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Biomedical subjects

F A Carey

Publications and source records attributed to F A Carey.

At least 19 recordsLinked to original sources
PubMed2006

Relationship between point gene mutation, chromosomal abnormality, and tumour suppressor gene methylation status in colorectal adenomas.

Epigenetic mechanisms in carcinogenesis may have a significant role in the development of colorectal cancer. To investigate this phenomenon in early-stage disease, promoter methylation status in the tumour suppressor genes APC, MGMT, hMLH1, P14/P14ARF, and CDKN2A/P16 was investigated in 78 colorectal adenomas. These had previously been characterized for mutations of APC, KRAS, and TP53 genes and for chromosomal abnormality by comparative genomic hybridization (CGH). APC hypermethylation was seen in 52 tumours (66.7%). APC showed either methylation or mutation in 66 lesions (84.6%), but these events were not statistically associated. MGMT methylation was detected in 39 cases (50%). Adenomas with this abnormality showed a significantly lower number of chromosomal changes by CGH (p < 0.02), confirming that DNA repair defect of this type is associated with a lower level of chromosomal instability. An hMLH1 methylation defect was seen in only one adenoma (1.3%), from a patient who had a synchronous cancer showing the same defect. Methylation of P14 (P14ARF) was seen in 31 adenomas (39.7%) and CDKN2A (P16) abnormality in 25 (32.1%). DNA methylation at two or more loci was seen in 46 tumours (59%), while 11 lesions (14.1%) showed no evidence of hypermethylation at any of the loci studied. Methylation at any or all of MGMT, P14 or P16 was significantly associated with APC methylation (p = 0.01). Those neoplasms with more than two methylated genes showed significantly fewer chromosomal abnormalities than adenomas with one or no methylated loci (p < 0.001). There was no association between specific individual chromosomal abnormalities, APC, KRAS or TP53 mutations and any pattern of methylation abnormality. We conclude that methylation abnormality is very common in pre-invasive colorectal neoplasia, and that high level methylation is associated with low level chromosomal instability.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Medications with anticoagulant properties increase the likelihood of a negative colonoscopy in faecal occult blood test population screening.

OBJECTIVE: The aim of this study was to evaluate the effect of medication with anticoagulant properties on the false positive rate in a population-based faecal occult blood test (FOBt) colorectal screening programme. METHODS: Eight hundred and forty-six consecutive individuals found to be FOBt-positive in the Scottish arm of the national colorectal cancer screening pilot were studied. All were aged between 50 and 69 years and underwent colonoscopy. Before the procedure the participants' current medication was recorded, and correlated with the colonoscopic findings. RESULTS: Of 846 participants, 301 (35.6%) were taking regular anticoagulant medication at the time of FOB testing. Of these, 143 (47.5%) had colorectal neoplasia found on colonoscopy, whereas of those not taking anticoagulant medication, 308 (56.5%) were found to have neoplasia. This 9% difference was statistically significant (P = 0.012). CONCLUSION: These results indicate that in a population screened for colorectal neoplasia by FOB testing, anticoagulant medication being taken at the time of testing is associated with an increased likelihood of a negative colonoscopy.

Aged↗
PubMed2005

The prognostic significance of K-ras, p53, and APC mutations in colorectal carcinoma.

BACKGROUND: Accumulation of molecular alterations, including mutations in Kirsten-ras (K-ras), p53, and adenomatous polyposis coli (APC), contribute to colorectal carcinogenesis. Our group has previously characterised a panel of sporadic colorectal adenocarcinomas for mutations in these three genes and has shown that p53 and K-ras mutations rarely occur in the same colorectal tumour. This suggests that mutations in these genes are on separate pathways to colorectal cancer development and may influence patient prognosis independently. AIMS: To correlate the presence or absence of mutations in K-ras, p53, and APC with survival in a cohort of colorectal cancer patients. PATIENTS: A series of 107 inpatients treated surgically for colorectal cancer in Tayside, Scotland between November 1997 and December 1999. METHODS: Colorectal tumours were characterised for mutations in K-ras, p53, and APC. Kaplan-Meier survival curves were constructed using overall survival and disease specific survival as the primary end points. Patient survival was analysed using the log rank test and Cox proportional hazards model. RESULTS: Patients with K-ras mutations had significantly poorer overall survival than patients without K-ras mutations (p = 0.0098). Multivariate analysis correcting for Dukes' stage, age, and sex confirmed this (hazard ratio 2.9 (95% confidence interval 1.4-6.2); p = 0.0040). K-ras mutations were also significantly associated with poorer disease specific survival. The presence of APC and p53 mutations did not affect survival in this cohort of patients (p = 0.9034 and p = 0.8290, respectively). CONCLUSIONS: Our data indicate that the presence of K-ras mutations predicts poor patient prognosis in colorectal cancer, independently of tumour stage.

