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A J Evans

Publications and source records attributed to A J Evans.

At least 19 recordsLinked to original sources
PubMed2001

Association of codon 72 polymorphism of p53 with lower prostate cancer risk.

BACKGROUND: A common germline polymorphism of p53 produces a protein with an Arg to Pro change at codon 72. This Pro variant has altered biochemical properties suggesting altered cancer susceptibility. METHODS: A case control study with 115 men with prostate cancer and 181 community control male subjects was conducted. Demographics, family history of cancer, and blood were obtained. Codon 72 genotypes were determined using PCR. RESULTS: The Pro/Pro genotype was associated with a markedly lower risk of prostate cancer (OR = 0.23, CI = 0.07-0.79, P = 0.012). Similar reduction in risk was observed when the analysis was limited to Caucasian subjects (86% of total). Reduction in risk remained significant in a logistic regression model after correcting for age and family history of prostate cancer (OR = 0.14, CI = 0.03-0.71, P = 0.017). CONCLUSIONS: Men with the p53 codon 72 Pro/Pro genotype appear to be at reduced risk of prostate cancer.

Adenocarcinoma↗
PubMed2001

Adenovirus-mediated heme oxygenase-1 gene delivery inhibits injury-induced vascular neointima formation.

BACKGROUND: Recent studies have demonstrated that systemic pharmacological induction of heme oxygenase-1 (HO-1), the inducible isoform of the initial and rate-limiting enzyme for heme catabolism, attenuates neointima formation after experimental vascular injury. We have now investigated the ability of localized adenovirus-mediated HO-1 (Ad-HO-1) gene delivery to modify arterial remodeling after balloon angioplasty. METHODS AND RESULTS: Two weeks after balloon angioplasty in the rat carotid artery, elevated HO-1 protein was observed in the Ad-HO-1 arteries compared with those exposed to empty adenovirus (Ad-E) or to PBS. The arteries exposed to Ad-HO-1 exhibited significantly reduced neointimal area, medial wall area, neointimal area/medial wall area ratio, and neointimal thickness compared with arteries exposed to Ad-E. The Ad-E vessels showed subtle reductions in each morphometric parameter compared with PBS vessels. In a separate group of animals, concomitant treatment of Ad-HO-1 with the HO-1 inhibitor tin protoporphyrin completely restored each morphometric parameter to control levels. Arteries exposed to Ad-HO-1 demonstrated significantly increased TUNEL labeling of apoptotic nuclei and significantly decreased PCNA labeling of DNA synthesis in the medial wall 48 hours after injury. CONCLUSIONS: These results indicate that HO-1 represents an important in vivo vasoprotective mediator that is capable of attenuating the pathophysiological remodeling response to endovascular injury and suggest that HO-1 may be a novel target for the treatment of vascular disease.

Adenoviridae↗
PubMed2001

Growth pattern of ductal carcinoma in situ (DCIS): a retrospective analysis based on mammographic findings.

The aim of this study was to obtain information concerning the direction and rates of growth of ductal carcinoma in situ (DCIS). The previous mammograms of 124 women diagnosed with DCIS were examined. If in retrospect calcifications were present on the previous examination, the exact size and position were recorded on both diagnostic and previous imaging. The rates of change and direction of change in extent of calcifications were calculated. 39 women with a diagnosis of DCIS in retrospect had calcifications visible on both their current and prior examinations; these formed the study group. For individual clusters of calcification, change occurred along an axis to the nipple at a mean of 5.5 mm y(-1)and along an axis at 90 degrees to the nipple at 2.6 mm y(-1). Increase in calcifications along the axis to the nipple occurred at 2.6 mm y(-1)toward and 2.8 mm y(-1)away from the nipple. Increase in the axis to the nipple occurred at 1.8 mm y(-1)for low grade, 4.2 mm y(-1)for intermediate grade and 7.1 mm y(-1)for high grade. DCIS growth along an axis to the nipple occurs at over twice the rate of growth in the other direction(s) and growth toward and away from the nipple occurred equally. Growth rates increased with increasing nuclear grade of DCIS. These results validate nuclear grading of DCIS. Additionally, the results suggest that increased importance should be placed on identifying the 'nipple' and 'anti-nipple' margins of DCIS represented by calcifications for both surgical excision and pathological scrutiny.

