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The safety of mesalamine in human pregnancy: a prospective controlled cohort study.

Diav-Citrin O. Park YH. Veerasuntharam G. Polachek H. Bologa M. Pastuszak A. Koren G.
Motherisk Program, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.
BACKGROUND & AIMS: Mesalamine is a first-line drug in the treatment of inflammatory bowel disease. Information regarding human pregnancy experience with mesalamine has been scarce and uncontrolled despite its frequent use in women of childbearing age. The aim of this study was to examine the fetal safety of mesalamine. METHODS: The Motherisk Program prospectively enrolled and followed up 165 women exposed to mesalamine during pregnancy, 146 of whom had first trimester exposure. Pregnancy outcome was compared with that of a matched control group, who were counseled for nonteratogenic exposure. RESULTS: There was no increase in major malformations (1 of 127 [0.8%] for mesalamine vs. 5 of 131 [3.8%] for nonteratogenic controls; P = 0.23). There was an increase in the rate of preterm deliveries (13.0% for mesalamine vs. 4.7% for nonteratogenic controls; P = 0.02), a decrease in the mean maternal weight gain during pregnancy (13.1 +/- 6.3 kg for mesalamine vs. 15.6 +/- 6.0 kg for nonteratogenic controls; P = 0.0002), and a decrease in the mean birth weight (3253 +/- 546 g for mesalamine vs. 3461 +/- 542 g for nonteratogenic controls; P = 0.0005). There were no significant differences in the maternal obstetric history, rates of live births, miscarriages, pregnancy terminations, ectopic pregnancies, delivery method, or fetal distress between the groups. CONCLUSIONS: This study suggests that mesalamine does not represent a major teratogenic risk in humans when used in the recommended doses.

Efficacy of open-label bismuth subsalicylate for the treatment of microscopic colitis.

Fine KD. Lee EL.
Division of Gastrointestinal Research, Baylor University Medical Center, Dallas, Texas, USA.
BACKGROUND & AIMS: The pathogenesis of the microscopic colitis syndrome is unknown but may involve bacteria, an intestinal luminal antigen, and/or autoimmunity. It was hypothesized that bismuth subsalicylate would resolve both diarrhea and colonic inflammation in microscopic colitis because it possesses antidiarrheal, antibacterial, and anti-inflammatory properties. METHODS: Thirteen patients with microscopic colitis (7 with subepithelial collagen deposition and 6 without) were treated with eight chewable 262-mg bismuth subsalicylate tablets per day for 8 weeks. Patients recorded the frequency of bowel movements daily. Forty-eight-hour stool collections and flexible sigmoidoscopy with 24 biopsies were performed before and after treatment in each patient. RESULTS: Twelve patients completed the trial. Eleven patients had a resolution of diarrhea and a reduction in fecal weight. The average time to respond was 2 weeks. In 9 patients, colitis resolved. When present before treatment, subepithelial collagen thickening disappeared. Those completing the trial experienced no side effects. Posttreatment follow-up for 7-28 months shows that 9 patients remain well having undergone no further treatment, 2 are well but required retreatment, and 1 has continued diarrhea. CONCLUSIONS: Bismuth subsalicylate treatment for 8 weeks is safe and well tolerated. This regimen appears to be efficacious for the treatment of microscopic colitis and is worthy of further study in a controlled trial.

Association of serum antibodies against p53 protein with poor survival in patients with Zollinger-Ellison syndrome.

Jais P. Vuagnat A. Terris B. Houillier AM. Bonfils S. Laurent-Puig P. Mignon M. Lewin MJ.
INSERM Unite 10 de Gastroenterologie, Hopital Bichat-Claude Bernard, Paris, France.
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.

The acid response to gastrin distinguishes duodenal ulcer patients from Helicobacter pylori-infected healthy subjects.

Gillen D. el-Omar EM. Wirz AA. Ardill JE. McColl KE.
University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland.
BACKGROUND & AIMS: Helicobacter pylori-induced hypergastrinemia is accompanied by increased acid secretion in patients with duodenal ulcer (DU) but not in infected healthy volunteers. The aim of this study was to investigate the mechanism underlying this difference. METHODS: Thirty-four H. pylori-negative and 20 H. pylori-positive healthy volunteers and 15 H. pylori-positive patients with DU were studied. Maximal acid output and sensitivity to gastrin (gastrin concentration required to achieve 50% maximal acid output) were assessed by examining the dose response to gastrin 17. Inhibitory control was tested by comparing the maximal acid response to cholecystokinin octapeptide with that for gastrin 17. RESULTS: Sensitivity to gastrin was similar in patients with DU (median, 69.5 ng.L-1; range, 26.2-142) and H. pylori-negative healthy volunteers (median, 82.2 ng.L-1; range, 17.7-410); H. pylori-positive healthy volunteers were less sensitive than either (164.5 ng.L-1; range, 44.8 to > 3360 ng.L-1). Patients with DU had higher maximal acid output (51.2 mmol.h-1; range, 30.8-73.7 mmol.h-1) than either infected healthy volunteers (37.8 mmol.h-1; range, 0.0-65.0 mmol.h-1; P < 0.04) or uninfected healthy volunteers (35.3 mmol.h-1; range, 21.3-67.3 mmol.h-1; P < 0.002). The maximal acid output in both groups of healthy subjects was similar. The proportion of maximal acid output to gastrin 17 achieved by cholecystokinin was similar in patients with DU (36.6%; range, 21.5%-58.2%) and H. pylori-negative healthy volunteers (28.7%; range, 5.9%-85.8%). CONCLUSIONS: A combination of decreased sensitivity to gastrin in infected healthy volunteers and increased maximal acid secretory capacity in patients with DU underlies their different acid response to H. pylori-induced hypergastrinemia.

High mucosal levels of tumor necrosis factor alpha messenger RNA in AIDS-associated cytomegalovirus-induced esophagitis.

Wilcox CM. Harris PR. Redman TK. Kawabata S. Hiroi T. Kiyono H. Smith PD.
Department of Medicine, University of Alabama School of Medicine, Birmingham, USA.
BACKGROUND & AIMS: To evaluate the role of tumor necrosis factor alpha (TNF-alpha), a key inflammatory cytokine, in cytomegalovirus-associated gastrointestinal disease, we quantitated the level of TNF-alpha messenger RNA (mRNA) in esophageal mucosa from patients with cytomegalovirus-associated esophagitis and acquired immunodeficiency syndrome. METHODS: Four patients underwent endoscopic biopsy of their cytomegalovirus-associated esophageal ulcers before and after ganciclovir therapy. The level of TNF-alpha mRNA in coded esophageal specimens was assessed by in situ hybridization, reverse-transcription polymerase chain reaction, and quantitative polymerase chain reaction. RESULTS: Esophageal mucosa from 3 patients whose ulcers healed or markedly improved contained before therapy numerous macrophages expressing TNF-alpha mRNA and high tissue levels of TNF-alpha mRNA that decreased substantially or were not detectable after therapy. In contrast, esophageal specimens from the single patient whose ulcer worsened after therapy contained many mucosal macrophages expressing TNF-alpha mRNA before as well as after therapy, and the high number of molecules of TNF-alpha mRNA present in the tissue before therapy increased further after treatment. CONCLUSIONS: Increased macrophage production and high tissue levels of TNF-alpha mRNA are associated with cytomegalovirus-associated esophageal ulcers and probably contribute to the inflammatory response associated with cytomegalovirus-induced gastrointestinal disease.

Pancreatic cancer cells selectively stimulate islet beta cells to secrete amylin.

Ding X. Flatt PR. Permert J. Adrian TE.
Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, Nebraska, USA.
BACKGROUND & AIMS: Patients with pancreatic adenocarcinoma have a high incidence of diabetes, profound insulin resistance, and high circulating amylin concentrations. It was hypothesized that pancreatic cancer cells produce a factor that stimulates islets to secrete amylin but not insulin. METHODS: Amylin and insulin secretion were measured after coculture of pancreatic cancer cells with beta cells (BRIN-BD11). The factor responsible was characterized by exposing beta cells to cancer cell-conditioned medium. RESULTS: Coculture with pancreatic (PANC-1 HPAF, and MiaPaCa2) but not colonic cancer cells (Colo 320) significantly increased amylin secretion but did not change insulin output. This effect was both time and cell number dependent. Coculture with PANC-1 or HPAF cells significantly decreased intracellular amylin, but not insulin, content. PANC-1 or HPAF cell-conditioned medium also increased amylin secretion and decreased intracellular amylin content. The factor responsible was extracted under both neutral and acidic conditions, was heat labile, and had a molecular weight of approximately 1500. CONCLUSIONS: A soluble factor from pancreatic cancer cells selectively stimulates amylin secretion from islet cells, explaining the excessive amylin secretion found in pancreatic cancer. Because elevation of amylin concentration is an early feature of pancreatic cancer, characterization and measurement of the tumor-derived amylin-releasing factor might be valuable in the early detection of this disease.

Collagens in the liver extracellular matrix bind hepatocyte growth factor.

Schuppan D. Schmid M. Somasundaram R. Ackermann R. Ruehl M. Nakamura T. Riecken EO.
Department of Gastroenterology and Hepatology, Klinikum Benjamin Franklin, Free University of Berlin, Germany.
BACKGROUND & AIMS: Hepatocyte growth factor (HGF), a potent mitogen for hepatocytes, binds to heparan sulfate. Because immunoreactive HGF can be detected in the interstitial extracellular matrix (ECM), where little heparan sulfate is found, the aim of this study was to investigate binding of HGF to several collagens and noncollagenous ECM proteins in vitro. METHODS: 125I-labeled HGF was incubated with collagens I-VI, single collagen chains and their cyanogen bromide peptides, with fibronectin, fibrinogen, and laminin that were either immobilized on polystyrene or blotted to nitrocellulose after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Biological activity of collagen-bound HGF was investigated in cell culture. RESULTS: HGF displayed binding of moderate affinity (Kd approximately 10(-9) mol/L) to immobilized collagen types I, III, IV, V, and VI. Binding of HGF to all collagens could be inhibited by single chains of either collagens I, III, or VI. Fragmentation with cyanogen bromide indicated unique collagenous peptides mediating the interaction. Collagen-bound HGF induced primary hepatocyte proliferation and MDCK cell scattering in a dose-dependent manner. CONCLUSIONS: Interstitial collagens I, III, V, and VI serve as abundant, low-affinity binding sites for HGF in the ECM. This interaction is mediated by unique collagenous peptides, opening the potential to modulate HGF availability and activity by collagen-derived peptide analogues.

