Mark Deakin - Academia.edu (original) (raw)

Papers by Mark Deakin

European Journal of Gastroenterology & Hepatology, 1997

Objective: To assess if therapeutic endoscopic retrograde cholangiopancreatography(ERCP) as a day... more Objective: To assess if therapeutic endoscopic retrograde cholangiopancreatography(ERCP) as a daycase procedure with a selective admission policy is safe and cost-effective. Design: An audit of case notes of patients who attended as a daycase for either a ...

International Journal of Oncology, 2004

Deregulated tumour expression of p16INK4a has previously been described in association with clini... more Deregulated tumour expression of p16INK4a has previously been described in association with clinical progression in sporadic colorectal cancer patients (CRC). Furthermore, p16INK4a promoter hypermethylation leading to gene silencing has been shown to occur in advanced colorectal tumours and has been associated with patient survival. p16INK4a is polymorphic, with variant alleles being associated with tumour progression in melanoma. In this study we have examined p16INK4a polymorphism as a marker of tumour progression in sporadic CRC. Polymorphic sites G/A(442), C/G(500), and C/T(540), were studied, these alleles obeyed Hardy Weinberg equilibrium in a control group, but not in the CRC cases. G/A(442) and CG(500) alleles were in linkage disequilibrium in both cases and controls. In controls the C/T(540) alleles demonstrated no linkage with either other site, whilst an association was demonstrated between C/G(500) and C/T(540) alleles in the cases (p=0.011). Furthermore, the distribution of C/T(540) genotypes was different between the groups (p=0.002). Within the CRC cases, patients with the GG(442) genotype were more commonly associated with decreased tumour differentiation (p=0.018), advancing Dukes' stage (p=0.006) and T-stage (p=0.007) than patients with the GA(442) and AA(442) genotypes. Patients with the CC(500) genotype were more commonly associated with decreased tumour differentiation (p=0.012), advancing Dukes' stage (p=0.015), and N-stage (p=0.031). No associations between patient C/T(540) genotype and clinical prognostic parameters were found. An analysis of patient tumour expression with p16INK4a genotype revealed patients with the CC(500) genotype were more commonly associated with reduced tumour p16 expression (p=0.046). In summary our data indicate that p16INK4a polymorphism is associated with tumour progression in patients with sporadic CRC.

World Journal of Surgery, 2008

Background The place of laparoscopic repair of perforated peptic ulcer followed by peritoneal toi... more Background The place of laparoscopic repair of perforated peptic ulcer followed by peritoneal toilet has been established, although it is not routinely practiced. This prospective study compared laparoscopic and open repair of perforated peptic ulcer disease. We evaluated whether the early results from laparoscopic repair resulted in improved patient outcome compared with conventional open repair. Methods All patients who underwent repair of perforated peptic ulcer disease during a 12-month period in our unit were included in the study. The primary end points that were evaluated were total operative time, nasogastric tube utilisation, intravenous fluid requirement, total time of urinary catheter and abdominal drainage usage, time taken to return to normal diet, intravenous/intramuscular opiate use, time to full mobilization, and total in-patient hospital stay.

Surgical Endoscopy, 2009

Percutaneous endoscopic gastrostomy (PEG) feeding tubes are required for an increasing number of ... more Percutaneous endoscopic gastrostomy (PEG) feeding tubes are required for an increasing number of patients with long-term nutritional requirements. "Buried bumper syndrome" (BBS) occurs in 2-6% of PEG placements. In the past, this has been a difficult problem to resolve. The authors aimed to design a safe and simple method of dealing with BBS that can be performed by any endoscopist on a routine endoscopic list with the patient under sedation. For 6 years, the authors have used a minimally invasive way to deal with BBS. They have successfully treated 20 BBS patients on a routine endoscopy list with the patient under sedation. The existing PEG is divided 5 cm from the skin. A pair of stent-grasping forceps is inserted via the tube. A snare then is passed via the gastroscope, caught in the stent-grasping forceps, and brought out via the PEG tube. Next, the tube is split as deeply as possible into the PEG exit site, and the snare is closed around the tube. Gentle traction is applied along the endoscope, allowing the internal bumper to concertina and pop through the mucosa. Another PEG can now be placed at a separate site, although the authors have successfully used the same tract. All the patients were followed up, with no further problems related to BBS. The authors' method is a simple way of addressing the difficult BBS problem. It can be used to remove and replace a PEG with a buried bumper on a routine endoscopy list with the patient under sedation.

Surgical Endoscopy, 2009

The role of laparoscopic ultrasound (LUS) during staging laparoscopy for pancreatic cancers is es... more The role of laparoscopic ultrasound (LUS) during staging laparoscopy for pancreatic cancers is established but remains debatable in evaluating oesophagogastric cancers. A retrospective consecutive case series consisting of patients undergoing staging laparoscopy in two centres (centre A and B) was carried out over a 5-year period (2000-2005). Patients in centre B underwent LUS following laparoscopic assessment using a 7.5-MHz probe. Staging laparoscopy in both centres was performed using a standardised three-port protocol using a 30 degrees laparoscope. All suspicious lesions were sent for histological assessment for confirmation of malignancy. There were 201 patients in centre A (83 gastric, 138 lower oesophageal/junctional cancers) and 119 patients in centre B (51 and 68, respectively). There were no differences between the two centres for patient demographics and tumour site. There was no difference between the two centres for the detection of metastatic disease using laparoscopic assessment alone (A 13% versus B 20%, p = 0.12). However, there was a significant difference (13% versus 28%, p = 0.001) with the additional use of LUS in centre B. The findings in the additional 8% (n = 9) were para-aortic lymphadenopathy (n = 5), liver metastasis (n = 3) and local extension (n = 1). Five had gastric and four lower oesophageal/junctional cancers. The negative predictive value was 6.4% for centre A and 4.5% for centre B. The addition of LUS increased the detection rate of metastasis by 8% but there was little impact on the false-negative rate. LUS is useful in detecting metastatic lymphadenopathy beyond the limits of curative resection and liver metastasis.

