PubMed Health⌕ Search

Biomedical subjects

G T Williams

Publications and source records attributed to G T Williams.

At least 19 recordsLinked to original sources
PubMed2007

Endocrine tumours of the gastrointestinal tract-selected topics.

This review provides an update on the pathogenesis and histopathological diagnosis of endocrine tumours of the gastrointestinal tract, concentrating on three different varieties whose careful assessment by pathologists is of particular clinical significance. These are the four types of enterochromaffin-like cell tumour of the gastric corpus, the periampullary somatostatin-containing D-cell tumour of the duodenum, and the frequently chromogranin A-negative L-cell tumour of the appendix and large intestine. In addition, the value of pathological factors in predicting the behaviour of gastrointestinal endocrine tumours and selecting therapy is discussed, and the crucial role of the pathologist in the multidisciplinary team management of these neoplasms is emphasized.

Biomarkers, Tumor↗
PubMed2005

Plasma fibrinogen in ulcerative colitis: the effect of disease activity and nicotine therapy in a randomised controlled trial.

BACKGROUND: Smoking increases plasma fibrinogen and cardiovascular risk whereas transdermal nicotine may not. Fibrinogen is an acute phase protein and may reflect disease activity in ulcerative colitis. AIMS: To examine the effect of topical nicotine on plasma fibrinogen and any relationship between fibrinogen and ulcerative colitis disease activity. PATIENTS: Forty-eight non-smokers with moderately active ulcerative colitis. METHODS: Patients were randomised to 6 mg nicotine enema or placebo for 6 weeks, followed by open nicotine therapy for 4 weeks. Plasma fibrinogen was measured at baseline and after 6 and 10 weeks; at each assessment sigmoidoscopy with a rectal biopsy was performed. RESULTS.: At 6 weeks median plasma fibrinogen was 3.30 g/l on nicotine compared to 3.05 g/l on placebo, P = 0.90 when adjusted for baseline values. There was a correlation between fibrinogen and the UC disease activity index (UCDAI) at weeks 0 and 10, P = 0.036 and 0.033, respectively, and between fibrinogen and sigmoidoscopic grade at each assessment, P = 0.014, 0.021 and 0.034. Changes in fibrinogen did not correlate with changes in disease severity. CONCLUSIONS: There was no significant effect of nicotine enemas, in either direction, on plasma fibrinogen-this was raised in moderately active UC and correlated with the sigmoidoscopic grade of colitis and the UCDAI; however, fibrinogen was not sufficiently sensitive to be of practical clinical value.

Colitis, Ulcerative↗
PubMed2005

Gastric epithelioid haemangioendothelioma: a rare cause of upper gastrointestinal bleeding.

Vascular tumours of the stomach are rare, representing 0.9%-3.3% of all gastric neoplasms. A 58 year old man was admitted as an emergency with a one day history of haematemesis and melaena. He underwent an emergency laparotomy for a tumour in the lesser curve of the stomach. The tumour showed the characteristic histological and immunohistochemical features of epithelioid haemangioendothelioma. Surgery in the form of wide excision seems to be the treatment of choice for this rare neoplasm. This case highlights the difficulty in diagnosing this rare tumour preoperatively and emphasises the need for long term follow up in view of its uncertain metastatic potential.

Anastomosis, Roux-en-Y↗
PubMed2004

Effectiveness of preoperative staging in rectal cancer: digital rectal examination, endoluminal ultrasound or magnetic resonance imaging?

In rectal cancer, preoperative staging should identify early tumours suitable for treatment by surgery alone and locally advanced tumours that require therapy to induce tumour regression from the potential resection margin. Currently, local staging can be performed by digital rectal examination (DRE), endoluminal ultrasound (EUS) or magnetic resonance imaging (MRI). Each staging method was compared for clinical benefit and cost-effectiveness. The accuracy of high-resolution MRI, DRE and EUS in identifying favourable, unfavourable and locally advanced rectal carcinomas in 98 patients undergoing total mesorectal excision was compared prospectively against the resection specimen pathological as the gold standard. Agreement between each staging modality with pathology assessment of tumour favourability was calculated with the chance-corrected agreement given as the kappa statistic, based on marginal homogenised data. Differences in effectiveness of the staging modalities were compared with differences in costs of the staging modalities to generate cost effectiveness ratios. Agreement between staging and histologic assessment of tumour favourability was 94% for MRI (kappa=0.81, s.e.=0.05; kappa(W)=0.83), compared with very poor agreements of 65% for DRE (kappa=0.08, s.e.=0.068, kappa(W)=0.16) and 69% for EUS (kappa=0.17, s.e.=0.065, kappa(W)=0.17). The resource benefits resulting from the use of MRI rather than DRE was 67164 UK pounds and 92244 UK pounds when MRI was used rather than EUS. Magnetic resonance imaging dominated both DRE and EUS on cost and clinical effectiveness by selecting appropriate patients for neoadjuvant therapy and justifies its use for local staging of rectal cancer patients.