Adenocarcinoma↗
PubMed2005

Lower gastrointestinal symptoms are not predictive of colorectal neoplasia in a faecal occult blood screen-positive population.

BACKGROUND: The aim of this study was to evaluate the incidence of lower gastrointestinal symptoms in faecal occult blood (FOB) test-positive participants in a colorectal screening programme, and to compare the colonoscopic findings in symptomatic and asymptomatic individuals. METHODS: Five hundred and sixty-three consecutive individuals with a positive FOB test in the Scottish arm of the national colorectal cancer screening pilot were studied. All were aged between 50 and 69 years and underwent colonoscopy. Before the procedure the participants were given a standard questionnaire to elicit gastrointestinal symptoms; these were correlated with the colonoscopic findings. RESULTS: Of the 563 participants, 439 (78.0 per cent) had one or more lower gastrointestinal symptoms and 124 (22.0 per cent) were symptom free. Taking adenoma and carcinoma together, 322 (57.2 per cent) of the subjects were found to have colorectal neoplasia, and 128 (22.7 per cent) had a completely normal colon. Rectal bleeding was the most common symptom, followed by change in bowel habit, abdominal pain, tenesmus, unexplained weight loss, rectal pain and unexplained anaemia. No significant associations were found between any of these symptoms and the findings at colonoscopy. CONCLUSION: In a FOB test-positive screened population, lower gastrointestinal symptoms are common, but are not predictive of colorectal neoplasia.

Abdominal Pain↗
PubMed2003

Effects of low dose fluticasone/salmeterol combination on surrogate inflammatory markers in moderate persistent asthma.

BACKGROUND: Noninvasive surrogate markers provide valuable information on the asthmatic inflammatory process. We wished to examine the effects of low dose fluticasone/salmeterol combination on different commonly used inflammatory markers in moderate persistent asthma. METHODS: Twenty-five moderate persistent atopic asthmatics were enrolled of whom 20 completed an open label study. Following an initial 4 week steroid washout period in which patients took salmeterol 50 microg dry powder inhaler 1 puff BD, they received the addition of fluticasone as fluticasone 100 microg/salmeterol 50 microg combination dry powder inhaler 1 puff BD for the next 2 weeks. Exhaled nitric oxide, spirometry, methacholine PD20, sputum/blood eosinophils and sputum/serum eosinophil cationic protein (ECP) were measured following the salmeterol only and fluticasone/salmeterol combination treatment periods. RESULTS: Compared to salmeterol alone (i.e. after the steroid washout), the use of fluticasone/salmeterol combination conferred significant improvements (P < 0.05) in all surrogate markers of inflammation apart from serum ECP. Geometric mean fold changes were 4.3-fold/1.3-fold for sputum/blood eosinophils, 2.2-fold/1.2-fold for sputum/serum ECP, 2.3-fold for methacholine PD20 and 1.8-fold for exhaled nitric oxide. CONCLUSIONS: Surrogate markers apart from serum ECP may be used as a guide to evaluate the anti-inflammatory effects of low dose inhaled corticosteroids. Sputum markers tend to be more sensitive than blood when assessing the anti-inflammatory response.

Administration, Inhalation↗
PubMed2003

Prognostic indicators for gastrointestinal stromal tumours: a clinicopathological and immunohistochemical study of 108 resected cases of the stomach.

AIMS: Whether immunohistochemical markers increase accuracy in predicting prognosis for gastrointestinal stromal tumours (GISTs) remains uncertain. However, past studies have used only small, heterogeneous patient groups. Our aim was to test previously studied and more novel morphological features as well as four immunohistochemical markers as prognostic indicators amongst a large cohort of surgically resected, gastric GISTs. METHODS AND RESULTS: Tissues from 127 gastric mesenchymal tumours were collected retrospectively and subjected to repeat histological assessment and immunophenotyping. Further immunohistochemistry was performed for Ki67, p53, Bcl-2 and cyclin D1. Complete follow-up data were collected for 108 patients with immunophenotyped diagnoses of GIST (i.e. c-kit+ tumours). At the census point, 52 patients were alive, 24 had died from their GISTs and the remainder of other causes. Univariate analysis showed the following predicted for shorter disease-specific survival: size > or =50 mm; necrosis, no intratumoral lymphocytes; mitotic count > or =5/50 high power fields; Ki67 labelling index > or =5%; p53 immunopositivity. Of these variables, multivariate analyses showed only mitotic count and, to a lesser extent, Ki67 labelling to be independent prognostic indicators. CONCLUSIONS: Mitotic count remains the best predictor of outcome following surgical resection of gastric GISTs. Ki67 immunohistochemistry does not provide better prognostication and p53, Bcl-2 and cyclin D1 immunohistochemistry provide no additional prognostication.