Surgical Endoscopy, 2014

Gallstone pancreatitis (GSP) is a common condition, accounting for 30-40 % of all pancreatitis ca... more Gallstone pancreatitis (GSP) is a common condition, accounting for 30-40 % of all pancreatitis cases. All GSP patients should undergo definitive treatment to prevent further attacks. This study aimed to investigate the long-term outcome after definitive treatment in England by cholecystectomy, endoscopic sphincterotomy (ES), or both. Hospital episode statistics data were used to identify patients admitted for the first time with GSP between January and December 2005. These patients were followed for 18 months to identify those who underwent definitive treatment. Treatment groups then were followed until December 2010 to identify readmissions with a further GSP attack as an emergency or admissions with complications of gallstone disease. 5,079 patients admitted with a first bout of GSP between January and December 2005. The in-hospital mortality rate was 7.8 %. Of those who survived the initial attack, 2,511 went on to have a cholecystectomy, 419 had an ES alone, and 496 had ES followed by cholecystectomy. Recurrent pancreatitis after definitive treatment was more common among patients treated with ES (6.7 %) than among those treated with cholecystectomy (4.4 %) or ES followed by cholecystectomy (1.2 %) (p < 0.05). Admissions with other complications attributable to gallstones in patients treated with ES alone were similar to those seen in patients who had received no definitive treatment (12.2 vs. 9.4 %). Cholecystectomy offers better protection than ES against further bouts of pancreatitis in patients with GSP, but ES is an acceptable alternative. Interval cholecystectomy in patients treated initially with ES was the most effective method of preventing further pancreatitis, and the patients who underwent treatment by ES alone remained at risk of readmission with gallstone-related problems. Patients who have undergone ES and are fit for surgery should have a cholecystectomy.

European Journal of Surgical Oncology (EJSO), 1998

To investigate the use of pre-operative chemo-irradiation in downstaging advanced rectal cancer p... more To investigate the use of pre-operative chemo-irradiation in downstaging advanced rectal cancer prior to surgical resection. We examined the pathological effects of chemo-irradiation on 24 rectal tumours and correlated the efficacy of treatment with the level of apoptosis, mitosis, P53 and bcl-2 protein expression on pre-treatment biopsies. All tumours were resectable following chemo-irradiation. Six cancers showed complete regression with no viable tumour in the resection specimen. A significant correlation was found between spontaneous tumour apoptosis and tumour regression. Our results suggest that in rectal cancer the apoptotic rate in untreated tumour tissue may predict sensitivity to radiation and cytotoxic agents. No relationship was found between regression and mitotic rate, p53 or bcl-2 expression.

Drugs, 1992

Duodenal ulcer healing depends on the degree and length of inhibition of gastric secretion and up... more Duodenal ulcer healing depends on the degree and length of inhibition of gastric secretion and upon the duration of therapy, while gastric ulcer healing is dependent mainly on the duration of therapy. Currently marketed doses of the histamine H2-receptor antagonists heal between 77 and 92% of duodenal ulcers at 4 weeks, and adjuvant treatment to eradicate Helicobacter pylori increases this rate. Once-daily administration is as effective as more frequent dosing regimens and may even result in higher healing rates. Gastric ulcers heal more slowly, but 75 to 88% of ulcers heal after 8 weeks of treatment. While newer more potent acid suppressors such as omeprazole heal ulcers slightly more quickly, the H2-receptor antagonists have an unparalleled safety record of over 15 years. It is unlikely that the prostaglandin analogues can improve on the efficacy of the H2-receptor antagonists with as low an incidence of side effects.

Carcinogenesis, 2005

Colorectal cancer (CRC) remains a significant cause of mortality accounting for approximately 10%... more Colorectal cancer (CRC) remains a significant cause of mortality accounting for approximately 10% of all deaths from malignancy in the western world. Polymorphism in the glutathione S-transferase GSTT1 gene has been associated with CRC risk in some but not all studies. In this study, we examined associations between GSTT1 genotypes and CRC risk, and prognosis in 361 cases and 881 unrelated controls. GSTT1 null was associated with a small but significant increase in risk (P = 0.0006, odds ratio (OR) = 1.65, 95% confidence interval (CI) = 1.22-2.24). GSTT1 null was also associated with a significantly younger age at diagnosis (mean 65.2 years) compared with GSTT1 A (mean 67.6 years, P = 0.031). There were no significant associations between GSTT1 genotypes and clinical factors (e.g. Dukes stage, differentiation and tumour node metastasis classification) in the total case group. However, following stratification by age (<70 versus > or =70 years at diagnosis), in the patients diagnosed <70 years of age, GSTT1 null was more common in Dukes grade A/B tumours (P = 0.046), stage T1/T2 tumours (P = 0.053) and those with a pushing margin (P = 0.066). We also identified associations between GSTT1 null and increased prevalence of host lymphocyte response, particularly in the younger patients (P = 0.036). Furthermore, GSTT1 null was associated with improved survival in younger patients (P = 0.017, hazards ratio (HR) = 0.52, 95% CI = 0.31-0.89) but poorer survival in older patients (P = 0.017, HR = 1.89, 95% CI = 1.12-3.20). We proposed a model based on the dual functionality of GSTT1 to explain these contrasting results. We suggest that the null genotype is associated with improved immune response in younger patients, but poorer detoxification in older patients. These findings may also provide an explanation for the contrasting finding of other studies on the role of this gene in CRC.