Adult↗
PubMed2004

Increased frequency of the k-ras G12C mutation in MYH polyposis colorectal adenomas.

Colorectal tumours from MYH polyposis patients display an excess of somatic G : C --> T : A transversions in the adenomatous polyposis coli gene. Here, we identify k-ras mutations in nine out of 54 (16.7%) MYH polyposis tumours. Their presence was associated with increased dysplasia and tubulovillous morphology (P=0.005). G : C --> T : A transversions in k-ras were significantly more frequent in MYH polyposis adenomas than in sporadic or familial adenomatous polyposis-associated tumours (P<or=0.002), and all resulted in a glycine-to-cysteine substitution at codon 12.

Adenoma↗
PubMed2004

Differential effect of nitric oxide synthase inhibition on sigmoid colon longitudinal and circular muscle responses to nicotine and nerve stimulation in vitro.

BACKGROUND: Nicotine has been shown to release nitric oxide from nerves in human sigmoid colon. This effect has been used to investigate the innervation and functional relationship of the longitudinal and circular muscle layers. METHODS: Strips of longitudinal and circular muscle were obtained from 19 patients with colorectal cancer. The strips from ten patients were subjected to electrical field stimulation (EFS) in vitro using stimulus parameters for selective stimulation of nerves. The effect of nicotine 1-10 micromol/l on EFS responses was then measured in the presence and absence of a nitric oxide synthase inhibitor, nitro-L-arginine methyl ester (L-NAME) 200 micromol/l. The effect of nicotine on spontaneous activity was investigated in the muscle strips from the other nine patients. RESULTS: Both longitudinal and circular strips responded to EFS with contraction. The time to achieve a peak contractile response (time to peak; TTP) was significantly longer (P<0.001) in circular strips. L-NAME reduced the mean(s.e.m.) TTP in circular muscle from 23.3(2.0) to 17.2(1.5) s (P=0.007) and altered its pattern of response to resemble that of longitudinal muscle. Nicotine 10 micromol/l reduced the contraction to EFS in circular (P<0.001) but not in longitudinal (P=0.347) muscle. The nicotine-induced reduction in circular muscle contraction was blocked by L-NAME 200 micromol/l (P=0.005). CONCLUSION: These findings suggest that nitric oxide release on neural stimulation is greater in circular than in longitudinal muscle.

Colon, Sigmoid↗
PubMed2003

Preoperative assessment of prognostic factors in rectal cancer using high-resolution magnetic resonance imaging.

BACKGROUND: The aim was to determine the accuracy of preoperative magnetic resonance imaging (MRI) in the evaluation of pathological prognostic factors that influence local recurrence and survival in rectal cancer. METHODS: Ninety-eight patients undergoing total mesorectal excision for biopsy-proven rectal cancer were assessed prospectively using high-resolution MRI for tumour (T) and nodal (N) staging using the tumour node metastasis classification, depth of extramural tumour spread, the presence or absence of extramural venous invasion, a threatened circumferential resection margin and serosal involvement at or above the peritoneal reflection. Preoperative magnetic resonance assessment of these prognostic factors was compared with histopathological findings in carefully matched whole-mount sections of the resection specimen. RESULTS: There was 94 per cent weighted agreement (weighted kappa = 0.67) between MRI and pathology assessment of T stage. Agreement between MRI and histological assessment of nodal status was 85 per cent (kappa = 0.68). Although involvement of small veins by tumour was not discernible using MRI, large (calibre greater than 3 mm) extramural venous invasion was identified correctly in 15 of 18 patients (kappa = 0.64). MRI predicted circumferential resection margin involvement with 92 per cent agreement (kappa = 0.81). Seven of nine patients with peritoneal perforation by tumour (stage T4) were identified correctly using MRI. CONCLUSION: High-resolution MRI of the rectum allows preoperative identification of important surgical and pathological prognostic risk factors. This may allow both better selection and assessment of patients undergoing preoperative therapy.

Adult↗
PubMed2003

Functional expression cloning reveals proapoptotic role for protein phosphatase 4.