Adult↗
PubMed2002

The colorectal adenoma-carcinoma sequence.

BACKGROUND: It is widely accepted that the adenoma-carcinoma sequence represents the process by which most, if not all, colorectal cancers arise. The evidence supporting this hypothesis has increased rapidly in recent years and the purpose of this article is to review this evidence critically and highlight its clinical significance. METHODS: Medline searches were used to identify recent key articles relating to the adenoma-carcinoma sequence. Further pertinent articles were obtained by manual scanning of the reference lists of identified papers. RESULTS: The evidence supporting the adenoma-carcinoma sequence can be classified as epidemiological, clinicopathological and genetic. The most recent and largest body of data relates to molecular genetic events and their cellular effects; however, many other approaches, such as cytogenetics, molecular cytogenetics and cytometry, have also yielded valuable information. CONCLUSION: Recent work continues to support the adenoma-carcinoma sequence, but there is a paucity of data on the interrelationship between different genetic mutations and on the relationship between molecular and other types of genetic abnormalities. The clinical utility of the observations described has yet to be fully realized and global genetic analysis of colorectal tumours may prove to be central in rational adenoma management.

Adenoma↗
PubMed2002

Primary T cell lymphoma of salivary gland: a report of a case and review of the literature.

Lymphoma of the salivary gland accounts for 5% of cases of extranodal lymphoma and 10% of malignant salivary gland tumours. Most primary salivary gland lymphomas are B marginal zone lymphomas arising on a background of sialadenitis associated with autoimmune disorders such as Sjorgen's syndrome. Primary T cell lymphoma of the salivary gland is rare. This report describes a case of primary T cell lymphoma arising in the parotid gland of an elderly white man, which was notable for its striking resemblance to a B cell extranodal marginal zone lymphoma. Immunohistochemistry and gene rearrangement studies confirmed the clonal T cell nature of the tumour. There was no molecular evidence of Epstein-Barr virus (EBV) infection of neoplastic or surroundings cells. Only 14 cases of primary T cell lymphoma of the salivary glands have been recorded in the literature, most being from the Orient and having extremely variable prognosis. Those with a T/natural killer cell phenotype are associated with EBV infection. This case highlights the fact that T cell lymphoma in the salivary gland can mimic closely the morphological features of B cell extranodal marginal zone lymphoma.

Aged↗
PubMed2001

Overexpression and poly-ubiquitylation of the DEAD-box RNA helicase p68 in colorectal tumours.

The DEAD box RNA helicase, p68, is upregulated in exponentially growing cells and shows cell cycle-dependent changes in nuclear localization. Although some other DEAD box proteins have been implicated in cancer, there have been no reports of any link between p68 status and carcinogenesis. In the present study we have analysed specimens from 50 patients with colorectal adenocarcinomas, including cases in which an adenomatous polyp was also present, by immunohistochemistry and Western blotting. Our data indicate that p68 protein is consistently overexpressed in tumours as compared with matched normal tissue. Examination of the levels of p68 mRNA from both normal and tumour tissue showed no obvious specific increase in p68 mRNA levels in tumours nor any evidence of underlying mutations in the p68 coding region. Interestingly, however, the accumulated p68 appears to be poly-ubiquitylated, suggesting a possible defect in proteasome-mediated degradation in these tumours. This overexpression/ubiquitylation is observed in both pre-invasive and invasive lesions suggesting that the dysregulation of p68 expression occurs early during tumour development. Finally, we demonstrate that ubiquitylation of p68 occurs in cultured cells, thereby providing a model for the molecular analysis of this process and its potential role in tumorigenesis.

Animals↗
PubMed2001

Chromosomal imbalances in gastric and esophageal adenocarcinoma: specific comparative genomic hybridization-detected abnormalities segregate with junctional adenocarcinomas.

