Michael J. G. Farthing

Abnormal immunoreactivity of the E-cadherin-catenin complex in gastric carcinoma: Relationship with patient survival

BACKGROUND & AIMS The E-cadherin-catenin complex plays a critical role in the maintenance of normal tissue architecture. Mutation of any of its components is believed to result in loss of cell-cell adhesion and contribute to neoplasia. The aim of this study was to examine the expression of E-cadherin and alpha-, beta-, and gamma-catenin in gastric carcinoma and dysplasia and determine any relationship with tumor characteristics and survival. METHODS Immunoperoxidase staining of E-cadherin and alpha-, beta-, and gamma-catenin was performed using 89 gastric carcinomas, lymph node metastases, and gastric biopsy specimens from 14 patients with dysplasia and 10 healthy controls. RESULTS Membranous staining was observed in control biopsy specimens for all components of the complex. Up to 57% of gastric dysplasia and 90% of tumors stained abnormally for one or more components of the cadherin-catenin complex. Abnormal E-cadherin and gamma-catenin staining occurred more frequently in diffuse than intestinal tumors (P < 0.0005 and < 0.05, respectively). No association with tumor grade or stage was found. A survival advantage was noted in intestinal and diffuse tumors retaining membranous expression of beta-catenin, independent of tumor type, grade, or stage (P < 0.005). CONCLUSIONS Abnormal expression of the E-cadherin-catenin complex occurs frequently in gastric carcinoma. The close correlation with poor survival suggests that abnormal beta-catenin may be a useful prognostic marker.

Diversity in the oesophageal phenotypic response to gastro-oesophageal reflux: immunological determinants

Background and aims: Approximately 10% of adults experience gastro-oesophageal reflux symptoms with a variable oesophageal response. A total of 60% have no endoscopic abnormality, 30% have oesophagitis, and 10% have Barretts oesophagus. We investigated whether the inflammatory cell infiltrate and cytokine profiles of these clinical phenotypes merely vary in severity or are fundamentally different. Methods: Patients with reflux symptoms and a normal oesophagus (n=18), oesophagitis (n=26), and Barretts oesophagus (n=22 newly diagnosed, n=28 surveillance) were recruited. Endoscopic and histopathological degrees of inflammation were scored. Cytokine expression was determined by competitive reverse transcriptase-polymerase chain reaction and immunohistochemistry. Results: In oesophagitis, endoscopic and histopathological grades of inflammation correlated highly. mRNA expression of proinflammatory interleukin (IL)-1β, IL-8, and interferon γ (IFN-γ) were increased 3–10-fold compared with non-inflamed squamous or Barretts oesophageal samples. There was a modest increase in anti-inflammatory IL-10 but no increase in IL-4. In Barretts oesophagus, 29/50 had no endoscopic evidence of inflammation and histopathological inflammation was mild in 17/50 and moderate in 24/50, independent of acid suppressants. Expression of IL-1β, IL-8, and IFN-γ was similar to non-inflamed squamous mucosa. IL-10 was increased 1.6-fold similar to oesophagitis. IL-4 was increased fourfold, with 100-fold increase in IL-4/T cell receptor expression, compared with squamous oesophagus or oesophagitis. Conclusions: Barretts oesophagus is characterised by a distinct Th-2 predominant cytokine profile compared with the proinflammatory nature of oesophagitis. The specific oesophageal immune responses may influence disease development and progression.

Fascin, an Actin-Bundling Protein, Modulates Colonic Epithelial Cell Invasiveness and Differentiation in Vitro

In epithelial tissue, cell-matrix and cell-cell adhesive interactions have important roles in the normal organization and stabilization of the cell layer. The malignant conversion of epithelial cells involves alterations in the expression and function of these adhesion systems that enable a switch to a migratory phenotype in tumor invasion and metastasis. Fascin is an actin-crosslinking protein that is found in the core actin bundles of cell-surface spikes and projections that are implicated in cell motility. We demonstrate that fascin is not detectable in normal colonic epithelium, but is dramatically up-regulated in colorectal adenocarcinoma. To test the hypothesis that fascin could participate in tumor invasive behavior, we developed a cell culture model to examine the effect of fascin expression on the adhesive interactions, invasiveness, and differentiation of colonic epithelial cells. We report marked effects on the organization of cell-surface protrusions, actin cytoskeleton, and focal adhesions in the absence of alterations in the protein levels of the major components of these structures. These effects correlate with alterations in cell movements on two-dimensional matrix, and increased invasiveness in three-dimensional matrix. The cells also show increased proliferation and decreased capacity for normal glandular differentiation in collagen gels. We propose that up-regulation of fascin, by promoting the formation of protrusive, actin-based, cell-motility structures, could be a significant component in the acquisition of invasive phenotype in colonic carcinoma.

