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International audience; BACKGROUND: & Aims: There is a need for a scoring system that provides a comprehensive assessment of structural bowel damage, including stricturing lesions, penetrating lesions, and surgical resection, that measures disease progression. We developed the Lémann Index and assessed its ability to measure cumulative structural bowel damage in patients with Crohn's disease (CD). METHODS: We performed a prospective, multicenter, international, cross-sectional study of patients with CD evaluated at 24 centers in 15 countries. Patients were stratified based on CD location and duration. All patients underwent clinical examination and abdominal magnetic resonance imaging analyses. Upper endoscopy, colonoscopy, and pelvic magnetic resonance imaging analyses were performed according to suspected disease locations. The digestive tract was divided into 4 organs and subsequently into segments. For each segment, investigators collected information on previous surgeries, predefined strictures, and/or penetrating lesions of maximal severity (grades 1-3), and then provided damage evaluations ranging from 0.0 (no lesion) to 10.0 (complete resection). Overall level of organ damage was calculated from the average of segmental damage. Investigators provided a global damage evaluation (from 0.0 to 10.0) using calculated organ damage evaluations. Predicted organ indexes and Lémann index were constructed using a multiple linear mixed model, showing the best fit with investigator organ and global damage evaluations, respectively. An internal cross-validation was performed using bootstrap methods. RESULTS: Data from 138 patients (24, 115, 92, and 59 with upper tract, small bowel, colon/rectum, and anus CD location, respectively) were analyzed. According to validation, the unbiased correlation coefficients between predicted indexes and investigator damage evaluations were 0.85, 0.98, 0.90, 0.82 for upper tract, small bowel, colon/rectum, anus, respectively, and 0.84 overall. CONCLUSIONS: Conclusions: In a cross-sectional study, we assessed the ability of the Lémann index to measure cumulative structural bowel damage in patients with CD. Provided further successful validation and good sensitivity to change, the index should be used to evaluate progression of CD and efficacy of treatment.

Background & Aims: The need for colonoscopy when small tubular adenomas with low-grade dysplasia are found on sigmoidoscopy is uncertain. The aim of this study was to examine the prevalence and characteristics of proximal adenomas in patients with distal adenomas. Methods: We studied 981 subjects with distal adenomas found on the index colonoscopy before randomization in the Polyp Prevention Trial. Results: Four hundred sixty patients (46.9%) had ≥1 distal adenoma that was pathologically advanced (villous component, high-grade dysplasia, or ≥1 cm); 21.5% (211 of 981) had any proximal adenoma; and 4.3% (42 of 981) (95% confidence interval [CI], 3.0–5.5) had an advanced proximal adenoma. A greater percentage of patients with an advanced distal adenoma (5.9%) (95% CI, 3.7–8.0) had an advanced proximal adenoma compared with those with a nonadvanced distal adenoma (2.9%) (95% CI, 1.4–4.3) (OR, 2.1; 95% CI, 1.1–4.3; P = 0.03). Not performing a colonoscopy in patients with a nonadvanced distal adenoma would have missed 36% (15 of 42) of the advanced proximal adenomas. Conclusions: Patients with an advanced distal adenoma are twice as likely to have an advanced proximal adenoma as patients with a nonadvanced distal adenoma. However, eschewing a colonoscopy in patients with a nonadvanced distal adenoma would result in not detecting a sizeable percentage of the prevalent advanced proximal adenomas. These data support performance of a colonoscopy in patients with a nonadvanced distal adenoma. Confirmation of these results in asymptomatic subjects undergoing screening sigmoidoscopy is advisable. GASTROENTEROLOGY 1998;115:533-541

