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Biomedical subjects

I C Talbot

Publications and source records attributed to I C Talbot.

At least 37 records · Page 2Linked to original sources
PubMed2001

Genetic alterations in gastric cancers from British patients.

Twenty-six gastric carcinoma and matching normal tissue DNAs, which had previously been analyzed for alterations of the APC (adenomatous polyposis coli) and MCC (mutated in colorectal cancer) genes were further investigated for the following genetic alterations: mutation and loss of heterozygosity (LOH) of the p53 gene, replication error (RER) and LOH at 12 microsatellite repeat loci, and mutation of the hMSH2 gene. In addition, 9 of the 26 gastric carcinomas were analyzed for genetic alterations using comparative genomic hybridization (CGH). Somatic mutations of the p53 gene were found to be frequent being detected in 31% of gastric carcinomas while LOH at the p53 locus was observed in 37.5% of informative cases. Loss of wild type p53 allele was detected in the majority (7 of 8) tumors found to be harboring a mutation. In the hMSH2 gene, an intronic 4 base pair insertion at 31 base pairs upstream of the beginning of exon 13 was detected in both tumor and normal tissue from one gastric carcinoma case. RER was detected in 11.5% of gastric carcinomas, at one or more microsatellite repeat loci. Of the 12 microsatellite repeat loci analyzed LOH was most frequently observed at D22S351 (30% informative cases) suggesting that a tumor suppressor gene on 22q may be important in gastric carcinogenesis. In support of this, CGH analysis carried out on 9 of the gastric carcinomas identified loss of chromosome 22 in 5 of these tumors.

Base Sequence↗
PubMed2001

Molecular and cellular biology of pre-malignancy in the gastrointestinal tract.

Important pathogenic alterations within established cancers are acquired during the pre-malignant stage. These genetic alterations can be grouped into specific neoplastic pathways that differ within and between anatomical sites. By understanding the mechanisms that determine the initiation and progression of each pathway, it will be possible to develop novel approaches to the diagnosis, prevention and treatment of cancer. This chapter outlines the principles underlying the molecular characterization of pre-malignant lesions, taking colorectal neoplasia as the main model.

Colonic Polyps↗
PubMed2001

Variability in the severity of colonic disease in familial adenomatous polyposis results from differences in tumour initiation rather than progression and depends relatively little on patient age.

INTRODUCTION: As large scale genetic analysis becomes increasingly efficient, attention is turning to problems arising from inaccurate measurement of the phenotype. We have investigated the underlying basis of variation in disease severity in the large intestine of familial adenomatous polyposis (FAP) patients. The development of objective and reproducible measures may have future use in genetic studies, such as analysis of modifier genes. METHODS: We examined the ratio of adenomas to crypts from microscopic slides taken from all parts of the colon of 44 resected FAP specimens. These findings were compared with a carefully reported macroscopic polyp count. Age dependency of adenoma counts (in the period around colectomy) was also analysed. RESULTS: The adenoma:crypt ratio strongly correlated with reported macroscopic polyp count (r=0.82, p<0.001) with no significant residual variation. Polyp density measured using the adenoma: crypt ratio did not vary significantly within an individual colon. Apparent visible variation in polyp density within any colon was not found at the microscopic level. There was no detectable age related increase in macroscopic adenoma count between siblings over the age range at which colectomies were performed. DISCUSSION: The severity of colonic polyposis in FAP can be determined accurately by counting the adenoma:crypt ratio in sections derived from stored tissue blocks. Variation between patients-dependent on APC genotype and, probably, modifier genes-is manifest at both the microscopic and macroscopic levels. Thus variation in disease severity is more likely to result from different rates of tumour initiation than from differences in progression of microadenomas to macroscopic tumours. The absence of a detectable relationship between adenoma number and age (over the range studied) suggests that most tumours may be initiated relatively early in the patient's life, perhaps at a time of particular susceptibility.

Adenomatous Polyposis Coli↗
PubMed2000

Loss of fragile histidine triad expression in colorectal carcinomas and premalignant lesions.

