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Endoscopic mucosal resection (EMR) of early gastric and esophageal tumors is effective and avoids the morbidity and mortality of surgery. We report the long-term results of a consecutive series of 93 endoscopic resections, during a 7-year period, in a U.K. population. Eighty-eight patients with 93 lesions were included. EMR was performed for 64 and 29 malignant and benign lesions, respectively. Patients with malignant disease were subgrouped into “high risk” or “low risk” for recurrence. Of the 35 lesions in the low-risk group, local control was achieved in 31; 29 after 1 EMR session. Two had residual invasive carcinoma, one had treatment ceased due to pancreatic cancer, and one patient did not attend follow-up. Of the 29 lesions in the high-risk group, local control was achieved in 15; 13 after 1 EMR session. Median follow-up was 53 months. Cancer specific survival for the 45 invasive cancers (T1m and T1sm) was 93%; three patients died from their disease. This study has shown for the first time in a U.K. population that EMR is effective in controlling disease in patients with local high grade dysplasia (HGD) and early invasive carcinoma, with no mortality and low morbidity.

Studies have indicated that hypoalbuminemia is associated with decreased survival of patients with gastric cancer. However, the prognostic value of albumin may be secondary to an ongoing systemic inflammatory response. The aim of the study was to assess the relation between hypoalbuminemia, the systemic inflammatory response, and survival in patients with gastric cancer. Patients diagnosed with gastric carcinoma attending the upper gastrointestinal surgical unit in the Royal Infirmary, Glasgow between April 1997 and December 2005 and who had a pretreatment measurement of albumin and C-reactive protein (CRP) were studied. Most of the patients had stage III/IV disease and received palliative treatment. The minimum follow-up was 15 months. During follow-up, 157 (72%) patients died of their cancer. On univariate analysis, stage (p

Background: Peptic ulcer bleeding (PUB) is a serious and sometimes fatal condition. The outcome of PUB strongly depends on the risk of rebleeding. A recent multinational placebo-controlled clinical trial (ClinicalTrials.gov identifier: NCT00251979) showed that high-dose intravenous (IV) esomeprazole, when administered after successful endoscopic haemostasis in patients with PUB, is effective in preventing rebleeding. From a policy perspective it is important to assess the cost efficacy of this benefit so as to enable clinicians and payers to make an informed decision regarding the management of PUB. Objective: Using a decision-tree model, we compared the cost efficacy of high-dose IV esomeprazole versus an approach of no-IV proton pump inhibitor for prevention of rebleeding in patients with PUB. Method: The model adopted a 30-day time horizon and the perspective of third-party payers in the USA and Europe. The main efficacy variable was the number of averted rebleedings. Healthcare resource utilization costs (physician fees, hospitalizations, surgeries, pharmacotherapies) relevant for the management of PUB were also determined. Data for unit costs (prices) were primarily taken from official governmental sources, and data for other model assumptions were retrieved from the original clinical trial and the literature. After successful endoscopic haemostasis, patients received either high-dose IV esomeprazole (80 mg infusion over 30 min, then 8 mg/hour for 71.5 hours) or no-IV esomeprazole treatment, with both groups receiving oral esomeprazole 40 mg once daily from days 4 to 30. Results: Rebleed rates at 30 days were 7.7% and 13.6%, respectively, for the high-dose IV esomeprazole and no-IV esomeprazole treatment groups (equating to a number needed to treat of 17 in order to prevent one additional patient from rebleeding). In the US setting, the average cost per patient for the high-dose IV esomeprazole strategy was $US14 290 compared with $US14 239 for the no-IV esomeprazole strategy (year 2007 values). For the European setting, Sweden and Spain were used as examples. In the Swedish setting the corresponding respective figures were Swedish kronor (SEK)67 862 ($US9220 at average 2006 interbank exchange rates) and SEK67 807 ($US9212) [year 2006 values]. Incremental cost-effectiveness ratios were $US866 and SEK938 ($US127), respectively, per averted rebleed when using IV esomeprazole. For the Spanish setting, the high-dose IV esomeprazole strategy was dominant (more effective and less costly than the no-IV esomeprazole strategy) [year 2008 values]. All results appeared robust to univariate/threshold sensitivity analysis, with high-dose IV esomeprazole becoming dominant with small variations in assumptions in the US and Swedish settings, while remaining a dominant approach in the Spanish scenario across a broad range of values. Sensitivity variables with prespecified ranges included lengths of stay and per diem assumptions, rebleeding rates and, in some cases, professional fees. Conclusion: In patients with PUB, high-dose IV esomeprazole after successful endoscopic haemostasis appears to improve outcomes at a modest increase in costs relative to a no-IV esomeprazole strategy from the US and Swedish third-party payer perspective. Whereas, in the Spanish setting, the high-dose IV esomeprazole strategy appeared dominant, being more effective and less costly.

