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P Quirke

Publications and source records attributed to P Quirke.

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

Methylation and colorectal cancer.

Statistics rate colorectal adenocarcinoma as the most common cause of cancer death on exclusion of smoking-related neoplasia. However, the reported accumulation of genetic lesions over the adenoma to adenocarcinoma sequence cannot wholly account for the neoplastic phenotype. Recently, heritable, epigenetic changes in DNA methylation, in association with a repressive chromatin structure, have been identified as critical determinants of tumour progression. Indeed, the transcriptional silencing of both established and novel tumour suppressor genes has been attributed to the aberrant cytosine methylation of promoter-region CpG islands. This review aims to set these epigenetic changes within the context of the colorectal adenoma to adenocarcinoma sequence. The role of cytosine methylation in physiological and pathological gene silencing is discussed and the events behind aberrant cytosine methylation in ageing and cancer are appraised. Emphasis is placed on the interrelationships between epigenetic and genetic lesions and the manner in which they cooperate to define a CpG island methylator phenotype at an early stage in tumourigenesis. Finally, the applications of epigenetics to molecular pathology and patient diagnosis and treatment are reviewed.

Adenocarcinoma↗
PubMed2001

Viewing apoptosis through a 'TUNEL'.

Apoptosis has an important role in carcinogenesis and cancer treatment. The end result of this complex pathway is the formation of apoptotic bodies. These can be difficult to quantify accurately, but quantitation is important if we wish to study this process. Several techniques are available which can help. 'TUNEL' is discussed, with its potential drawbacks, and newer antibody techniques, such as M30 and caspase 3, are then reviewed.

Animals↗
PubMed2001

Overexpression of HER2/neu in solid tumours: an immunohistochemical survey.

AIMS: Using a standardized immunohistochemical assay we have evaluated 575 primary neoplasms of different histogenesis to determine the incidence of HER2 overexpression in some of the most common categories of human solid neoplasms. This study addresses the variable incidence of HER2 overexpression previously published for some tumour types. METHODS AND RESULTS: The immunohistochemical staining was performed on paraffin sections of surgical specimens and a well-defined scoring system based upon numbers of HER2 receptors expressed on the cell surface was applied. Overexpression of HER2 as defined as a HER2 score of equal or greater than 2 was seen in breast cancer (22%), pulmonary adenocarcinoma (28%), colorectal adenocarcinomas (17%), pulmonary squamous (11%) and gastric adenocarcinomas (11%). As expected, the proportion of cases with a HER2 score of 3 was highest in breast cancer. Contrary to published results prostate and pancreas adenocarcinomas showed a very low incidence of HER2 overexpression. CONCLUSIONS: Overexpression of HER2 is detected immunohistochemically in a proportion of epithelial neoplasms of diverse histogenesis in addition to ductal breast cancer. The standardized format of the assay will allow comparative analyses of studies performed at different institutions.

Female↗
PubMed2001

Evaluation of the role of pre-operative magnetic resonance imaging in the management of rectal cancer.

OBJECTIVES: This study assesses the ability of body coil magnetic resonance imaging (MRI) to pre-operatively stage mural penetration, nodal status and circumferential resection margin (CRM) involvement of rectal cancer. PATIENTS AND METHODS: Between 1995 and 1997, MRI using a body coil was performed in consecutive patients with primary rectal carcinomas. Group A: 67 patients underwent surgery without long course neo-adjuvant therapy. Predicted tumour stage was compared to the histology of the specimen. Group B: 21 patients with MRI evidence of advanced disease, underwent long course neo-adjuvant therapy followed by repeat MRI prior to surgery. The second scan assessed response to treatment and likelihood of CRM involvement at subsequent surgery. RESULTS: Group A: Accuracy of pre-operative staging was: 'T' stage - 54%, 'N' stage - 77%, involvement of CRM by tumour - 97%. Group B: After long course neo-adjuvant therapy the second MRI scan was 95% accurate in predicting CRM involvement by tumour. CONCLUSION: In this study pre-operative rectal cancer staging with MRI and a body coil lacks accuracy in predicting mural penetration and nodal involvement. Body coil MRI can accurately predict the potential for CRM involvement. This technique may help determine which patients require long course neo-adjuvant therapy.

Journal Article↗
PubMed2001

Circumferential resection margin involvement: an independent predictor of survival following surgery for oesophageal cancer.