Carcinogenesis, 1996

Allelism in glutathione S-transferase GSTM1 and GSTT1 has been suggested as a risk factor in vari... more Allelism in glutathione S-transferase GSTM1 and GSTT1 has been suggested as a risk factor in various cancers. Accordingly, we describe a group of case-control studies carried out to identify associations between GSTT1 genotypes and susceptibility to lung, oral, gastric and colorectal cancers. The frequencies of the putatively high risk GSTT1 null genotype were not increased in the lung, oral or gastric cancer cases compared with controls but the frequency of this genotype was significantly increased (P = 0.0011, odds ratio = 1.88) in the colorectal cancer cases. No significant interactions between the GSTT1 and GSTM1 null genotypes types were identified in the cancer groups studied. Indeed, no significant associations between GSTM1 genotypes and susceptibility were identified though further evidence was obtained that the protective effect of GSTM1*A and GSTM1*B is not equal. The data complement studies showing that GSTT1 null is associated with an increased susceptibility to total u...

Exposure to carcinogens present in the diet, cigarette smoke, or the environment may be associate... more Exposure to carcinogens present in the diet, cigarette smoke, or the environment may be associated with increased risk of coloréela! cancer. Aromatic amines (aryl- and heterocyclic) are a class of carcinogens that are important in these exposures. These compounds can be N- or 0-acetylated by the NATI or NAT2 enzymes, resulting in activation or in some cases detoxification. Recent studies

Pharmacogenetics, 2001

Sulphation is an important detoxification pathway for numerous xenobiotics; however, it also play... more Sulphation is an important detoxification pathway for numerous xenobiotics; however, it also plays an important role in the metabolism and bioactivation of many dietary and environmental mutagens, including heterocyclic amines implicated in the pathogenesis of colorectal and other cancers. A major sulphotransferase (SULT) enzyme in humans, SULT1A1, is polymorphic with the most common variant allele, SULT1A1*2, occurring at a frequency of about 32% in the Caucasian population. This allele codes for an allozyme with low enzyme activity and stability compared to the wild-type (SULT1A1*1) enzyme, and therefore SULT1A1 genotype may influence susceptibility to mutagenicity following exposure to heterocyclic amines and other environmental toxins. Previously, a significant association of SULT1A1*1 genotype with old age has been observed, suggesting a 'chemoprotective' role for the high-activity phenotype. Here we have compared the frequencies of the most common SULT1A1 alleles in 226 colorectal cancer patients and 293 previously described control patients. We also assessed whether SULT1A1 genotype was related to various clinical parameters in the patient group, including Duke's classification, differentiation, site, nodal involvement and survival. There was no significant difference in allele frequency between the control and cancer patient populations, nor was there a significant association with any of the clinical parameters studied. However, when the age-related difference in allele frequency was considered, a significantly reduced risk of colorectal cancer (odds ratio = 0.47; 95% confidence interval = 0.27-0.83; P = 0.009), was associated with homozygosity for SULT1A1*1 in subjects under the age of 80 years. These results suggest that the high activity SULT1A1*1 allozyme protects against dietary and/or environmental chemicals involved in the pathogenesis of colorectal cancer.

International Journal of Cancer, 2002

(LOH)onchromosome10qisafrequenteventinanumber oftumourtypesincludingcolorectalcancers.Becauseprev... more (LOH)onchromosome10qisafrequenteventinanumber oftumourtypesincludingcolorectalcancers.Becausepreviousstudieshaveusedmarkerslocatedmainlydistallyon chromosome10,wehaveexamined114sporadiccolorectal adenocarcinomasforLOHusingapanelof9highlypolymorphicmicrosatellitemarkersspanningthelongarmofchro-mosome10.Usingmicrodissectedtumourmaterial,LOHof oneormorechromosome10qmarkerswasafrequentevent (75of114;66%).Thehighestfrequencyofloss(42of96;44%) wasobservedatthemarkerD10S1790locatedat10q21.1. Themeanageofpresentation,ofpatientswithLOHof D10S1790wassignificantly(p‫)6000.0؍‬lower(67.1years) comparedtopatientswithretentionofthismarker(73.5 years).Whenwecomparedfrequencyoflossatthismarker inpatientspresentingbefore70yearsofage(68%)tothose above70years(23%)weobservedasignificantdifference (p<0.0001).Statisticalanalysisbetweenloss,orinstabilityat othermarkersandclinicopathologicalfeaturesdidnotshow anysignificantassociations.InadditionLOHatD10S1790was infrequentinadenomas(2of20;10%)comparedtoadenocarcinomas(42of96;44%)(p‫,)7400.0؍‬suggestingthatloss withinthisregionisalateeventincolorectaltumorigenesis. TheassociationoflossatD10S1790andanearlierageof presentationinadenocarcinomassuggeststhatthislocus mayharboratumoursuppressorgene(s),whichaffectsthe rateofcolorectaltumourprogression.Identificationofthis regionofgeneticlossfurtherrefinesourunderstandingofthe paradigminthistumourtypeofmultiple-stepsresponsible forinitiationandprogression.