Clinical staging in patients with gastro-oesophageal cancer, is of crucial importance in determining the likely benefit of treatment. Despite recent advances in clinical staging, overall survival remains poor. The aim of the present study was to examine the relationship between pre-treatment clinical prognostic factors and cancer-specific survival. Two hundred and seventeen patients, undergoing staging investigations including host factors (Edinburgh Clinical Risk Score (ECRS)) and the systemic inflammatory response (Glasgow Prognostic score (mGPS)), in the upper GI surgical unit at Glasgow Royal Infirmary, were studied. During the follow-up period, 188 (87%) patients died; 178 of these patients died from the disease. The minimum follow-up was 46 months, and the median follow-up of the survivors was 65 months. On multivariate survival analysis of the significant factors, only cTNM stage (HR 1.84, 95% CI 1.56–2.17, p

It remains unclear whether any aspect of quality of life has a role in predicting survival in an unselected cohort of patients with gastro-oesophageal cancer. Therefore the aim of the present study was to examine the relationship between quality of life (EORTC QLQ-C30), clinico-pathological characteristics and survival in patients with gastro-oesophageal cancer. Patients presenting with gastric or oesophageal cancer, staged using the UICC tumour node metastasis (TNM) classification and who received either potentially curative surgery or palliative treatment between November 1997 and December 2002 (n=152) participated in a quality of life study, using the EORTC QLQ-C30 core questionnaire. On univariate analysis, age (P

There is increasing evidence that the presence of an ongoing systemic inflammatory response is associated with poor outcome in patients undergoing resection for a variety of tumours. The aim of the present study was to examine the relationship between clinico-pathological status, preoperative C-reactive protein concentration and cancer-specific survival in patients undergoing resection for gastro-oesophageal cancer. One hundred and twenty patients attending the upper gastrointestinal surgical unit in the Royal Infirmary, Glasgow, who were selected for potentially curative surgery, were included in the study. Laboratory measurements of haemoglobin, white cell, lymphocyte and platelet counts, albumin and C-reactive protein were carried out at the time of diagnosis. All patients underwent en-bloc resection with lymphadenectomy and survived at least 30 days following surgery. On multivariate analysis, only the positive to total lymph node ratio (hazard ratio (HR) 2.02, 95% confidence interval (CI) 1.44-2.84, P0.001) and preoperative C-reactive protein concentration (HR 3.53, 95% CI 1.88-6.64, P0.001) were independent predictors of cancer-specific survival. The patient group with no evidence of a preoperative systemic inflammatory response (C-reactive proteinor =10 mg l(-1)) had a median survival of 79 months compared with 19 months in the elevated systemic inflammatory response group (P0.001). The results of the present study indicate that in patients selected to undergo potentially curative resection for gastro-oesophageal cancer, the presence of an elevated preoperative C-reactive protein concentration is an independent predictor of poor cancer-specific survival.

There is increasing evidence that the presence of an ongoing systemic inflammatory response is associated with poor outcome in patients with advanced cancer. The aim of the present study was to examine whether an inflammation-based prognostic score (Glasgow Prognostic score, GPS) was associated with survival, in patients with inoperable gastro-oesophageal cancer. Patients diagnosed with inoperable gastro-oesophageal carcinoma and who had measurement of albumin and C-reactive protein concentrations, at the time of diagnosis, were studied (n=258). Clinical information was obtained from a gastro-oesophageal cancer database and analysis of the case notes. Patients with both an elevated C-reactive protein (>10 mg l−1) and hypoalbuminaemia (

According to the published medical literature to date, prophylactic gastrectomy undertaken in the context of carriage of a germline truncating E-cadherin mutation and an appropriate positive family history will lead to the discovery of occult foci of adenocarcinoma in all gastrectomy specimens. We describe the first published case of a patient whose prophylactic gastrectomy in this setting failed to reveal any dysplastic or malignant foci. Furthermore the patient's nephew, who was found to carry an identical E-cadherin mutation on family screening and also underwent prophylactic gastrectomy, was shown to have multi-focal diffuse adenocarcinoma after analysis of the gastrectomy specimen. Both patients were also found to have penetrant genetic haemochromatosis. Within this case, we discuss the clinical manifestations and penetrance of germline E-cadherin mutations and the difficult decisions facing both clinicians and families with this mutation. We also speculate on how these patients' undiagnosed genetic haemochromatosis may have influenced the pathology encountered.