The pathobiology of peritonitis.

Hall JC. Heel KA. Papadimitriou JM. Platell C.
University Department of Surgery, Royal Perth Hospital, Australia.
The peritoneum is more than a mechanical covering that allows for the easy gliding of opposed peritoneal surfaces. The peritoneal mesothelial cells facilitate the action of powerful innate immune mechanisms. In addition, the peritoneal-associated lymphoid tissues contain unique cells that may play a crucial role in the localization of intraperitoneal infection. A clearer understanding of the molecular and cellular events underlying peritoneal functions in both the unstimulated and stimulated state will aid future treatment of peritonitis.

Enhancing clinical efficacy of oral rehydration therapy: is low osmolality the key?

Thillainayagam AV. Hunt JB. Farthing MJ.
Digestive Diseases Research Centre, St. Bartholomew's, London, England.
Many empirical clinical trials have used complex carbohydrate as substrate in oral rehydration solutions (ORSs) instead of glucose and have shown a number of important clinical benefits. Foremost among these are reduced stool volumes, shorter duration of diarrheal illness, and lower ORS intake. The underlying mechanisms to explain this clinical advantage have not been fully established, but a number of possible factors have been proposed: (1) increased substrate availability, (2) a "kinetic advantage" for glucose absorption by glucose polymer, (3) differential handling of glucose monomer and polymer by the small intestine, (4) low osmolality, (5) a separate effect of peptides and amino acids on solute-linked sodium absorption, (6) an antisecretory moiety in rice, and (6) enhanced mucosal repair and regeneration by luminal nutrients. In this report, we assess the relative contribution of these factors using evidence from laboratory-based studies, mainly in disease-related intestinal perfusion systems in animals and humans, and the relevant clinical studies available to date. We advance the hypothesis that of all the possible mechanisms proposed to underlie the enhanced clinical efficacy of complex carbohydrate ORSs, their hypotonicity plays the dominant role. If confirmed, this concept could guide future development of glucose and complex carbohydrate-based ORSs.

Balsalazide is more effective and better tolerated than mesalamine in the treatment of acute ulcerative colitis. The Abacus Investigator Group.

Green JR. Lobo AJ. Holdsworth CD. Leicester RJ. Gibson JA. Kerr GD. Hodgson HJ. Parkins KJ. Taylor MD.
Gastroenterology unit, City General Hospital, Stoke-on-Trent, England.
BACKGROUND & AIMS: Aminosalicylates are widely used in the treatment of ulcerative colitis (UC). Balsalazide is a novel mesalamine prodrug, activated by colonic bacteria. The aim of this study was to compare the efficacy and safety of balsalazide with that of a pH-dependent formulation of mesalamine in active UC. METHODS: A randomized, double-blind study was performed comparing balasalazide, 6.75 g daily, with mesalamine, 2.4 g daily, administered for 4, 8, or 12 weeks to 101 (99 evaluable) patients with symptomatic, sigmoidoscopically verified UC. RESULTS: More patients treated with balsalazide achieved symptomatic remission after 2 (64% [balsalazide] vs. 43% [mesalamine]), 4 (70% vs. 51%), 8 (78% vs. 45%), and 12 weeks (88% vs. 57%) and complete remission (none/mild symptoms, sigmoidoscopy grade 0/1, no rectal steroid use within 4 days) after 4 (38% vs. 12%), 8 (54% vs. 22%), and 12 weeks (62% vs. 37%). Patients taking balsalazide experienced more asymptomatic days (4 weeks, 24% vs. 14%) and achieved the first asymptomatic day more rapidly (median, 10 vs. 25 days). Fewer patients in the balsalazide group reported adverse events (48% vs. 71%); four serious adverse events occurred in the mesalamine group. CONCLUSIONS: Balsalazide is more effective and better tolerated than mesalamine as treatment for acute UC.

Yearly colonoscopy, liver CT, and chest radiography do not influence 5-year survival of colorectal cancer patients.

Schoemaker D. Black R. Giles L. Toouli J.
Department of Surgery, Flinders Medical Centre, Bedford Park, Adelaide, Australia.
BACKGROUND & AIMS: Guidelines on the type and frequency of follow-up of patients after curative surgery for colorectal cancer are unclear. The aim of this study was to determine the survival benefit of a planned follow-up program. METHODS: Three hundred twenty-five patients who underwent curative resection of colorectal cancer were prospectively randomized to either intensive or standard follow-up. After stratification according to Dukes' stage and site in the colon or rectum, patients were randomized to intensive follow-up of yearly colonoscopy, computerized tomography (CT) of the liver, and chest radiography and clinical review and simple screening vs. structured clinical review and simple screening tests only. RESULTS: On completion of 5-year follow-up, there was no significant difference in survival between the two groups. Yearly colonoscopy failed to detect any asymptomatic local recurrences. Only one asymptomatic curable metachronous colon tumor was detected. Liver CT resulted in earlier detection of hepatic metastases but did not increase the number of curative hepatectomies. Only 1 patient had an asymptomatic CT-detected liver metastasis, and another had an asymptomatic chest radiography-detected lung metastasis. Both had curative resections. CONCLUSIONS: Yearly colonoscopy, liver CT, and chest radiography will not improve survival from colorectal cancer when added to symptom and simple screening review.

Infection of Helicobacter pylori in gastric adaptation to continued administration of aspirin in humans.

Konturek JW. Dembinski A. Konturek SJ. Stachura J. Domschke W.
Department of Medicine B, University of Munster, Germany. jan.konturek@uni-muenster.de
BACKGROUND & AIMS: Involvement of Helicobacter pylori in aspirin-induced gastropathy and adaptation to aspirin remains unclear. The aim of this study was to compare gastric damage and adaptation after repeated exposures to acetylsalicylic acid in the same subjects before and after eradication of H. pylori. METHODS: Before and after H. pylori eradication, 8 volunteers were given aspirin, 2 g/day during 14 days. Mucosal damage was evaluated by endoscopy and histological analysis of biopsy samples. Gastric microbleeding, DNA synthesis, prostaglandin E2 generation, and luminal contents of transforming growth factor alpha and its immunohistochemical expression were determined on days 0, 3, 7, and 14 of aspirin course. RESULTS: In all subjects, aspirin-induced gastric damage that reached maximum on day 3. In H. pylori-positive subjects, this damage was maintained at a similar level up to day 14. After H. pylori eradication, the damage was significantly lessened both in endoscopy and histology at day 14 and accompanied by increased mucosal expression and luminal release of transforming growth factor alpha. Prostaglandin E2 generation was significantly greater in H. pylori-positive subjects than after H. pylori eradication, but aspirin treatment resulted in >90% reduction of this generation independent of H. pylori status. CONCLUSIONS: Gastric adaptation to aspirin is impaired in H. pylori-positive subjects, but eradication of this bacterium restores this process.

A low rate of reinfection following effective therapy against Helicobacter pylori in a developing nation (China).

Mitchell HM. Hu P. Chi Y. Chen MH. Li YY. Hazell SL.
School of Microbiology and Immunology, University of New South Wales, Sydney, Australia.
BACKGROUND & AIMS: In developed countries, reinfection after successful eradication of Helicobacter pylori appears unusual. High prevalences of H. pylori in developing countries may result in high reinfection rates. The aim of this study was to determine the rate of reinfection and ulcer recurrence in Chinese patients cured of H. pylori and duodenal ulcer disease. METHODS: One hundred eighty-four patients with duodenal ulcer disease shown by endoscopic examination (1 month) and 14C-urea breath test (3 months) after termination of treatment to have cleared their H. pylori were investigated. Patients were followed up by endoscopy (12 and 24 months) and breath test (6, 9, 12, 18, and 24 months). H. pylori status at endoscopic examination was determined by rapid urease, histology, and culture. In reinfected patients, random amplification of polymorphic DNA fingerprinting was used to compare isolates before and after therapy. RESULTS: Four patients were reinfected with H. pylori over 24 months (3 within 6 months and 1 at 24 months; average annual recurrence rate, 1.08%). Fingerprinting of isolates from 3 patients showed 1 patient (6 months) to have identical strains and the remainder to have nonidentical strains before and after treatment. Ulcer relapse occurred in 6 patients (4 H. pylori positive). CONCLUSIONS: Reinfection with H. pylori is rare in developing countries where treatment is effective.

Early lesions of recurrent Crohns disease caused by infusion of intestinal contents in excluded ileum.

D'Haens GR. Geboes K. Peeters M. Baert F. Penninckx F. Rutgeerts P.
Department of Internal Medicine, University Hospital Gasthuisberg, Leuven, Belgium.
BACKGROUND & AIMS: Postoperative recurrence of Crohn's disease may be triggered by agents in the fecal stream. The aim of this study was to examine intestinal mucosal inflammation induced by contact with intestinal fluids in surgically excluded ileum. METHODS: The effects of infusion of intestinal luminal contents into excluded ileum in 3 patients with Crohn's disease who had undergone a curative ileocolonic resection with ileocolonic anastomosis and temporary protective proximal loop ileostomy were studied by histopathology and electron microscopy. RESULTS: Contact with intestinal fluids for 8 days induced focal infiltration of mononuclear cells, eosinophils, and polymorphonuclear cells in the lamina propria, small vessels, and epithelium in the excluded neoterminal ileum that was previously normal. Epithelial HLA-DR expression increased, and mononuclear cells expressed the KP-1 antigen associated with activation. Marked up-regulation of RFD-7, RFD-9, intercellular adhesion molecule 1, and lymphocyte function-associated antigen 1 was observed after infusion, reflecting epithelioid transformation and transendothelial lymphocyte recruitment. At the ultrastructural level, dilatation of the endoplasmic reticulum and Golgi apparatus occurred in epithelial cells, where also basally located transport vesicles were identified. CONCLUSIONS: Intestinal contents trigger postoperative recurrence of Crohn's disease in the terminal ileum proximal to the ileocolonic anastomosis in the first days after surgery.

Proapoptotic gene BAX is frequently mutated in hereditary nonpolyposis colorectal cancers but not in adenomas.