Growth failure occurs through a decrease in insulin-like growth factor 1 which is independent of undernutrition in a rat model of colitis

BACKGROUND Linear growth retardation is a frequent complication of inflammatory bowel disease in children. The precise mechanisms causing growth failure are not known. AIMS To determine the relative contribution of reduced calorie intake and inflammation to linear growth delay and to determine the effect of inflammation on the hypothalamic-pituitary-growth axis. METHODS Linear growth was assessed in prepubertal rats with trinitrobenzenesulphonic acid (TNBS) induced colitis, in healthy free feeding controls, and in a pair-fed group (i.e. healthy animals whose daily food intake was matched to the colitic group thereby distinguishing between the effects of undernutrition and inflammation). RESULTS Changes in length over five days in the TNBS colitis and pair-fed groups were 30% and 56%, respectively, of healthy free feeding controls. Linear growth was significantly reduced in the colitic group compared with the pair-fed group. Nutritional supplementation in the colitic group increased weight gain to control values but did not completely reverse the growth deficit. Plasma interleukin 6 (IL-6) concentrations were sixfold higher in the colitic group compared with controls. Plasma concentrations of insulin-like growth factor 1 (IGF-1) but not growth hormone (GH) were significantly lower in the colitic compared with the pair-fed group. Administration of IGF-1 to the colitic group increased plasma IGF-1 concentrations and linear growth by approximately 44–60%. CONCLUSIONS It seems likely that approximately 30–40% of linear growth impairment in experimental colitis occurs as a direct result of the inflammatory process which is independent of undernutrition. Inflammation acts principally at the hepatocyte/IGF-1 level to impair linear growth. Optimal growth in intestinal inflammation may only be achieved by a combination of nutritional intervention and anticytokine treatment.

Inflammatory gradient in Barrett’s oesophagus: implications for disease complications

Introduction: Barrett’s oesophageal epithelium (BE) is clinically important due to the associated inflammatory and malignant complications which are unevenly distributed throughout the BE segment. As the immunoregulatory environment may influence disease manifestations, we analysed the inflammatory and cytokine responses throughout the BE mucosa. We then investigated whether the inflammatory gradient is related to the distribution of metaplastic cell subtypes, epithelial exposure to the components of refluxate, or squamocolumnar cell interactions. Methods: Fifty consecutive patients with long segment BE were recruited. The segmental degree of endoscopic and histopathological inflammation was graded, and expression of interleukin (IL)-1β, IL-8, IL-4, and IL-10 were determined by ELISA following organ culture with or without addition of acid or bile salts. Mucin staining and IL-10 immunohistochemistry were performed. The effect of squamocolumnar interactions on cytokine expression were analysed using cocultures of squamous (OE-21) and BE (TE7) carcinoma cell lines. Results: There was a histopathological inflammatory gradient in BE. Inflammation was maximal at the new squamocolumnar junction with ≥2-fold increase in proinflammatory IL-8 and IL-1β expression. The proximal proinflammatory response could not be explained by the distribution of metaplastic subtypes. Pulsatile exposure of BE to acid and bile, as well as juxtaposition of BE to squamous epithelial cells in culture, increased expression of IL-1β. In contrast, inflammation was minimal distally with a significant increase in anti-inflammatory IL-10 expression and 4/6 cancers occurred distally. Conclusions: Specific cytokine responses may contribute to the localisation of inflammatory and malignant complications within BE.

Lactobacilli to Prevent Traveler's Diarrhea?

To the Editor: Acute diarrhea is the most common illness in travelers to high-risk areas, with up to half of those engaged in short-term travel affected.1 Although most episodes are mild and self-l...