The aim of this study was to investigate the origin of globus pharyngis with particular reference to esophageal disorders such as gastroesophageal reflux disease (GERD), motility disorders, structural abnormalities, other gastrointestinal tract diseases, and psychological profile. Previous studies on this subject using 24-hour pH monitoring give conflicting results and are hampered by the high background prevalence of asymptomatic GERD in the normal Western population. The local Chinese population is known to have a very low background level of GERD and therefore is an ideal study population. Twenty-six patients with globus pharyngis underwent 24-hour ambulatory pH monitoring, esophageal manometry, and esophagogas-troduodenoscopy with lower esophageal biopsy. A control group of 20 patients presenting with non-ulcer dyspepsia was similarly investigated. Personality profiles of the globus pharyngis subjects and an appropriate control group were assessed. Eight of the globus pharyngis group (30.7%) had evidence of GERD, whereas only one of the controls (5%) demonstrated GERD on 24-hour esophageal pH monitoring (P < 0.05). The manometric and personality profile studies did not show significant differences between study and control groups. We concluded that the finding of GERD in patients with globus pharyngis is not a coincidental finding but that there is a true association between GERD and globus pharyngis.

Background Gastric outlet obstruction secondary to chronic duodenal ulceration is an indication for surgery as conservative management with balloon dilatation frequently fails. The standard operation is truncal vagotomy and a drainage procedure. However, development of minimally invasive surgery has revolutionized the surgical approach to this clinical problem. Methods Twelve male patients with pyloric stenosis secondary to duodenal ulceration underwent laparoscopic truncal vagotomy and gastrojejunostomy. The perioperative and long term outcome of this group of patients were analyzed. Results The median operating time was 210 (range 180 to 240) minutes. Median postoperative stay was 6 (range 4 to 41) days. Conversion to laparotomy was necessary in one patient. Delayed gastric emptying occurred in two patients but resolved on conservative measures. At a median postoperative followup of 6 (range 1 to 12) months all patients had a good symptomatic outcome (Visick grades I or II). Conclusions Laparoscopic truncal vagotomy and gastrojejunostomy is a feasible technique. Intermediate followup shows good symptomatic results when used for pyloric stenosis.

Background & Aims Esophageal adenocarcinoma (EA) is increasingly common among patients with Barrett's esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. Methods We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. Results Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. Conclusions We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.

Efficacy of a continuous high-dose intravenous infusion of esomeprazole, followed by an oral regimen after successful endoscopic therapy for peptic ulcer bleeding (PUB) was established in the PUB study (ClinicalTrials. gov identifier: NCT00251979). Mortality rates and detailed safety and tolerability results from this study are reported here. This was a double-blind, randomized study in patients a parts per thousand yen18 years with overt signs of upper gastrointestinal bleeding, following endoscopic diagnosis of a single gastric or duodenal ulcer (a parts per thousand yen5 mm) with stigmata indicating current/ recent bleeding (Forrest class Ia, Ib, IIa, or IIb). Postendoscopic hemostasis, patients received intravenous esomeprazole (80 mg/30 minutes, then 8 mg/hour for 71.5 hours) or placebo. Postinfusion, all patients received open-label oral esomeprazole 40 mg once daily for 27 days. Mortality rates were analyzed using Fisher's exact test; other safety variables were analyzed descriptively. A total of 767 patients were randomized; 764 comprised the safety analysis set (375 patients received esomeprazole, 389 placebo). Baseline characteristics were similar across the two treatment groups. Three deaths from the esomeprazole treatment group and eight from the placebo group occurred during the trial (0.8% versus 2.1%; P=0.22). From these 11 all-cause deaths, one (esomeprazole group; rebleeding from duodenal ulcer) occurred during the 72-hour intravenous treatment phase. Adverse event (AE) frequency was similar for the two groups over the intravenous treatment phase (esomeprazole, 39.2%; placebo, 41.9%), with gastrointestinal disorders being most commonly reported (12.3% and 19.8%, respectively). Serious AEs were mostly related to bleeding events. Infusion-site reactions (mild, transient) were reported in 4.3% of esomeprazole-treated patients versus 0.5% of placebo patients. These did not lead to treatment discontinuation. Esomeprazole, given as a continuous high-dose intravenous infusion followed by an oral regimen after successful endoscopic therapy for PUB, was well tolerated, with no apparent safety concerns from either the high-dose intravenous treatment or oral phases.