Background & Aims: Long-term survival of patients with Zollinger–Ellison syndrome (ZES) is largely determined by the presence or absence of liver metastases. However, because of the lack of precision of these criteria, development of further indicators is still required. Recent evidence showing that autoantibodies directed against the p53 protein could predict poor survival for some types of cancers prompted us to investigate the presence of such antibodies in sera from patients with ZES and their potential value as survival indicator. Methods: Anti-p53 antibodies were detected in the sera of 44 consecutive patients with ZES using both an enzyme-linked immunosorbent assay (ELISA) and Western blotting. The mean follow-up of these patients was 92 months. Results: Anti-p53 antibodies were detected in 7 of the patients with ZES (16%) by both ELISA and Western blotting. Univariate and multivariate analyses showed that the presence of anti-p53 antibodies ( P = 0.0009 and P = 0.017, respectively) and liver metastases ( P = 0.0009 and P = 0.012, respectively) was independently associated with shorter survival. Conclusions: These results suggest that anti-p53 antibodies are an indicator of survival and could be used in combination with staging to determine which patients with ZES have poor prognoses and therefore require reinforced therapy. GASTROENTEROLOGY 1998;114:37-43

Background: Linxian, China, has one of the highest rates of esophageal cancer in the world. To design a logical biopsy strategy for large-scale endoscopic surveys in Linxian, the aim of this study was to determine whether squamous dysplasia and early squamous cancer are associated with visible lesions that can be targeted for biopsy. Methods: Sixty-three Linxian patients with balloon cytological evidence of squamous dysplasia or early cancer of the esophagus had biopsy specimens taken every 4 cm and additional specimens taken from all visually abnormal areas. The appearance of the 398 biopsy sites was described, and abnormal-appearing areas were photographed. The endoscopic descriptions were then compared with the biopsy diagnoses. Results: Twenty-five of 31 (81%) moderately dysplastic or worse specimens (including all nine specimens of invasive cancer) came from visually abnormal sites classified as friability, focal red area, erosion, plaque, or nodule. Fifteen of 16 (94%) patients with moderate dysplasia or worse biopsy diagnoses would have been identified if only these visible target lesions had been sampled. Conclusions: For surveillance in this high-risk population, random biopsy specimens may be unnecessary; sampling the target lesions described appears sufficient to detect nearly all invasive cancer and most dysplasia. Awareness of these lesion appearances may also aid in earlier detection of squamous cancers of the esophagus in lower-risk populations such as those in Europe and North America.

Electron microscopic examination of upper gastrointestinal biopsies with x-ray microanalysis was used to detect electron-dense particles of bismuth in the mucosa of the upper gastrointestinal tract, 30–60 minutes after oral dosing with either tripotassium dicitrato bismuthate [De-Noltab; Brocades (Great Britain) Ltd., Weybridge, UK; five patients] or bismuth salicylate (Pepto-Bismol; Richardson Vicks Ltd., Egham, UK; five patients), or without dosing (two patients). Transmucosal penetration of bismuth particles was observed in the gastric antral mucosa of all patients who had been dosed with tripotassium dicitrato bismuthate, but there was no penetration after oral dosing with bismuth salicylate. Persorption of bismuth particles through the gastric mucosa to the vascular endothelium provides an explanation for the rapid rise of plasma bismuth concentration observed only after oral dosing with tripotassium dicitrato bismuthate.

Background & Aims: Visceral mechanoreceptors are critical for perceived sensations and autonomic reflex control of gastrointestinal function. However, the molecular mechanisms underlying visceral mechanosensation remain poorly defined. Degenerin/epithelial Na+ channel (DEG/ENaC) family ion channels are candidate mechanosensory molecules, and we hypothesized that they influence visceral mechanosensation. We examined the influence of the DEG/ENaC channel ASIC1 on gastrointestinal mechanosensory function, on gastric emptying, and on fecal output. We also compared its role in gastrointestinal and somatic sensory function. Methods: To assess the role of ASIC1 we studied wild-type and ASIC1−/− mice. Reverse-transcription polymerase chain reaction (RT-PCR) and Western blot analysis determined expression of ASIC1 messenger RNA and protein in vagal and spinal sensory ganglia. Colonic, gastroesophageal, and cutaneous afferent fibers were characterized by functional subtype and their mechanical stimulus-response relationships were determined. Gastric emptying was determined by using a 13CO2 breath test. Behavioral tests assessed somatic mechanical and thermal sensitivity. Results: ASIC1 was expressed in sensory ganglia and was lost after disruption of the ASIC1 gene. Loss of ASIC1 increased mechanosensitivity in all colonic and gastroesophageal mechanoreceptor subtypes. In addition, ASIC1−/− mice showed almost double the gastric emptying time of wild-type mice. In contrast, loss of ASIC1 did not affect function in any of the 5 types of cutaneous mechanoreceptors, nor did it affect paw withdrawal responses or fecal output. Conclusions: ASIC1 influences visceral but not cutaneous mechanoreceptor function, suggesting that different mechanisms underlie mechanosensory function in gut and skin. The role of ASIC1 is highlighted by prolonging gastric emptying of a meal in ASIC1−/− animals.