Breast Neoplasms↗
PubMed2001

Matrix-dependent mechanism of neutrophil-mediated release and activation of matrix metalloproteinase 9 in myocardial ischemia/reperfusion.

BACKGROUND: A key component of reperfusion of myocardial infarction is an immediate inflammatory response, which enhances tissue repair. Matrix turnover is crucial to tissue repair, and matrix metalloproteinases (MMPs) are key enzymes involved in matrix degradation. The hypothesis tested is that one inflammation-based effector of tissue repair is the secretion and activation of MMP-9 by infiltrating neutrophils. METHODS AND RESULTS: Cardiac lymph and tissue were assayed for atent and active MMP-2 and MMP-9 by zymography and immunochemistry. Dual-labeling immunofluorescence determined the cellular source of MMP-9 protein. Isolated canine neutrophils were incubated with preischemic and postischemic cardiac lymph in the presence and absence of collagen-fibronectin pads, and the supernatants were assayed for latent and active MMP-9. MMP-9 increased during the first hours of reperfusion in both lymph supernatants and myocardial extracts, and this increase was of neutrophil origin. MMP-9 in the cardiac lymph remained latent but was activatable. In contrast, MMP-9 in the myocardium was in both latent and active forms. In situ zymography demonstrated that activated MMP-9 surrounded the infiltrated neutrophils. When postischemic cardiac lymph was incubated with neutrophils in vitro, MMP-9 secretion and activation occurred only in the presence of a collagen-fibronectin substrate; preischemic cardiac lymph did not induce significant secretion or activation. CONCLUSIONS: Infiltrating neutrophils are an early source of MMP-9 after reperfusion, and a portion of MMP-9 in the myocardium is active. Infiltrating neutrophils may localize MMP-9 activation by secreting MMP-9 and as a source of activating proteases.

Animals↗
PubMed2001

Reactive oxygen intermediates induce monocyte chemotactic protein-1 in vascular endothelium after brief ischemia.

Chemokine expression is associated with reperfusion of infarcted myocardium in the setting of tissue necrosis, intense inflammation, and inflammatory cytokine release. The specific synthesis of monocyte chemotactic protein (MCP)-1 mRNA by cardiac venules in reperfused infarcts corresponded to the region where leukocytes normally localize. MCP-1 could be induced by exogenous tumor necrosis factor (TNF)-alpha or by postischemic cardiac lymph containing TNF-alpha. However, the release of TNF-alpha during early reperfusion did not explain the venular localization of MCP-1 induction. To better understand the factors mediating MCP-1 induction, we examined the role of ischemia/reperfusion in a model of brief coronary occlusion in which no necrosis or inflammatory response is seen. Adult mongrel dogs were subjected to 15 minutes of coronary occlusion and 5 hours of reperfusion. Ribonuclease protection assay revealed up-regulation of MCP-1 mRNA only in ischemic segments of reperfused canine myocardium. Pretreatment with the reactive oxygen scavenger N-(2-mercaptopropionyl)-glycine completely inhibited MCP-1 induction. In situ hybridization localized MCP-1 message to small venular endothelium in ischemic areas without myocyte necrosis. Gel shift analysis of nuclear extracts from the ischemic area showed enhanced DNA binding of the transcription factors AP-1 and nuclear factor (NF)-kappaB, crucial for MCP-1 expression, in ischemic myocardial regions. Immunohistochemical staining demonstrated reperfusion-dependent nuclear translocation of c-Jun and NF-kappaB (p65) in small venular endothelium, only in the ischemic regions of the myocardium, that was inhibited by N-(2-mercaptopropionyl)-glycine. In vitro, treatment of cultured canine jugular vein endothelial cells with the reactive oxygen intermediate H2O2 induced a concentration-dependent increase in MCP-1 mRNA levels, which was inhibited by the antioxidant N-acetyl-L-cysteine, a precursor of glutathione, but not pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB and activator of AP-1. In contrast to our studies with infarction, incubation of canine jugular vein endothelial cells with postischemic cardiac lymph did not induce MCP-1 mRNA expression suggesting the absence of cytokine-mediated MCP-1 induction after a sublethal ischemic period. These results suggest that reactive oxygen intermediate generation, after a brief ischemic episode, is capable of inducing MCP-1 expression in venular endothelium through AP-1 and NF-kappaB. Short periods of ischemia/reperfusion, insufficient to produce a myocardial infarction, induce MCP-1 expression, potentially mediating angiogenesis in the ischemic noninfarcted heart.