Background: Variceal bleeding is an acute medical emergency with high mortality. Although less common than oesophageal variceal haemorrhage, gastric variceal bleeding is more severe and more difficult to control. The optimal therapy for gastric variceal bleeding remains unclear although endoscopic injection of N -Butyl-2-Cyanoacrylate (Histoacryl) glue is often used. However, its long-term efficacy is poorly described. We studied the immediate and long-term effects of Histoacryl glue injection as treatment for bleeding gastric varices in a large UK hospital. Method: Endoscopy records and case notes were used to identify patients receiving Histoacryl injection for gastric variceal bleeding over a 4-year period. Results: Thirty-one patients received Histoacryl for gastric variceal bleeding. Seventy-four per cent patients had alcohol-related liver disease and 61% of cirrhotics were Childs Pugh grade B or C. Fifty-eight per cent were actively bleeding during the procedure with 100% haemostasis rates achieved. Two patients developed pyrexia within 24 h of injection settling with antibiotics. No other complications were encountered. Mean overall follow-up was 35 months, with mean follow-up of survivors 57 months. Forty-eight per cent patients had endoscopic ultrasound assessment of varices during follow-up with no effect on rebleeding rates. Thirteen per cent required subsequent transjugular intrahepatic portosystemic shunt placement. Gastric variceal rebleeding rate was 10% at 1 year and 16% in total. One- and two-year mortality was 23% and 35%, respectively. Conclusion: Endoscopic injection of Histoacryl glue appears to be a safe and effective treatment for gastric variceal bleeding. Further data are required to compare it with other therapies in this situation.

A number of accepted criteria, including pathological tumor, node, metastasis system stage, lymph node metastasis, and tumor differentiation, predict survival in patients undergoing surgery for gastroesophageal cancer. We examined the interrelationships between standard clinicopathological factors, systemic and local inflammatory responses, tumor proliferative activity, and survival. The interrelationships between the systemic inflammatory response (Glasgow prognostic score, mGPS), standard clinicopathological factors, local inflammatory response (Klintrup criteria, macrophage infiltration), and tumor proliferative activity (Ki-67) were examined by immunohistochemistry in 100 patients (44 esophageal [19 squamous, 25 adenocarcinoma], 19 junctional, and 37 gastric cancers) selected for potentially curative resection. The minimum follow-up was 59 months. On multivariate survival analysis, lymph node ratio (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.11–2.40, P

There has been growing interest in the measurement of breath ethane as an optimal non-invasive marker of oxidative stress. High concentrations of various breath alkanes including ethane have been reported in a number of malignancies. Our aim was to investigate the use of novel laser spectroscopy for rapid reporting of exhaled ethane and to determine whether breath ethane concentration is related to a diagnosis of upper gastrointestinal malignancy. Two groups of patients were recruited. Group A (n = 20) had a histo-pathological diagnosis of either esophageal or gastric malignancy. Group B (n = 10) was made up of healthy controls. Breath samples were collected from these subjects and the ethane concentration in these samples was subsequently measured to an accuracy of 0.2 parts per billion, ppb. Group A patients had a corrected exhaled breath ethane concentration of 2.3 +/- 0.8 (mean +/- SEM) ppb. Group B patients registered a mean of 3.1 +/- 0.5 ppb. There was no statistically significant difference between the two groups (p = 0.39). In conclusion, concentrations of ethane in collected breath samples were not significantly elevated in upper gastrointestinal malignancy. The laser spectroscopy system provided a reliable and rapid turnaround for breath sample analysis.