Yagi OK. Akiyama Y. Nomizu T. Iwama T. Endo M. Yuasa Y.
Department of First Surgery, Tokyo Medical and Dental University School of Medicine, Japan.
BACKGROUND & AIMS: The p53 and BAX genes have been linked to apoptosis. p53 was not frequently found to be mutated in colorectal carcinomas with a microsatellite mutator phenotype, but frame-shift mutations in a tract of eight guanines within BAX were frequently found in these carcinomas. To understand the roles of these genes in hereditary nonpolyposis colorectal cancer (HNPCC) tumorigenesis, we examined whether BAX mutations occur in adenoma and carcinoma specimens from patients with HNPCC and also determined the frequencies of p53 mutations. METHODS: Thirteen colorectal adenomas and 24 adenocarcinomas from patients with HNPCC showing a microsatellite instability phenotype were screened by polymerase chain reaction followed by denaturing polyacrylamide gel electrophoresis and direct sequencing. RESULTS: Two of the 13 adenomas (15.4%) and 13 of the 24 adenocarcinomas (54.2%) showed mutation patterns and were confirmed to have frame-shift mutations at the BAX repeat site by direct sequencing. For p53, only 1 of the 24 adenocarcinomas (4.2%) showed a missense mutation. CONCLUSIONS: In HNPCC colorectal carcinomas, BAX was significantly (P = 0.024) more mutated than in adenomas. p53 was not frequently found to be mutated in these carcinomas. These data suggest that mutations in BAX, rather than mutations in p53, may contribute to the adenoma-carcinoma transition in HNPCC tumorigenesis.

Genetic analysis of long-term Barretts esophagus epithelial cultures exhibiting cytogenetic and ploidy abnormalities.

Palanca-Wessels MC. Barrett MT. Galipeau PC. Rohrer KL. Reid BJ. Rabinovitch PS.
Department of Pathology, University of Washington, Seattle, USA.
BACKGROUND & AIMS: Progression to cancer in Barrett's esophagus occurs through an accumulation of cell cycle and genetic abnormalities that have been documented in vivo. To better study neoplastic evolution in Barrett's esophagus, the aim of this study was to establish in vitro cultures from preneoplastic tissues. METHODS: Mechanical and enzymatic dissociation methods were used to initiate Barrett's epithelial cultures from endoscopic biopsy specimens, and the cells were characterized using flow-cytometric, cytogenetic, and molecular genetic analyses. RESULTS: Four long-term cultures were established from 39 attempts. All cultures contain cytogenetic abnormalities and elevated flow-cytometric 4N DNA content fractions. Molecular genetic abnormalities detected include the following: 9p and/or CDKN2/p16 abnormalities in 4 of 4 cultures, 17p loss of heterozygosity and p53 mutation in 3 of 4 cultures, and 5q loss of heterozygosity in 1 of 4 cultures. Inactivation of p53 was statistically associated with successful long-term culture. CONCLUSIONS: These cultures contain cell cycle and molecular genetic abnormalities that closely parallel those previously documented to occur early in cancer development in Barrett's esophagus in vivo. These alterations also appear to be associated with successful growth in vitro. The cultures may provide a premalignant in vitro system in which to test potential therapies for Barrett's esophagus as well as to examine etiologic factors and genetic intermediates important in neoplastic progression.

Use of macroaggregated albumin lung perfusion scan to diagnose hepatopulmonary syndrome: a new approach.

Abrams GA. Nanda NC. Dubovsky EV. Krowka MJ. Fallon MB.
Division of Gastroenterology and Hepatology, Liver Center, University of Alabama at Birmingham, 35294-0007, USA.
BACKGROUND & AIMS: We have reported that contrast echocardiography is a sensitive screening test for the hepatopulmonary syndrome (HPS). However, contrast echocardiography lacks specificity because many cirrhotic patients have positive study results with normal arterial blood gases and therefore do not fulfill criteria for HPS. The aim of this study was to assess the role of macroaggregated albumin lung perfusion scans (MAA scans) in the diagnosis of HPS. METHODS: MAA scans were performed in 25 patients with HPS, 25 cirrhotic patients without HPS, and 15 hypoxemic subjects with intrinsic lung disease alone. An MAA shunt fraction was calculated from brain and lung counts. RESULTS: MAA scan results were positive in 21 of 25 patients with HPS and negative in all controls. All 21 patients with positive MAA scans had PO2 values of

Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis.

George DK. Goldwurm S. MacDonald GA. Cowley LL. Walker NI. Ward PJ. Jazwinska EC. Powell LW.
Clinical Sciences Unit, Queensland Institute of Medical Research, Brisbane, Australia.
BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that occasionally progresses to cirrhosis but usually has a benign course. The aim of this study was to investigate the role of the hemochromatosis mutation Cys282Tyr in development of the mild hepatic iron overload found in some patients with NASH and its association with hepatic damage in these patients. METHODS: Fifty-one patients with NASH were studied. The presence of the Cys282Tyr mutation was tested in all patients, and the data were analyzed with respect to the histological grade of steatosis, inflammation, Perls' staining, hepatic iron concentration (HIC), and serum iron indices. RESULTS: Thirty-one percent of patients with NASH were either homozygous or heterozygous for the Cys282Tyr mutation. This mutation was significantly associated with Perls' stain grade (P < 0.005), HIC (P < 0.005), and transferrin saturation percentage (P < 0.005) but not with serum ferritin levels. Linear regression analysis showed that increased hepatic iron (Perls' stain or HIC) had the greatest association with the severity of fibrosis (P < 0.0001). CONCLUSIONS: The Cys282Tyr mutation is responsible for most of the mild iron overload found in NASH and thus has a significant association with hepatic damage in these patients. Heterozygosity for the hemochromatosis gene mutation therefore cannot always be considered benign.

Members of the glutathione S-transferase gene family are antigens in autoimmune hepatitis.

Wesierska-Gadek J. Grimm R. Hitchman E. Penner E.
Institute of Tumor Biology-Cancer Research, University of Vienna, Austria. Jozefa.Antonia.Gadek-Wesierski@univie.ac.at
BACKGROUND & AIMS: Autoimmmune hepatitis (AIH), a chronic liver disorder, can be classified into two subtypes on the basis of the specificities of circulating autoantibodies. Type I AIH is defined by antibodies to nuclear and/or smooth muscle antigens (SMA), and type II is characterized by antibodies to cytochrome P450IID6. There is an additional type of AIH characterized by antibodies to a cytosolic soluble liver antigen (SLA), which can occur alone or in combination with antinuclear antibodies and SMA. The aim of this study was to identify the reactive antigen in SLA, a heterogenous cytosolic fraction consisting of at least 100 extremely soluble proteins. METHODS: Sera from 31 patients with AIH reacting with SLA and from 30 disease controls were tested. The immunoreactive antigens were determined using immunoprecipitation and immunoblotting after one- and two-dimensional polyacrylamide gel electrophoresis. The antigens were identified by microsequencing of the corresponding protein spots. RESULTS: Twenty-five of 31 anti-SLA-positive sera (80, 7%) reacted with a set of proteins ranging from 25 to 27 kilodaltons that were identified as three subunits of glutathione S-transferases: Ya, Yb1, and Yc. CONCLUSIONS: Glutathione S-transferase subunit proteins represent the major autoantigen in anti-SLA-positive AIH. This new finding permits the establishment of standardized immunoassays for routine diagnosis.

Increased adrenomedullin levels in cirrhosis: relationship with hemodynamic abnormalities and vasoconstrictor systems.

Guevara M. Gines P. Jimenez W. Sort P. Fernandez-Esparrach G. Escorsell A. Bataller R. Bosch J. Arroyo V. Rivera F. Rodes J.
Department of Medicine, Hospital Clinic i Provincial, University of Barcelona, Spain.
BACKGROUND & AIMS: Arterial vasodilation in cirrhosis may be related to increased circulating levels of vasodilators. This study was designed to assess the circulating levels of adrenomedullin, a recently described vasodilator peptide, in cirrhosis. METHODS: Plasma adrenomedullin levels were measured in 17 healthy subjects and 34 cirrhotic patients. Hemodynamic parameters, renal function, and levels of vasoactive substances were also assessed. RESULTS: Patients with ascites had increased adrenomedullin levels (289 +/- 47 pg/mL) compared with healthy subjects and patients without ascites (135 +/- 17 and 142 +/- 32 pg/mL, respectively; P < 0.05). Adrenomedullin levels correlated inversely with arterial pressure, glomerular filtration rate, and renal plasma flow and correlated directly with pulse rate, endothelin levels, and aldosterone and plasma renin activity. In cirrhotic patients, no significant differences in adrenomedullin levels were found between samples obtained from hepatic vein, renal vein, pulmonary artery, and femoral artery. Plasma expansion with albumin suppressed the renin-angiotensin system but did not affect adrenomedullin levels. CONCLUSIONS: Circulating levels of adrenomedullin are increased in patients with ascites and correlate with hemodynamic and renal abnormalities and activation of vasoconstrictor systems. These increased levels seem to result from a generalized increase in adrenomedullin production from vascular tissue and are not suppressed by plasma expansion. Adrenomedullin may participate in the pathogenesis of arterial vasodilation in cirrhosis.

Course of Crohns disease after allogeneic marrow transplantation.

Year 1998
Lopez-Cubero SO. Sullivan KM. McDonald GB.
Clinical Research Division, Fred Hutchinson Cancer Research Center, and University of Washington School of Medicine, Seattle 98109-1024, USA.
BACKGROUND & AIMS: Remission of several autoimmune diseases has been described after allogeneic marrow transplantation. The aim of this study was to determine if the natural history of Crohn's disease was altered by hematopoietic cell transplants from healthy allogeneic donors. METHODS: Between 1982 and 1992, 6 patients with Crohn's disease and leukemia underwent allogeneic marrow transplantation and were followed up clinically. RESULTS: Five patients had active Crohn's disease before transplantation, and 3 had clinical evidence of sclerosing cholangitis. Four marrow donors were HLA-identical siblings, 1 related donor was mismatched at the DR locus, and 1 unrelated donor was HLA-matched. One patient died of septicemia 97 days after transplantation; 5 patients were observed for 4.5, 5.8, 8.4, 9.9, and 15.3 years after transplantation. Four of 5 patients evaluated had no signs or symptoms of Crohn's disease after transplantation. One patient with mixed donor-host hematopoietic chimerism had a relapse of Crohn's disease 1.5 years after transplantation. CONCLUSIONS: Four of 5 patients followed up for 4.5 to 15.3 years after allogeneic hematopoietic cell transplantation remained free of Crohn's disease. These observations suggest that host immune dysregulation plays a role in the perpetuation of Crohn's disease that can be corrected by allogeneic hematopoietic cell transplantation.