BACKGROUND: For rectal carcinoma, the presence of tumour within 1 mm of the circumferential margin is an important independent prognostic factor for both local recurrence and survival. Similar prospective data have not been reported for oesophageal carcinoma and we wished to ascertain the prognostic importance of this variable following potentially curative resection for oesophageal carcinoma. AIM: To prospectively assess the impact of circumferential margin involvement (tumour within 1 mm) following potentially curative resection for oesophageal carcinoma. PATIENTS AND METHODS: In a prospective study, resection specimens of 135 patients treated with potentially curative oesophageal resection alone were studied for the presence of tumour within 1 mm of the circumferential margin (margin positive), using inked margins and cross sectional slicing of the specimen. All tumours were also staged using the 1987 UICC TNM classification. Patients were followed for a mean of 19 months, and overall and cancer specific survival analysed. RESULTS: The finding of tumour cells within 1 mm of the circumferential margin (CRM+) was a significant and independent predictor of survival following potentially curative oesophageal resection. Overall, 64 (47%) patients were CRM+. Median survival in this group was 21 months compared with 39 months in the CRM- group (p=0.015). The impact of CRM status on survival was only seen in patients with a low nodal metastatic burden (<25% nodes positive). The odds ratio for the risk of dying from oesophageal cancer was 2.08 when the CRM was involved (p=0.013). CONCLUSIONS: The presence of tumour within 1 mm of the circumferential margin following potentially curative resection for oesophageal carcinoma is an important independent prognostic variable and should be reported routinely.

Adenocarcinoma↗
PubMed2000

A comparison of microsatellite instability in early onset gastric carcinomas from relatively low and high incidence European populations.

We have investigated the genetic basis of gastric carcinomas occurring in patients aged under 40 years from a Portuguese population with a relatively high incidence of gastric cancer. We analysed a panel of 12 microsatellite loci in DNA extracted from gastric carcinomas arising in 16 patients aged 24-39 years from Braga, Portugal. Overall, microsatellite instability (MI) in at least 1 locus was detected in 44% (7 of 16) of carcinomas. A single patient demonstrated a mutator phenotype suggestive of the hereditary nonpolyposis colorectal cancer syndrome with instability in 82% of loci. This carcinoma showed loss of expression of the hMLH1 mismatch repair protein. In a previous study, we found no evidence of MI among 10 cases of early onset gastric carcinomas from an English population, which has a relatively low incidence of gastric cancer. Comparing the 2 series, we found that there was a significant difference (p = 0.04) in the prevalence of MI (at least 1 marker affected). This geographical difference in low-level MI may be related to a significantly higher prevalence of background chronic atrophic gastritis (8 of 16 vs. 0 of 8) and Helicobacter pylori infection (15 of 16 vs. 2 of 8) in Portuguese carcinomas compared with English cases. Genetic mechanisms underlying the hereditary non-polyposis colorectal cancer syndrome may play a role in a small number of early onset gastric carcinomas. The difference in prevalence of low-level MI between these relatively high and low incidence European populations requires further investigation.

Adult↗
PubMed2000

Assessing the relative costs of standard open surgery and laparoscopic surgery in colorectal cancer in a randomised controlled trial in the United Kingdom.

The role of laparoscopic surgery for the treatment of colorectal cancer is being explored in a multi-centre, randomised clinical trial in the UK, the MRC CLASICC Trial (Conventional versus Laparoscopic-assisted Surgery in Colorectal Cancer). An important end-point of the trial is the cost-effectiveness of laparoscopic surgery compared with that of conventional open surgery. The economic evaluation of this trial has been modelled on that in a similar trial being conducted in the USA in colon cancer. The aim of this paper is to discuss the rationale for modelling the UK trial on the US trial, and to describe the adaptations necessary for the UK trial. The parallel design of the economic evaluation in both trials will provide a unique opportunity to compare the cost implications of incorporating laparoscopic surgery in the UK and the USA, and to determine any cross-cultural differences. The UK trial will also provide information about the cost-effectiveness of laparoscopic surgery in rectal cancer.

Colorectal Neoplasms↗
PubMed2000

Defective hMSH2/hMLH1 protein expression is seen infrequently in ulcerative colitis associated colorectal cancers.