Background and Aim Endoscopic Ultrasound (EUS) has increased the staging accuracy of oesophageal cancer. The addition of EUS guided fine needle aspiration (EUS-FNA) appears superior to standard EUS for nodal staging. Our aim was to study the impact of EUS-FNA in the management of patients with oesophageal cancer. Methods We studied patients undergoing EUS for this indication between May 2003 and May 2006. EUS was performed in patients who were candidates for radical therapy following CT scanning. If suspicious non-peritumoural nodes were seen on EUS, EUS-FNA was undertaken. Further staging was performed as appropriate and all cases were discussed at our multidisciplinary meeting. Results and decisions were prospectively recorded. Results One hundred and ninety one patients underwent EUS for staging of oesophageal cancer during this period and 44 EUS-FNA were performed in 42 patients (mean age 62.2 years). Sixty two per cent of patients had adenocarcinoma and 48% sampled nodes were < 10mm diameter. Overall, 48% nodes were positive and two “suspicious” for malignancy. Following a positive EUS-FNA and MDM discussions, 15 patients had palliative and two neoadjuvant therapy. Eleven patients with a negative EUSFNA underwent radical therapy. Therefore, EUS-FNA appeared to alter management in 28 (67%) patients. Conclusion EUS-FNA appears to help direct patients towards appropriate treatment strategies.

To compare detection of Barrett's dysplasia and adenocarcinoma by systematic versus nonsystematic surveillance biopsy protocols.Upper GI consultation and open-access endoscopy are provided jointly at Glasgow Royal Infirmary by medical and surgical teams. The surgical team adopted annual systematic four-quadrant biopsy Barrett's surveillance in 1995. The medical team continued annual Barrett's surveillance with nonsystematic biopsy until 2004. We compare detection of Barrett's dysplasia and esophageal adenocarcinoma in unselected patients by these two biopsy strategies over 10 yr. All patients hador = 3 cm Barrett's esophagus and histological proof of intestinal metaplasia. Patients referred for dysplasia management or with prevalent adenocarcinoma were excluded. Cohort A (N = 180) had four-quadrant biopsy every 2 cm while cohort B (N = 182) had nonsystematic biopsies.Cohort A versus cohort B: Median number of biopsies per endoscopy: 16 versus 4. Prevalence of low-grade dysplasia (per patient): 18.9% versus 1.6% (P0.001). Prevalence of high-grade dysplasia: 2.8% versus 0% (P = 0.03). Incidence of low-grade dysplasia: 2.2% versus 6.6% (NS). Incidence of high-grade dysplasia: 2.8% versus 0% (P = 0.03). Nine cohort A patients (total 5%, 1.4% per patient-year) were treated for HGD (eight endoscopically, one by esophagectomy). Two had intramucosal adenocarcinoma. No cohort A patient developed advanced cancer but three cohort B patients developed and died of invasive Barrett's adenocarcinoma (0.6% per patient-year).Patient age, gender, Barrett's segment length, and follow-up were similar (though not identical) in both cohorts, but confounding seems unlikely to account for a 13-fold difference in detection of prevalent dysplasia between the two groups. Our data support the hypothesis that systematic four-quadrant biopsy is considerably more effective than nonsystematic biopsy sampling in detecting Barrett's dysplasia and early adenocarcinoma. Greater biopsy numbers and the systematic pattern of biopsy taking may both contribute to this greater effectiveness.

Aim: The aim of the present study was to compare an inflammation-based prognostic score (Glasgow Prognostic Score, GPS) with performance status (ECOG-ps) in patients receiving platinum-based chemotherapy for palliation of gastroesophageal cancer. Methods: Sixty-five patients presenting with gastroesophageal carcinoma to the Royal Infirmary, Glasgow between January 1999 and December 2005 and who received palliative chemotherapy or chemo-radiotherapy were studied. ECOG-ps, C-reactive protein, and albumin were recorded at diagnosis. Patients with both an elevated C-reactive protein (>10 mg/L) and hypoalbuminemia (