Aspirin and nonsteroidal anti-inflammatory agents and risk for colorectal adenomas.

Year 1998
Sandler RS. Galanko JC. Murray SC. Helm JF. Woosley JT.
Center for Gastrointestinal Biology and Disease, and Department of Epidemiology, University of North Carolina at Chapel Hill, 27599-7080, USA.
BACKGROUND & AIMS: Aspirin and nonsteroidal anti-inflammatory drugs have been reported to protect against the development of colorectal cancer. Because adenomas are precursors to most colorectal cancers, the aim of this study was to examine the relationship of these medications to the risk for colorectal adenomas in a colonoscopy-based case-control study. METHODS: Study participants were drawn from patients who underwent colonoscopy at the University of North Carolina Hospitals. Medication use was assessed by telephone using a comprehensive list of prescription and nonprescription drugs as well as questions about dietary and lifestyle factors that might be relevant for adenoma development. RESULTS: There were 210 patients with adenomas and 169 adenoma-free controls. After adjusting for potential confounders, regular users were half as likely to currently have adenomas compared with nonusers (adjusted odds ratio, 0.56; 95% confidence interval, 0.34-0.92). Regular users who stopped medication at least 1 year before colonoscopy were still protected (adjusted odds ratio, 0.59; 95% confidence interval, 0.21-1.67), although small numbers make this conclusion tentative. The protective effects of aspirin and the nonaspirin nonsteroidal anti-inflammatory drugs were similar. CONCLUSIONS: The results suggest that aspirin and nonsteroidal anti-inflammatory drugs cause early disruption of the adenoma-carcinoma sequence. The challenge for the future will be to learn more about dose, duration, and mechanism of action.

Photodynamic ablation of high-grade dysplasia and early cancer in Barretts esophagus by means of 5-aminolevulinic acid.

Year 1998
Gossner L. Stolte M. Sroka R. Rick K. May A. Hahn EG. Ell C.
Department of Medicine II, Klinikum der Landeshauptstadt Wiesbaden, Germany.
BACKGROUND & AIMS: The first therapeutic experiences with the conventional photosensitizer dihematoporphyrinester in the treatment of Barrett's esophagus show the curative potential of photodynamic therapy (PDT). The aim of this study was to test 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX, a photosensitizer with a high mucosa specificity without phototoxic side effects on the skin, as a new form of PDT. METHODS: Thirty-two patients (mean age, 68.5 years) with histologically proven high-grade dysplasia (n = 10) and mucosal cancer (n = 22) in Barrett's esophagus were treated. Four to 6 hours after oral ingestion of 5-ALA (dose, 60 mg/kg body wt), irradiation was conducted with a dye laser system (635 nm) with a light dose of 150 J/cm2. The patients received 20-80 mg omeprazole daily after PDT. RESULTS: High-grade dysplasia was eradicated in all patients (10 of 10), and mucosal cancer was eliminated in 17 of 22 patients (77%) at a mean follow-up of 9.9 months (range, 1-30 months). All tumors < or = 2 mm in thickness were completely ablated (17 of 17). The method-related mortality and morbidity was 0%. CONCLUSIONS: Severe dysplasia and thin (< or = 2 mm) mucosal cancer of Barrett's esophagus can be completely ablated. PDT might offer a minimally invasive treatment modality as an alternative to esophagectomy.

Gastric pacing improves emptying and symptoms in patients with gastroparesis.

Year 1998
McCallum RW. Chen JD. Lin Z. Schirmer BD. Williams RD. Ross RA.
Department of Medicine, University of Kansas Medical Center, Kansas City 66160-7350, USA.
BACKGROUND & AIMS: No effective treatment is available for patients with gastroparesis refractory to standard medical therapy. The aim of this study was to investigate the effects of gastric pacing on gastric electrical activity, gastric emptying, and symptoms in patients with gastroparesis. METHODS: Nine patients with gastroparesis participated in this study. Four pairs of cardiac pacing wires were implanted on the serosa of the stomach. The protocol consisted of two portions: a temporary inpatient study period and an outpatient study for a period of 1 month or more. RESULTS: Gastric pacing entrained the gastric slow wave in all subjects and converted tachygastria in 2 patients into regular 3-cpm slow waves. Gastric emptying was significantly improved after the outpatient treatment with gastric pacing. The gastric retention at 2 hours was reduced from 77.0% +/- 3.3% to 56.6% +/- 8.6% (P < 0.05). Symptoms of gastroparesis were substantially reduced at the end of the outpatient treatment (1.51 +/- 0.46 vs. 2.84 +/- 0.61; P < 0.04). Eight of 9 patients no longer relied on jejunostomy tube feeding, and no adverse events were noted related to the pacing unit. CONCLUSIONS: Gastric pacing seems to be able to improve symptoms of gastroparesis and to accelerate gastric emptying in patients with gastroparesis. More controlled studies are necessary to further investigate the role of gastric pacing in clinical practice.

Dimeric sialyl-Le(x) expression in gastric carcinoma correlates with venous invasion and poor outcome.

Year 1998
Amado M. Carneiro F. Seixas M. Clausen H. Sobrinho-Simoes M.
Institute of Molecular Pathology and Immunology of University of Porto, IPATIMUP, Medical Faculty of Porto, Hospital S. Joao, Portugal.
BACKGROUND & AIMS: High expression of sialyl-Le(x) in tumors of different organs correlates with hematogenous metastasis and adverse outcome. Dimeric sialyl-Le(x) expression in gastric carcinoma was evaluated, and its prognostic significance within this setting was determined. METHODS: Dimeric sialyl-Le(x) immunohistochemical expression in 97 gastric carcinomas was analyzed using the FH6 monoclonal antibody. Scoring was based on the percentage of immunoreactive cells: negative, low expression (< or = 25%), and high expression (> 25%). RESULTS: Immunoreactivity was observed in 45 cases (46.4%), encompassing 27 and 18 cases with low and high expression, respectively. Significant relationships were found between dimeric sialyl-Le(x) expression and venous invasion (P = 0.0025) and histological classification (P = 0.05). No correlation was observed with other clinicopathologic features. Patients with tumors showing high expression of dimeric sialyl-Le(x) had a significantly shorter survival time than those with low or no expression (P = 0.03). By multivariate analysis, pathological TNM (pTNM) staging and venous invasion emerged as independent prognostic factors in the whole series. Within the group of patients with tumors in pTNM stages II and III, dimeric sialyl-Le(x) was the only independent prognostic factor. CONCLUSIONS: High expression of dimeric sialyl-Le(x) correlates with venous invasion and poor outcome in gastric carcinoma.

Abnormal intestinal intraepithelial lymphocytes in refractory sprue.

Year 1998
Cellier C. Patey N. Mauvieux L. Jabri B. Delabesse E. Cervoni JP. Burtin ML. Guy-Grand D. Bouhnik Y. Modigliani R. Barbier JP. Macintyre E. Brousse N. Cerf-Bensussan N.
Department of Gastroenterology, Hopital Laennec, Paris, France.
BACKGROUND & AIMS: The etiology of refractory sprue is unclear. To gain insight into its pathogenesis, the phenotype and T-cell receptor (TCR) gene rearrangement status of intestinal lymphocytes were analyzed in a group of patients with clinical or biological features of celiac disease but either initially or subsequently refractory to a gluten-free diet. METHODS: Intestinal biopsy specimens were obtained from 26 adults: 6 patients with refractory sprue, 7 patients with active celiac disease, and 13 normal controls. The phenotype of intestinal lymphocytes was studied by immunohistochemistry and, in 3 patients with refractory sprue, by cytometry of lymphocytes purified from intestinal biopsy specimens. TCR rearrangements were assessed by studying TCRgammaV-J junctional regions from DNA extracted from intestinal biopsy specimens and purified intestinal lymphocytes. RESULTS: In the 6 patients with refractory sprue, but not in normal controls or patients with active celiac disease, the intestinal epithelium was massively infiltrated by small lymphocytes that lacked CD8, CD4, and TCR, contained intracytoplasmic but not surface CD3epsilon chains, and exhibited restricted TCRgamma gene rearrangements. CONCLUSIONS: Refractory sprue is associated with an abnormal subset of intraepithelial lymphocytes containing CD3epsilon and restricted rearrangements of the TCRgamma chain but lacking surface expression of T-cell receptors.

Poly(ADP-ribose) synthetase activation mediates increased permeability induced by peroxynitrite in Caco-2BBe cells.

Year 1998
Kennedy M. Denenberg AG. Szabo C. Salzman AL.
Division of Gastroenterology, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
BACKGROUND & AIMS: Peroxynitrite induces cytotoxicity by generating DNA single-strand breaks and activating poly(ADP-ribose) synthetase (PARS), a nuclear enzyme that consumes oxidized nicotinamide adenine dinucleotide (NAD+) and depletes cellular adenosine triphosphate (ATP). The aim of this study was to examine this mechanism of injury in an intestinal epithelial cell model after exposure to exogenous peroxynitrite (ONOO-) and nitric oxide (NO). METHODS: Caco-2BBe cell monolayers exposed to donors of peroxynitrite (3-morpholino-sydnonimine [SIN-1], 3 mmol/L) or NO (S-nitroso-N-acetyl penicillamine [SNAP]; 3 mmol/L) were analyzed for DNA strand breaks, [NAD+], [ATP], and transepithelial flux of fluorescein sulfonic acid. RESULTS: SIN-1 but not SNAP induced DNA single-strand breakage. Both SIN-1 and SNAP reduced [ATP], but only SIN-1 reduced [NAD+]. Inhibition of PARS activity by the PARS inhibitors 5-iodo-6-amino 1,2-benzopyrone or 3-aminobenzamide prevented the SIN-1-induced reduction in [NAD+] and [ATP] but had no effect on the SNAP-induced reduction in [ATP]. PARS inhibition reduced SIN-1-but not SNAP-induced hyperpermeability. CONCLUSIONS: Peroxynitrite but not NO increases transepithelial permeability by inducing DNA strand breaks that activate the PARS pathway and cause the depletion of intracellular energy stores. Inhibition of PARS activity may represent a novel strategy in ameliorating peroxynitrite-mediated epithelial injury during intestinal inflammation.