International Journal of Cancer, 2001

We investigated the expression of the cell cycle regulatory proteins cyclin D1 and p21(WAF1/CIP1)... more We investigated the expression of the cell cycle regulatory proteins cyclin D1 and p21(WAF1/CIP1) (p21) in human colorectal carcinomas using immunohistochemistry. Cyclin D1 was not detected in normal colonic epithelium; however, expression was observed in 74/126 (58.7%) of the tumour samples studied. Protein was detected in the nucleus in 22/126 (17.4%) and exclusively in the cytoplasm in 52/126 (41.3%) tumours. Nuclear expression of cyclin D1 was associated with poorly differentiated tumours (p = 0.035) and was more common in right- than in left-sided tumours (p = 0.005). Tumours displaying either, expression of cytoplasmic, (p = 0.05, HR 0.56, 95% CI 0.31-1.0) or nuclear (p = 0.021, HR 0.24, 95% CI 0.07-0.81) cyclin D1 were associated with improved patient survival compared with tumours negative for cyclin D1. p21 protein was strongly expressed mainly in the upper crypts of normal colonic epithelial cells, but in 63/126 (50%) of the tumour samples studied p21 expression was absent. Patients with tumours in which &amp;amp;gt;50% of cells expressed p21 had improved survival compared to patients whose tumours were negative or had &amp;amp;lt; or =50% of cells expressing p21 (p = 0.06, HR 0.33, 95% CI 0.1-1.0). We also observed a significant association between cyclin D1 subcellular localisation and p21 expression: 21/22 (95.5%) tumours expressing cyclin D1 in the nucleus also expressed p21, whereas only 17/52 (32.7%) of the tumours displaying exclusive cytoplasmic cyclin D1 staining were positive for p21 (p &amp;amp;lt; 0.001). These data highlight the significance of exclusive cytoplasmic expression of cyclin D1 in colorectal cancer and lend support to recent in vitro studies suggesting that p21 protein may modulate the subcellular localisation of the cyclin D1 protein. Thus, deregulated expression of the cyclin D1 and p21 proteins are important in colorectal tumourigenesis and have implications for patient prognosis.

International Journal of Cancer, 2000

In humans, aromatic and heterocyclic amine carcinogens may be acetylated by the expression produc... more In humans, aromatic and heterocyclic amine carcinogens may be acetylated by the expression products of either of the N-acetyltransferase genes, NAT1 or NAT2. This conjugation reaction can result in either activation or detoxication of these carcinogens depending on the tissue involved. Recent studies suggest that polymorphisms in NAT1 or NAT2 may modulate cancer risk. To determine if genetic differences in NAT1 and NAT2 could alter risk of gastric cancer, we tested for the presence of polymorphic N-acetyltransferase alleles (both NAT1 and NAT2) in a preliminary study of 94 gastric adenocarcinoma patients and 112 control subjects from North Staffordshire, England. We used established PCR protocols to genotype for NAT2 and NAT1 alleles (NAT2*4, NAT2*5, NAT2*6, NAT2*7, NAT2*14; NAT1*3, NAT1* 4, NAT1*10, and NAT1*11), and implemented an oligonucleotide ligation assay (OLA) to test for low-activity NAT1 alleles [NAT1*14 (G560A), NAT1*15 (C559T), and NAT1*17 (C190T)]. No significant increased risk was observed for NAT2 acetylation genotypes. However, among all cases, we found that individuals inheriting a variant NAT1 allele, NAT1*10, have a significantly elevated risk for gastric cancer (OR ‫؍‬ 2.2, 95% CI 1.2-3.9, P < 0.01). Interestingly, the risk observed for NAT1*10 appears to be solely associated with advanced-stage tumors (OR ‫؍‬ 4.8, P < 0.001), suggesting a possible role in progression to advanced disease. This preliminary finding needs confirmation in a larger, detailed epidemiological study. Int.

Genes, Chromosomes and Cancer, 2007

Genes implicated in tumor evolution and progression, including those in apoptotic pathways, are a... more Genes implicated in tumor evolution and progression, including those in apoptotic pathways, are associated with methylationassociated gene silencing in different tumor types. By exploiting differential methylation we recently isolated a novel pituitary tumor derived apoptosis gene (PTAG) that augments drug-induced apoptosis. The importance of PTAG was determined in other tumor types, and these studies show that the majority of primary colorectal tumors fail to express the PTAG gene, indicating an important role for PTAG in colorectal tumorigenesis. The effects of expression of PTAG were examined through stable transfection of the colorectal cell lines HCT116 and SW480. Expression of PTAG, per se, had no discernible effects on cell viability or cell kinetics. In contrast to these findings, in cells subject to drug challenges that engaged either a death-receptor mediated or mitochondrial pathway, all of the experiments indicated a role for PTAG in the intrinsic pathway of apoptosis. Loss of PTAG therefore contributes to a blunted apoptotic response and is likely to predispose cells toward malignant transformation and resistance to chemotherapeutic interventions. V

European Journal of Surgical Oncology (EJSO), 2000

Colorectal cancer is the commonest cause of death due to malignancy in non-smokers in the western... more Colorectal cancer is the commonest cause of death due to malignancy in non-smokers in the western countries. The two main hereditary types of colorectal cancer are familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC), constituting approximately 10% of all cases of colorectal cancer. The main aim of this review is to reappraise the current advances in the genetics and diagnosis of HNPCC. Methods: A Medline search was carried out to identify papers published from 1970 to 1999 on HNPCC. Embase and Cochrane databases were also searched. Reference lists of retrieved articles were carefully searched for additional articles. Results and conclusions: Recent technological advances in the genetics of HNPCC have refined the criteria for diagnosis and management of HNPCC, however current policies regarding the testing of pedigrees are not clearly established. We believe that with the rapid development in this area definitive clinical guidelines will need to be available in future for the management of HNPCC.