Acetylcysteine↗
PubMed2001

Heme oxygenase-1 attenuates vascular remodeling following balloon injury in rat carotid arteries.

The heme oxygenase-1 (HO-1) system of heme catabolism has been proposed to exert protective actions upon the cardiovascular system. This investigation examined the influence of HO-1 induction on vascular remodeling following arterial injury. Rats were subjected to left carotid artery (LCA) balloon injury following pre-treatment with either vehicle, the HO-1 inducer hemin (50 mg/kg, SC), or concomitant treatment with hemin and the HO-1 inhibitor tin-protoporphyrin IX (SnPP-IX; 50 micromol/kg, IP). Animals were injected daily for 14 days post-injury, after which animals were sacrificed and tissues obtained. Western blot analyses revealed vascular HO-1 induction after 2 and 16 days of hemin treatment. Positive immunostaining for HO-1 was detected in the endothelial and adventitial layers following 48 h of hemin treatment and positive medial staining for HO-1 after 16 days of hemin treatment. The injured LCA of hemin-treated animals demonstrated significantly attenuated neointimal (NI) area (-57%), NI thickness (-58%), and NI area/medial wall area ratio (-40%) compared to the injured LCA of vehicle controls. The cross-sectional medial wall areas of both LCA and uninjured RCA were also significantly reduced in the hemin-treated animals. SnPP-IX treatment, however, completely restored the NI area, NI thickness, NI area/medial wall area ratio, and partially restored the medial wall area towards control levels. These results directly implicate HO-1 and the products of heme catabolism in attenuating the arterial response to injury and ensuing vascular wall remodeling.

Animals↗
PubMed2001

Mammographic size of ductal carcinoma in situ does not predict the presence of an invasive focus.

A proportion of women thought to have ductal carcinoma in situ (DCIS) on mammography and a core biopsy showing DCIS only, in fact have an invasive focus on surgical excision. This study aims to identify the percentage of such patients who harbour an invasive focus and to ascertain features which can predict the presence of invasion. 140 patients had a core biopsy diagnosis of DCIS without invasion. All patients had their core biopsy graded and mammography was performed on 128 patients. Mammographic findings were classified by a radiologist blinded to the surgical findings into normal, mass/distortion or microcalcification. The extent of the microcalcifications was measured. The core biopsies were graded into high, intermediate or low grade DCIS groups. The core biopsy and radiological findings were compared to see if they could predict the presence of invasive disease at surgical excision. Of the 140 patients, 61 (44%) had an invasive focus. 8 (47%) of 17 patients with normal mammography had an invasive focus. 4 (36%) of 11 patients with a mammographic mass had evidence of invasion. Of the 100 patients with mammographic microcalcifications 48 (48%) had an invasive focus. In the 10 patients with low grade DCIS on core biopsy, 3 (30%) had an invasive focus. Comparative studies in patients with intermediate and high grade DCIS, were 7 of 18 (39%) and 51 of 112 (46%), respectively. Thus, 44% of women thought to have DCIS only on preoperative investigation had an invasive focus. In contrast to previous expressed opinions, neither mammography or grade were predictive. We have not identified any factor capable of predicting a higher likelihood of an invasive focus.

Adult↗
PubMed2001

The use of blood tumour markers in the monitoring of metastatic breast cancer unassessable for response to systemic therapy.