Functional expression cloning strategies are highly suitable for the analysis of the molecular control of apoptosis. This approach has two critical advantages. Firstly, it eliminates prior assumptions about the properties of the proteins involved, and, secondly, it selectively targets proteins that are causally involved in apoptosis control and which affect the crucial cellular decision between survival and death. The application of this strategy to the isolation of cDNAs conferring resistance to dexamethasone and gamma-irradiation resulted in the isolation of a partial cDNA for the catalytic subunit of protein phosphatase 4 (PP4). Cells transfected with this partial cDNA in an expression vector downregulated PP4 and were resistant to both dexamethasone and UV radiation, as demonstrated by both membrane integrity and colony-forming assays. These observations suggest that PP4 plays an important proapoptotic role in T lymphocytes.

Animals↗
PubMed2003

Effect of smoking and transdermal nicotine on colonic nicotinic acetylcholine receptors in ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is a disease largely of non-smokers, in which nicotine is of therapeutic value. The mode of action is unknown, but may involve nicotinic acetylcholine receptors (nAChRs) in the bowel wall. AIM: To investigate the presence of nAChRs in rectal mucosa, and the effect of smoking and nicotine on their expression. DESIGN: Prospective case-control study. METHODS: In situ hybridization (ISH) and immunocytochemistry (ICC) were used to show alpha3 nAChRs in colonic mucosa. Rectal mucosa was examined from controls (n=55) and patients with inactive UC (n=62), both smokers and non-smokers, by ICC, using two antibodies to show the density and distribution of receptors in the mucosa. Non-smokers with UC (n=43) were given transdermal nicotine or placebo patches for 6 months, and rectal biopsies, taken before and after treatment, were examined by ICC to show nAChRs. RESULTS: In normal colon, ISH and ICC showed alpha3 subunit in a wide variety of cells, including mucosal epithelium. In rectal biopsies, neither smoking nor nicotine influenced the expression of alpha3 immunoreactivity in epithelium, either in controls or UC. However, controls had a significantly greater density of immunodetectable mucosal epithelium alpha3 subunit, compared with UC patients. DISCUSSION: The presence of nAChRs in colonic epithelium may be pertinent to the beneficial effect of nicotine in UC, but since neither smoking nor nicotine treatment is associated with any change in the expression of epithelial alpha3 nAChRs, the effect may be due to functional changes in the receptor. The decreased number of alpha3 nAChRs in UC compared with controls may be related to an increased cell turnover in UC.

Administration, Cutaneous↗
PubMed2003

Histological changes in the oesophageal squamous mucosa: correlation with ambulatory 24 hour pH monitoring.

AIMS: To determine the value of squamous mucosal histology in the assessment of patients with gastro-oesophageal reflux symptoms. METHODS: Sixty six patients with reflux symptoms underwent endoscopy with oesophageal biopsy, manometry, and 24 hour oesophageal pH testing. The following histological features were assessed in squamous mucosa: the degree of basal cell hyperplasia, the degree of papillary zone elongation, and the density of neutrophil and eosinophil infiltration. Comparisons were made between the histological findings and the oesophageal function tests. RESULTS: The correlation between the traditionally accepted histological markers of gastro-oesophageal reflux disease in squamous mucosa and 24 hour pH testing was predominantly negative, with the exception of neutrophil inflammation in the squamous mucosa of patients with complicated reflux disease. CONCLUSIONS: This study was unable to confirm the value of the Ismail-Beigi criteria as histological markers of acid reflux. By inference, biopsy of the oesophageal squamous mucosa is of limited value in the assessment of patients with reflux symptoms.

Adult↗
PubMed2002

The implementation of guidelines and computerised forms improves the completeness of cancer pathology reporting. The CROPS project: a randomised controlled trial in pathology.

The aim of this study was to determine whether reporting guidelines and computerised form-based reports improve the completeness of histopathological cancer data available for patient management and population cancer registration and to evaluate the acceptability of the intervention. The study was a randomised controlled trial with a split unit design and stratified cluster randomisation. All 16 hospital pathology laboratories in Wales were randomly allocated to report either breast or colorectal resection specimens by computerised form or conventional free text. 1044 reports were analysed in the study arm, 998 in the control arm. Use of pre-defined forms led to a 28.4% (95% confidence interval (CI): 15.7-41.2%) increase in complete reporting of a minimum dataset required for cancer registration and a 24.5% (95% CI: 11.0-38.0%) increase in complete reporting of minimum data required for patient management. Form-based reporting was acceptable to pathologists and preferred by clinicians. In conclusion, guidelines and computerised forms significantly improve the quality of histopathology reporting.

Breast Neoplasms↗
PubMed2002

Commitment to apoptosis induced by tumour necrosis factor-alpha is dependent on caspase activity.