Fundic gland polyps (FGPs) are the most common type of gastric polyp and are seen in up to 5% of patients on endoscopy. Although considered benign, FGPs are more common in patients with familial adenomatous polyposis (FAP). FGPs occur sporadically in up to 1.9% of the general population and in 84% of patients with syndromic FAP. Dysplasia in FGP is reported in 53% of syndromic FGPs and in only 2.3% of sporadic FGPs. The aim of this study is to compare patients with FGPs with dysplasia and those with FGPs without dysplasia. The pathology files from two institutions were searched from 1/1/2009 to 10/1/2013 for FGPs with dysplasia (FGPD). A similar number of control cases of FGP with no dysplasia (FGPND) were also randomly retrieved. All biopsies were reviewed, and diagnoses were agreed upon by three pathologists. Patient demographic data was recorded and included age, gender, race, diagnosis of FAP, and PPI use. Twenty-five patients with FGPD were identified (Male: 15, Female: 10, mean age: 60). Five patients had a confirmed history of FAP (mean age: 36), 9 had a high probability of FAP based on family or personal GI history (mean age: 61), 3 had no indication of FAP (such as family or personal history of colon cancer or polyps) (mean age: 63), and in 8 patients the family or personal history was not recorded (mean age: 62). Seventeen patients (68%) were on a protein pump inhibitor (PPI). The mean age of FGPD patients with FAP is significantly lower than patients without FAP (p< 0.001). The 26 patients with FGPND included 10 males and 16 females (mean age: 60). None of the patients had a history of FAP, 12 had a high probability of FAP based on family or personal GI history (mean age: 61), 6 had no indication of FAP (mean age: 59), and in 8 patients the family or personal history was not recorded (mean age: 55). Eighteen patients (69%) were on a PPI. There were no ethnic/racial differences between the two groups of patients. Of all biopsies from patients with FGPD, 88% of all fragments were smaller than 5 mm2 and 5% were greater than10 mm2. In contrast, of all the biopsies from patients with FGPND, 68% of all fragments were smaller than 5 mm2 and 20% were greater than 10 mm2. These data show no correlation between PPI use and the presence of low grade dysplasia in FGP. FGPND tended to result in larger biopsy fragments than FGPD; however there was no significant difference in the number of polyps described endoscopically between the two groups. Patients who have low-grade dysplasia in FGP are more likely to have FAP or a high probability of FAP than those without dysplasia. Low grade dysplasia in FGP is seen at a younger age in patients with FAP than in those without FAP. Finding low grade dysplasia in FGP, particularly in patients younger than 40 years, should raise a suspicion for FAP.

Background & Aims: Leptin is a circulating hormone that communicates the peripheral nutritional status to the hypothalamus, which controls food intake, energy expenditure, and body weight. This study characterizes leptin receptors and leptin-sensitive STAT proteins in the antrum and investigates the effects of leptin on gastric secretions. Methods: The effects of leptin on gastrin messenger RNA (mRNA), plasma gastrin, gastric acid in vivo in the rat, and on somatostatin and gastrin secretions by isolated antral cells were determined in vitro. Leptin receptors were investigated in isolated rat antral cells by reverse transcription-polymerase chain reaction and binding of [ 125 I]-leptin studies. The effects of in vivo and in vitro leptin on transduction signal STAT proteins were investigated by immunoblotting antral extracts. Results: Peripheral injection of leptin inhibited in a dose-dependent manner, basal gastric secretion, gastrinemia, and mucosal gastrin mRNA in vivo. mRNAs encoding the long (Ob-Rb) and short (Ob-Ra) receptor forms were detected in rat antral mucosa, as were STAT-1, -3, and -5b immunoreactive proteins. Isolated antral cells specifically bound [ 125 I]-leptin, and addition of leptin to these cells inhibited the release of somatostatin and increased the release of gastrin. These effects were associated with an increase in nuclear STAT-3 proteins in vitro and in vivo. Conclusions: This study provides the first molecular evidence for the coexpression of leptin receptors and STAT-3 in antral mucosa. It provides further evidence for the involvement of leptin in the control of gastric secretions. GASTROENTEROLOGY 2001;121:1417-1427