The role of blood tumour markers is established in the monitoring of response to systemic therapy for patients with metastatic breast cancer assessable by UICC criteria. This paper examines the use of marker measurements (in the form of a previously devised biochemical index score comprising CA15.3, CEA and ESR) in patients with metastatic lesions unassessable for response by UICC criteria. Of 218 patients with metastatic breast cancer treated over a 2-year period in the Nottingham Breast Unit, 43 patients (20%) had unassessable disease and 36 of them with blood marker results available were studied. Eighty-six per cent of patients were biochemically assessable. All patients who achieved biochemical response remained unassessable by UICC criteria. Twenty-two patients progressed initially or subsequently (after an initial biochemical response), either biochemically or by UICC criteria. Biochemical assessment completely paralleled UICC assessment in all eight patients who progressed by both assessments. Biochemical progression occurred ahead of UICC assessment in four of them with a median lead-time of 4.5 months. Biochemical assessment by blood tumour markers is useful in patients with metastatic breast cancer unassessable for response to systemic therapy. These findings need to be confirmed in a larger patient series.

Biomarkers, Tumor↗
PubMed2001

Imaging of metastatic breast cancer: distribution and radiological assessment at presentation.

This prospective study was performed to document the distribution of sites of disease in breast cancer patients with newly diagnosed metastatic disease, and to identify those with assessable or measurable disease by International Union Against Cancer (UICC) criteria. Data were collected on a consecutive series of 100 patients presenting with metastatic breast cancer. Imaging findings recorded included whether patients had assessable or measurable disease and which potentially assessable sites were rendered unassessable by radiotherapy. Radiologically diagnosable complications were recorded. Skeletal metastases comprised the majority, with 67 patients having skeletal involvement, although of these only 33 (49%) had assessable disease and 24 (36%) measurable disease. Sixteen (24%) patients had radiographically occult metastases. Liver ultrasound examination showed metastatic disease in 32 patients, of whom 28 (88%) had measurable lesions and 12% diffuse disease. Chest radiographs demonstrated metastatic disease in 42 patients, with assessable disease in 39 (93%) and measurable disease in 18 (43%). In total, 80 patients had radiologically assessable disease, with five rendered unassessable by the administration of radiotherapy to the only assessable site. Therefore, of the 100 patients, 75% (95% confidence interval (CI) 65-83) had radiologically assessable disease, with 55% (95% 45-65 CI) having measurable lesions by UICC criteria.

Adult↗
PubMed2001

False-negative breast screening assessment: what lessons can we learn?

AIM: To review women who have had breast cancer diagnosed following previous assessment of a screen-detected mammographic abnormality in order to ascertain the frequency and characteristics of false-negative assessment. MATERIALS AND METHODS: The assessment process was reviewed in the study population of 28 women. This included the nature of the lesion recalled for assessment, additional mammography, clinical and ultrasound findings, and the results of fine needle aspiration cytology and needle histology. RESULTS: The frequency of false-negative assessment was approximately 0.56%. The median time between false-negative assessment and diagnosis of breast cancer was 33 months. The most common mammographic lesion resulting in false-negative assessment was micro-calcification seen in 12 cases (43%). Only five of these 12 cases had image-guided biopsy, the remainder were thought to be benign on magnification views. Other mammographic abnormalities were nine masses (32%), five architectural distortions (18%) and two asymmetric densities (7%). Of the 16 women with mammographic lesions other than micro-calcifications 10 had a normal ultrasound. CONCLUSION: Radiological interpretation of indeterminate micro-calcifications as benign or malignant is unreliable. An isolated cluster of micro-calcification requires image-guided core biopsy with representative micro-calcification obtained on specimen radiography. Further mammography done at assessment, particularly paddle compression views, should be carefully analysed to ensure areas of architectural distortion have truly resolved. If one imaging modality shows a significant abnormality and another does not the cases must be managed on the basis of the abnormal finding. Burrell, H.C.et al. (2001). Clinical Radiology56, 385-388.

Adult↗
PubMed2001

Predicting invasion in mammographically detected microcalcification.