Photodynamic therapy of nonresectable cholangiocarcinoma.

Year 1998
Ortner MA. Liebetruth J. Schreiber S. Hanft M. Wruck U. Fusco V. Muller JM. Hortnagl H. Lochs H.
Fourth Medical Department, Medical Faculty Charite, Humboldt University, Berlin, Germany.
BACKGROUND & AIMS: Successful treatment in nonresectable Bismuth type III and IV cholangiocarcinoma is seldom achieved. The aim of this study was to evaluate the effect of photodynamic therapy on cholestasis, quality of life, and survival in these patients. METHODS: Nine patients with advanced nonresectable cholangiocarcinomas Bismuth type III and IV, who showed no sufficient drainage (bilirubin decrease

Inflammation and intestinal metaplasia of the gastric cardia: the role of gastroesophageal reflux and H. pylori infection.

Year 1998
Goldblum JR. Vicari JJ. Falk GW. Rice TW. Peek RM. Easley K. Richter JE.
Center for Swallowing and Esophageal Disorders, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
BACKGROUND & AIMS: Whether inflammation of the cardia indicates gastroesophageal reflux disease (GERD) and/or is a manifestation of pangastritis caused by Helicobacter pylori infection is unknown. The aim of this study was to evaluate the relationship between cardia inflammation, H. pylori infection, and cardia intestinal metaplasia in patients with and without GERD. METHODS: Patients with GERD were compared with controls undergoing endoscopy for a variety of other conditions. Endoscopic biopsy specimens from the distal esophagus and cardia, fundus, and antrum were evaluated for inflammation, H. pylori infection, and intestinal metaplasia. RESULTS: Neither the prevalence of H. pylori infection (controls, 48%; GERD, 41%) nor cardia inflammation (controls, 41%; GERD, 40%) differed between groups. All 11 controls and 22 of 23 patients with GERD (96%) and cardia inflammation had H. pylori infection. Esophagitis was more common among GERD patients (33%) than controls (7%; P = 0.01). Cardia intestinal metaplasia was more common among controls (22%) than GERD patients (3%; P = 0.01); all had cardia inflammation, 7 had H. pylori infection, and 6 had metaplasia elsewhere in the stomach. CONCLUSIONS: The prevalence of cardia inflammation is similar in patients with and without GERD and is associated with H. pylori infection (P < 0.001). Cardia intestinal metaplasia is associated with H. pylori-related cardia inflammation (P = 0.01) and intestinal metaplasia elsewhere in the stomach, indicating that it is distinct from Barrett's esophagus.

Hepatic Helicobacter species identified in bile and gallbladder tissue from Chileans with chronic cholecystitis.

Year 1998
Fox JG. Dewhirst FE. Shen Z. Feng Y. Taylor NS. Paster BJ. Ericson RL. Lau CN. Correa P. Araya JC. Roa I.
Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307, USA. jgfox@mit.edu
BACKGROUND & AIMS: Cancer of the gallbladder is the number one cause of cancer mortality in Chilean women. Incidence rates for this tumor vary widely on a worldwide basis, being approximately 30 times higher in high-risk than in low-risk populations, suggesting that environmental factors such as infectious microorganisms, carcinogens, and nutrition play a role in its pathogenesis. Because several Helicobacter sp. colonize the livers of animals and induce hepatitis, the aim of this study was to determine whether Helicobacter infection was associated with cholecystitis in humans. METHODS: Bile or resected gallbladder tissue from 46 Chileans with chronic cholecystitis undergoing cholecystectomy were cultured for Helicobacter sp. and subjected to polymerase chain reaction (PCR) analysis using Helicobacter-specific 16S ribosomal RNA primers. RESULTS: Recovery of Helicobacter sp. from frozen specimens was unsuccessful. However, by PCR analysis, 13 of 23 bile samples and 9 of 23 gallbladder tissues were positive for Helicobacter. Eight of the Helicobacter-specific PCR amplicons were sequenced and subjected to phylogenetic analysis. Five sequences represented strains of H. bilis, two strains of "Flexispira rappini" (ATCC 49317), and one strain of H. pullorum. CONCLUSIONS: These data support an association of bile-resistant Helicobacter sp. with gallbladder disease. Further studies are needed to ascertain whether similar Helicobacter sp. play a causative role in the development of gallbladder cancer.

Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes.

Year 1998
Berson A. De Beco V. Letteron P. Robin MA. Moreau C. El Kahwaji J. Verthier N. Feldmann G. Fromenty B. Pessayre D.
INSERM Unite 481 and Centre de Recherche sur les Hepatites Virales (Association Claude Bernard), Hopital Beaujon, Clichy, France.
BACKGROUND & AIMS: 4,4'-Diethylaminoethoxyhexestrol (DEAEH), amiodarone, and perhexiline cause steatohepatitis in humans. The mechanisms of these effects are unknown for DEAEH and have not been completely elucidated for amiodarone and perhexiline. The aim of this study was to determine these mechanisms. METHODS: Rat liver mitochondria, cultured rat hepatocytes, or rats were treated with these drugs, and the effects on mitochondrial respiration, beta-oxidation, reactive oxygen species formation, and lipid peroxidation were determined. RESULTS: DEAEH accumulated in mitochondria and inhibited carnitine palmitoyl transferase I and acyl-coenzyme A dehydrogenases; it decreased beta-oxidation and caused lipid deposits in hepatocytes. DEAEH also inhibited mitochondrial respiration and decreased adenosine triphosphate (ATP) levels in hepatocytes. DEAEH, amiodarone, and perhexiline augmented the mitochondrial formation of reactive oxygen species and caused lipid peroxidation in rats. CONCLUSIONS: Like amiodarone and perhexiline, DEAEH accumulates in mitochondria, where it inhibits both beta-oxidation (causing steatosis) and respiration. Inhibition of respiration decreases ATP and also increases the mitochondrial formation of reactive oxygen species. The latter oxidize fat deposits, causing lipid peroxidation. We suggest that ATP depletion and lipid peroxidation may cause cell death and that lipid peroxidation products may account, in part, for other steatohepatitis lesions.

Guanylin stimulates regulated secretion from human neuroendocrine pancreatic cells.

Year 1998
John M. Wiedenmann B. Kruhoffer M. Adermann K. Ankorina-Stark I. Schlatter E. Ahnert-Hilger G. Forssmann WG. Kuhn M.
Department of Gastroenterology, Klinikum Benjamin Franklin, Freie Universitat Berlin, Berlin, Germany.
BACKGROUND & AIMS: Gastroenteropancreatic neuroendocrine cells secrete chemical messengers in a calcium-dependent fashion. So far, other second messenger systems involved in regulated secretion have gained little attention. The aim of this study was to characterize guanosine 3',5'-cyclic monophosphate (cGMP)-mediated vesicular secretion in pancreatic neuroendocrine cells. METHODS: In a human pancreatic cell line, BON, cyclic nucleotide levels and chromogranin A release were monitored with specific immunoassays. Uptake and release of gamma-aminobutyric acid were measured. Intracellular Ca2+ concentration was monitored with fura-2. Guanylyl cyclase C was analyzed by reverse-transcription polymerase chain reaction. RESULTS: Guanylin increased cGMP concentrations in BON cells via guanylyl cyclase C. Stimulation of the cGMP pathway by guanylin or Escherichia coli heat-stable enterotoxin increased the release of chromogranin A and gamma-aminobutyric acid from BON cells. This effect was mimicked by the cGMP analogue 8-bromo-cGMP. CONCLUSIONS: Guanylin and STa stimulate the regulated secretion from BON cells via guanylyl cyclase C and cGMP. Our study yields novel information about secretory properties of guanylin, mediated via a signal transduction pathway, increasing cGMP and leading to regulated secretion of neuroendocrine cells.

Suppression of fibroblast growth factor receptor signaling inhibits pancreatic cancer growth in vitro and in vivo.

Year 1998
Wagner M. Lopez ME. Cahn M. Korc M.
Division of Endocrinology, Diabetes and Metabolism, University of California, Irvine, California 92697, USA.
BACKGROUND & AIMS: Fibroblast growth factors (FGFs) are mitogenic polypeptides that activate specific cell surface FGF receptors (FGFRs). Pancreatic cancers overexpress basic FGF (bFGF) and the type I FGF receptor (FGFR-1), and overexpression of bFGF has been correlated with decreased patient survival. The aim of this study was to examine the effects of abrogation of FGFR-1-dependent signaling on pancreatic cancer cell growth. METHODS: PANC-1 human pancreatic cancer cells were transfected with a truncated FGFR-1 complementary DNA (FGFR405), resulting in the expression of a kinase-deficient receptor. Activation of endogenous FGFR-1 was assessed in immunoblot studies with antiphosphotyrosine and anti-active mitogen-activated protein (MAP) kinase antibodies. Effects on cell growth were determined in vitro and in nude mice. RESULTS: PANC-1 clones expressing the truncated receptor showed attenuated receptor tyrosine phosphorylation and MAP kinase activation in response to bFGF, decreased basal cell growth, and a marked decrease in tumor-forming potential in vivo. Confirmatory experiments with MIA PaCa-2 pancreatic cancer cells indicated that FGFR405 also attenuated FGF-dependent MAP kinase activation in this cell line. CONCLUSIONS: The findings suggest that FGFR-dependent signaling is crucial for pancreatic cancer growth and raise the possibility that inhibition of FGFR signaling may ultimately prove useful as a therapeutic option in patients with pancreatic cancer.

Octreotide suppression test predicts beneficial outcome from antrectomy in a patient with gastric carcinoid tumor.

Year 1998
Higham AD. Dimaline R. Varro A. Attwood S. Armstrong G. Dockray GJ. Thompson DG.
Physiological Laboratory, University of Liverpool, Liverpool, England, UK.
Multiple gastric carcinoids are a well-recognized complication of hypergastrinemia associated with chronic atrophic gastritis. However, the management of large tumors (>2 cm in diameter) remains uncertain, with the decision between antrectomy or total gastrectomy being empirical. This report describes the investigation of a patient with chronic atrophic gastritis and multiple large gastric carcinoid tumors. Before surgery, octreotide was infused for 72 hours to suppress enterochromaffin-like (ECL) cell and gastrin cell function. The infusion decreased plasma gastrin and gastrin synthesis; moreover, there were marked reductions in markers of ECL cell function, e.g., histidine decarboxylase and chromogranin A messenger RNA abundance, in carcinoid tumor tissue and macroscopically normal corpus mucosa. An antrectomy was performed, after which the patient made an uneventful recovery. Six months after surgery, a single residual polyp, enriched with smooth muscle cells but not ECL cells, was removed. One year after antrectomy, the remaining stomach was normal. The response of ECL cell markers in carcinoid tissue to octreotide suggested that these cells were under neuroendocrine control and, therefore, predicted a beneficial outcome for antrectomy. It is suggested that an octreotide supression test coupled with assay of histidine decarboxylase or chromogranin A gene expression is useful in the assessment of gastric carcinoid tumors.

