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This study tested the effect of a new gastrin receptor antagonist, CR2945, on colorectal cancer induced by 1,2-dimethylhydrazine (DMH) in mice. 75 CD1 male mice were divided into 3 groups: group 1 received 1 weekly injection of 20 mg/kg of DMH and 2 daily intraperitoneal injections of 0.5 ml of NaCl 0.9% solution for 5 weeks; groups 2 and 3 received the same weekly dose of DMH and 2 daily injections of CR2945 at the respective doses of 2.5 and 7.5 mg/kg for 5 weeks. The animals were sacrificed 25 and 38 weeks after the first injection. No tumours were found at the 25th week. A lower cancer frequency (4%) was observed in treated animals compared to controls (37.4%) at the 38th week (p = 0.002). These data show that CR2945 could prevent chemically induced colon cancer development in mice.

In a series of 13 pancreas cancer specimens, EGF-R was evaluated by means of both immunohistochemistry (IHC) for protein expression and FISH for genetic amplification. The results were discording in 7 cases (IHC positive, FISH negative), while in the remaining 6 cases both IHC and FISH were negative. The possible clinical implications of these results are discussed.

Introduction In chronic villous atrophy plasma citrulline concentration (PCC) is decreased at the same severity and extent of mucosal lesions of villous architecture. Marsh-Oberhuber classification is conventionally used for grading villous atrophy in coeliac disease and a correlation with plasma citrulline concentrations has been found in pioneering studies. The Corazza-Villanacci classification gives better inter-observer agreement then Marsh-Oberhuber classification. Our primary aim was to correlate PCC to Corazza-Villanacci classification in coeliac disease. We aimed also to yield information in respect of PCC after one year of gluten free diet. Methods Forty subjects with a diagnosis of acute celiac disease have been studied. Nine out of forty patients were on gluten challenge diet. All patients underwent OGD with multiple biopsies and a blood test for plasma citrulline concentration at baseline and after one year of gluten free diet (GFD). Routine haematological and biochemical investigations were performed including, IgA tTG, IgA EMA and IgA/G antigliadin, ESR, haemoglobin and haematinics, albumin, liver function tests and creatinine. BMI and clinical symptoms were monitored. Histology was interpreted according to Marsh-Oberhuber and Corazza-Villanacci Classification. Plasma citrulline concentration was analysed by High Performance Liquid Chromatography Results Mean plasma citrulline concentration was lower (15.12 μmol/l) at baseline, in patients with active celiac disease, than in the same group of patients after one year of GFD (16.47 μmol/l) however we did not observe any overall change in citrulline concentration after one year of gluten-free diet. All patients were only partially histopathologically and clinically responsive to one year of GFD. Plasma citrulline concentrations correlated with Villanacci-Corazza classification (P = 0.05) in patients on gluten challenge diet. Patients with a score of 2 had lower citrulline values compared to those with a score of 1, on average 4 units. Correlation was not found between plasma citrulline concentrations and Marsh-Oberhuber classification at baseline and after one year of gluten-free diet. Conclusion Plasma citrulline concentration may be considered a reliable marker of severity and extent of small bowel villous atrophy in acute coeliac disease, more data are warranted to determine its role in the long-term management. Disclosure of Interest None Declared.

