Biomedical subjects

M W R Reed

Publications and source records attributed to M W R Reed.

13 recordsLinked to original sources

PubMed2006

The effect of photodynamic therapy (PDT) on oesophageal motility and acid clearance in patients with Barrett's oesophagus.

BACKGROUND: Barrett's oesophagus is the major risk factor for oesophageal adenocarcinoma. It is proposed that long-term re-epithelialisation, which has been achieved following ablation using 5-aminolaevulinic acid (5-ALA) photodynamic therapy (PDT) may reduce the risk of malignant change. However, it is not known whether PDT modifies oesophageal motility. AIM: To assess oesophageal pH and motility before and after PDT ablation in treated and untreated areas of the oesophagus. METHODS: Twelve patients (10 male) with Barrett's oesophagus, median segment length 4 cm, were treated with PDT ablation. Twenty-four hours pH assessment and oesophageal manometry were performed before and 4-6 weeks after ablation. PDT was carried out using 635 nm red light, 4-6h after administration of 30 mg/kg 5-ALA. Proximal (untreated) and distal (treated) oesophageal resting pressure, wave amplitude, percentage peristalsis and percentage study time oesophageal pH<4, were assessed. Proton pump inhibitors (PPI) were administered throughout the study. RESULTS: There were no significant differences in oesophageal motility in treated or untreated areas of the oesophagus after PDT compared to pre-treatment values. Patients who continued to experience oesophageal acid exposure required more treatments to achieve complete Barrett's ablation. CONCLUSIONS: Oesophageal motility following ALA-PDT suggests a trend toward enhanced wave propagation however continued oesophageal acid exposure may affect PDT efficacy.

Aged↗

PubMed2006

Expression of receptor activator of nuclear factor kappabeta ligand (RANKL) and tumour necrosis factor related, apoptosis inducing ligand (TRAIL) in breast cancer, and their relations with osteoprotegerin, oestrogen receptor, and clinicopathological variables.

BACKGROUND: Receptor activator of nuclear factor kappabeta ligand (RANKL) has an important role in bone remodelling, and tumour necrosis factor related, apoptosis inducing ligand (TRAIL) can induce apoptosis in cancer cells. Their functions are linked by their interactions with osteoprotegerin (OPG). OBJECTIVE: To investigate the expression of RANKL and TRAIL in a large series of unselected breast cancers and to analyse the relations between these expressions and the expression of OPG, oestrogen receptor, and clinicopathological variables. METHODS: 395 breast cancers were sampled into tissue microarrays and immunohistochemistry undertaken for RANKL and TRAIL. RESULTS: There was strong expression of RANKL in 14% of the cancers and strong expression of TRAIL in 30%. Expression of RANKL had a negative association with expression of oestrogen receptor (p = 0.036). Expression of TRAIL had a negative association with the Nottingham Prognostic Index (p = 0.021). There was a significant negative relation between expression of RANKL and TRAIL (p<0.005). Unsupervised cluster analysis produced a dendrogram that showed a clear division into two groups, and the expression of oestrogen receptor was significantly higher in one of those groups (p = 0.012). CONCLUSIONS: There is apparent loss of expression of RANKL in 86% of breast cancers; those tumours that retain expression tend to be oestrogen receptor negative and of a high histological grade. There is strong expression of TRAIL in 30% of breast cancers and these tend to be of better prognostic type. These results may be important in the processes of metastasis to bone and the apoptotic cell death pathway in cancer.

Apoptosis Regulatory Proteins↗

PubMed2006

Macrophages promote angiogenesis in human breast tumour spheroids in vivo.

An in vivo model has been established to study the role of macrophages in the initiation of angiogenesis by human breast tumour spheroids in vivo. The extent of the angiogenic response induced by T47D spheroids implanted into the dorsal skinfold chamber in nude mice was measured in vivo and compared to that induced by spheroids infiltrated with human macrophages prior to implantation. Our results indicate that the presence of macrophages in spheroids resulted in at least a three-fold upregulation in the release of vascular endothelial growth factor (VEGF) in vitro when compared with spheroids composed only of tumour cells. The angiogenic response measured around the spheroids, 3 days after in vivo implantation, was significantly greater in the spheroids infiltrated with macrophages. The number of vessels increased (macrophages vs no macrophages 34+/-1.9 vs 26+/-2.5, P<0.01), were shorter in length (macrophages vs no macrophages 116+/-4.92 vs 136+/-6.52, P<0.008) with an increased number of junctions (macrophages vs no macrophages 14+/-0.93 vs 11+/-1.25, P<0.025) all parameters indicative of new vessel formation. This is the first study to demonstrate a role for macrophages in the initiation of tumour angiogenesis in vivo.