Intractable upper gastrointestinal ulceration due to aspirin in patients who have undergone surgery for peptic ulcer.

Year 1998
Hirschowitz BI. Lanas A.
Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0007, USA.
BACKGROUND & AIMS: Postsurgical ulcer recurrence is a challenging problem. The aim of this study was to define the role of aspirin in postsurgical ulcers. METHODS: We studied 30 patients with postsurgical ulcer and aspirin abuse. Preoperatively 13 had stenosis, 7 bleeding, and 7 perforation or penetration; 18 had undergone vagotomy and 11 gastrectomy. RESULTS: Of 30 patients, 15 admitted long-term aspirin use (1-4 g/day), whereas 15 denied use but had positive salicylate blood levels (15.1 +/- 2.25 mg/100 mL; >1 mmol/L). Gastrin or gastric secretion was normal in the 24 patients tested. On follow-up, 3 (10%) healed after surgery (all stopped taking aspirin), whereas 27 continued and had new ulcers; 12 (44%) developed stenosis, and 6 (23%) developed bleeding. A second operation was required in 16 patients who had continued aspirin abuse, which was surreptitious in 10 (63%). Thirteen of these 16 had recurrent ulceration (7 [43%] with stenosis and 1 with bleeding); 1 died and 2 stopped taking aspirin and healed. A third operation was required in 8 patients. All had continued aspirin abuse (75% surreptitiously), and all again had relapses (3 with stenosis); 1 underwent an unsuccessful fourth operation, and 3 died. CONCLUSIONS: With continued aspirin abuse, recurrent ulceration is the rule, and complications, especially stenosis, are common. Surreptitious aspirin abuse, if discovered, is a clear contraindication to elective ulcer surgery, because aspirin-abuse ulceration is incurable by gastric surgery.

Cost analysis of alternative approaches to colorectal screening in familial adenomatous polyposis.

Year 1998
Cromwell DM. Moore RD. Brensinger JD. Petersen GM. Bass EB. Giardiello FM.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
BACKGROUND & AIMS: The commercial availability of gene testing for familial adenomatous polyposis (FAP) represents an important advance in screening for inherited colon cancer. We investigated the financial impact of this diagnostic tool on colorectal screening for FAP. METHODS: Decision analysis was used to compare per-person costs with third-party payers of three colorectal screening strategies used to diagnose FAP in at-risk persons. The strategies included conventional serial flexible sigmoidoscopy and two different APC gene testing approaches. RESULTS: For 1 at-risk relative who begins screening at age 12 years, average screening costs are $2625 when genotyping the proband first, $2674 when genotyping the at-risk relative first, and $3208 for conventional sigmoidoscopy. The cost advantage of genotyping increases as the pedigree size increases. For a pedigree of 5 at-risk relatives, sigmoidoscopy would have to cost less than $85.60 (professional plus facility fee) for conventional screening to compete with genotyping. The cost advantage of genotyping is diminished for at-risk relatives who begin FAP screening at older ages. CONCLUSIONS: The choice of least expensive FAP screening strategy depends on the cost of flexible sigmoidoscopy, patient age when screening starts, and pedigree size. Genotyping can substantially reduce the cost of FAP screening and, when possible, should start with the proband.

Bone mineral density assessment in children with inflammatory bowel disease.

Year 1998
Gokhale R. Favus MJ. Karrison T. Sutton MM. Rich B. Kirschner BS.
Section of Pediatric Gastroenterology, University of Chicago, Chicago, Illinois 60614, USA.
BACKGROUND & AIMS: Children with inflammatory bowel disease (IBD) are at risk for osteoporosis because of undernutrition, delayed puberty, and prolonged corticosteroid use. The aim of this study was to compare bone mineral density (BMD) in children with IBD with that in normal children and to assess the effects of nutritional and hormonal factors and corticosteroid dosages on BMD. METHODS: One hundred sixty-two subjects (99 with IBD and 63 healthy sibling controls) were enrolled. Patients underwent anthropometric assessment, pubertal staging, bone age radiography, and BMD assessment by dual energy x-ray absorptiometry of the lumbar spine, femoral neck, and radius. Laboratory evaluations included serum calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, parathyroid hormone, osteocalcin, urinary N-telopeptides, albumin, insulin-like growth factor I, and testosterone or estradiol. Cumulative corticosteroid doses were calculated. RESULTS: BMD Z scores at the lumbar spine and femoral neck were lower in patients with IBD, and lower in those with Crohn's disease compared with those with ulcerative colitis. Low BMD persisted after correction for bone age in girls with Crohn's disease (lumbar spine, P = 0.004; femoral neck, P = 0.002). Cumulative corticosteroid dose was a significant predictor of reduced BMD. BMD did not correlate with measures of calcium homeostasis, except elevated serum phosphate and urine calcium levels in girls. CONCLUSIONS: Low BMD occurs in children with IBD (more in Crohn's disease than in ulcerative colitis), especially pubertal and postpubertal girls. Cumulative corticosteroid dose is a predictor of low BMD, but other factors in Crohn's disease remain undetermined.

Tropomyosin isoforms in intestinal mucosa: production of autoantibodies to tropomyosin isoforms in ulcerative colitis.

Year 1998
Geng X. Biancone L. Dai HH. Lin JJ. Yoshizaki N. Dasgupta A. Pallone F. Das KM.
Division of Gastroenterology and Hepatology, Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, USA.
BACKGROUND & AIMS: Autoantibodies against tropomyosins (TMs) have been reported in ulcerative colitis (UC). In this study the hTM isoforms (hTM1-5) present in intestinal epithelial cells and in smooth muscle were investigated, and the immunoreactivity against hTMs by immunoglobulin G (IgG) produced in vitro by colonic mucosal lymphocytes (LPMCs) from patients with UC, Crohn's disease (CD), and controls was examined. METHODS: TMs were extracted from colonic and jejunal epithelial cells and smooth muscle, and hTM isoforms were identified using isoform-specific monoclonal antibodies by enzyme-linked immunosorbent assay and transblot analysis. The immunoreactivity of IgG produced by colonic LPMCs was analyzed against the recombinant hTM isoforms. RESULTS: The major hTM isoforms present in colonic and jejunal epithelial cells are hTM5 and hTM4, whereas intestinal smooth muscle contains the hTM1-3 isoforms. The IgG synthesized in vitro by LPMCs from UC (n = 19) recognized hTM5 and hTM1, more significantly (P < 0.04 to

Inhibition of epidermal growth factor receptor kinase induces protease-dependent apoptosis in human colon cancer cells.

Year 1998
Karnes WE Jr. Weller SG. Adjei PN. Kottke TJ. Glenn KS. Gores GJ. Kaufmann SH.
Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota 55905, USA. karnes@ralph.mayo.edu
BACKGROUND & AIMS: The epidermal growth factor receptor (EGFR) is under investigation as a therapeutic target for cancers. Colon cancer cell lines are variably dependent on autocrine stimulation of EGFR. We therefore examined the effects of a selective EGFR tyrosine kinase inhibitor, PD 153035, on proliferation and survival of five colon cancer cell lines whose autonomous proliferation is either EGFR ligand dependent or EGFR ligand independent. METHODS: Effects of inhibitors were screened by MTS growth assays, [3H]thymidine incorporation, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay, fluorescence microscopy, immunoblotting, and in vitro protease assays. RESULTS: PD 153035 caused dose-dependent cytostasis (200 nmol/L to 1 micromol/L) and apoptosis (>10 micromol/L) in ligand-dependent cell lines and caused variable apoptosis (>10 micromol/L) but no cytostasis in ligand-independent cell lines. Apoptosis induced by 10 micromol/L PD 153035 was not associated with induction of p53 protein expression but was accompanied by activation of caspases that cleave poly(ADP-ribose) polymerase, lamin B1, and Bcl-2. Inhibition of caspase 3-like protease activity by DEVD-fluoromethylketone significantly delayed the onset of PD 153035-induced apoptosis. CONCLUSIONS: The EGFR tyrosine kinase inhibitor PD 153035 induces cytostasis and caspase-dependent apoptosis in EGFR ligand-dependent colon cancer cell lines. These observations encourage further investigation of EGFR tyrosine kinase inhibitors for treatment of colorectal neoplasms.

Salvage transjugular intrahepatic portosystemic shunts: gastric fundal compared with esophageal variceal bleeding.

Year 1998
Chau TN. Patch D. Chan YW. Nagral A. Dick R. Burroughs AK.
Department of Liver Transplantation and Hepatobiliary Medicine, Royal Free Hospital, Hampstead, London, England.
BACKGROUND & AIMS: The optimal emergency treatment for gastric fundal variceal bleeding is still unclear. In this study, the efficacy of transjugular intrahepatic portosystemic stent/shunt (TIPS) in patients with uncontrolled gastric fundal vs. esophageal variceal bleeding was compared. METHODS: One hundred twelve consecutive patients with uncontrolled variceal bleeding required emergency TIPS, 84 with esophageal varices (EV group) unresponsive to endoscopic and vasoconstrictor therapy and 28 with gastric fundal varices (GV group) unresponsive to vasoconstrictor therapy. Clinical and biochemical data were retrieved, and the two groups were compared. RESULTS: Variceal bleeding was controlled in all patients after TIPS except for 1 in each group. There were no significant differences between the two groups in terms of markers of disease severity, severity of bleeding, or portal hemodynamics. During a median follow-up period of 7 months, 20 in the EV group (24%) and 8 in the GV group (29%) developed clinical rebleeding. Most early rebleeding (within 7 days after TIPS) was related to esophageal ulceration secondary to previous sclerotherapy. Rates of mortality were similar in both groups. CONCLUSIONS: These results suggest that emergency TIPS is equally effective in the immediate short-term control of gastric fundal variceal bleeding compared with esophageal variceal bleeding.

Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial.

Year 1998
Sokal EM. Conjeevaram HS. Roberts EA. Alvarez F. Bern EM. Goyens P. Rosenthal P. Lachaux A. Shelton M. Sarles J. Hoofnagle J.
Cliniques St. Luc, Pediatric Hepatology, Universite Catholique de Louvain, Brussels, Belgium. sokal@pedilucl.ac.be
BACKGROUND & AIMS: Treatment of chronic hepatitis B with interferon alfa is not approved in children. The aim of this study was to evaluate the safety and efficacy of interferon alfa (IFN-alpha) in children with chronic hepatitis B and increased transaminase levels. METHODS: Children were given either IFN-alpha2b (6 megaunits/m2 thrice weekly for 24 weeks) or no treatment. Clearance of markers of viral replication was evaluated 24 weeks after therapy and after 48 weeks of observation in controls. RESULTS: Of 149 children enrolled, 144 were evaluable (70 treated and 74 controls). Serum hepatitis B e antigen and viral DNA became negative in 26% of treated children and 11% of controls (P < 0.05). Serum aminotransferase levels normalized and liver histology improved among responders. Hepatitis B surface antigen became undetectable in 10% of treated patients and 1% of controls. Female gender and interferon treatment were the only significant predictors of response. Ethnic origin, baseline aminotransferase level, initial DNA levels, and histology did not correlate with response. Most adverse reactions were mild or moderate, and dose was reduced in 24% of children. CONCLUSIONS: In children with chronic hepatitis B, INF-alpha promotes loss of viral replication markers and surface antigen and improves aminotransferases and histology.

Cholesterol saturation, not proteins or cholecystitis, is critical for crystal formation in human gallbladder bile.

Year 1998
Miquel JF. Nunez L. Amigo L. Gonzalez S. Raddatz A. Rigotti A. Nervi F.
Departamentos de, Facultad de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile.
BACKGROUND & AIMS: Biliary proteins are promoters of cholesterol crystallization in artificial model bile. However, their pathogenic importance for cholesterol precipitation in native gallbladder bile (GB) is uncertain. The aim of this study was to evaluate the significance of biliary lipids and proteins on cholesterol crystal detection time (ChCDT) of GB in patients with gallstones. METHODS: ChCDT and concentrations of lipids, albumin, mucins, aminopeptidase N, alpha1-acid glycoprotein, haptoglobin, and immunoglobulins (Igs) were measured in GB of 92 patients, 52 of whom had cholesterol gallstones. RESULTS: ChCDT was markedly reduced in gallstone patients. Compared with patients without gallstones, they had a significant increase in cholesterol saturation and total protein, albumin, mucin, and IgG biliary concentrations. In univariate analysis, ChCDT of GB was significantly correlated with cholesterol saturation and total lipid, protein, Ig, aminopeptidase N, and alpha1-acid glycoprotein concentrations. However, stepwise logistic regression analysis showed that only cholesterol saturation independently correlated to ChCDT. Gallbladder inflammation correlated with the concentration of Igs, but subtraction of IgG from GB did not modify the ChCDT. CONCLUSIONS: Biliary cholesterol transport and saturation, but not proteins, appear critical for the cholesterol crystallization abnormality observed in native bile from patients with gallstones.

Hypercalcemia due to endogenous overproduction of 1,25-dihydroxyvitamin D in Crohns disease.

Year 1998
Bosch X.
Internal Medicine Unit, Hospital Casa Maternitat, Corporacio Sanitaria Clinic, Barcelona, Spain.
Hypercalcemia may occur in various granulomatous diseases. Two patients with Crohn's disease who had hypercalcemia, hypercalciuria, and excessively high serum levels of 1,25-dihydroxyvitamin D [1,25(OH)2D] are described. Both had numerous noncaseating, epithelioid granulomas in bowel biopsy samples. A direct correlation was observed between serum 1,25(OH)2D levels and both serum and urinary calcium concentrations. Also, calcium and 1,25(OH)2D levels strongly paralleled the clinical activity of disease. Prompt therapy with prednisone in the patient who had symptomatic hypercalcemia and with prednisone and mesalamine in the other patient without hypercalcemic symptoms led to normalization of calcium and serum 1,25(OH)2D levels, but 25-hydroxyvitamin D [25(OH)D] levels remained unchanged. Four months after discharge, recurrence of Crohn's disease symptomatology together with an increase in calcium and serum 1,25(OH)2D levels was observed in 1 patient; after increasing the prednisone dose, levels decreased and rapid clinical resolution was noted. These cases appear to be the first reported instances of hypercalcemia in patients with Crohn's disease. Excessive synthesis of 1,25(OH)2D may have been inhibited by an action of corticosteroids on the 1alpha-hydroxylation of 25(OH)D in the activated macrophage of Crohn's granulomas. Crohn's disease should be added to the list of granulomatous diseases responsible for 1,25(OH)2D-mediated hypercalcemia.

Leukocyte-endothelial cell interactions: molecular mechanisms and implications in gastrointestinal disease.

Year 1998
Panes J. Granger DN.
Department of Gastroenterology, Institut d' Investigacions Biomediques August Pi i Sunyer, Hospital Clinic, Barcelona, Spain.
Leukocyte-endothelial cell adhesion is now recognized to represent an early and rate-limiting step in the leukocyte infiltration and accompanying tissue injury that is associated with acute and chronic inflammatory diseases of the gastrointestinal tract. Adhesive interactions such as leukocyte rolling, adherence, and transendothelial migration are influenced by a variety of physical, chemical, and molecular factors that ultimately result in a net up-regulation or down-regulation of the inflammatory response. Coordination of this process is made possible by the mediator-specific, time-sensitive expression of adhesion glycoproteins on the surface of leukocytes and/or vascular endothelial cells. In this review, the different families of relevant adhesion molecules that participate in the coordinated recruitment of leukocytes into inflamed tissue are described and then discussed in terms of the pathophysiological alterations observed in selected experimental models of gastrointestinal disease. These include ischemia/reperfusion injury, radiation enteritis, inflammatory bowel disease, and the inflammatory responses to substances liberated by Helicobacter pylori and Clostridium difficile.

A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohns disease.

Year 1998
Yacyshyn BR. Bowen-Yacyshyn MB. Jewell L. Tami JA. Bennett CF. Kisner DL. Shanahan WR Jr.
Division of Gastroenterology, University of Alberta, Edmonton, Canada.
BACKGROUND & AIMS: Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the trafficking and activation of leukocytes and is up-regulated in inflamed mucosa in Crohn's disease. ISIS 2302 is an antisense phosphorothioate oligodeoxynucleotide that inhibits ICAM-1 expression. The aim of this study was to obtain preliminary assessment of tolerability, pharmacology, and efficacy of ISIS 2302 in Crohn's disease. METHODS: Twenty patients with active, steroid-treated Crohn's disease were randomized (3:1, ISIS 2302 to placebo) to receive over 26 days 13 intravenous infusions of ISIS 2302 (0.5, 1, or 2 mg/kg) or saline placebo in a double-blinded study. The patients were followed up for 6 months. RESULTS: At the end of treatment. 47% (7 of 15) of ISIS 2302-treated and 20% (1 of 5) of the placebo-treated patients were in remission (Crohn's Disease Activity Index [CDAI] < 150). At the end of month 6, 5 of these 7 ISIS 2302-treated remitters were still in remission, and a 6th patient had a CDAI of 156. Corticosteroid usage was significantly lower (P = 0.0001) in the ISIS 2302-treated patients. These findings were corroborated by significant increases in beta7 and alpha d bearing CD3+ peripheral blood lymphocytes and by decreases in intestinal mucosal ICAM-1 expression during the treatment period. CONCLUSIONS: ISIS 2302 seems to be a well-tolerated and promising therapy for steroid-treated Crohn's disease.

Clinical course of colorectal Crohns disease: a 35-year follow-up study of 507 patients.

Year 1998
Lapidus A. Bernell O. Hellers G. Lofberg R.
Department of Gastroenterology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden. Annika.Lapidus.Kau@medhs.ki.se
BACKGROUND & AIMS: Crohn's disease (CD) confined to the colon and rectum is an increasing clinical entity. The aim of this study was to assess the features and clinical course of colorectal CD. METHODS: This was a retrospective cohort study of 507 patients in whom colonic or rectal CD had been diagnosed between 1955 and 1989. RESULTS: Colonic distribution was segmental in 40%, total in 31%, and left-sided in 26%. Perianal/rectal fistulas occurred in 37%. In patients who attained clinical remission, the 5-year cumulative relapse rate after diagnosis was 67% (95% confidence interval [CI], 62-72). At the initial presentation of CD, the frequency of major surgery decreased from 24% to 14% (P < 0.005) over time. Still, the overall long-term probability of major surgery after 10 years was unaltered (49% vs. 47%). The presence of fistulas increased the probability of surgical resection (relative risk [RR], 1.7 [95% CI, 1.3-2.2]), whereas left-sided disease was associated with a decrease (RR, 0.6 [95% CI, 0.4-0.8]). Twenty-four percent of the patients developed inflammation in the small bowel. The cumulative risk for a permanent ileostomy was 25% (95% CI, 21-29) 10 years after diagnosis. CONCLUSIONS: Colorectal CD is an increasing entity carrying substantial morbidity. Half of the patients will undergo surgical resection within the first 10 years, and half of those will ultimately undergo ileostomy. Changed management at diagnosis has not affected the long-term probability of resection.

Crohns disease in Olmsted County, Minnesota, 1940-1993: incidence, prevalence, and survival.