Abnormal expression of the fragile histidine triad (FHIT) candidate tumor suppressor gene has been observed in a variety of human tumors, but little is known about its expression during colorectal tumorigenesis. Sections of 70 aberrant crypt foci (ACF), 55 adenomas, 84 primary colorectal carcinomas, and 13 metastatic lesions were evaluated immunohistochemically for Fhit expression. All normal colonic epithelium showed a strong expression of Fhit; 44% of carcinomas showed a marked loss or absence of Fhit expression. The proportion of carcinomas with reduced expression showed an increasing trend (a) with decreasing differentiation and (b) in tumors with metastases (62%) compared with tumors without metastases (38%). The proportion of metastatic lesions (12 of 13) with reduced expression of Fhit was even greater. Although only a small proportion of ACF and adenomas showed a reduction of Fhit expression, the reduced expression of Fhit was strongly associated with the degree of dysplasia in both ACF (P = 0.0002) and adenomas (P = 0.0085). The findings of reduced expression of Fhit in a small proportion of colonic precancerous lesions and in increased proportions of primary and metastatic colorectal cancers suggest that Fhit plays a role in the development and progression of some colon carcinomas.

Acid Anhydride Hydrolases↗
PubMed2000

Endoscopic management of polypoid early colon cancer.

Endoscopic management of polypoid early colonic cancer (malignant polyps and polypoid carcinomas) is no longer controversial. When the endoscopist is satisfied that excision is complete and histology is "favorable" (a resection margin of 2 mm and well or moderately well differentiated tumor), surgery is unnecessary. When histology show "unfavorable" characteristics (which a few histologists still take to include invasion into lymphatics), surgical or laparoscopic resection may be indicated, providing the patient is considered at suitable risk. Surgery kills some patients without finding residual cancer and cannot save others with metastases, so it should be recommended only with due clinical consideration. Sessile or broad-based polyps, especially those in the rectum, are more likely to be "high risk" and merit specialist management if local removal is to be attempted and to allow proper histologic assessment. Endoscopic approaches such as saline injection polypectomy, india-ink tattooing, and use of the argon beam coagulator are applicable in some cases. New approaches that still require trials include ultrasonographic probes, which occasionally clarify the degree of invasion, and prototype stapling devices to allow full-thickness histologic specimens to be obtained.

Colonic Polyps↗
PubMed2000

Fundal gastritis as a potential cause of reflux oesophagitis.

The transient lower oesophageal sphincter relaxations which allow reflux may be due to altered afferent pathways from the fundus. We aimed to determine whether fundal inflammation is the underlying cause. Two endoscopic biopsies were taken from each of the gastric antrum and fundus in 25 asymptomatic controls with a normal endoscopy (median age 54 range 13-83 years), and 33 patients with erosive oesophagitis (median age 52, 11-78 years). No patient had taken acid suppression therapy or antibiotics for at least 1 month. Sections were stained with haematoxylin and eosin and Giemsa stain and examined in a blinded fashion by one pathologist for the presence of gastritis (Sydney classification) and Helicobacter pylori. Chronic gastritis was common in both groups, but was usually mild. In Helicobacter pylori-negative subjects, there was significantly less chronic gastritis in the antrum and the fundus in oesophagitis patients than in controls (p < 0.05). When present, gastric atrophy was usually antral and mild in severity. There was no difference in the incidence of gastric atrophy in patients with oesophagitis compared with controls (24% compared with 40%; p > 0.05). Chronic gastritis is not more common in patients with oesophagitis, and is unlikely to play a part in the pathogenesis of this disease.

Adolescent↗
PubMed2000

Early changes of ileoanal pouch mucosa in patients with ulcerative colitis.