European Journal of Gastroenterology & Hepatology, 1997

Objective: To assess if therapeutic endoscopic retrograde cholangiopancreatography(ERCP) as a day... more Objective: To assess if therapeutic endoscopic retrograde cholangiopancreatography(ERCP) as a daycase procedure with a selective admission policy is safe and cost-effective. Design: An audit of case notes of patients who attended as a daycase for either a ...

International Journal of Oncology, 2004

Deregulated tumour expression of p16INK4a has previously been described in association with clini... more Deregulated tumour expression of p16INK4a has previously been described in association with clinical progression in sporadic colorectal cancer patients (CRC). Furthermore, p16INK4a promoter hypermethylation leading to gene silencing has been shown to occur in advanced colorectal tumours and has been associated with patient survival. p16INK4a is polymorphic, with variant alleles being associated with tumour progression in melanoma. In this study we have examined p16INK4a polymorphism as a marker of tumour progression in sporadic CRC. Polymorphic sites G/A(442), C/G(500), and C/T(540), were studied, these alleles obeyed Hardy Weinberg equilibrium in a control group, but not in the CRC cases. G/A(442) and CG(500) alleles were in linkage disequilibrium in both cases and controls. In controls the C/T(540) alleles demonstrated no linkage with either other site, whilst an association was demonstrated between C/G(500) and C/T(540) alleles in the cases (p=0.011). Furthermore, the distribution of C/T(540) genotypes was different between the groups (p=0.002). Within the CRC cases, patients with the GG(442) genotype were more commonly associated with decreased tumour differentiation (p=0.018), advancing Dukes&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; stage (p=0.006) and T-stage (p=0.007) than patients with the GA(442) and AA(442) genotypes. Patients with the CC(500) genotype were more commonly associated with decreased tumour differentiation (p=0.012), advancing Dukes&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; stage (p=0.015), and N-stage (p=0.031). No associations between patient C/T(540) genotype and clinical prognostic parameters were found. An analysis of patient tumour expression with p16INK4a genotype revealed patients with the CC(500) genotype were more commonly associated with reduced tumour p16 expression (p=0.046). In summary our data indicate that p16INK4a polymorphism is associated with tumour progression in patients with sporadic CRC.

World Journal of Surgery, 2008

Background The place of laparoscopic repair of perforated peptic ulcer followed by peritoneal toi... more Background The place of laparoscopic repair of perforated peptic ulcer followed by peritoneal toilet has been established, although it is not routinely practiced. This prospective study compared laparoscopic and open repair of perforated peptic ulcer disease. We evaluated whether the early results from laparoscopic repair resulted in improved patient outcome compared with conventional open repair. Methods All patients who underwent repair of perforated peptic ulcer disease during a 12-month period in our unit were included in the study. The primary end points that were evaluated were total operative time, nasogastric tube utilisation, intravenous fluid requirement, total time of urinary catheter and abdominal drainage usage, time taken to return to normal diet, intravenous/intramuscular opiate use, time to full mobilization, and total in-patient hospital stay.

Surgical Endoscopy, 2009

Percutaneous endoscopic gastrostomy (PEG) feeding tubes are required for an increasing number of ... more Percutaneous endoscopic gastrostomy (PEG) feeding tubes are required for an increasing number of patients with long-term nutritional requirements. &amp;amp;quot;Buried bumper syndrome&amp;amp;quot; (BBS) occurs in 2-6% of PEG placements. In the past, this has been a difficult problem to resolve. The authors aimed to design a safe and simple method of dealing with BBS that can be performed by any endoscopist on a routine endoscopic list with the patient under sedation. For 6 years, the authors have used a minimally invasive way to deal with BBS. They have successfully treated 20 BBS patients on a routine endoscopy list with the patient under sedation. The existing PEG is divided 5 cm from the skin. A pair of stent-grasping forceps is inserted via the tube. A snare then is passed via the gastroscope, caught in the stent-grasping forceps, and brought out via the PEG tube. Next, the tube is split as deeply as possible into the PEG exit site, and the snare is closed around the tube. Gentle traction is applied along the endoscope, allowing the internal bumper to concertina and pop through the mucosa. Another PEG can now be placed at a separate site, although the authors have successfully used the same tract. All the patients were followed up, with no further problems related to BBS. The authors&amp;amp;#39; method is a simple way of addressing the difficult BBS problem. It can be used to remove and replace a PEG with a buried bumper on a routine endoscopy list with the patient under sedation.

Surgical Endoscopy, 2009

The role of laparoscopic ultrasound (LUS) during staging laparoscopy for pancreatic cancers is es... more The role of laparoscopic ultrasound (LUS) during staging laparoscopy for pancreatic cancers is established but remains debatable in evaluating oesophagogastric cancers. A retrospective consecutive case series consisting of patients undergoing staging laparoscopy in two centres (centre A and B) was carried out over a 5-year period (2000-2005). Patients in centre B underwent LUS following laparoscopic assessment using a 7.5-MHz probe. Staging laparoscopy in both centres was performed using a standardised three-port protocol using a 30 degrees laparoscope. All suspicious lesions were sent for histological assessment for confirmation of malignancy. There were 201 patients in centre A (83 gastric, 138 lower oesophageal/junctional cancers) and 119 patients in centre B (51 and 68, respectively). There were no differences between the two centres for patient demographics and tumour site. There was no difference between the two centres for the detection of metastatic disease using laparoscopic assessment alone (A 13% versus B 20%, p = 0.12). However, there was a significant difference (13% versus 28%, p = 0.001) with the additional use of LUS in centre B. The findings in the additional 8% (n = 9) were para-aortic lymphadenopathy (n = 5), liver metastasis (n = 3) and local extension (n = 1). Five had gastric and four lower oesophageal/junctional cancers. The negative predictive value was 6.4% for centre A and 4.5% for centre B. The addition of LUS increased the detection rate of metastasis by 8% but there was little impact on the false-negative rate. LUS is useful in detecting metastatic lymphadenopathy beyond the limits of curative resection and liver metastasis.