Introduction The traditional diagnosis of celiac disease (CD) requires a small bowel biopsy to identify at histology the characteristic mucosal changes. The current biopsy practise among endoscopists for celiac disease is in most part unknown. The aims of this study were to compare the different diagnostic criteria in various centres in Italy, Iran, Lithuania, Romania and the UK, the methodological approach to the biopsy and to investigate the pitfalls of CD diagnosis. To measure the number of specimens submitted during duodenal biopsy among patients in Italy, Iran, Lithuania, Romania and the UK, and to determine the incremental diagnostic yield of adherence to the recommended number of specimens. Methods A total of 931 patients who underwent duodenal biopsy for CD were recruited prospectively at nine centres in European and Middle East countries. Small-bowel biopsies were obtained from the duodenal bulb and the second part of the duodenum (and from the duodenal bulb when it had a micronodular appearance). The histopathological appearances were described according to the modified Marsh classification. Results The most frequent degree of villous atrophy amongst Iranian subjects was 3A and that of the rest of the study population was 3C. The most common number of biopsy specimens for Romanian subjects was 1 (52%) followed by 2 for Iranian (56%), 3 for Lithuanian (66.7%) and British patients (65%) and 4 for Italian patients (48.3%). The main presenting symptom was anaemia (18.7%) followed by malabsorption (10.5%), diarrhoea (9.3%) and dyspepsia (8.2%). Conclusion Taking less biopsy samples than recommended will have a negative impact in detecting massive number of undiagnosed cases. As CD is more common with atypical presentation, taking 4 duodenal biopsies is mandatory for an accurate diagnosis or its exclusion. Disclosure of Interest None Declared

Treatment of inflammatory bowel disease (IBD) is traditionally based on several drugs, including salicylates, corticosteroids, and antibiotics; in addition, the therapeutic armamentarium has considerably evolved with the advent of newer, effective therapeutic measures (such as the biological agents) that are able to improve in a considerable manner both the clinical and endoscopic variables. Thus, mucosal healing, at least considered from an endoscopic point of view, is today regarded as the ultimate endpoint for treatment of these conditions. However, it is also increasingly clear that endoscopic healing is not necessarily paralleled by histological healing; There are few doubts that the latter should be considered as a true, objective healing and the ultimate goal to reach when treating patients with IBD. Unfortunately, and surprisingly, only a few, incomplete, and somewhat conflicting data exist on this topic, especially because there is still the need to standardize both histological assessment and the severity grading of these disorders; Issues that have not been yet been resolved for clinical practice and therapeutic trials. Hopefully, with the help of an increased awareness on the clinical researchers’ side, and the availability of dedicated pathologists on the other side, this matter will be effectively faced and resolved in the near future.

Following the international guidelines criteria an adequate “diagnostic conclusion” of inflammatory bowel disease (IBD) can be achieved only if clinical, endoscopic and laboratory findings, together with sample technical adequacy and unequivocal histomorphological signs of the disease are available. Thus, a conclusive diagnosis requires a complex combination of clinical, endoscopic and histological data. A considerable number of endoscopic biopsies obtained from IBD patients do not meet the above-mentioned requirements. The aim of the present proposal is to introduce a binary system of evaluation in the “diagnostic conclusion” of the histopathological report that will help to simplify the clinical decisions and consequent patient management. In patients with no history of disease, the pathologist should classify the biopsies in “Diagnostic”, when the criteria established by the international guidelines are satisfied and “not diagnostic” when one or more of the above-mentioned criteria are not met. The term “not diagnostic” should replace “highly suggestive” and “probable”. This new terminology could avoid ambiguous expressions that encourage the clinician to classify the patient as affected by IBD without fulfilling all of the requirements for an accurate diagnostic approach.

Background Reported frequencies of celiac disease in selective IgA deficiency in childhood vary widely and this is probably due to the different characteristics of the patients studied and to the different criteria used for intestinal biopsy: all patients or only those with symptoms of malabsorption. Diagnosis of celiac disease is of considerable importance in IgA deficiency because of its increased frequency and also because avoidance of dietary gluten permits elimination of the symptoms and complications of celiac disease. Objectives To obtain a more reliable estimate of the incidence of celiac disease in childhood IgA deficiency, jejunal biopsies were performed in 65 consecutively diagnosed IgA-deficient children whose parents consented. Some clinical and laboratory parameters including IgA-antigliadin and IgG-antigliadin antibodies were evaluated to predict their usefulness in selecting IgA-deficient patients for intestinal biopsy. Methods All IgA-deficient patients had serum IgA levels below 5 mg/mL and salivary IgA below 0.5 mg/dL. Jejunal biopsy was performed using a peroral Watson capsule and IgA-antigliadin and IgG-antigliadin antibodies were performed by an ELISA assay. Results Biopsy findings of severe villous atrophy permitted diagnosis of celiac disease in 7.7% (5/65 children). IgG-antigliadin antibody levels, elevated in 16 patients including all five celiacs, were the best parameter for predicting celiac disease and gave no false negatives. Conclusions The 7.7% frequency of celiac disease observed in these IgA-deficient children is about 20 times higher than in the general Italian population, and the lowest among the studies biopsying all patients; this is probably attributable to the presence of a substantial proportion of healthy children (20/65) and very few (2/65) with autoimmune disorders. The elevated sensitivity and negative-predictive value of IgG-antigliadin antibodies lead us to suggest that positive IgG-antigliadin antibodies can be used to select IgA-deficient children for jejunal biopsy with a very low probability of missing celiac disease while allowing a drastic reduction in the number of biopsies performed.

