. Post-operatively ileus is common and there is debate about the routine use of NG tubes. Early enteral feeding is a modern concept but not yet proven. In the long-term there can be problems such as diarrhoea and B12 deficiency. All of these issues are discussed in this review using the latest available evidence.

Cystectomy↗
PubMed2005

Concomitant chemoradiotherapy for muscle-invasive bladder cancer: the way forward for bladder preservation?

Muscle-invasive bladder cancer is a common malignancy with a high mortality rate. Despite ongoing debates about the optimal primary intervention, radical cystectomy remains the cornerstone of first-line therapy in many institutions. Over the past decade, bladder-preserving strategies involving transurethral resection (TUR), chemotherapy and radiotherapy have evolved. However, the advantage of these approaches over radiation treatment as monotherapy has yet to be fully evaluated. In other tumour models, most notably cervical and anal cancer, radiation and chemotherapy delivered concomitantly have resulted in significant survival advantages. Here, we consider the potential value of this approach in the treatment of invasive bladder cancer. Concomitant chemoradiotherapy is currently the mainstay of several bladder-preserving programmes reported in the medical literature. Overall, local control and survival rates compare favourably with contemporary cystectomy series; however, difficulties in drawing valid conclusions are highlighted. Concomitant chemoradiotherapy may have a role in the management of certain patient subgroups, and the debate should remain open. Further large-scale randomised trials are needed, and information regarding bladder function and quality of life after treatment is lacking at present. The importance of close follow-up and prompt salvage cystectomy is emphasised.

Antineoplastic Agents↗
PubMed2005

Oxidative stress and cyclooxygenase activity in prostate carcinogenesis: targets for chemopreventive strategies.

Over the last decade, epidemiological, experimental and clinical studies have implicated oxidative stress in the development and progression of prostate cancer. Oxidative stress may be linked to the effects of androgens, anti-oxidant systems and the pre-malignant condition, high-grade prostatic intraepithelial neoplasia. Cyclooxygenase-2 activity has been linked with prostate carcinogenesis. Evidence suggests that oxidative stress and cyclo-oxygenase-2 activity may be mechanistically linked. Agents such as anti-oxidants and cyclo-oxgenase-2 inhibitors may be of value in the chemoprevention of prostate cancer. The feasibility of intervention with such agents will depend on the development and validation of biomarkers for clinical trials, particularly markers of oxidative damage caused by reactive oxygen species (ROS). A greater understanding of the molecular events associated with oxidative stress will enhance the development of such biomarkers and should result in better strategies for the chemoprevention of prostate cancer.

Aged↗
PubMed2005

erbB receptor expression patterns in human bladder cancer.

OBJECTIVES: To investigate expression patterns of erbB receptors in a panel of 58 human bladder tumors. Aberrant functional and structural interactions of erbB type I receptor tyrosine kinase cell surface receptors are important in the development and maintenance of the malignant phenotype. Few studies have focused on the remaining family members or patterns of receptor coexpression in urothelial cancer. METHODS: Frozen tumor samples from 58 patients with newly diagnosed bladder cancer were collected; 18 had Stage Ta, 20 Stage T1, and 20 had Stage T2 or worse. The grade was G1 in 5, G2 in 24, and G3 in 29 patients. Seven normal urothelial samples were obtained from patients with benign urologic conditions. The tumor material was probed using conventional immunoblotting and enhanced chemiluminescence. The blots were captured with digital imaging, and protein expression was quantified with gel analysis software. RESULTS: Most tumors exhibited detectable expression of at least one erbB receptor. Examples of coexpression of epidermal growth factor receptor (EGFr) and erbB-2 were also found. Detectable erbB-3 or erbB-4 protein expression was lacking in this series. Compared with other tumors, the T1 samples exhibited the greatest mean levels of erbB-2 protein expression (P = 0.0028). Of the 58 tumors, 10 (17.2%) coexpressed EGFr and erbB-2; this was associated with T1 disease (P = 0.03). CONCLUSIONS: Varied levels of expression of both EGFr and erbB-2 appear to exist in human bladder cancer. These preliminary data do not support erbB-3/4 as major protagonists in this tumor system. The observations presented suggest a role for EGFr and erbB-2 in the development and progression of bladder cancer that should be explored further.

ErbB Receptors↗
PubMed2004

The management of lymph node metastasis from bladder cancer.