The incidence of adenocarcinoma arising at the esophagogastric junction (EGJ) is increasing at a rate greater than that for any other form of solid malignancy. Commensurate with this, the incidence of histologically similar tumors arising in the gastric body and antral mucosa is declining. The increased incidence of the proximal group of tumors may reflect, in part, the higher prevalence of Barrett esophagus. These epidemiological features suggest that histologically similar tumors arising at the EGJ and from the distal stomach are different, which may be reflected in the genetic abnormalities that characterize the two groups of tumors. The purpose of this study was to screen genomic DNA from adenocarcinomas of the esophagus and stomach for regions of chromosomal imbalance, using comparative genomic hybridization to determine whether tumors at the EGJ (junctional tumors) have a different profile compared with tumors of the distal stomach. Tumor samples were derived from a series of 48 gastroesophageal adenocarcinomas (20 junctional and 28 distal) that were acquired prospectively from patients undergoing esophagogastrectomy. These tumors are characterized by several regions of chromosomal imbalance with no obvious correlation between most regions of abnormal copy number and tumor type. However, our study shows for the first time cytogenetic abnormalities (5p+ and 18q-) that identify statistically significant differences (P < 0.02 and < 0.05, respectively) between junctional and distal gastric tumors. These differences are gain of 5p (55% [11/20] of junctional tumors vs. 21% [6/28] of distal gastric tumors) and loss of 18q (25% [5/20] cases of junctional tumors vs. 4% [1/28] of distal tumors) segregating with tumors of the EGJ. These abnormalities may distinguish distinct tumor subtypes that are recognized in epidemiological and clinical studies but that are otherwise histologically identical.

Adenocarcinoma↗
PubMed2001

Lymphangioleiomyomatosis. A series of three case reports illustrating the link with high oestrogen states.

Lymphangioleiornyomatosis is a rare lung disorder characterised by cystic air spaces and smooth muscle proliferation. The condition, which most commonly presents with dyspnoea, pneumothoraces or cough, is only described in females and is most commonly diagnosed during childbearing years. Three cases are presented which illustrate typical features of the disease and the association with high oestrogen levels. The first had recurrent pneumothoraces during her first pregnancy. The second lady was post menopausal at diagnosis but her symptoms predated her menopause. The third, presented with dyspnoea, abnormal chest sensations and a pneumothorax. She had a history of hyperprolactinaemia with secondary amenorhoea due to low oestrogen levels which had been corrected prior to her presentation. All three patients had reduced gas transfer and abnormalities in spirometry, two had reticular shadowing on their chest radiograph and all had typical appearances on lung computerised tomography. Although disease progression was variable, all patients showed a gradual decline in lung function.

Adult↗
PubMed2000

Patch incorporation in diaphragmatic hernia.

BACKGROUND/PURPOSE: Biomaterial insertion often is required for closure of congenital diaphragmatic hernia (CDH). The optimal biomaterial remains uncertain. This study was designed to compare a commonly used patch (polytetrafluoroethylene) with a recently available fabric, fluorinated polyester. The aim of this study was to determine the clinical performance, histological tissue-polymer interaction, bacterial adhesion, and shrinkage rates of biomaterial inserted endoscopically into a CDH lamb model. METHODS: Polytetrafluoro-ethylene (PTFE) and fluorinated polyester (FP) were randomised for laparoscopic patch insertion into 12 lambs. All lambs (age <4 weeks) underwent 3-port laparoscopy, surgical creation of diaphragmatic hernia, and sutured patch placement. Two PTFE and 2 FP lambs were killed at 1-, 3-, and 6-month intervals postoperatively. Postmortem examination histopathology, electron microscopy, and specific bacterial broth immersion (Escherichia coil, Staphylococcus aurens, and epidermidis) were performed. RESULTS: All 12 lambs completed the study with intact patches that were fully peritonised. One abdominal adhesion was noted in a FP lamb at 6 months. FP was comparatively easier to insert, manipulate, and suture endoscopically. Histopathology findings showed that PTFE patches created a strong peripheral foreign body reaction with dystrophic calcification, whereas FP was well incorporated with intrapatch fibroblastic activity and neovascularsation. No significant difference in resistance to bacterial adhesion of relevant organisms was noted between the materials. Graft shrinkage for FP was 7% in one direction only, evident by 3 months. CONCLUSIONS: Fluorinated polyester has advantages in this laparoscopic lamb model. It shows rapid and sustained incorporation with intrapatch neovascularisation when compared with polytetrafluoro-ethylene's significant foreign body reaction. It was preferred for its endoscopic handling and suturing properties. The laparoscopic techniques used may contribute to the general lack of adhesions, and insufficient data are available to comment on the comparative effect of the materials on adhesion formation. No difference was demonstrated in resistance to bacterial adherence in the harvested materials.

Animals↗
PubMed2000

Expression of the p53 homologue p63alpha and deltaNp63alpha in normal and neoplastic cells.