Surgical Endoscopy, 2014

Gallstone pancreatitis (GSP) is a common condition, accounting for 30-40 % of all pancreatitis ca... more Gallstone pancreatitis (GSP) is a common condition, accounting for 30-40 % of all pancreatitis cases. All GSP patients should undergo definitive treatment to prevent further attacks. This study aimed to investigate the long-term outcome after definitive treatment in England by cholecystectomy, endoscopic sphincterotomy (ES), or both. Hospital episode statistics data were used to identify patients admitted for the first time with GSP between January and December 2005. These patients were followed for 18 months to identify those who underwent definitive treatment. Treatment groups then were followed until December 2010 to identify readmissions with a further GSP attack as an emergency or admissions with complications of gallstone disease. 5,079 patients admitted with a first bout of GSP between January and December 2005. The in-hospital mortality rate was 7.8 %. Of those who survived the initial attack, 2,511 went on to have a cholecystectomy, 419 had an ES alone, and 496 had ES followed by cholecystectomy. Recurrent pancreatitis after definitive treatment was more common among patients treated with ES (6.7 %) than among those treated with cholecystectomy (4.4 %) or ES followed by cholecystectomy (1.2 %) (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Admissions with other complications attributable to gallstones in patients treated with ES alone were similar to those seen in patients who had received no definitive treatment (12.2 vs. 9.4 %). Cholecystectomy offers better protection than ES against further bouts of pancreatitis in patients with GSP, but ES is an acceptable alternative. Interval cholecystectomy in patients treated initially with ES was the most effective method of preventing further pancreatitis, and the patients who underwent treatment by ES alone remained at risk of readmission with gallstone-related problems. Patients who have undergone ES and are fit for surgery should have a cholecystectomy.

European Journal of Surgical Oncology (EJSO), 1998

To investigate the use of pre-operative chemo-irradiation in downstaging advanced rectal cancer p... more To investigate the use of pre-operative chemo-irradiation in downstaging advanced rectal cancer prior to surgical resection. We examined the pathological effects of chemo-irradiation on 24 rectal tumours and correlated the efficacy of treatment with the level of apoptosis, mitosis, P53 and bcl-2 protein expression on pre-treatment biopsies. All tumours were resectable following chemo-irradiation. Six cancers showed complete regression with no viable tumour in the resection specimen. A significant correlation was found between spontaneous tumour apoptosis and tumour regression. Our results suggest that in rectal cancer the apoptotic rate in untreated tumour tissue may predict sensitivity to radiation and cytotoxic agents. No relationship was found between regression and mitotic rate, p53 or bcl-2 expression.

Drugs, 1992

Duodenal ulcer healing depends on the degree and length of inhibition of gastric secretion and up... more Duodenal ulcer healing depends on the degree and length of inhibition of gastric secretion and upon the duration of therapy, while gastric ulcer healing is dependent mainly on the duration of therapy. Currently marketed doses of the histamine H2-receptor antagonists heal between 77 and 92% of duodenal ulcers at 4 weeks, and adjuvant treatment to eradicate Helicobacter pylori increases this rate. Once-daily administration is as effective as more frequent dosing regimens and may even result in higher healing rates. Gastric ulcers heal more slowly, but 75 to 88% of ulcers heal after 8 weeks of treatment. While newer more potent acid suppressors such as omeprazole heal ulcers slightly more quickly, the H2-receptor antagonists have an unparalleled safety record of over 15 years. It is unlikely that the prostaglandin analogues can improve on the efficacy of the H2-receptor antagonists with as low an incidence of side effects.

Carcinogenesis, 2005

Colorectal cancer (CRC) remains a significant cause of mortality accounting for approximately 10%... more Colorectal cancer (CRC) remains a significant cause of mortality accounting for approximately 10% of all deaths from malignancy in the western world. Polymorphism in the glutathione S-transferase GSTT1 gene has been associated with CRC risk in some but not all studies. In this study, we examined associations between GSTT1 genotypes and CRC risk, and prognosis in 361 cases and 881 unrelated controls. GSTT1 null was associated with a small but significant increase in risk (P = 0.0006, odds ratio (OR) = 1.65, 95% confidence interval (CI) = 1.22-2.24). GSTT1 null was also associated with a significantly younger age at diagnosis (mean 65.2 years) compared with GSTT1 A (mean 67.6 years, P = 0.031). There were no significant associations between GSTT1 genotypes and clinical factors (e.g. Dukes stage, differentiation and tumour node metastasis classification) in the total case group. However, following stratification by age (&lt;70 versus &gt; or =70 years at diagnosis), in the patients diagnosed &lt;70 years of age, GSTT1 null was more common in Dukes grade A/B tumours (P = 0.046), stage T1/T2 tumours (P = 0.053) and those with a pushing margin (P = 0.066). We also identified associations between GSTT1 null and increased prevalence of host lymphocyte response, particularly in the younger patients (P = 0.036). Furthermore, GSTT1 null was associated with improved survival in younger patients (P = 0.017, hazards ratio (HR) = 0.52, 95% CI = 0.31-0.89) but poorer survival in older patients (P = 0.017, HR = 1.89, 95% CI = 1.12-3.20). We proposed a model based on the dual functionality of GSTT1 to explain these contrasting results. We suggest that the null genotype is associated with improved immune response in younger patients, but poorer detoxification in older patients. These findings may also provide an explanation for the contrasting finding of other studies on the role of this gene in CRC.