AIM: The presence of pelvic lymph node metastasis from bladder cancer has traditionally been associated with a very poor prognosis. The aim of this paper is to review the literature with regard to the management of patients with nodal disease, particularly gross nodal metastasis and suggest a strategy for management of these patients. METHODS: We performed a literature search in the PubMed database and the reference lists of relevant papers describing the management of locally advanced bladder cancer. FINDINGS: There are no randomised studies relating specifically to the management of nodal metastasis in bladder cancer. It is clear however that a significant number of patients with micrometastatic nodal disease may be cured. Few studies exist which address the management of patients with gross nodal disease and consist of series from a limited number of institutions. In patients with gross nodal disease detected pre-operatively or at the time of surgery, a multimodality approach consisting of surgery, chemotherapy and possibly radiotherapy seems appropriate. The prognosis of such patients relates to the pathological stage of the primary tumour and the degree of lymph node involvement. In addition a good response to neoadjuvant chemotherapy may identify patients who are likely to survive longer. CONCLUSIONS: The prognosis for patients with gross nodal disease from bladder cancer is poor although cure may be possible in a small number of patients. In such cases a multimodality approach is appropriate and management decisions should be made on an individual patient basis.

Combined Modality Therapy↗
PubMed2004

Gefitinib ('Iressa', ZD1839) inhibits the growth response of bladder tumour cell lines to epidermal growth factor and induces TIMP2.

The effect of EGF stimulation and its inhibition with gefitinib ('Iressa', ZD1839), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has been investigated in two EGFR-positive human bladder tumour cell lines, RT112 and RT4. The growth of RT112 cells in a medium containing 10% foetal bovine serum was inhibited by 50% with 10 microM gefitinib, whereas this dose completely inhibited RT4 cell growth. Cells were more sensitive to growth inhibition in the serum-free medium. Increased growth of cells in the serum-free medium was observed with 10 or 50 ng x ml(-1) EGF and the proliferative effect of EGF stimulation in both cell lines was inhibited in the presence of 1 microM, but not 0.1 microM gefitinib. Zymography of the conditioned medium from RT112 cells treated with EGF and gefitinib showed a decrease in matrix metalloproteinase 2 (MMP2) concentrations. Western blot analysis showed that tissue inhibitor of metalloproteinase 1(TIMP1) increased in the conditioned medium from RT112 cells treated with EGF, and this was partially inhibited with both 1 and 5 microM gefitinib. Conversely, TIMP2 decreased with EGF stimulation and this was reversed with gefitinib. Tissue inhibitor of metalloproteinase 1 had no effect on the growth of either cell line. These studies show alterations in the balance of MMPs and their inhibitors in EGF-stimulated bladder tumour cells, which are reversed by gefitinib, suggesting gefitinib should be investigated for its effect on human bladder tumours.

Antineoplastic Agents↗
PubMed2004

Evolving immunotherapeutic strategies in bladder and renal cancer.

For patients with urological cancers, immunotherapy is currently a treatment option for metastatic renal cell carcinoma, and those with "high risk" superficial bladder cancers. In this review, our current understanding of tumour immune escape is discussed. The principles and role of current immunotherapies for these tumours are described, and new areas of immunotherapeutic promise are highlighted.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Measurements using the alkaline comet assay predict bladder cancer cell radiosensitivity.

In the UK, the two main treatments of invasive bladder cancer are radiotherapy or cystectomy. However, approximately 50% of patients undergoing radiotherapy fail to respond. If tumour radiosensitivity could be predicted in advance, it may be possible to improve control rates significantly by selecting for radiotherapy those patients whose tumours are radiosensitive. Additionally, patients who would benefit from surgery would be identified earlier. The alkaline comet assay (ACA) is a sensitive method for the detection of DNA strand break damage in cells. In the present study, using six bladder cancer cell lines of differing radiosensitivities, cell survival was compared to the manifestation of radiogenic DNA damage as assessed by ACA. For all the cell lines, the extent of comet formation strongly correlates with cell killing (R2>0.96), with a greater response being noted in radiosensitive cells. In repair studies, measures of residual damage correlate with survival fraction at 2 Gy (R2>0.96), but for only five of the cell lines. Finally, cells from human bladder tumour biopsies reveal a wide range of predicted radiosensitivies as determined by ACA. Overall, these studies demonstrate ACA to be a good predictive measure of bladder cancer cell radiosensitivity at low dose, with potential clinical application.

Carcinoma, Transitional Cell↗
PubMed2003

Matrix metalloproteinases (MMPs) in bladder cancer: the induction of MMP9 by epidermal growth factor and its detection in urine.