With this appropriate title (The normal gastric cardia fact or fiction?) John R. Goldblum [7] and Sony P. Kilgore et al. [8] in recent reviews outlined one of the most great histopathological controversies in recent years: the real existence of the gastric cardia as a normal structure or not. In Histology for Pathologists [9], David A. Owen described the gastric cardia as “a narrow strip of mucosa separating the most distal portion of the esophageal squamous mucosa from the acid-producing fundic mucosa (oxyntocardiac mucosa OCM) histologically composed exclusively by mucus secreting glands”. In recent years, the group of Parakrama T. Chandrasoma at the University of Southern California USC [1, 2, 3, 4, 10] have suggested that the gastric cardia is not a normal structure as previously described and, in reality, is the expression of a metaplasia of esophageal mucosa related to gastro-esophageal reflux. Under normal condition, there is a direct continuity between esophageal mucosa and acid-producing fundic mucosa or oxyntocardiac mucosa (OCM). This assertion was based on an autopsy study [2] in which Chandrasoma examined 72 patients who had an evaluable section across the squamocolumnar junction. Thirty percent of all cases, including 9 of 11 patients younger than age 20 years, did not have any cardiac mucosa, the squamous epithelium transitioned directly to the oxyntic mucosa of the gastric fundus. In those who had cardiac mucosa, the length of this mucosa was short, being less than 1 cm in all but two cases. In contrast, in a series [3] of 71 patients with gastroesophageal reflux disease (GERD) who had multiple biopsies, all 71 patients had cardiac mucosa, and 30% had cardiac mucosal lengths of over 2 cm. “The results of this comparison strongly suggest that cardiac mucosa is not a normal structure but is an abnormal mucosa that results from the metaplastic transformation of the squamous epithelium damaged by reflux.” In agreement with this observation, there was recently the experience of Young S. Park et al. [11], in which the entire gastroesophageal junction (EGJ) and the proximal part of the stomach from 23 fetal and pediatric autopsies was examined. In 78% of cases, the transitional zone between the EGJ and fundic mucosa was always characterized by some scattered parietal cells in mucous glands. The parietal cells were consistently identified adjacent to the EGJ in all cases. The conclusion was that the cardiac mucosa composed of pure mucous cells does not exist as a normal developmental structure. In contrast to this evaluation, S.P. Kilgore [8] et al. evaluated the entire EGJ in 30 pediatric autopsies from patients aged 18 years or younger with no known history of GERD or Barret’s esophagus. In all cases, cardiac mucosa was present, always on the gastric side of the EGJ, although it was quite small, ranging from only 1 mm to 4 mm in length. The results of this study support the concept that the gastric cardiac-type mucosa is present from birth as a normal structure and is not related to GERD or Helicobacter pylori infection. More recently, Derdoy et al. [5] examined the EGJ in 100 pediatric autopsies, and their conclusions were that cardiac-type mucosa on the distal side of the EGJ was present in all 100 pediatric autopsy specimens; therefore, there is a normal, variably narrow developmental zone at the EGJ covered by cardiac mucosa and is present at birth. It does not necessarily represent evidence of a mucosal metaplastic response to GERD. Similar results were also obtained from J.N. Glickman et al. [6]. These authors examined the mucosal biopsies of the cardia of 74 pediatric patients (age range 0.1– 18 years). The results were correlated with the patient’s V. Villanacci ()) Department of Surgical Pathology, University of Brescia, Piazzale Spedali Civili 1, 25124 Brescia, Italy e-mail: villan@iol.it Tel.: +39-030-3995479 Fax: +39-030-3995053