A burgeoning family of p53-related genes have been described recently, including p73 and p63. Both these genes encode proteins with many similarities to p53 but also with the potential for forming a range of related species by alternative promoter usage and alternative splicing. In order to begin the characterization of p63, we generated a polyclonal serum (designated SC1) that recognizes the C-terminus of p63alpha. We have shown that this reagent recognizes p63alpha but not p53 nor p73. By western blot analysis both p63alpha and the N-terminal truncated form of p63alpha (DeltaNp63alpha) were found in a range of cell lines. Similar immunoblot analysis of tissues reveals considerable complexity with at least four SC1-immunoreactive isoforms being identified. In immunohistological studies SC1 immunoreactivity is widely detectable, being predominantly associated with proliferative compartments in epithelia. However, non-proliferative populations can also show SC1 immunostaining. No simple relationship between the isoforms identified by immunoblotting of tissue lysates and the tissue immunostaining characteristics was identified. A previously unrecognized species intermediate in mobility between p63alpha and DeltaNp63alpha was found in several tissues, including nerve and peripheral blood lymphocytes. Interestingly, there is suppression of p63alpha expression in HaCat cells in a time- and concentration-dependent manner after UV and MMS treatment. Our data provide further information about the complexity of p63 and the SC1 serum will prove to be a useful tool in further studies of this p53 homologue.

Amino Acid Sequence↗
PubMed2000

An investigation of the Peutz-Jeghers gene (LKB1) in sporadic breast and colon cancers.

AIMS: To explore the role of the Peutz-Jeghers gene (LKB1) in sporadic breast and colon cancers. METHODS: Thirty consecutive sporadic carcinomas of the breast and 23 of the colon were selected. DNA was extracted from paraffin wax embedded tissue and analysed for loss of heterozygosity (LOH) at microsatellite markers D19S886 and D19S565 close to the LKB1 gene. Tumours showing LOH were screened for LKB1 mutations by single strand conformational polymorphism (SSCP). RESULTS: Five breast carcinomas showed LOH (21% and 7% of those informative for D19S886 and D19S565, respectively). Five of the colorectal carcinomas showed LOH (15% and 36% of those informative for D19S886 and D19S565, respectively), with one sample showing allele loss with both markers. Screening of these 10 carcinomas by SSCP identified one migrational shift but sequencing revealed an intronic polymorphism only. Therefore, no coding mutations were found in these carcinomas. CONCLUSIONS: These findings suggest that although allele loss at the LKB1 locus occurs relatively frequently in sporadic breast and colon cancers, mutations do not seem to be a feature.

AMP-Activated Protein Kinase Kinases↗
PubMed1999

Merkel cells in the human oesophagus.

Merkel cells (MCs) are well recognized in the basal layers of the skin and oral mucosa, but this paper describes for the first time the presence of MCs in the human oesophagus. These cells are not identified in neonatal oesophagus, but are seen singly and in clusters in adult specimens. Application of stereological techniques shows that MCs are more numerous in the mid-oesophageal region. Cells expressing established markers of MCs have also been demonstrated in two out of six primary small cell carcinomas of the oesophagus. Further investigation of the role of MCs in oesophageal innervation and epithelial biology will be of interest.

Adult↗
PubMed1998

Pulmonary adenocarcinoma: classification and molecular biology.

Pulmonary adenocarcinoma is increasing in incidence. Current classification systems based purely on morphological features are of little clinical relevance. Recent descriptions of genetic abnormalities, particularly in K-ras, p53, and c-erb-B2, may form the basis of a new taxonomy having direct prognostic relevance. Study of these molecular lesions has also helped to define a new pathway of tumourigenesis in the lung parenchyma, through alveolar atypical hyperplasia (AAH) to clinical adenocarcinoma.

Adenocarcinoma↗
PubMed1997

Neuroendocrine differentiation in lung cancer.

The human lung has a resident population of neuroendocrine (NE) cells. These are characterised by the presence of neurosecretory granules and by a number of histochemical and immunocytochemical reactions. NE differentiation is a defining feature of classical and atypical carcinoid tumours and is seen in most small cell lung cancers (SCLC). Such differentiation has also been described in up to one third of non-small cell lung cancers (NSCLC). As demonstrated in an accompanying paper in this issue of the Journal, the reporting of NE differentiation varies with the technical approach used and with the nature of the tissue specimen. This phenomenon is a reflection of the histological and biological heterogeneity of lung cancer and has not been shown to be of clinical utility.

Carcinoid Tumor↗