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P Quirke

Publications and source records attributed to P Quirke.

At least 19 recordsLinked to original sources
PubMed2003

Quantitative analysis of colorectal tissue microarrays by immunofluorescence and in situ hybridization.

The accuracy and reliability of in situ studies may be compromised by qualitative interpretations. Quantitation imposes a greater degree of objectivity, is more reproducible, and facilitates the clarity of definitions. The aim of this study was to validate the utility of laser imaging systems for the in situ quantitative analysis of gene expression in tissue microarrays. Immunofluorescence was employed to quantify the expression of the tumour suppressor p53, a marker of proliferation (Ki67), an endothelial cell marker (CD31), and the mismatch repair proteins human Mut L homologue 1 and human Mut S homologue 2 in an arrayed series of colorectal tissues (n = 110). Quantitative data on this panel of antigens were compared objectively with qualitative scoring of immunohistochemical chromogen deposition. In addition, the expression of vascular endothelial growth factor (VEGF)-A, placental growth factor, hepatocyte growth factor, and c-Met mRNA was quantified by phosphor image analysis of in situ hybridization reactions. The quantified data on p53, Ki67, and CD31 expression were significantly associated with the pathologist's score (p < or = 0.001). While hepatocyte growth factor and placental growth factor were not up-regulated, c-Met expression was increased up to 2.5-fold and the median VEGF-A expression was elevated 4-fold (p = 0.003) in this series of colorectal tumours. Laser imaging systems are therefore feasible for high-throughput, quantitative profiling of tissue microarrays.

Biomarkers, Tumor↗
PubMed2003

Genomics in colorectal cancer: godsend or gimmick?

Genomics and the new techniques it embraces, such as cDNA and tissue arrays, comparative genomic hybridization and single nucleotide polymorphism analysis, offer the opportunity to generate massive amounts of data relating to screening, aetiology, diagnosis, prognostication and optimal treatment in colorectal cancer. To make progress, studies must be designed to stringently test these new technologies and compare them to the tried and tested gold standards. This is best done in the form of large randomized controlled trials. Genomics undoubtedly offers the prospect of exciting new developments in the field of colorectal cancer but these should be regarded with caution until they are proved superior to present practices and models.

Colorectal Neoplasms↗
PubMed2003

Modern management of colorectal cancer--a pathologist's view.

Colorectal cancer is an increasingly significant cause of both mortality and morbidity due to wider adoption of the Western lifestyle and a progressively ageing population. Recently steps forward have been made both in surgical and chemoradiotherapeutic management of this disease. Well performed total mesorectal excision surgery has now become the gold standard for rectal cancer resection. Several prognostic markers, both clinicopathological and molecular, have been identified allowing better patient counselling and targeting of treatment. The rationale for patient selection, timing and dose of radiotherapy has been further elucidated. New chemotherapy agents are under trial and predictive factors allowing selection of those patients most likely to respond to them have been identified. Many of these factors will increase in importance as colorectal cancer becomes a chronic disease with lengthening survival times. As we will discuss the pathologist has important roles in all of these developments and at all stages of colorectal cancer management.

Colorectal Neoplasms↗
PubMed2002

DNA markers predicting benefit from adjuvant fluorouracil in patients with colon cancer: a molecular study.

BACKGROUND: Present clinical algorithms assign adjuvant chemotherapy according to prognosis, but clinical decision-making would be greatly improved if reliable predictive markers were available to identify which subsets of patients benefit most from treatment. We examined molecular markers in preserved tissue from patients with Dukes' B or C colon cancer randomised to receive, or not, adjuvant fluorouracil, and assessed each marker's prognostic and predictive value. METHODS: Formalin-fixed paraffin-embedded paired normal and tumour samples were obtained from 393 patients with colon cancer from the UK AXIS trial of postoperative portal vein infusion fluorouracil versus control. We measured loss of heterozygosity (LOH) and microsatellite instability at four loci: P53 (17p13), D18S61 (18q22.3), D18S851 (18q21.1), and DP1 (5q21). The prognostic value of each marker was assessed with the log-rank test, and the predictive value by comparison of treatment hazard ratios with the chi(2) test for heterogeneity (CSH). FINDINGS: In 228 (58%) patients informative for LOH at D18S61, this marker was significantly predictive: benefit from fluorouracil was significantly greater in patients retaining heterozygosity than in those with LOH (CSH p=0.02). Conversely, LOH at D18S61 was a significant prognostic marker of improved outcome in untreated patients. 314 (80%) patients were informative for LOH at at least one of the three 17p and 18q sites, of whom half retained heterozygosity at one or more site. The effect of chemotherapy in these patients was striking (hazard ratio 0.45, 95% CI 0.28-0.73), whereas chemotherapy had no effect in patients with no retained heterozygosity (0.91; 0.56-1.48), CSH p=0.039. INTERPRETATION: Retention of heterozygosity at one or more 17p or 18q sites was associated with the ability to benefit from adjuvant fluorouracil. These results support the principle of developing molecular markers as predictive factors in treatment decisions.

Aged↗
PubMed2002

Prognosis and response to therapy in colorectal cancer.

Colorectal cancer is Europe's second biggest cancer killer. Yet despite advances in knowledge and changes in chemotherapy practice, we have not seen great strides in improved survival. Histopathological staging is at present the most accurate prognostic factor for survival and recurrence. Improvements in staging have led to the recognition of the importance of the circumferential resection margin (CRM) and how the quality of surgery influences local recurrence rates. Further refinements in staging and increasing knowledge of tumour biology will have a large contribution to play in the future.

Colorectal Neoplasms↗
PubMed2002

Pathology--a molecular prognostic approach.

Colorectal cancer affects 29,000 people and kills approximately 15,000 in England and Wales each year, most of these deaths resulting from the effects of local or distant recurrence. There is a need to give these patients accurate prognoses and individualised treatment regimens. At present, the best prognostic markers are clinicopathological. Post-genomic science and the new high throughput technologies offer unrivalled opportunities to understand the biology and molecular pathology of colorectal cancer. These technologies should be used in the context of large randomised controlled trials to identify new molecular prognostic and predictive markers and also new targets for therapy.

Biomarkers, Tumor↗
PubMed2001

Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study.

Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras in-colorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P = 0.004, HR 1.3) and overall survival (P = 0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P = 0.008, HR 1.5; overall survival P = 0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P = 0.46, HR 1.12; overall survival P = 0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer.

Adolescent↗
PubMed2001

Unlocking the archive--gene expression in paraffin-embedded tissue.

The histopathology archive represents a vast, well-characterized source of specimens covering virtually every disease and is available for molecular biological investigation. The archive has in recent years become widely used for molecular genetic analysis and DNA can be routinely extracted from formalin-fixed, paraffin-embedded tissue. More recently, archival specimens have become a source of material for extensive analysis of mRNA expression utilizing DNA microarrays, real-time quantitative reverse transcriptase polymerase chain reaction (PCR), and in situ hybridization and amplification techniques. These techniques will enable a greater understanding of the changes that occur in gene function during every stage of the development of disease and will lead to better diagnosis, better evaluation of prognosis, and better treatment through targeted therapeutic regimes.

Biological Specimen Banks↗
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↗