Background Alterations of small intestinal transit and gallbladder (GB) motility have been reported in celiac disease (CD) in studies involving, in most cases, non-physiological experimental conditions and artificial stimuli to motility. Our aims were to quantitate non-invasively small intestinal transit time and GB emptying during administration of a physiological and palatable solid meal, and to assess the effect of gluten-free diet (GFD). Methods We simultaneously measured mouth-to-cecum transit time (MCTT) using a validated H2 breath test, and GB motility using ultrasonography. We studied CD patients before (n = 19) and during (n = 14) GFD, and healthy volunteers (n = 24) following administration of a physiological solid meal (Kcal 539). Key Results Mouth-to-cecum transit time was more prolonged in CD (mean ± SEM: 235 ± 96 min) than in controls (169 ± 65 min, P = 0.0039). The GB fasting volume and postprandial residual volume were significantly higher in CD than in controls, and GB emptying constant was slower in CD than in controls. During GFD, GB emptying reverted to normal, but MCTT remained unchanged (229 ± 69 min) and more prolonged in CD than in controls (P = 0.0139). During GFD, duodenal infiltration with lymphocytes and mast cells persisted higher than that in controls, and the number of mast cells lying in proximity of nervous endings did not change. Conclusions & Inferences Slow postprandial MCTT in response to a physiological meal does not revert to normal during GFD, an effect mirroring incomplete histopathologic recovery.

AIM: To investigate whether this might be related to the presence of hyperhomocysteinemia. METHODS: From January 1998 to December 2008, we evaluated the presence of hyperhomocysteinemia in a series of 165 adult celiac disease (CD) patients (138 females and 27 males, mean age 43 years). RESULTS: Hyperhomocysteinemia was evident in 32 patients (19.3%), although most of them had moderate levels (mean value 25 mcg/ml; range 15-30). Only one patient had a history of myocardial infarction (heterozygosis for N5-N10-metil tetrahydrofolate reductase mutation). CONCLUSION: The systematic assessment of hyperhomocysteinemia seems, at present, unjustified in CD patients. © 2011 Baishideng. All rights reserved

Background: A causal association between acute diverticulitis of the sigmoid colon and arthritis has rarely been reported. Case Report: We report the case of a 60-year-old patient who developed migrating arthritis of the knee and ankle during the recurring episode of acute diverticulitis of the sigmoid colon. Treatment with NSAIDs and antibiotics had little effect on joint disease, but medical treatment was successful in reducing the diverticulitis-related symptoms. Arthritis promptly improved after surgical resection of the sigmoid colon, and 30 months later the patient is free of symptoms in the previously affected joints. Conclusions: Five cases of diverticulitis-associated arthritis have been reported. The similar case reported here reconfirms that joint disease has a limited response to medical approaches. Colon resection is recommended for patients with diverticulitis-associated arthritis which does not respond promptly to antibiotic therapy.