BACKGROUND: Ulcerative colitis is associated with an increased risk of colorectal cancer above that of the normal population. The relative risk correlates with the extent and duration of the disease but the genetic basis of ulcerative colitis associated cancer risk is not known. AIMS: To assess the prevalence of microsatellite instability and mismatch repair gene abnormalities in ulcerative colitis associated colorectal cancer. PATIENTS: Forty six patients with colorectal cancer, with a previous histological diagnosis of ulcerative colitis. METHODS: The frequency of microsatellite instability and/or immunohistochemical expression of hMSH2 and hMLH1 was assessed. Thirty three cases were investigated using both approaches. RESULTS: Although 6/41 (14.6%) cases showed microsatellite instability at one or more markers, only one case (2. 4%) exhibited high level instability (at least two markers affected). Of 38 cases which were assessed using antibodies against hMSH2 and hMLH1, only one case (2.6%) showed loss of expression. This case, which showed loss of hMSH2 expression, was the same case which exhibited high level microsatellite instability. The 33 cases which were investigated using both approaches showed that loss of expression of either hMSH2 or hMLH1 was not seen in any case which exhibited microsatellite instability in no more than one marker. CONCLUSIONS: This study suggests that both high level microsatellite instability and loss of expression of hMSH2/hMLH1 are infrequent events in ulcerative colitis associated colorectal cancers. Low level microsatellite instability was not associated with loss of expression of either hMSH2 or hMLH1.

Biomarkers↗
PubMed2000

Direct multiplex amplification of DNA from a formalin fixed, paraffin wax embedded tissue section.

The extraction of DNA from formalin fixed, paraffin wax embedded tissue can be problematical, with long protocols producing low yields. This report describes a very simple and useful method for amplifying DNA from formalin fixed, paraffin wax embedded tissue without the need for prior DNA extraction. This method allows direct polymerase chain reaction (PCR) based molecular analysis of fixed tissue. It is an invaluable method if clinical biopsy specimens are to be investigated, because extraction of uncontaminated DNA from such small samples can be very difficult or even impossible. It will also facilitate the study of intratumour heterogeneity, with the analysis of multiple small areas from within a single tumour section. In addition, this method can be used for other samples where only a few tests are to be carried out and a stock of DNA is not required, thus shortening the analysis time.

Biopsy↗
PubMed1999

Preimplantation genetic diagnosis using fluorescent polymerase chain reaction: results and future developments.

PURPOSE: Fluorescent polymerase chain reaction (PCR) is a multipurpose technique that can be used for diagnosing sex, single-gene defects, and trisomies as well as determining DNA fingerprints from single cells. However, its effectiveness must be assessed before clinical preimplantation genetic diagnosis (PGD) application. METHODS: Single and multiplex fluorescent PCR was applied to single cells and blastomeres. RESULTS: Fluorescent PCR can be used to diagnose sex from blastomeres and has been successfully applied in a clinical PGD sexing program resulting in a confirmed pregnancy. A further major advantage of fluorescent PCR is the ability to multiplex, providing multiple diagnoses and DNA fingerprints with a high reliability (approximately 75% for trisomy, 86% for DNA fingerprint) and good accuracy (70-80%). Allele dropout in multiplex PCR is approximately 20% per allele and does not appear to be associated with the fragment size. CONCLUSIONS: Fluorescent PCR is a powerful technique for PGD, and the effects of allele dropout must be considered, particularly in multiplex PCR.

Blastomeres↗
PubMed1999

Flat adenomas.

Explore the source record for details and available documents.

Adenoma↗
PubMed1999

Choice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair.

BACKGROUND: Despite intensive research into the molecular abnormalities associated with colorectal cancer (CRC), no diagnostic tests have emerged which usefully complement standard histopathological assessments. AIMS: To assess the feasibility of using immunohistochemistry to detect replication error (RER) positive CRCs and determine the incidence of RER positivity within distinct patient subgroups. METHODS: 502 CRCs were analysed for RER positivity (at least two markers affected) and/or expression of hMSH2 and hMLH1. RESULTS: There were 15/30 (50%) patients with metachronous CRCs, 16/51 (31%) with synchronous CRCs, 14/45 (31%) with a proximal colon carcinoma, and 4/23 (17%) who developed a CRC under the age of 50 showed RER positivity. However, 0/54 patients who developed a solitary carcinoma of the rectum/left colon over the age of 50 showed RER positivity. Immunohistochemical analysis revealed that 66/66 (100%) RER positive carcinomas were associated with complete lack of expression of either hMSH2 or hMLH1. This correlation was confirmed using a further 101 proximal colon carcinomas. Patients with a mismatch repair defective carcinoma showed improved survival but a 5.54 times relative risk of developing a metachronous CRC. A prospective immunohistochemical study revealed 13/117 (11%) patients had a mismatch repair defective carcinoma. A fivefold excess of hMLH1 defective cases was noted. CONCLUSIONS: All RER positive carcinomas were identified by the immunohistochemical test. This is the first simple laboratory test which can be performed routinely on all CRCs. It will provide a method for selecting patients who should be investigated for HNPCC, offered long term follow up, and who may not respond to standard chemotherapy regimens.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Correlation between epithelial cell proliferation and histological grading in gastric mucosa.