AIM: To identify pre-operative factors which predict presence of invasive disease within mammographically detected malignant microcalcification. MATERIALS AND METHODS: A retrospective analysis was undertaken of 116 serial stereotactic core needle biopsies (SCNBs) performed on malignant mammographic calcification. Final surgical pathology was correlated with pre-operative features (clinical, radiological and core histology) in an attempt to predict the presence of an invasive component. RESULTS: Thirty-eight clusters contained invasive carcinoma. The sensitivity of SCNB for invasion was 55%. Clinical features, calcium morphology and cluster size were not shown to be predictive of invasive disease. Ductal carcinoma in situ (DCIS) of high grade on core histology and increasing number of calcifications were predictive of increased risk of invasion (high grade core biopsy DCIS and > 40 calcifications 48% invasive at surgical histology; high grade core biopsy DCIS and < 40 calcifications 15% invasive; non-high grade core biopsy DCIS 0% invasive). CONCLUSIONS: Identification of those clusters diagnosed as DCIS by percutaneous biopsy which are likely to harbour an invasive component is possible. It would seem reasonable to consider staging the axilla at therapeutic surgery in these patients.

Adult↗
PubMed2001

Detecting which invasive cancers at mammographic screening saves lives?

OBJECTIVES: Assessment of the features of primary operable breast carcinomas arising in women known to subsequently develop metastatic disease, to show for which invasive breast cancers earlier detection by mammographic screening is potentially beneficial. These data were applied to a separate series of screen detected cancers. METHODS: Features associated with the development of metastatic disease after a previous operable breast cancer were ascertained from examination of histological sections of the initial primary carcinoma and in particular the incidence of nodal positivity and definite vascular invasion. Trends in the frequency of nodal involvement and vascular invasion according to histological grade, invasive size, and tumour type were then examined in a further group of 573 screen detected invasive cancers to predict the likelihood of development of systemic disease in these women. RESULTS: Of 173 women who developed metastatic disease after a previous operable breast cancer, 79 (72%) had nodal metastases and 62 (59%) had definite vascular invasion. A high proportion (84%) had either lymph node metastases or vascular invasion or both. The absence of vascular invasion and nodal involvement in invasive breast cancer indicated a low risk of subsequent development of metastatic disease. In the screen detected group, grade 1 invasive cancers <20 mm in size and grade 2 and 3 cancers <10 mm in size had low rates of nodal involvement and vascular invasion. There was a gradual trend to small size, lymph node negativity, and less vascular invasion when comparing screen detected ductal carcinoma of no special type, tubular mixed carcinoma, and tubular carcinoma. Cancers with a lobular component tended to be larger and more often lymph node positive than ductal and no specific type carcinomas. CONCLUSIONS: These data suggest that identification of grade 1 cancers less than 20 mm in size and grade 2 and 3 cancers less than 10 mm in size at screening is likely to be beneficial, with a lower likelihood of developing metastatic disease from these lesions. The detection of tubular mixed carcinomas and ductal carcinomas of no specific type also appears beneficial. However the detection of tumours with lobular features at breast screening does not seem to significantly benefit the patient.

Breast Neoplasms↗
PubMed2001

Screen detected ductal carcinoma in situ (DCIS): overdiagnosis or an obligate precursor of invasive disease?

OBJECTIVES: Ductal carcinoma in situ (DCIS) represents 20%-25% of malignancy detected at mammographic screening. This study aims to clarify the value of detecting DCIS at mammographic screening by assessing its biological characteristics and by comparing screen detected DCIS with a series of symptomatic DCIS lesions. METHODS: 222 Screen detected and 151 symptomatic cases of pure DCIS were identified. Their histological grade and the prevalence of necrosis were ascertained and compared. RESULTS: Of the screen detected lesions 28 (13%) were low grade, 40 (18%) intermediate grade, and 153 (69%) high grade. Of screen detected lesions 186 (87%) were necrotic and 29 (13%) were not. Of the 151 symptomatic lesions 24 (16%) were low grade, 34 (23%) intermediate grade, and 89 (61%) high grade. Of symptomatic lesions 112 (75%) were necrotic and 36 (24%) were not necrotic. Screen detected DCIS was more often necrotic (p=0.008) than symptomatic DCIS. CONCLUSIONS: As most DCIS detected at screening is high grade and necrotic, aggressive investigation of suspicious microcalcification at mammographic screening is advocated. Given the biological features of screen detected DCIS, the existence of an upper limit for the detection of DCIS by the NHS breast screening programme seems to be inappropriate.

Adult↗
PubMed2001

Brief murine myocardial I/R induces chemokines in a TNF-alpha-independent manner: role of oxygen radicals.