BACKGROUND/AIMS: Following closure of the protective ileostomy the mucosa of ileoanal pouches undergoes characteristic changes, which are thought to be caused by the new luminal environment Conventional histopathology and immunohistochemical markers were compared in serial pouch biopsies from patients with ulcerative colitis (UC) in the early period of function. METHODS: Biopsy specimens were obtained from nine patients during ileostomy closure, 24 h after the first bowel action, then 6 days, 6 weeks and 3 months postoperatively. Cryostat sections were stained with haematoxylin and eosin (H&E) for assessment of mucosal inflammation and morphometry, and for lymphocyte subtypes (CD3, CD4, CD8), macrophages (CD68), common leucocyte antigen (CD45), and HLA-DR, using a three-stage immunoperoxidase reaction. RESULTS: Within 5 days of pouch function the index for mucosal atrophy (villous height/total mucosal thickness ratio) decreased significantly from a median (range) of 0.66 (0.39-0.69) to 0.52 (0.37-0.61)(P = 0.02). Intraepithelial lymphocyte counts diminished from 10.1 (5.6-21.1) to 7.0 (2.2-8.2)(P = 0.007) per 100 epithelial cells and remained so. In the lamina propria, apart from a transient increase in CD3 positive cells at 5 days (from 92.7 (58-165) to 100.5 (57-234) per unit area; P = 0.038), no significant changes were observed. H&E grading and HLA-DR expression remained unchanged. CONCLUSIONS: While there was no significant change in mucosal morphology and mucosal leucocyte subpopulations after 24 h of pouch function, the ileal pouch mucosa in UC patients had responded significantly within 5 days. Further studies into cell function and signalling are required.

Adult↗
PubMed2000

The inflammatory response within Dukes' B colorectal cancers: implications for progression of micrometastases and patient survival.

OBJECTIVES: The aim of this study was to determine the relationship between the inflammatory response in primary colorectal carcinomas, patient outcome, and the fate of bone marrow micrometastases. METHODS: The populations studied were a) 155 consecutive patients with Dukes' B colorectal cancer and follow-up for a mean of 5 yr, from the Mercy Hospital, Cork, and b) 260 consecutive patients with rectal carcinoma Dukes' B and follow-up for >10 yr, from St. Mark's Hospital, London. The primary tumor was assessed for the Jass and "Crohn's-like" lymphoid reactions. In 36 consecutive patients, bone marrow aspirates were examined for micrometastases before and > or = 6 months postoperatively. RESULTS: The relationship between prognosis and the inflammatory reactivity in the tumors was similar in both populations. In the Mercy group there were two deaths among 40 patients who had coexistent Jass and Crohn's-like infiltrates. This contrasted with 25 deaths among 58 patients in whom both infiltrates were absent (p < 0.005). Results were intermediate in cases in which either type of inflammatory reaction was present alone. In the St. Mark' s patients similar prognostic differences were sustained for up to 10 yr. Bone marrow micrometastases were present in 12/36 patients preoperatively and in 14/36 postoperatively. Seven of 12 patients with preoperative micrometastases were negative postoperatively, indicating clearance of tumor cells. Nine of 24 who tested negative preoperatively had micrometastases postoperatively. The clearance and presence of postoperative micrometastases was related to the immunological responses in the primary tumor. CONCLUSIONS: These results demonstrate an association between the inflammatory reaction, prognosis, and clearance of micrometastases, indicating a systemic antitumor reaction that confers a survival advantage.

Aged↗
PubMed1999

Early expression of cyclo-oxygenase-2 during sporadic colorectal carcinogenesis.

Regular administration of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the incidence of colorectal cancer by targeting cyclo-oxygenase-2 (Cox-2), a key enzyme in arachidonic acid metabolism. To evaluate the role of Cox-2 in sporadic colorectal cancer development, Cox-2 expression was investigated by immunohistochemistry in 85 adenomas, 53 carcinomas, 34 hyperplastic lesions and 104 samples of histologically normal mucosa adjacent to adenoma or carcinoma. In addition, Cox-2 mRNA expression was assessed by reverse transcription-polymerase chain reaction (RT-PCR) in six adenomas and 14 carcinomas with paired grossly normal mucosa. Immunohistochemistry for the proliferation-associated antigen Ki-67 and in situ end labelling for demonstrating apoptotic bodies were also used to analyse the associations between Cox-2 expression and proliferation and apoptosis. Cox-2 protein expression was increased in 76/85 (89.4 per cent) adenomas and 44/53 (83.0 per cent) carcinomas compared with normal mucosa. Cox-2 protein expression was unrelated either to the degree of dysplasia or to the size of the adenomas (p > 0.50, p > 0.10, respectively) or to differentiation, Dukes stage or lymph node metastasis of carcinomas (all p > 0.50). Interestingly, 20/34 (58.8 per cent) hyperplastic lesions adjacent to adenomas or carcinomas displayed expression higher than in normal mucosa (18.3 per cent) (p < 0.0001) but lower than in adenomas or carcinomas (p < 10(-5), p < 0.001, respectively). There were no correlations between Cox-2 protein expression and proliferative or apoptotic index in either adenomas or carcinomas (all p > 0.25). Cox-2 mRNA expression was significantly increased in adenomas and carcinomas compared with normal mucosa (p < 0.005, p < 0.001, respectively). There were no differences between adenomas and carcinomas in either protein or mRNA levels (p > 0.25, p > 0.90, respectively). These data indicate that enhanced expression of Cox-2 occurs early during colorectal carcinogenesis and may contribute to tumour formation.