Carcinogenesis, 1996

Allelism in glutathione S-transferase GSTM1 and GSTT1 has been suggested as a risk factor in vari... more Allelism in glutathione S-transferase GSTM1 and GSTT1 has been suggested as a risk factor in various cancers. Accordingly, we describe a group of case-control studies carried out to identify associations between GSTT1 genotypes and susceptibility to lung, oral, gastric and colorectal cancers. The frequencies of the putatively high risk GSTT1 null genotype were not increased in the lung, oral or gastric cancer cases compared with controls but the frequency of this genotype was significantly increased (P = 0.0011, odds ratio = 1.88) in the colorectal cancer cases. No significant interactions between the GSTT1 and GSTM1 null genotypes types were identified in the cancer groups studied. Indeed, no significant associations between GSTM1 genotypes and susceptibility were identified though further evidence was obtained that the protective effect of GSTM1*A and GSTM1*B is not equal. The data complement studies showing that GSTT1 null is associated with an increased susceptibility to total u...

Exposure to carcinogens present in the diet, cigarette smoke, or the environment may be associate... more Exposure to carcinogens present in the diet, cigarette smoke, or the environment may be associated with increased risk of coloréela! cancer. Aromatic amines (aryl- and heterocyclic) are a class of carcinogens that are important in these exposures. These compounds can be N- or 0-acetylated by the NATI or NAT2 enzymes, resulting in activation or in some cases detoxification. Recent studies

Pharmacogenetics, 2001

Sulphation is an important detoxification pathway for numerous xenobiotics; however, it also play... more Sulphation is an important detoxification pathway for numerous xenobiotics; however, it also plays an important role in the metabolism and bioactivation of many dietary and environmental mutagens, including heterocyclic amines implicated in the pathogenesis of colorectal and other cancers. A major sulphotransferase (SULT) enzyme in humans, SULT1A1, is polymorphic with the most common variant allele, SULT1A1*2, occurring at a frequency of about 32% in the Caucasian population. This allele codes for an allozyme with low enzyme activity and stability compared to the wild-type (SULT1A1*1) enzyme, and therefore SULT1A1 genotype may influence susceptibility to mutagenicity following exposure to heterocyclic amines and other environmental toxins. Previously, a significant association of SULT1A1*1 genotype with old age has been observed, suggesting a &#39;chemoprotective&#39; role for the high-activity phenotype. Here we have compared the frequencies of the most common SULT1A1 alleles in 226 colorectal cancer patients and 293 previously described control patients. We also assessed whether SULT1A1 genotype was related to various clinical parameters in the patient group, including Duke&#39;s classification, differentiation, site, nodal involvement and survival. There was no significant difference in allele frequency between the control and cancer patient populations, nor was there a significant association with any of the clinical parameters studied. However, when the age-related difference in allele frequency was considered, a significantly reduced risk of colorectal cancer (odds ratio = 0.47; 95% confidence interval = 0.27-0.83; P = 0.009), was associated with homozygosity for SULT1A1*1 in subjects under the age of 80 years. These results suggest that the high activity SULT1A1*1 allozyme protects against dietary and/or environmental chemicals involved in the pathogenesis of colorectal cancer.

International Journal of Cancer, 2002

(LOH)onchromosome10qisafrequenteventinanumber oftumourtypesincludingcolorectalcancers.Becauseprev... more (LOH)onchromosome10qisafrequenteventinanumber oftumourtypesincludingcolorectalcancers.Becausepreviousstudieshaveusedmarkerslocatedmainlydistallyon chromosome10,wehaveexamined114sporadiccolorectal adenocarcinomasforLOHusingapanelof9highlypolymorphicmicrosatellitemarkersspanningthelongarmofchro-mosome10.Usingmicrodissectedtumourmaterial,LOHof oneormorechromosome10qmarkerswasafrequentevent (75of114;66%).Thehighestfrequencyofloss(42of96;44%) wasobservedatthemarkerD10S1790locatedat10q21.1. Themeanageofpresentation,ofpatientswithLOHof D10S1790wassignificantly(p‫)6000.0؍‬lower(67.1years) comparedtopatientswithretentionofthismarker(73.5 years).Whenwecomparedfrequencyoflossatthismarker inpatientspresentingbefore70yearsofage(68%)tothose above70years(23%)weobservedasignificantdifference (p<0.0001).Statisticalanalysisbetweenloss,orinstabilityat othermarkersandclinicopathologicalfeaturesdidnotshow anysignificantassociations.InadditionLOHatD10S1790was infrequentinadenomas(2of20;10%)comparedtoadenocarcinomas(42of96;44%)(p‫,)7400.0؍‬suggestingthatloss withinthisregionisalateeventincolorectaltumorigenesis. TheassociationoflossatD10S1790andanearlierageof presentationinadenocarcinomassuggeststhatthislocus mayharboratumoursuppressorgene(s),whichaffectsthe rateofcolorectaltumourprogression.Identificationofthis regionofgeneticlossfurtherrefinesourunderstandingofthe paradigminthistumourtypeofmultiple-stepsresponsible forinitiationandprogression.