Animals↗

PubMed2005

Microvessel density does not predict outcome in high grade soft tissue sarcoma.

UNLABELLED: The induction of new blood vessel growth into tumours from a pre-existing vascular bed (angiogenesis) is a characteristic of virtually all malignant tumours studied. Previous studies have demonstrated a consistent correlation between the extent of angiogenesis and disease prognosis for a wide range of carcinomas, but not for sarcomas. AIMS: To investigate the most appropriate method for assessment of microvessel density (MVD) using a cohort of patients with large (>5 cm), deep (intramuscular), high grade soft tissue sarcoma and investigate any relationship between MVD, vascular endothelial growth factor (VEGF) expression and prognosis. METHODS: Forty-two patients were included in the study. MVD was evaluated in peripheral, central, necrotic and hotspot areas within the tumour by either Chalkley count or total count of immunostained vessels in five high power (x 200) visual fields. RESULTS: Hot spots of angiogenesis were only present in 33% of specimens. There was a strong correlation p<0.001 between the two methods of quantification with Chalkey method being recommended. VEGF expression evaluated by immunohistochemistry was seen in all but one tumour with strong diffuse cytoplasmic staining within tumour cells, which was not correlated with microvessel density, metastasis or survival. There was a positive correlation between MVD and histological subtype (p<0.01), and primary tumour size and the development of metastasis (p=0.049) but MVD was not predictive of metastasis or overall survival. CONCLUSIONS: Unlike the majority of previous studies involving various types of carcinoma, there was no correlation between microvessel density and metastasis or survival in a group of patients with large (>5 cm), deep, high grade soft tissue sarcoma.

Aged↗

PubMed2005

Case-mix fails to explain variation in mastectomy rates: management of screen-detected breast cancer in a UK region 1997-2003.

Wide variation in the surgical management of breast cancer exists at hospital, regional, national and international level. To demonstrate whether variation in surgical practice observed at aggregate level between breast units persists following adjustment for case-mix, individual patient-level data from the Trent Breast Screening Programme Quality Assurance database (1997-2003) was analysed. Expected case-mix adjusted mastectomy rates were derived by logistic regression using the variables tumour size, site and grade, patient age and year of presentation, employing the region's overall case-mix adjusted practice as the reference population. The region's 11 breast screening units detected 5109 (3989 invasive) surgically managed primary breast cancers over the 6-year period. A total of 1828 mastectomies (Mx) were performed (Mx rate 35.8%, 95% confidence interval: 34.5-37.1%). Significant variation in mastectomy rates were observed between units (range 25-45%, P<0.0001), and persists following case-mix adjustment (P<0.0001). Two-fold variation in observed to expected unit mastectomy rate coefficient is demonstrated overall (range 0.66-1.36), increasing to almost four-fold variation in cancers less than 15 mm diameter (range 0.55-1.95). Significant variation in surgery for screen-detected primary breast cancer is not explained by case-mix. Further research is required to investigate potential patient and professional causative factors.

Aged↗

PubMed2004

Stage and treatment variation with age in postmenopausal women with breast cancer: compliance with guidelines.

Breast cancer-specific mortality is static in older women despite having fallen in younger age groups, possibly due to lack of screening and differences in treatment. This study compared stage and treatment between two cohorts of postmenopausal women (55-69 vs >70 years) in a single cancer network over 6 months. A total of 378 patients were studied (>70: N=167, 55-69 years: N=210). Older women presented with more advanced disease (>70: metastatic/locally advanced 12%, 55-69 years: 3%, P<0.01). Those with operable cancer had a worse prognosis (Nottingham Prognostic Index (NPI) >70: median NPI 4.4, 55-69 years: 4.25, P<0.03). These stage differences were partially explained by higher screening rates in the younger cohort. Primary endocrine therapy was used in 42% of older patients compared with 3% in the younger group (P<0.001). Older women with cancers suitable for breast conservation were more likely to choose mastectomy (>70: 57.5% mastectomy rate vs 55-69 years: 20.6%, P<0.01). Nodal surgery was less frequent in older patients (>70: 6.7% no nodal surgery, 55-69 years: 0.5%, P<0.01) and was more likely to be inadequate (>70: 10.7% <4 nodes excised, 55-69 years: 3.4%, P<0.02). In summary, older women presented with more advanced breast cancer, than younger postmenopausal women and were treated less comprehensively.

Age Factors↗

PubMed2004

Comparison of high- vs low-dose 5-aminolevulinic acid for photodynamic therapy of Barrett's esophagus.