Adenoma↗
PubMed1999

Changes in the expression of syndecan-1 in the colorectal adenoma-carcinoma sequence.

Syndecan-1, a transmembrane heparan sulphate proteoglycan (HSPG), functions as a matrix receptor on the basal surface of epithelial cells. It also co-localizes with E-cadherin at the lateral cell surface where its function is uncertain. Tumour development in the large bowel is associated with loss of normal epithelial adhesion and altered patterns of expression of cell adhesion molecules, possibly including syndecan-1. To evaluate changes in syndecan-1 expression during the development of colorectal neoplasia, 59 adenomas and 20 carcinomas arising from adenomas were investigated by immunohistochemistry. The staining intensity and distribution of syndecan-1 and E-cadherin in sequential sections was examined, semi-quantified and compared. Staining of syndecan-1 and E-cadherin was uniform in normal colorectal epithelial cells, and located at the basolateral surface. No significant change was seen in either molecule in mildly or moderately dysplastic adenomas. A significant reduction in expression of both syndecan-1 and E-cadherin was seen in severely dysplastic epithelium as compared to moderate dysplasia (P = 0.001 and P = 0.004 respectively). Similarly, there was a significant reduction of both molecules in carcinomas compared with associated adenomas (syndecan-1 P = 0.00003; E-cadherin P = 0.002). In both cases the loss of syndecan-1 expression was more striking than that of E-cadherin. Previous in vitro studies have shown that epithelial cells made deficient in syndecan-1 cease to express E-cadherin, suggesting a causal association. Our results support these findings and indicate that disruption of cell-matrix adhesion is critical in colorectal carcinogenesis, probably preceding changes in the purely homotypic cell-cell adhesion mediated by E-cadherin.

Adenoma↗
PubMed1998

The APC variants I1307K and E1317Q are associated with colorectal tumors, but not always with a family history.

Classical familial adenomatous polyposis (FAP) is a high-penetrance autosomal dominant disease that predisposes to hundreds or thousands of colorectal adenomas and carcinoma and that results from truncating mutations in the APC gene. A variant of FAP is attenuated adenomatous polyposis coli, which results from germ-line mutations in the 5' and 3' regions of the APC gene. Attenuated adenomatous polyposis coli patients have "multiple" colorectal adenomas (typically fewer than 100) without the florid phenotype of classical FAP. Another group of patients with multiple adenomas has no mutations in the APC gene, and their phenotype probably results from variation at a locus, or loci, elsewhere in the genome. Recently, however, a missense variant of APC (I1307K) was described that confers an increased risk of colorectal tumors, including multiple adenomas, in Ashkenazim. We have studied a set of 164 patients with multiple colorectal adenomas and/or carcinoma and analyzed codons 1263-1377 (exon 15G) of the APC gene for germ-line variants. Three patients with the I1307K allele were detected, each of Ashkenazi descent. Four patients had a germ-line E1317Q missense variant of APC that was not present in controls; one of these individuals had an unusually large number of metaplastic polyps of the colorectum. There is increasing evidence that there exist germ-line variants of the APC gene that predispose to the development of multiple colorectal adenomas and carcinoma, but without the florid phenotype of classical FAP, and possibly with importance for colorectal cancer risk in the general population.