their first re-evaluation. To avoid any bias, to both patient and doctor, the questionnarie was administered by a second operator, just before taking duodenal biopsies, except for 6 cases (maximum time elapse: 3 months). The score obtained was compared with persistence of both villous atrophy (VA) and endomysial antibodies (EMA) tested on monkey oesophagus. Results: The questionnaire was fulfilled in less than one minute. The table shows that patients scoring the lowest results were more frequent among the patients with persistence of both VA and positive EMA.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterised by epistaxis, telangiectases, and multiorgan vascular dysplasia. Mutations of the ENG and ACVRL1 genes cause at least 80% of cases. We report the first case of merkeloma found in a patient with HHT carrying an ENG mutation. We analysed the tumour with immunohistochemical methods using primary antibodies against CD105 (endoglin), TGF-β, Smad4, CD31 and CD34. Tumour cells were positive for Smad4, weakly positive for TGF-β, and negative for CD105. Vasal endothelial cells were highly positive for CD105, CD31 and CD34. No remarkable differences between cancer and normal cells in our patient or between the patient’s merkeloma and two control merkelomas were observed. The presence of a merkeloma in an HHT patient could be an occasional association, but to certainly assume it further investigations are needed.

AIM: To assess linear endoscopic ultrasound (L-EUS) and magnetic resonance imaging (MRI) in biliary tract dilation and suspect small ampullary tumor. METHODS: L-EUS and MRI data were compared in 24 patients with small ampullary tumors; all with subsequent histological confirmation. Data were collected prospectively and the accuracy of detection, histological characterization and N staging were assessed retrospectively using the results of surgical or endoscopic treatment as a benchmark. RESULTS: A suspicion of ampullary tumor was present in 75% of MRI and all L-EUS examinations, with 80% agreement between EUS and histological findings at endoscopy. However, L-EUS and histological TN staging at surgery showed moderate agreement (κ = 0.54). CONCLUSION: L-EUS could be a useful adjunct as a diagnostic tool in the evaluation of patients with suspected ampullary tumors.

This is a double randomized trial aimed at evaluating the efficacy of antioxidants in reducing the incidence of metachronous adenomas (MA) of the large bowel after endoscopic polypectomy. A 50% reduction in the incidence of MA was expected in patients (pts) allocated to an active compound (intervention) arm as compared to those assigned to a placebo. Eligible for the study were pts aged 25–75 years with a clean colon after adenomas removal. Pts with FAP, invasive carcinoma in adenoma, previous polypectomy, IBD, bowel resection, cancer at any site, life-threatening diseases, current use of vitamins or calcium were excluded. Pts were randomly allocated to receive daily, for 5 years, either an antioxidant compound (selenomethionine 200 g, zinc 30 mg, vitamin A 6000 IU, vitamin C 180 mg and vitamin E 30 mg) or a placebo, both were provided by Pharma Nord. Total Colonoscopy (TC) was planned on year one, three and five after randomization and then according to current guidelines. The primary endpoint of the study was the occurrence of MA detected during TC examinations. The study was approved by the Ethical Committee of the Natl. Institute for Cancer Research of Genoa. Three GI endoscopy units in northern Italy participated in the study. The study started on March 1988 and was stopped on June 1996 when 411 patients had been enrolled. Of them, 200 were assigned to the intervention arm and 211 to the placebo arm. On June 2009, information on survival was available for 396 pts (96.4%); follow up information (at least one TC performed after randomization) was available for 311 pts (80.5%): 165 in the intervention and 166 in the placebo arm. Predictors of MA (gender, age, number of adenomas and rate of advanced adenomas) were similar in pts who had follow up TC and in those who were lost. Of the 311 patients, 144 (43.5%) assumed more than 2/3 of the total amount of the assigned treatment: the rates were similar in the two arms. An intention to treat analysis was performed. The 311 pts provided 1.743 py of follow-up and 98 pts developed MA (2 with invasive carcinoma). The observed incidence of MA was 4.2% (37 cases/886 py) in the intervention arm and 7.2% (62 cases/857 py) in the placebo arm (crude RR=0.56, 95% CI 0.36–0.87; P=0.007). The 15-year actuarial MA-free survival was 48.3% in pts assigned to the intervention arm and 30.5% in those assigned to the placebo arm (P=0.006). A Cox proportional hazard model was fitted to the data and GI endoscopy unit, gender, age, number of adenomas, presence of advanced adenoma were included in the model as covariates: a 41% reduction in the risk of MA was observed in the intervention as compared to the placebo arm (HR=0.59, 95% CI 0.39–0.90; P=0.013). Among pts who had advanced adenomas at randomization, those assigned to the intervention arm had a 10-fold lower risk of advanced MA as compared to those assigned to the placebo (RR=0.11, 95%CI 0.02–0.49; P=0.004). To our knowledge, this is the first time that a specifically designed trial shows the persistence of a statistically significant reduction of colorectal MA in pts treated with a selenium-based antioxidant compound long time after the treatment cessation. In particular, the effect observed in pts with advanced index adenoma is intriguing. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A80.