World Gastroenterology Organisation Global Guidelines on Celiac Disease

CONTENTS1 Definitions2 Key points3 Epidemiology4 Diagnosis of celiac disease5 Management of celiac diseaseDEFINITIONSCeliac disease (CD) is a chronic, immunologically determined form of enteropathy affecting the small intestine in genetically predisposed children and adults. It is precipitated by th

Management of infectious diarrhoea

Infectious diarrhoea is the most common cause of diarrhoea worldwide and is the leading cause of death in childhood. Gastrointestinal infections have their major impact in the developing world. In the developed world, despite improvements in public health and economic wealth, the incidence of intestinal infection remains high and continues to be an important clinical problem. During the past 10 years there have been some major improvements in our knowledge base regarding the treatment of infectious diarrhoea. Oral rehydration therapy (ORT) remains central to case management but advances have been made by the introduction of hypotonic solutions and there is early evidence that resistant starch may be the substrate of the future. The search for antisecretory drugs continues, with real progress having been made by the introduction of a new class of drugs, the enkephalinase inhibitors. Other new drugs are in the early phases of development. The role of antimicrobial agents in the management of infective diarrhoea continues to be clarified with the emergence of new agents and simplified treatment regimens. Probiotics are popular with diarrhoea sufferers and have been shown to have some efficacy but further scrutiny is required to determine the magnitude of their effects. Infectious diarrhoea is the most common cause of diarrhoea worldwide and is responsible for more deaths than gastrointestinal cancers, peptic ulcer, or inflammatory bowel disease. Diarrhoeal disease is the leading cause of childhood death and the second most common cause of death worldwide. Gastrointestinal infections have their major impact in the developing world: diarrhoeal diseases are responsible, directly or indirectly, for approximately three million deaths each year among children under five years of age—that is, 1 every 10 seconds. There are an estimated 1.8 billion episodes of childhood diarrhoea per year and virtually all of these acute diarrhoeal episodes are related to infectious …

5-Hydroxytryptamine and human small intestinal motility: effect of inhibiting 5-hydroxytryptamine reuptake.

Parenteral 5-hydroxytryptamine stimulates small intestinal motility, but the effect of continuous stimulation with 5-hydroxytryptamine on the human migrating motor complex is unknown. Using a selective 5-hydroxytryptamine reuptake inhibitor, paroxetine, this study investigated the effect of indirect 5-hydroxytryptamine agonism on fasting small intestinal motility and transit. Eight healthy subjects were studied while receiving paroxetine 30 mg daily for five days and while receiving no treatment, in random order. Ambulant small intestinal motility was recorded from five sensors positioned from the duodenojejunal flexure to the ileum for 16-18 hours. Paroxetine reduced the migrating motor complex periodicity mean (SEM) from 81 (6) min to 67 (4) min (p < 0.05), and increased the propagation velocity of phase III from 3.1 to 4.7 cm/min in the proximal jejunum (p < 0.01), and from 1.6 to 3.4 cm/min distally (p < 0.001). Orocaecal transit time measured by lactulose hydrogen breath test was reduced by paroxetine from 70 (9) min to 48 (7) min (p < 0.05). These data suggest that 5-hydroxytryptamine participates in the control of migrating motor complexes in humans, and that selective 5-hydroxytryptamine reuptake inhibitors have a prokinetic action in the human small intestine.

Rigorous surveillance protocol increases detection of curable cancers associated with Barrett's esophagus

Esophageal adenocarcinoma is increasing in incidence and has a high mortality unless detected early. Barretts esophagus is the only known risk factor for this cancer; however, whether endoscopic surveillance reduces morbidity and mortality is controversial. Endoscopic cancer surveillance programes for Barretts esophagus are not routinely practiced in the UK, and this is the first study to examine whether a rigorous surveillance protocol increases the detection rate of early oesophageal cancer. All patients with a diagnosis of Barretts esophagus or associated adenocarcinoma attending Havering Hospitals NHS Trust between 1992 and 1998 were included. A retrospective analysis was made of patients undergoing informal surveillance (96 patients, 1992–1997) and a prospective analysis was conducted following the implementation of a rigorous protocol (108 patients, 1997–1998). Over the same time periods Barretts associated cancers diagnosed in patients not undergoing surveillance were analyzed (262 patients 1992–1997, 98 patients 1997–1998). From 1992 to 1997, one case of high-grade dysplasia was detected (N = 96, 1%). From 1997 to 1998, two cancers and three high-grade dysplasias were detected during rigorous surveillance (N = 108, 4.6%). Three of these patients have had curative esophagectomies (one high-grade dysplasia and two T1,N0,M0 tumors). In 1992–1997, 10 patients were found to have cancer in previously undiagnosed Barretts esophagus (N = 262, 3.8%). Of 3/10 cancers treated surgically, one patient had a curative procedure (T1,N0,M0). In 1997–1998, nine patients were found to have de novo Barretts esophagus cancer (N = 88, 10.2%) and three had curative resections (T1,N0,M0). Two of the patients with T1 lesions had no endoscopic evidence of cancer but were detected as a result of the multiple biopsy protocol. In conclusion, a rigorous biopsy protocol increases the detection of early cancer in Barretts esophagus.