Adult↗
PubMed1998

Population based randomized study of uptake and yield of screening by flexible sigmoidoscopy compared with screening by faecal occult blood testing.

OBJECTIVES: To compare the feasibility of mass screening by flexible sigmoidoscopy with screening by faecal occult blood testing (Haemoccult) and both tests combined. DESIGN: Patients were randomised to screening by flexible sigmoidoscopy, faecal blood testing, or both tests. The flexible sigmoidoscopy examinations were performed by a general practitioner. SETTING: General practice. SUBJECTS: 3744 patients aged 50-75 years. MAIN OUTCOME MEASURES: Uptake, positive results, detection of neoplasia, complications, and recall for diagnostic colonoscopy. RESULTS: Uptake was significantly higher in the flexible sigmoidoscopy group (46.6%) than in the faecal blood test group (31.6%; P<0.001) or than in the group having both tests (30.1%; P<0.001). Telephone reminders increased uptake of sigmoidoscopy to 61.8%. In total, 1116 sigmoidoscopy examinations were performed without major complication. Polyps were found in 19. 3% (95% confidence interval 17.0% to 21.6%) but only 6.8% (5.3% to 8. 3%) had adenomas and 2.4% (1.5% to 3.3%) "high risk" adenomas. Cancer was detected in four subjects. The faecal blood test yielded positive results in 0.8% (0.2% to 1.4%) but missed at least one cancer and 30 cases of adenoma which were found by sigmoidoscopy in the combined group. Use of histological criteria-shown elsewhere to correlate with future risk of colorectal cancer-to select "positive" patients could reduce recall for diagnostic colonoscopy from about 20% to less than 5%. CONCLUSIONS: Some of the predicted obstacles to screening with flexible sigmoidoscopy are surmountable. Clear evidence relating to efficacy will be obtained only from a randomised controlled trial.

Aged↗
PubMed1998

Predicting the risk of metachronous colorectal cancer in patients with rectosigmoid adenoma using quantitative pathological features. A case-control study.

The prognostic value of quantitative pathological features in rectosigmoid adenomas was investigated, in search of more precise identifiers of adenoma-bearing patients at high risk of metachronous colorectal cancer. In a "nested case-control study" design, 21 cases with metachronous colon cancer during an average follow-up time of 16 years (range 3-30 years) after polypectomy and 67 controls were selected from a cohort of 1618 patients. The most advanced adenoma of each patient was analysed. Cases were matched with up to three controls simultaneously for size, grade of dysplasia, histological type, and number of adenomas, as well as for duration of follow-up. The patients did not undergo any post-polypectomy surveillance. Geometric characteristics of tumour nuclei, the arrangement of nuclei in the epithelium, and glandular changes were measured, and mitoses were counted. Several quantitative features measuring nuclear polymorphism and crowding showed significant prognostic value, while those measuring glandular changes and mitotic activity did not. A multivariate combination of the average distance between nuclei and the standard deviation of nuclear area discriminated an unfavourable group (n = 44) with 17 metachronous cancers from a favourable group (n = 44) with four metachronous cancers (P = 0*001, RR = 6*3). With the optimum cut-off, 28 patients without any metachronous cancer were discriminated from a group of 60 patients with 21 metachronous cancers. In conclusion, in the present study, quantitative pathological features assessed in rectosigmoid adenomas showed prognostic value additional to traditional measures. These features may therefore be useful in guiding post-polypectomy surveillance.

Adenoma↗
PubMed1998

Defects in mismatch repair occur after APC mutations in the pathogenesis of sporadic colorectal tumours.