Background: Incidence of the gastro-oesophageal junction adenocarcinoma is increasing. Siewert’s classification subdivides junctional adenocarcinomas anatomically. Cytokeratin (CK) 7 and 20 immunophenotypes differentiate Barrett’s intestinal metaplasia (IM) from gastric IM. Comparing CK immunostaining with Siewert’s classification may establish tumour origin and influence surgical choice. Methods: In this experimental study, 57 patients with gastro-oesophageal junction adenocarcinoma were subdivided endoscopically into 15 type 1, 26 type 2 and 16 type 3 adenocarcinomas. Representative biopsies were immunostained for CK7 and CK20. Results: Intestinal metaplasia was associated with type 1 adenocarcinoma in 12 of 15 patients, 80%; with type 2 in 13 of 26 patients, 50% and type 3 in 6 of 16 patients, 37.5%. All type 1 patients showed Barrett’s CK7/CK20 phenotype within IM; type 2 a mixture: 69% (n = 9) Barrett’s CK7/CK20 and 31% (n = 4) gastric CK7/CK20 whereas type 3 patients had a gastric CK7/CK20 pattern in 83% (n = 5). Immunostaining within the adenocarcinoma was variable. Conclusion: Siewert’s type 1 adenocarcinomas express Barrett’s CK7/CK20 pattern, type 3 a gastric CK7/CK20 pattern and type 2 tumours a mixture of Barrett’s and gastric CK7/CK20 patterns within associated IM. CK immunostaining may refine Siewert’s classification into oesophageal type 1 or gastric type 2 adenocarcinoma with IM.

Aims : Intestinal metaplasia and gastro-oesophageal reflux disease typify classical Barrett's oesophagus. Cytokeratin (CK) 7 and 20 phenotypes differentiate intestinal metaplasia in long segment Barrett's oesophagus from gastric intestinal metaplasia. This study examines the relationship between CK7/20 phenotypes and reflux disease in intestinal metaplasia of the distal oesophagus. Methods and results : Eighty patients with oesophageal pH studies included 30 with long segment Barrett's, 16 with short segment Barrett's and 34 with intestinal meatplasia of the gastro-oesophageal junction. Representative biopsy specimens were immunostained for CK7 and CK20. All 30 long segment patients demonstrated a Barrett's CK7/20 phenotype. All nine short segment patients with gastro-oesophageal reflux had a Barrett's CK7/20 phenotype, while four of seven short segment patients without reflux had a gastric CK7/20 phenotype (P = 0.019). Of 14 patients with intestinal metaplasia of the gastro-oesophageal junction and reflux, 10 (71%) had a Barrett's CK7/20 phenotype, compared with 11 (55%) of the 20 non-reflux patients. Conclusions : CK7/20 immunoreactivity for patients with intestinal metaplasia of the distal oesophagus without long segment Barrett's oesophagus suggests a heterogeneous group, with an association between Barrett's CK7/20 pattern and gastro-oesophageal reflux disease in both short segment Barrett's and intestinal metaplasia of the gastro-oesophageal junction.

Glandular dysplasia in Barrett's esophagus may regress spontaneously but can also progress to cancer. The human telomerase RNA template and the human telomerase reverse transcriptase enzyme which do not, of themselves, correlate strongly with telomerase activity, are too often overexpressed in Barrett's dysplasia to predict individual cancer risk. This study relates telomerase activity, mucosal phenotype, and dysplasia in Barrett's esophagus. Biopsies (n = 256) from squamous esophagus, columnar-lined esophagus every 2 cm, esophago-gastric junction, gastric body, and antrum from 32 patients with long-segment Barrett's esophagus were evaluated by telomerase repeat assay protocol (TRAP). Three biopsies for histology (n = 794) were simultaneously taken at each anatomical level. These and all prior and subsequent biopsies (n = 1917) were reviewed for mucosal phenotypes and dysplasia severity. Intestinal-type Barrett's mucosa was present at all levels in Barrett's esophagus. At least one Barrett's biopsy was TRAP(+) in 22 of 32 patients. TRAP positivity of intestinal-type Barrett's mucosa increased distally, possibly as a consequence of mucosal exposure to acid or bile reflux. Native gastric mucosa was rarely TRAP(+) (1/31 corpus, 2/32 antrum), whereas native squamous mucosa usually was TRAP(+) (31/32). Dysplasia almost always involved intestinal-type Barrett's mucosa (85/87; P.00001), without evidence of proximal-distal zoning. TRAP could be positive without dysplasia and negative in extensive, even high-grade, dysplasia. TRAP activity merits evaluation as a candidate biomarker for increased risk of persistent dysplasia and cancer progression in Barrett's esophagus.