The need for colonoscopy when small tubular adenomas with low-grade dysplasia are found on sigmoidoscopy is uncertain. The aim of this study was to examine the prevalence and characteristics of proximal adenomas in patients with distal adenomas.We studied 981 subjects with distal adenomas found on the index colonoscopy before randomization in the Polyp Prevention Trial.Four hundred sixty patients (46.9%) had/=1 distal adenoma that was pathologically advanced (villous component, high-grade dysplasia, or/=1 cm); 21.5% (211 of 981) had any proximal adenoma; and 4.3% (42 of 981) (95% confidence interval [CI], 3.0-5.5) had an advanced proximal adenoma. A greater percentage of patients with an advanced distal adenoma (5.9%) (95% CI, 3.7-8.0) had an advanced proximal adenoma compared with those with a nonadvanced distal adenoma (2.9%) (95% CI, 1.4-4.3) (OR, 2.1; 95% CI, 1.1-4.3; P = 0.03). Not performing a colonoscopy in patients with a nonadvanced distal adenoma would have missed 36% (15 of 42) of the advanced proximal adenomas.Patients with an advanced distal adenoma are twice as likely to have an advanced proximal adenoma as patients with a nonadvanced distal adenoma. However, eschewing a colonoscopy in patients with a nonadvanced distal adenoma would result in not detecting a sizeable percentage of the prevalent advanced proximal adenomas. These data support performance of a colonoscopy in patients with a nonadvanced distal adenoma. Confirmation of these results in asymptomatic subjects undergoing screening sigmoidoscopy is advisable.

BACKGROUND & AIMS: Hepatocyte growth factor (HGF) and its receptor c- Met are presumed to play a morphogenic role during embryogenesis. The possible implication of HGF and c-Met during the digestive system development was approached by investigating their ontogeny, distribution, and functionality in human fetal tissues. METHODS: Thirty fetuses, 7-24 weeks old, were obtained. HGF and c-Met messenger RNAs and proteins were detected in liver, pancreas, esophagus, stomach, and small and large intestine. Tyrosine phosphorylation assays were realized on homogenates and membrane preparations from fetal tissues. RESULTS: The temporal appearance of HGF and c-Met was established between 7 and 8 weeks of gestation in digestive tissues. Immunoblot analysis showed the presence of the c-Met beta-subunit 145-kilodalton band and of the HGF alpha-subunit 70-kilodalton band. c-Met was localized in epithelia, especially in fundic parietal cells, pancreatic and gut endocrine cells, and in muscular layers. HGF immunoreactivity was first detected in epithelia and then in mesenchyme and muscular layers. In young fetal stages, the c-Met immunoprecipitated 145- kilodalton band showed tyrosine phosphorylation after HGF stimulation. CONCLUSIONS: This study provides evidence for HGF and c-Met expression early in all human fetal digestive tissues and implicates HGF-c-Met in the digestive system morphogenesis. (Gastroenterology 1997 May;112(5):1635-47)

G A A b st ra ct s clinical depression was not significant. Using corticosteroids was associated with less fatigue (OR 0.12; 95% CI 0.03-0.52). The different hospitals settings (academic vs general), age and other medication use were not associated with higher fatigue scores. In group B, 545 pts were included (64% female, 77.4% CD, 22.6% UC, mean age 42 (SD 14)) and this group verified the results of group A. However, overall only 60% experienced fatigue and mean CIS score was lower (mean 37 (range 8-56) compared with group A. Furthermore, the use of anti-TNF and male gender were associated with lower percentage of fatigue in CD pts. Conclusion: A high percentage of IBD pts experience severe fatigue. Depression and disease activity were associated with fatigue in these patients. The use of anti-TNF and male gender in CD pts showed the opposite effect and were associated with less fatigue. In UC pts the use of corticosteroids showed less fatigue.