International Journal of Cancer, 2001

We investigated the expression of the cell cycle regulatory proteins cyclin D1 and p21(WAF1/CIP1)... more We investigated the expression of the cell cycle regulatory proteins cyclin D1 and p21(WAF1/CIP1) (p21) in human colorectal carcinomas using immunohistochemistry. Cyclin D1 was not detected in normal colonic epithelium; however, expression was observed in 74/126 (58.7%) of the tumour samples studied. Protein was detected in the nucleus in 22/126 (17.4%) and exclusively in the cytoplasm in 52/126 (41.3%) tumours. Nuclear expression of cyclin D1 was associated with poorly differentiated tumours (p = 0.035) and was more common in right- than in left-sided tumours (p = 0.005). Tumours displaying either, expression of cytoplasmic, (p = 0.05, HR 0.56, 95% CI 0.31-1.0) or nuclear (p = 0.021, HR 0.24, 95% CI 0.07-0.81) cyclin D1 were associated with improved patient survival compared with tumours negative for cyclin D1. p21 protein was strongly expressed mainly in the upper crypts of normal colonic epithelial cells, but in 63/126 (50%) of the tumour samples studied p21 expression was absent. Patients with tumours in which &amp;amp;gt;50% of cells expressed p21 had improved survival compared to patients whose tumours were negative or had &amp;amp;lt; or =50% of cells expressing p21 (p = 0.06, HR 0.33, 95% CI 0.1-1.0). We also observed a significant association between cyclin D1 subcellular localisation and p21 expression: 21/22 (95.5%) tumours expressing cyclin D1 in the nucleus also expressed p21, whereas only 17/52 (32.7%) of the tumours displaying exclusive cytoplasmic cyclin D1 staining were positive for p21 (p &amp;amp;lt; 0.001). These data highlight the significance of exclusive cytoplasmic expression of cyclin D1 in colorectal cancer and lend support to recent in vitro studies suggesting that p21 protein may modulate the subcellular localisation of the cyclin D1 protein. Thus, deregulated expression of the cyclin D1 and p21 proteins are important in colorectal tumourigenesis and have implications for patient prognosis.

International Journal of Cancer, 2000

In humans, aromatic and heterocyclic amine carcinogens may be acetylated by the expression produc... more In humans, aromatic and heterocyclic amine carcinogens may be acetylated by the expression products of either of the N-acetyltransferase genes, NAT1 or NAT2. This conjugation reaction can result in either activation or detoxication of these carcinogens depending on the tissue involved. Recent studies suggest that polymorphisms in NAT1 or NAT2 may modulate cancer risk. To determine if genetic differences in NAT1 and NAT2 could alter risk of gastric cancer, we tested for the presence of polymorphic N-acetyltransferase alleles (both NAT1 and NAT2) in a preliminary study of 94 gastric adenocarcinoma patients and 112 control subjects from North Staffordshire, England. We used established PCR protocols to genotype for NAT2 and NAT1 alleles (NAT2*4, NAT2*5, NAT2*6, NAT2*7, NAT2*14; NAT1*3, NAT1* 4, NAT1*10, and NAT1*11), and implemented an oligonucleotide ligation assay (OLA) to test for low-activity NAT1 alleles [NAT1*14 (G560A), NAT1*15 (C559T), and NAT1*17 (C190T)]. No significant increased risk was observed for NAT2 acetylation genotypes. However, among all cases, we found that individuals inheriting a variant NAT1 allele, NAT1*10, have a significantly elevated risk for gastric cancer (OR ‫؍‬ 2.2, 95% CI 1.2-3.9, P < 0.01). Interestingly, the risk observed for NAT1*10 appears to be solely associated with advanced-stage tumors (OR ‫؍‬ 4.8, P < 0.001), suggesting a possible role in progression to advanced disease. This preliminary finding needs confirmation in a larger, detailed epidemiological study. Int.

Genes, Chromosomes and Cancer, 2007

Genes implicated in tumor evolution and progression, including those in apoptotic pathways, are a... more Genes implicated in tumor evolution and progression, including those in apoptotic pathways, are associated with methylationassociated gene silencing in different tumor types. By exploiting differential methylation we recently isolated a novel pituitary tumor derived apoptosis gene (PTAG) that augments drug-induced apoptosis. The importance of PTAG was determined in other tumor types, and these studies show that the majority of primary colorectal tumors fail to express the PTAG gene, indicating an important role for PTAG in colorectal tumorigenesis. The effects of expression of PTAG were examined through stable transfection of the colorectal cell lines HCT116 and SW480. Expression of PTAG, per se, had no discernible effects on cell viability or cell kinetics. In contrast to these findings, in cells subject to drug challenges that engaged either a death-receptor mediated or mitochondrial pathway, all of the experiments indicated a role for PTAG in the intrinsic pathway of apoptosis. Loss of PTAG therefore contributes to a blunted apoptotic response and is likely to predispose cells toward malignant transformation and resistance to chemotherapeutic interventions. V

European Journal of Surgical Oncology (EJSO), 2000

Colorectal cancer is the commonest cause of death due to malignancy in non-smokers in the western... more Colorectal cancer is the commonest cause of death due to malignancy in non-smokers in the western countries. The two main hereditary types of colorectal cancer are familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC), constituting approximately 10% of all cases of colorectal cancer. The main aim of this review is to reappraise the current advances in the genetics and diagnosis of HNPCC. Methods: A Medline search was carried out to identify papers published from 1970 to 1999 on HNPCC. Embase and Cochrane databases were also searched. Reference lists of retrieved articles were carefully searched for additional articles. Results and conclusions: Recent technological advances in the genetics of HNPCC have refined the criteria for diagnosis and management of HNPCC, however current policies regarding the testing of pedigrees are not clearly established. We believe that with the rapid development in this area definitive clinical guidelines will need to be available in future for the management of HNPCC.