Proton pump inhibitors (PPIs) are highly effective agents for the treatment of gastric acid-related disorders. They are metabolized by the cytochrome P450 (CYP) system, mainly via the enzyme CYP2C19. A genetically determined defect in this pathway results in impaired metabolism of PPIs, giving rise to three distinct phenotypes: rapid extensive (fast), extensive (medium), and poor (slow) metabolizers. These genetic mutations are more common in certain races, and there is, therefore, considerable inter-individual and -ethnic variation in the capacity to metabolize PPIs. The incidence of mutant alleles in a population treated for acid-related disorders may influence the efficacy of the treatment, with clinical implications for the prescribers of PPIs. Therapeutic failure, such as lack of symptom relief, or ineffective Helicobacter pylori eradication, can occur in rapid metabolizers who will have less available drug at a given dose. Conversely, poor metabolizers may be at risk of over-treatment, with increased incidence of adverse effects and unnecessary financial burden. Approaches to this problem include phenotyping or, preferably, genotyping patients prior to treatment with PPIs. This will allow tailoring dose regimens to the individual's metabolic capacity. An alternative strategy is the development of drugs that are either metabolized by genotype-independent pathways or are less susceptible to inter-individual genetic variation. Non-racemic PPIs fall into the latter category, and the first such agent, esomeprazole, is now commercially available.

We have examined four polymorphic elements in the human interleukin-6 (IL-6) locus and described their allele distribution in 73 unrelated, healthy individuals from the West-of-Scotland. These comprised three single nucleotide polymorphisms (SNP) in the 5' promoter region of the gene and one VNTR in the 3' region of IL-6. A statistical consideration of the relationship between alleles at each locus was carried out. Of a total of 12 possible haplotypes observed in the population, the analysis suggested that four were prominent. These accounted for 41.1%, 28.1%, 14.4% and 3.4% respectively; in total, 87% of the haplotypes present. Frequently, these proposed haplotypes were supported by homozygosity across all four loci within individuals. We propose that these haplotypes be identified as IL6.0103, IL6.0204, IL6.0207 and IL6.0307, in recognition of their frequency in this population and the alleles that they contain.

Background: Use of proton-pump inhibitors in the management of peptic ulcer bleeding is controversial because discrepant results have been reported in different ethnic groups. Objective: To determine whether intravenous esomeprazole prevents recurrent peptic ulcer bleeding better than placebo in a multi-ethnic patient sample. Design: Randomized trial conducted between October 2005 and December 2007; patients, providers, and researchers were blinded to group assignment. Setting: 91 hospital emergency departments in 16 countries. Patients: Patients 18 years or older with peptic ulcer bleeding from a single gastric or duodenal ulcer showing high-risk stigmata. Intervention: Intravenous esomeprazole bolus, 80 mg, followed by 8-mg/h infusion, over 72 hours or matching placebo, each given after successful endoscopic hemostasis. Intervention was allocated by computer-generated randomization. After infusion, both groups received oral esomeprazole, 40 mg/d, for 27 days. Measurements: The primary end point was rate of clinically significant recurrent bleeding within 72 hours. Recurrent bleeding within 7 and 30 days, death, surgery, endoscopic re-treatment, blood transfusions, hospitalization, and safety were also assessed. Results: Of 767 patients randomly assigned, 764 provided data for an intention-to-treat analysis (375 esomeprazole recipients and 389 placebo recipients). Fewer patients receiving intravenous esomeprazole (22 of 375) had recurrent bleeding within 72 hours than those receiving placebo (40 of 389) (5.9% vs. 10.3%; difference, 4.4 percentage points [95% Cl, 0.6% to 8.3%]; P = 0.026). The difference in bleeding recurrence remained significant at 7 days and 30 days (P = 0.010). Esomeprazole also reduced endoscopic retreatment (6.4% vs. 11.6%; difference, 5.2 percentage points [95% Cl of difference, 1.1 percentage points to 9.2 percentage points]; P = 0.012), surgery (2.7% vs. 5.4%), and all-cause mortality rates (0.8% vs. 2.1%) more than placebo, although differences for the latter 2 comparisons were not significant. About 10% and 40% of patients in both groups reported serious and nonserious adverse events, respectively. Limitation: Endoscopic therapy was not completely standardized; some patients received epinephrine injection, thermal coagulation, or hemoclips alone, whereas others received combination therapy, but there were similar proportions with single therapy in each group. Conclusion: High-dose intravenous esomeprazole given after successful endoscopic therapy to patients with high-risk peptic ulcer bleeding reduced recurrent bleeding at 72 hours and had sustained clinical benefits for up to 30 days.