BACKGROUND: Barrett's esophagus is the major risk factor for esophageal adenocarcinoma, the incidence of which is increasing rapidly in the Western world. Aminolevulinic acid for photodynamic therapy (ALA-PDT) is effective in the treatment of Barrett's esophagus, but controversy exists regarding optimum ALA dosage. The aim of this study was to establish the optimum dosage regime for ALA-PDT for Barrett's esophagus. METHODS: Twenty-five patients with Barrett's esophagus were randomized to receive 30 (low-dose) or 60 (high-dose) mg/kg oral ALA at 4 or 6 h or 30 mg/kg in two fractions 4 and 6 h before PDT. PDT was standardized using red (635 nm) light. Biopsy specimens were taken for protoporphyrin IX (PpIX) quantification. Endoscopy was repeated 4 weeks later. RESULTS: All patients showed a macroscopic response, with squamous re-epithelialization. This response was greatest in the 30 mg/kg and fractionated ALA groups. There was no significant difference in response between dosing 4 or 6 h prior to PDT. Tissue levels of PpIX were similar for all dosage groups and were not predictive of clinical response. Side effects were more common with the higher dose of ALA. CONCLUSION: Low-dose ALA-PDT appears to be a safe protocol for the ablation of Barrett's esophagus.

Administration, Oral↗

PubMed2004

Endoscopic ablation of Barrett's oesophagus: a randomized-controlled trial of photodynamic therapy vs. argon plasma coagulation.

BACKGROUND: Barrett's oesophagus is the major risk factor for oesophageal adenocarcinoma. 5-Aminlevulinic acid-induced photodynamic therapy and argon plasma coagulation have been shown to be effective for ablating Barrett's oesophagus, but a comparative trial of these two modalities has not been reported. AIMS: To compare photodynamic therapy and argon plasma coagulation for the ablation of Barrett's oesophagus. METHODS: A total of 68 patients (54 male, 14 female; median age 61) with Barrett's oesophagus were randomized to photodynamic therapy (n = 34) or argon plasma coagulation (n = 34). Photodynamic therapy was performed using 5-aminlevulinic acid (30 mg/kg) and red light. Argon plasma coagulation was administered at a power setting of 65 W. Multiple treatment sessions were performed, with follow-up to 24 months. RESULTS: All patients showed a macroscopic reduction in the area of Barrett's oesophagus. This was greatest in the argon plasma coagulation group with 33 of 34 (97%) ablated, compared with 17 of 34 (50%) in the photodynamic therapy group; in the remainder, there was a reduction in the length of Barrett's oesophagus (median 50%, range: 5-90). Buried glands were found in 24% of photodynamic therapy patients, and in 21% of argon plasma coagulation patients. The median follow-up is 12 months (range: 6-24). CONCLUSIONS: Photodynamic therapy and argon plasma coagulation are both effective for ablating Barrett's oesophagus. Argon plasma coagulation appears more effective than photodynamic therapy, but the impact of both on carcinoma development requires larger studies with long-term follow-up.

Adult↗

PubMed2003

The need for targeted research into breast cancer in the elderly.

BACKGROUND: Breast cancer is a major source of morbidity and mortality in elderly women. Despite this, many trials on which clinical practice is based have under-represented the elderly. Consequently there is little evidence to guide best practice in this age group. METHODS: A search of the major literature databases was performed using the search terms 'breast cancer' and 'elderly'. Articles relevant to the treatment of breast cancer in the elderly were selected. RESULTS: The elderly receive less aggressive treatment for breast cancer compared with younger patients. Primary endocrine therapy is sometimes substituted for operation, and axillary surgery, adjuvant chemotherapy and adjuvant radiotherapy are commonly omitted. Evidence for and against such treatment strategies is inadequate, making it difficult to determine what constitutes best practice. CONCLUSION: There is a need for research to be targeted at the older age group of patients with breast cancer to enable the development of specific treatment guidelines.

Aged↗

PubMed2003

Eradication of dysplastic Barrett's oesophagus using photodynamic therapy: long-term follow-up.

BACKGROUND AND STUDY AIMS: Barrett's oesophagus is a major risk factor for oesophageal adenocarcinoma, a condition which is rapidly increasing in incidence. Photodynamic therapy (PDT) is a developing treatment in which tissue damage is caused by the action of light on a previously administered photosensitizing agent. We present the results of long-term follow-up of its efficacy in patients with dysplastic Barrett's oesophagus. PATIENTS AND METHODS: A total of 40 patients with low-grade dysplasia in Barrett's oesophagus were treated with oral 5-aminolaevulinic acid (ALA) at a dose of 30 mg/kg, followed by laser endoscopy 4 hours later. Patients were treated between December 1995 and December 1998, and all were followed up regularly with endoscopy and biopsies in our surveillance programme. RESULTS: Among the patients, 35 (88%) showed a macroscopic reduction in the area of the columnar epithelium, and in all 40 patients dysplasia was found to be eradicated at 1 month. The effect has been maintained for a median follow-up of 53 months (range 18-68 months), although one patient developed a late carcinoma in an untreated area of Barrett's oesophagus 3 years after the intervention. CONCLUSIONS: Safe and effective ablation of low-grade dysplastic Barrett's oesophagus can be achieved with the use of ALA-induced PDT, and the effects are maintained in the long term.