The authors' previous observation that many of the monoclonal antibodies against Helicobacter pylori cross-react with the cells of the human gastric mucosa prompted them to investigate the possibility that gastric self-antigens cross-reacting with H. pylori could be involved in the immune response against this organism. It was found that three antibodies against H. pylori, CB-4, CB-10, and CB-14, that cross-react with the human gastric mucosa also intensely cross-reacted with murine gastric epithelial cells. A strong reaction against autologous mucosa was also evident in the sera of mice immunized with H. pylori but not with other bacteria. A serological study performed in a group of 82 patients undergoing gastroscopy showed that the presence of seropositivity against H. pylori was strongly correlated with the presence of autoantibodies against human antral gastric mucosa. This activity was neutralized after absorption of the sera with H. pylori but not with other gram-negative bacteria. The antibodies in the mouse and in the human did not react with other segments of the gastrointestinal tract or with most of the other organs. Mice bearing hybridomas secreting a cross-reacting antibody (CB-4) had histopathologic abnormalities in their stomachs. These lesions were absent in the stomachs of mice bearing hybridomas secreting a non-cross-reacting antibody (CB-26). It was concluded that H. pylori infection can stimulate antibodies cross-reacting with gastric autoantigens and that this immunologic mechanism may represent a pathogenic link between H. pylori and gastritis.

The role of enteric glial cells has somewhat changed from that of mere mechanical support elements, gluing together the various components of the enteric nervous system, to that of active participants in the complex interrelationships of the gut motor and inflammatory events. Due to their multiple functions, spanning from supporting elements in the myenteric plexuses to neurotransmitters, to neuronal homeostasis, to antigen presenting cells, this cell population has probably more intriguing abilities than previously thought. Recently, some evidence has been accumulating that shows how these cells may be involved in the pathophysiological aspects of some diseases. This review will deal with the properties of the enteric glial cells more strictly related to gastrointestinal motor function and the human pathological conditions in which these cells may play a role, suggesting the possibility of enteric neuro-gliopathies.

To evaluate endoscopic mucosal resection (EMR) in patients with high-grade dysplasia (HGD) and/or intramucosal cancer (IMC) in Barrett's esophagus (BE).Between June 2000 and December 2003, 39 consecutive patients with HGD (35) and/or IMC (4) underwent EMR. BE30 mm was present in 27 patients. In three patients with short segment BE (25.0%), HGD was detected in a normal appearing BE. Lesions had a mean diameter of 14.8+/-10.3 mm. Mucosal resection was carried out using the cap method.The average size of resections was 19.7+/-9.4 x 14.6+/-8.2 mm. Histopathologic assessment post-resection revealed 5 low-grade dysplasia (LGD) (12.8%), 27 HGD (69.2%), 2 IMC (5.1%), and 5 SMC (-12.8%). EMR changed the pre-treatment diagnosis in 10 patients (25.6%). Three patients with SMC underwent surgery. Histology of the surgical specimen revealed 1 T0N0 and 2 T1N0 lesions. The remaining two patients were cancer free at 32.5 and 45.6 mo, respectively. A metachronous lesion was detected after 25 mo in one patient with HGD. Intra-procedural bleeding, controlled at endoscopy, occurred in four patients (10.3%). After a median follow-up of 34.9 mo, all patients remained in remission.In the medium term, EMR is effective and safe to treat HGD and/or IMC within BE and is a valuable staging method. It could become an alternative to surgery.