Tumour Necrosis Factor alpha binding at the cell surface induces a complex series of signaling events culminating in the caspase cascade, which is central to apoptosis. However, recent work from several laboratories has questioned caspase involvement in commitment to cell death. We have therefore investigated the involvement of caspases in the crucial commitment stage of tumour necrosis factor-induced apoptosis in human T-leukaemic CEM-C7 cells and breast carcinoma MCF-7 cells, using both peptide-based and viral caspase inhibitors. Our observations converge on the conclusion that commitment to death in these systems is dependent on caspase activity, e.g. baculovirus p35 produces over 50-fold protection of colony-forming ability, the most stringent criterion of cell survival. These observations strongly support the view that the caspase family is of great biological and medical significance, since caspase dysfunction resulting in failure to commit to cell death after treatment with tumour necrosis factor or other stimuli may contribute to cancer development.

Acridine Orange↗
PubMed2002

Candidate tumour suppressor LUCA-15 can regulate multiple apoptotic pathways.

Functional screening of a human bone marrow cDNA library for suppressors of CD95-mediated apoptosis has led to the identification of a 326 bp fragment (Je2), which not only suppresses CD95-induced apoptosis in Jurkat T-cells, but maps to 3p21.3, to an intronic region of the candidate TSG LUCA-15 locus. Here we report that overexpression of Je2 in CEM-C7 T-cell line is able to suppress CD95-mediated apoptosis, and apoptosis induced by TNFalpha and the glucocorticoid analogue dexamethasone, but was not able to suppress death induced by the topoisomerase II inhibitor etoposide. Je2 inhibition of apoptosis is also associated with a change in the pattern of expression of LUCA-15-encoded proteins. Je2 might therefore function to inhibit apoptosis by destabilising message expression of LUCA-15 and promoting the degradation of its RNA and protein. This suppression of apoptosis by Je2 also appears to be associated with up-regulation of the apoptosis inhibitory protein Bcl-x(L). This study confirms that Je2 is a selective inhibitor of cell death and further implicates LUCA-15 gene locus in the control of apoptosis.

Apoptosis↗
PubMed2002

An insight into the genetic pathway of adenocarcinoma of the small intestine.

BACKGROUND: Although the adenoma to carcinoma pathway in colorectal cancer is well described, the mechanisms of carcinogenesis in the small intestine remain unclear. AIMS: The aim of this study was to investigate candidate genes in the genetic pathway of adenocarcinoma of the small intestine. SUBJECTS AND METHODS: A total of 21 non-familial, non-ampullary adenocarcinomas of the small intestine were analysed. DNA was extracted from formalin fixed paraffin wax embedded tissue using standard techniques. The replication error (RER) status was determined by amplification of BAT26. The mutation cluster region (MCR) of the adenomatous polyposis coli (APC) gene was screened using polymerase chain reaction single strand conformational polymorphism and direct sequencing. Immunohistochemistry was performed on formalin fixed paraffin wax embedded tissue using monoclonal antibodies for hMLH1, hMSH2, beta-catenin, E-cadherin, and p53. RESULTS: Fourteen male and seven female patients with a median age of 64 years (range 21-85) presented with adenocarcinoma of the duodenum (10), jejunum (7), and ileum (4). One cancer (5%) was found to be RER+, and all tumours stained positive for hMLH1 and hMSH2. No mutations were detected in the MCR of the APC gene. beta-Catenin showed increased nuclear expression with loss of membranous staining in 10 cancers (48%). Absent or decreased membrane expression of E-cadherin was found in eight cancers (38%). Strong staining of p53 was found in the nucleus of five cancers (24%). CONCLUSION: We did not detect mutations in the MCR of the APC gene, and this suggests that adenocarcinoma of the small intestine may follow a different genetic pathway to colorectal cancer. Abnormal expression of E-cadherin and beta-catenin was common and reflects an early alternative to APC in this pathway in which mutations may be found in adenocarcinoma of the small intestine.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Production of antigen-specific human monoclonal antibodies: comparison of mice carrying IgH/kappa or IgH/kappa/lambda transloci.

Here we compare human monoclonal antibody (MAb) production from mouse strains that carry disruptions of their endogenous mouse IgH/IgK loci and harbor human IgM + Igkappa(BABkappa) or human IgM + Igkappa + IgA transloci (BABkappa,lambda). We found that whereas both strains proved effective for the isolation of antigen-specific IgM antibodies, many of the IgM MAbs elicited from BABkappa comprise human mu chains that are associated with mouse lambda chains. In contrast, BABkappa,lambda mice gave rise to fully functional, polymeric human IgM antibodies comprising both human IgH and human IgL chains. Therefore, the inclusion of a human Iglambda translocus (in addition to the human IgH + Igkappa transloci) not only diminishes problems of endogenous mouse Iglambda expression but also provides a strain of mice that yields fully human MAbs to a wide range of antigens, as witnessed by the isolation of MAbs to human blood cells, tumor cell lines, and an immunoglobulin idiotype.

Animals↗