Adult↗

PubMed2002

Role of genetic polymorphisms in tumour angiogenesis.

Angiogenesis plays a crucial role in the development, growth and spread of solid tumours. Pro- and anti-angiogenic factors are abnormally expressed in tumours, influencing tumour angiogenesis, growth and progression. Polymorphisms in genes encoding angiogenic factors or their receptors may alter protein expression and/or activity. This article reviews the literature to determine the possible role of angiogenesis-related polymorphisms in cancer. Further research studies in this potentially crucial area of tumour biology are proposed.

Animals↗

PubMed2002

Aminolaevulinic acid-induced photodynamic therapy: cellular responses to glucose starvation.

Photodynamic therapy is a cancer treatment based on the interaction of light, oxygen and a photosensitiser. Protoporphyrin. IX is an endogenous photosensitiser derived from the pro-drug aminolaevulinic acid. Tumours contain areas of hypoxia and hypoglycaemia. Tumour cells adapt to these conditions by stress protein induction which may induce resistance to cancer therapies. The effect of chronic hypoglycaemia on sensitivity to aminolaevulinic acid-induced photodynamic therapy in vitro was studied in MCF-7, human breast cancer cells. Following chronic exposure to 0, 1 or 25 mM, glucose, cells were treated with aminolaevulinic acid and the generation of intracellular protoporphyrin. IX measured by spectrofluorimetry. Aminolaevulinic acid-induced photodynamic therapy sensitivity was compared between cells following chronic exposure to 0, 1 or 25 mM glucose. Percentage cell survival was determined by clonogenic assay. Cells cultured in low glucose generated higher levels of protoporphyrin IX compared to standard glucose medium (0 mM glucose: 0.88 x 10(-5) ng cell(-1), 1 mM: 0.86 x 10(-5) ng cell(-1), 25 mM: 0.60 5x 10(-5) ng cell(-1), P<0.05). However, photodynamic therapy sensitivity was reduced in glucose deprived cells (0 mM glucose: 61% survival, 1 mM: 80.5% and 25 mM: 39.6%, P<0.05). Chronic exposure to low glucose induces photodynamic therapy resistance despite increased intracellular concentrations of protoporphyrin IX and may reflect cellular adaptation to chronic glucose deprivation.

Aminolevulinic Acid↗

PubMed2002

Expression of proteinases and inhibitors in human breast cancer progression and survival.

AIMS: The expression of proteinases and their inhibitors determines the extracellular matrix (ECM) turnover in normal and pathological processes. In cancer, proteolysis is abnormally regulated, favouring ECM degradation, which aids tumour invasion and metastasis. Previous studies have determined the expression of proteinases and inhibitors in breast cancer using a variety of techniques, including immunohistochemistry; however, most have looked at the expression of individual proteinases and/or inhibitors. Therefore, the aim of the current study was to determine the simultaneous cellular expression of matrix metalloproteinases (MMPs), plasminogen activators (PAs), and tissue inhibitors of metalloproteinases (TIMPs) in patients with breast cancer and correlate this with clinical pathological staging and survival. METHODS: Immunohistochemistry was used to determine the expression of proteinases (MMP-1, MMP-2, MMP-3, MMP-9, urokinase-type PA, and tissue-type PA) and inhibitors (TIMP-1 and TIMP-2) in 44 patients with breast cancer. RESULTS: The expression of all the factors studied was stronger or equivalent in tumour cells than in fibroblasts or inflammatory cells within the tumour section. Both positive and negative trends have emerged in the correlation between the cellular expression of proteinases and inhibitors and breast tumour pathology (tumour grade, lymphovascular invasion, and Nottingham prognostic index). CONCLUSIONS: The interactions between proteinases and their inhibitors in breast cancer progression are complex. Although there are differences in the expression of these factors that relate to differences in breast cancer pathology, there are no outstanding individual factors that consistently correlate with prognosis. Therefore, different factors are probably important at different stages of the process, and the balance in the relative concentrations of proteinases and inhibitors probably determines ECM degradation in breast tumour invasion and metastasis in vivo.

Adult↗