AIM: To determine if there is a correlation between the histological findings in the gastric mucosa and the degree of cell proliferation in gastric antral biopsies. METHODS: Cell proliferation in gastric antral biopsies was determined by in vitro bromodeoxyuridine labelling. Histological sections were assessed using the Sydney System. RESULTS: There was a positive correlation between antral mucosal cell proliferation and the acute inflammatory cell infiltrate (r = 0.29; p = 0.03). There was a stronger correlation with the chronic inflammatory cell infiltrate (r = 0.53; p < 0.0001) and the density of H pylori colonisation (r = 0.54; p < 0.0001). There was no correlation between gastric epithelial proliferation and the degree of atrophy. Stepwise multiple regression indicates that the only independent predictor of epithelial cell proliferation is the density of H pylori colonisation (p < 0.0001). CONCLUSIONS: H pylori increases gastric epithelial cell proliferation through the mucosal inflammatory response and probably by other means. The strong correlation between epithelial proliferation, the chronic inflammatory cell infiltrate, and the density of H pylori colonization may have implications for gastric carcinogenesis.

Adolescent↗
PubMed1999

Expression of the 17-1A antigen in gastric and gastro-oesophageal junction adenocarcinomas: a potential immunotherapeutic target?

BACKGROUND: A murine monoclonal antibody against the 17-1A epithelial antigen has been shown to be a useful adjuvant therapy in colorectal cancer. Its clinical use could be extended to patients with upper gastrointestinal adenocarcinoma. AIM: To determine the distribution of the antigen in gastric and oesophageal adenocarcinoma. METHODS: The activity of two monoclonal antibodies active against 17-1A epithelial antigen was studied in gastric and gastro-oesophageal junction adenocarcinomas: fresh frozen tissue from both the carcinoma and adjacent mucosa was stained using immunocytochemistry with a murine monoclonal antibody (17-1A edrecolomab, Glaxo Wellcome); paraffin embedded tissue was stained using the humanised monoclonal antibody 3622W94 (Glaxo Wellcome). RESULTS: 29 of 33 cancers (88%) stained with the murine antibody and 39 of 40 (98%) with the humanised antibody. The degree of staining was greater in well differentiated and moderately differentiated tumours. There was no staining of the normal background gastric or oesophageal mucosa, but areas of intestinal metaplasia stained intensely. The humanised monoclonal 3622W94 antibody produced more intense staining than the murine antibody. CONCLUSIONS: The high incidence of expression of the 17-1A antigen in patients with gastric and gastro-oesophageal junction adenocarcinomas suggests a potential role for these antibodies as an adjuvant treatment for these common cancers.

Adenocarcinoma↗
PubMed1998

WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors.

Wnt family members are critical to many developmental processes, and components of the Wnt signaling pathway have been linked to tumorigenesis in familial and sporadic colon carcinomas. Here we report the identification of two genes, WISP-1 and WISP-2, that are up-regulated in the mouse mammary epithelial cell line C57MG transformed by Wnt-1, but not by Wnt-4. Together with a third related gene, WISP-3, these proteins define a subfamily of the connective tissue growth factor family. Two distinct systems demonstrated WISP induction to be associated with the expression of Wnt-1. These included (i) C57MG cells infected with a Wnt-1 retroviral vector or expressing Wnt-1 under the control of a tetracyline repressible promoter, and (ii) Wnt-1 transgenic mice. The WISP-1 gene was localized to human chromosome 8q24.1-8q24.3. WISP-1 genomic DNA was amplified in colon cancer cell lines and in human colon tumors and its RNA overexpressed (2- to >30-fold) in 84% of the tumors examined compared with patient-matched normal mucosa. WISP-3 mapped to chromosome 6q22-6q23 and also was overexpressed (4- to >40-fold) in 63% of the colon tumors analyzed. In contrast, WISP-2 mapped to human chromosome 20q12-20q13 and its DNA was amplified, but RNA expression was reduced (2- to >30-fold) in 79% of the tumors. These results suggest that the WISP genes may be downstream of Wnt-1 signaling and that aberrant levels of WISP expression in colon cancer may play a role in colon tumorigenesis.

Amino Acid Sequence↗