Early chemokine induction in the area at risk of an ischemic-reperfused (I/R) myocardium is first seen in the venular endothelium. Reperfusion is associated with several induction mechanisms including increased extracellular tumor necrosis factor (TNF)-alpha, reactive oxygen intermediate (ROI) species formation, and adhesion of leukocytes to the venular endothelium. To test the hypothesis that chemokine induction in cardiac venules can occur by ROIs in a TNF-alpha-independent manner, and in the absence of leukocyte accumulation, we utilized wild-type (WT) and TNF-alpha double-receptor knockout mice (DKO) in a closed-chest mouse model of myocardial ischemia (15 min) and reperfusion (3 h), in which there is no infarction. We demonstrate that a single brief period of I/R induces significant upregulation of the chemokines macrophage inflammatory protein (MIP) -1 alpha, -1 beta, and -2 at both the mRNA and protein levels. This induction was independent of TNF-alpha, whereas levels of these chemokines were increased in both WT and DKO mice. Chemokine induction was seen predominantly in the endothelium of small veins and was accompanied by nuclear translocation of nuclear factor-kappa B and c-Jun (AP-1) in venular endothelium. Intravenous infusion of the oxygen radical scavenger N-2-mercaptopropionyl glycine (MPG) initiated 15 min before ischemia and maintained throughout reperfusion obviated chemokine induction, but MPG administration after reperfusion had begun had no effect. The results suggest that ROI generation in the reperfused myocardium rapidly induces C-C and C-X-C chemokines in the venular endothelium in the absence of infarction or irreversible cellular injury.

Animals↗
PubMed2000

YC-1, a benzyl indazole derivative, stimulates vascular cGMP and inhibits neointima formation.

The pathobiologic process of arterial stenosis following balloon angioplasty continues to be an enigmatic problem in clinical settings. This research project investigates the ability of YC-1, a benzyl indazole derivative that sensitizes sGC/cGMP, to stimulate endogenous cGMP and attenuate balloon injury-induced neointima (NI) formation in the rat carotid artery. Northern and Western blot analyses revealed enhanced acute expression of iNOS and inducible heme oxygenase (HO-1) mRNA and protein in the injured artery. The contralateral uninjured artery also demonstrated acute HO-1 mRNA and protein induction without detectable iNOS expression. Perivascular application of YC-1 immediately following injury significantly stimulated acute vessel wall cGMP compared to untreated controls. YC-1 treated sections demonstrated significant reduction in NI area (-74%), NI area/medial wall area (-72%), and NI thickness (-76%) 2 weeks post-injury. These results directly implicate YC-1 as a potent new therapeutic agent capable of reducing post-angioplasty stenosis through endogenous CO- and/or NO-mediated, cGMP-dependent processes.

Angioplasty, Balloon↗
PubMed2000

Genetic polymorphisms in head and neck cancer risk.

OBJECTIVE: To assess whether genetic polymorphisms implicated as risk factors for other tobacco-associated malignancies are associated with altered risk of head and neck squamous cell carcinoma. DESIGN: Case-control study. SUBJECTS: One hundred sixty patients with head and neck squamous cell carcinoma recruited from a university-based head and neck oncology clinic and 149 population-based controls. METHODS: Genotyping of the CYP1A1 (Ile462Val), GSTM1 (null), GSTP1 (Ile105Val), GSTT1 (null), and P53 (Arg72Pro) genes was performed by polymerase chain reaction-based techniques on DNA prepared from peripheral blood. In addition, a questionnaire was used to collect demographic information from each subject. RESULTS: Cases were significantly older (p <.0001) and had significantly greater tobacco use (p <.0001) and were more likely to be male (p <.0001) than were control subjects, thus confirming known risk factors for this disease. When cases and controls were compared by simple chi-square analysis, only the frequency of CYP1A1 (Ile462Val) polymorphism was significantly different between cases and controls (OR =.42; 95% CI =.18-.99; p <.04). However, with a logistic regression model to control for known risk factors, we were unable to demonstrate a significant association with head and neck cancer for any of the polymorphisms tested, including CYP1A1. CONCLUSIONS: This population fails to identify a relationship between the above-mentioned polymorphisms and head and neck cancer.

Carcinoma, Squamous Cell↗