The roles of the intrinsic mutation rate and genomic instability in tumorigenesis are currently controversial. In most colorectal tumours, it is generally supposed that the first mutations occur at the adenomatous polyposis coli (APC) locus; APC mutations are thought to provide cells with a selective advantage but have no known effect on the mutation rate. It has also been suggested that genomic instability is the initiating event in colorectal tumorigenesis and, if this is true, mutations of DNA mismatch repair (MMR) genes (or at similar loci) are the most likely candidates. If defective MMR precedes APC mutations, the APC mutations of colon tumours with defective MMR and hence replication errors (RER+) should differ from those of RER- tumours, in at least three specific ways: (1) a higher frequency of allele loss at APC in RER- tumours; (2) more frameshift than nonsense mutations in RER+ tumours; and (3) APC mutations in simple repeat sequences [(N)n, (N1N2)n, or (N1N2N3)n] in RER+ tumours. We found no evidence that sporadic RER+ and RER- colon cancers (including cell lines) differ in any of these three ways. Although it remains possible that MMR is abnormal in tumours from HNPCC families before APC mutations occur, it is likely that in sporadic colon tumours, APC mutations, rather than genomic instability, are the initiating events in tumorigenesis.

Alleles↗
PubMed1998

Patterns of distribution of endoscopic and histological changes in the ileal reservoir after restorative proctocolectomy for ulcerative colitis. A long-term follow-up study.

OBJECTIVE: This study was undertaken to assess the long-term macroscopic appearance of the ileal reservoir after restorative proctocolectomy for ulcerative colitis, to determine whether there is any correlation between macroscopic and histological changes and whether the distribution of these is homogeneous, focal or patchy. BACKGROUND: No study has examined the macroscopic appearance of the ileal reservoir over a long period and it is still unknown to what degree histological changes are diffuse or patchy. Moreover, the relationship between macroscopic and histological changes is poorly understood. METHOD: Fifty-nine patients were examined by one clinician (PSC) 5.3-14.5 years (median 8.2 years) postoperatively. A rigid sigmoidoscopy of the reservoir was performed. Four zones in the posterior midline at 5-cm intervals from the ileoanal anastomosis were inspected. At each level a macroscopic score of severity of inflammation was given and a biopsy taken. The degree of acute and chronic inflammation was assessed using a histopathological scoring system. RESULTS: All reservoirs showed macroscopic abnormalities, which were more marked distally in 14 (24%). There was no case in which severity of inflammation was greater in proximal than in distal zones. Endoscopy overall correlated with both acute and chronic histological changes. On histological examination the patients could be divided into three groups as follows: (1) all four biopsies were normal (group 1, n = 8, 14%), (2) the score of acute and chronic inflammation decreased from distal to proximal zones (group 2, n = 25, 42%) and (3) all four biopsies were abnormal with the same score (group 3, n = 26, 44%). The latter group significantly correlated with a present or past history of pouchitis. CONCLUSION: The study has shown that when there is a gradation of inflammation within the ileal reservoir this is more severe in distal than in proximal zones.

Adolescent↗
PubMed1998

Imbalance between proliferation and apoptosis in the development of colorectal carcinoma.

To evaluate the relationship between cell proliferation and apoptosis in sporadic colorectal carcinogenesis, immunohistochemistry for proliferation-associated antigen Ki-67 and in situ end labelling for identifying apoptotic bodies were performed on paraffin sections from 59 adenomas and 22 carcinomas. These results were correlated with the expression of the proliferation and apoptosis modulators Bcl-2 and p53. Carcinomas showed increased proliferation and apoptosis compared with adenomas (P<0.0001, P<0.001, respectively). There were positive linear correlations between proliferation and apoptosis in adenomas and carcinomas (P<0.02, P<0.05, respectively). The proliferative rate increased significantly from mild to moderate, and from moderate to severe dysplasia (P<0.002, P<0.001, respectively). Apoptotic rate also increased in this sequence, but the increases did not reach statistical significance (both P>0.05). Expression of Bcl-2 was associated with lower apoptotic rate in adenomas (P<0.025) but not in carcinomas (P>0.25), whereas p53 expression was correlated with higher proliferative rate in both adenomas and carcinomas (P<0.01, P<0.05, respectively). An inverse relationship between Bcl-2 and p53 expression was seen in both adenomas and carcinomas (P<0.05, P<0.005, respectively). These data suggest that the normal balance between proliferation and apoptosis is disturbed in colorectal carcinogenesis, both being increased, but proliferation occurs in excess. Bcl-2 and p53 may each play a role in modulating cell apoptosis or proliferation during the development of colorectal carcinoma.

Adenoma↗