OBJECTIVES: To investigate the matrix metalloproteinases (MMPs) 2 and 9 in bladder cancer cell lines stimulated with epidermal growth factor (EGF), and to investigate the presence of gelatinases in the urine of patients with bladder tumours, in relation to the stage and grade of tumour and the EGF receptor (EGFR) status. PATIENTS, SUBJECTS AND METHODS: Conditioned media from cultured tumour cells were analysed by zymography. Urine samples from 28 patients with transitional cell carcinoma and 12 normal volunteers were also analysed. Western blotting was used to verify the bands of gelatinolytic activity. The EGFR status of the tumours was assessed by immunohistochemistry. RESULTS: MMP9 was induced by EGF in the RT112 but not the RT4 bladder tumour cell line, whereas MMP2 production was unaffected by EGF. Gelatin zymography of urine samples from patients with bladder tumours showed high levels of MMP activity, with 78% positive for MMP9 and 28% positive for MMP2. The total gelatinolytic and MMP9 activity were significantly higher in patients with high-stage invasive tumours than in those with superficial tumours (P < 0.05), and were higher than in normal controls. Gelatinolytic activity at 130 and 200 kDa in urine was identified as MMP9 and MMP2. There was no significant relationship of urinary MMP9 activity to EGFR status of the tumour. CONCLUSION: EGF induces MMP9 but not MMP2 in bladder cells. Analysis of urinary gelatinases is a useful noninvasive technique and both total gelatinase and MMP9 activity are associated with high stages of bladder tumours.

Blotting, Western↗
PubMed2003

Chemoprevention of prostate cancer by diet-derived antioxidant agents and hormonal manipulation (Review).

Cancer of the prostate is the most commonly diagnosed solid malignancy and the second leading cause of cancer-related death in men living in developed countries. With an ageing population, the number of men living with early stages of prostate cancer is expected to increase. There is an increasing need to prevent the onset of cancer or delay the progression of carcinogenesis in this organ. Chemoprevention is the administration of pharmacological agents to prevent, delay or reverse carcinogenesis. An example is the reversal of high grade intraepithelial neoplasia by hormonal manipulation using anti-oestrogens in breast carcinogenesis or anti-androgens in prostate carcinogenesis. Epidemiological data showing ethnic and geographic variations in the incidence of, and mortality from, prostate cancer have suggested that the consumption of certain dietary factors, particularly anti-oxidants, may be protective. These factors include the vitamins D and E, soy, lycopene and selenium. The administration of 5-alpha reductase inhibitors to patients with benign prostatic hyperplasia may also constitute a potentially chemopreventive intervention. The efficacy of chemopreventive agents needs to be investigated in randomised, placebo-controlled trials in suitable cohorts of high-risk individuals. In parallel, reliable assays of potential biomarkers of the efficacy of intervention need to be developed and validated rigorously.

5-alpha Reductase Inhibitors↗
PubMed2002

Epidermal growth factor receptor and bladder cancer.

Muscle-invasive bladder cancer is a disease which causes significant morbidity and mortality. The two main forms of treatment for this disease include radical cystectomy and radical radiotherapy, but five year survival after treatment remains low at 40%. Many clinical and molecular risk factors have been shown to be associated with poor prognosis. One such factor is the expression of epidermal growth factor receptor (EGFR), which is overexpressed by many epithelial tumours, including bladder cancers. There are several methods of inhibiting the activity of EGFR and it may be that use of an anti-EGFR therapy, in combination with more conventional treatment, provides a method of improving the prognosis for muscle-invasive bladder cancer.

ErbB Receptors↗
PubMed2002

Improving the utility of prostate specific antigen (PSA) in the diagnosis of prostate cancer: the use of PSA derivatives and novel markers.

Prostate specific antigen (PSA) testing is now a routine part of the investigation of men with suspected prostate cancer. While a very useful test it still has its problems, in particular its lack of specificity means abnormal results are often caused by benign disease. This review describes the current problems with PSA testing in prostate cancer diagnosis and highlights potential ways in which these may be reduced.

Adult↗
PubMed2002

No effect of soybean lipoxygenase on aflatoxin production in Aspergillus flavus-inoculated seeds.

Soybean lines lacking lipoxygenase (LOX) activity were compared with soybean lines having LOX activity for the ability to support growth and aflatoxin B1 production by the fungal seed pathogen Aspergillus flavus. Whole seeds, broken seeds, and heat-treated (autoclaved) whole seeds were compared. Broken seeds, irrespective of LOX presence, supported excellent fungal growth and the highest aflatoxin levels. Autoclaved whole seeds, with or without LOX, produced good fungal growth and aflatoxin levels approaching those of broken seeds. Whole soybean seeds supported sparse fungal growth and relatively low aflatoxin levels. There was no significant difference in aflatoxin production between whole soybean seeds either with or without LOX, although there did seem to be differences among the cultivars tested. The heat treatment eliminated LOX activity (in LOX+ lines), yet aflatoxin levels did not change substantially from the broken seed treatment. Broken soybean seeds possessed LOX activity (in LOX+ lines) and yet yielded the highest aflatoxin levels. The presence of active LOX did not seem to play the determinant role in the susceptibility of soybean seeds to fungal pathogens. Seed coat integrity and seed viability seem to be more important characteristics in soybean seed resistance to aflatoxin contamination. Soybean seeds lacking LOX seem safe from the threat of increased seed pathogen susceptibility.

Aflatoxins↗