Year 1998
Loftus EV Jr. Silverstein MD. Sandborn WJ. Tremaine WJ. Harmsen WS. Zinsmeister AR.
Inflammatory Bowel Disease Clinic, Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA. loftus.edward@mayo
BACKGROUND & AIMS: Many centers worldwide have reported an increased incidence of Crohn's disease, but population-based data in North America are sparse. We studied the incidence and prevalence of Crohn's disease in Olmsted County, Minnesota, and examined temporal trends in incidence and survival. METHODS: Residents diagnosed with Crohn's disease between 1970 and 1993 were incidence cases, and residents with Crohn's disease who were alive on January 1, 1991, were prevalence cases. Cases from previous studies were reconfirmed. Rates were adjusted using 1990 U.S. Census figures for whites. Incidence trends were evaluated with a Poisson regression model. Survival from diagnosis was compared with that expected for U.S. north-central whites. RESULTS: Between 1940 and 1993, 225 incidence cases were identified, for an adjusted incidence rate of 5.8 per 100,000 person-years. On January 1, 1991, there were 145 residents with Crohn's disease, an adjusted prevalence rate of 133 per 100,000, 46% higher than that seen in 1980. Incidence rates before 1964 were significantly lower than those of 1989-1993. Observed survival was less than expected (P = 0.007). CONCLUSIONS: The incidence of Crohn's disease has stabilized since the 1970s at a rate higher than that seen previously. Prevalence has increased by 46% since 1980. Overall survival is slightly decreased.

Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer.

Year 1998
Huang JQ. Sridhar S. Chen Y. Hunt RH.
Department of Medicine, McMaster University Medical Center, Hamilton, Ontario, Canada.
BACKGROUND & AIMS: Reports in the literature regarding the relationship of Helicobacter pylori infection to gastric cancer are conflicting. The aim of this study was to identify the source of heterogeneity between studies. METHODS: Meta-analysis of cohort or case-control studies with age- and/or sex-matched controls, providing raw data on H. pylori infection detected by serology, was used. RESULTS: A fully recursive literature search identified 19 qualified studies with 2491 patients and 3959 controls. Test for homogeneity found a significant difference in odds ratio between patients with early and advanced gastric cancer (6.35 vs. 2.13; P = 0.01), patients with cardiac and noncardiac gastric cancer (1.23 vs. 3.08; P = 0.003), and population- and hospital-based controls (2.11 vs. 1.49; P < 0.001). The summary odds ratio for gastric cancer in H. pylori-infected patients is 1.92 (95% confidence interval [CI], 1.32-2.78), 2.24 (95% CI, 1.15-4.4), and 1.81 (95% CI, 1.16-2.84) for all studies, cohort, and case-control studies, respectively. H. pylori-infected younger patients have a higher relative risk for gastric cancer than older patients with odds ratios decreasing from 9.29 at age < or = 29 years to 1.05 at age > or = 70 years. H. pylori infection is equally associated with the intestinal or diffuse type of gastric cancer. CONCLUSIONS: H. pylori infection is a risk factor for gastric cancer. The heterogeneity of reported results is caused by differences in the selection of controls, patient age, and the site and stage of gastric cancer.

Allelic loss on chromosome 18q as a prognostic marker in stage II colorectal cancer.

Year 1998
Martinez-Lopez E. Abad A. Font A. Monzo M. Ojanguren I. Pifarre A. Sanchez JJ. Martin C. Rosell R.
Laboratory of Molecular Biology of Cancer, University Hospital Germans Trias i Pujol, Barcelona, Spain.
BACKGROUND & AIMS: Loss of heterozygosity (LOH) on chromosome 18q is frequent in colorectal cancer (CRC) and has been associated with poor prognosis in stage II tumors. This study investigated the frequency of LOH in sporadic CRC and its effect on patient prognosis. METHODS: One hundred forty-four patients were screened for LOH at 18q by polymerase chain reaction using three polymorphic microsatellite markers. RESULTS: Nineteen patients were excluded because their tumors showed microsatellite instability in at least one marker. Of the remaining 125 patients, 121 were informative in at least one marker; 45% (54 of 121) showed 18q LOH. Five-year survival was 42% in those with 18q LOH and 73% in those without 18q LOH (P = 0.008). Multivariate analysis showed that tumor side (P = 0.0001) and 18q LOH (P = 0.01) were the only independent prognostic factors. Examining markers individually showed that only the lost of D18S474 had a significant influence on survival in patients with stage II CRC (P = 0.016). CONCLUSIONS: 18q LOH indicates an unfavorable outcome in patients with stage II CRC. Our results emphasize the importance of the 18q21.1 region, where several tumor-suppressor genes have been mapped. Microsatellite analysis may be useful in identifying high-risk patients who might benefit from adjuvant therapy.

Prognostic significance of allelic lost at chromosome 18q21 for stage II colorectal cancer.

Year 1998
Carethers JM. Hawn MT. Greenson JK. Hitchcock CL. Boland CR.
Department of Medicine, University of California, San Diego, USA. jcarethers@ucsd.edu
BACKGROUND & AIMS: Allelic loss of a portion of chromosome 18q and lack of expression of deleted in colorectal cancer (DCC) protein has been reported as an adverse prognostic indicator for stage II (i.e., Dukes' B2) colorectal cancer. Our aim was to assess whether the DCC gene locus was responsible. METHODS: We amplified five DNA microsatellite markers located on chromosome 18q21 surrounding or within the DCC gene locus, including a DCC intragenic (TA)n microsatellite, from DNA microdissected and isolated from paraffin-embedded, formalin-fixed specimens of 70 patients with stage II colorectal cancer. Epidemiological and survival data were blinded from the microsatellite analysis to avoid bias. RESULTS: The average follow-up time was 63.3 months for all patients. Eleven patients died of colorectal cancer by the end of the study. Loss of heterozygosity of 18q21 was present in 30 of 70 (43%) tumors. After adjustment for all other evaluated factors, 18q21 allelic loss was not a predictor of survival (hazard ratio, 1.17; 95% confidence interval, 0.27-5.10; P = 0.84). CONCLUSIONS: Loss of heterozygosity of 18q21 does not seem to predict a survival disadvantage in stage II colorectal cancer in our patient population, and its proposed use as a prognosticator of survival or chemotherapy stratification marker for stage II tumors is not substantiated.

Abnormal expression of CD44 variants in the exfoliated cells in the feces of patients with colorectal cancer.

Year 1998
Yamao T. Matsumura Y. Shimada Y. Moriya Y. Sugihara K. Akasu T. Fujita S. Kakizoe T.
Department of Medicine, National Cancer Center Hospital, Tokyo, Japan.
BACKGROUND & AIMS: Recent investigations have shown that CD44 variant exons are frequently overexpressed in human colorectal adenocarcinoma. The aim of this study was to investigate abnormal expression of the CD44 gene in exfoliated cells from patients with colorectal cancer. METHODS: Exfoliated cells in feces from 25 patients with colorectal cancer before and after surgery and from 15 healthy volunteers were analyzed. CD44 standard, variant 6, and variant 10 messenger RNA (mRNA) expressions were examined in the exfoliated cells in feces by using reverse-transcription polymerase chain reaction followed by Southern hybridization with exon-specific probes. RESULTS: CD44 standard mRNA was detected in all samples before and after surgery and in all healthy volunteers. CD44 variant 6 and variant 10 mRNA were detected in 17 of 25 patients (68%) and 15 of 25 patients (60%), respectively, in individual feces obtained before surgery. CD44 variant 6 mRNA and variant 10 mRNA were detected in postoperative samples in 3 of 25 patients (12%) and 7 of 25 patients (28%), respectively. Fifteen of 17 patients who were positive for CD44v6 based on preoperative fecal samples became negative after surgery (88.2%). Similarly, 12 of 15 patients who were CD44v10 positive in preoperative fecal samples were negative postoperatively (80%). CONCLUSIONS: These results suggest that analysis of CD44 variant expression in the exfoliated cells in feces can provide a noninvasive diagnostic test for colorectal cancer.

Tylosis esophageal cancer locus on chromosome 17q25.1 is commonly deleted in sporadic human esophageal cancer.

Year 1998
Iwaya T. Maesawa C. Ogasawara S. Tamura G.
Department of Pathology, Iwate Medical University School of Medicine, Morioka, Japan.
BACKGROUND & AIMS: Tumor-suppressor genes found in inherited cancer predisposition syndromes are also responsible for sporadic cancers of the same type. Recently, the tylosis oesophageal cancer (TOC) gene locus has been mapped to 17q25 by linkage analyses of pedigrees with focal nonepidermolytic palmoplantar keratoderma associated with a high risk of esophageal cancer development. The aim of this study was to clarify whether the TOC locus is affected in sporadic esophageal cancers. METHODS: We investigated loss of heterozygosity (LOH) on 17q in 58 sporadic esophageal squamous cell carcinomas (ESCs) using 20 microsatellite markers focusing on the TOC locus. RESULTS: LOH on 17q was observed in 37 of 52 (71%) informative cases at one or more loci, 80% (33/37) of which included the TOC locus. The smallest common deleted region was at D17S1839 within the TOC locus. CONCLUSIONS: The constructed deletion map revealed that the TOC locus is commonly deleted in sporadic ESCs, suggesting that a tumor-suppressor gene responsible for ESC is contained within this locus.

Expression of transforming growth factor beta receptors in normal human colon and sporadic adenocarcinomas.

Year 1998
Eskinazi R. Resibois A. Svoboda M. Peny MO. Adler M. Robberecht P. Van Laethem JL.
Laboratoire de Chimie Biologique et de la Nutrition, Faculte de Medicine, Hopital Erasme, Universite Libre de Bruxelles, Belgium.
BACKGROUND & AIMS: An absence or a presence of mutated transforming growth factor (TGF)-beta receptors is a possible hypothesis explaining the resistance of cancer cells to the growth-inhibitory effect of TGF-beta. Mutations involving microsatellite-like regions of the type II TGF-beta receptor have been described in subgroups of colorectal cancers. The aim of this study was to investigate the expression and distribution of TGF-beta receptors in sporadic colorectal cancers and normal tissues. METHODS: Thirty-three sporadic colorectal cancers and 20 normal colonic tissues were explored by immunohistochemistry for the expression of type I and type II TGF-beta receptors. Eighteen tumor and 20 normal samples were used for radioactive thermocycling and sequencing of the two microsatellite-like regions of the type II receptor. RESULTS: Both receptors were overexpressed in tumors compared with normal samples. There was a relationship between the abundance of type II receptor expression and the degree of differentiation of the tumors but not the Dukes' staging or the localization of the neoplasias. No mutation was observed in the microsatellite-like regions of receptor II in any of the samples. CONCLUSIONS: Sporadic colorectal cancers do not show an absence or a presence of mutated TGF-beta receptors that could explain a resistance to TGF-beta-mediated growth inhibition. The pathways to tumorigenesis of sporadic colorectal cancers may be different from those of some hereditary ones.

Interleukin 15 activity in the rectal mucosa of inflammatory bowel disease.

Year 1998
Sakai T. Kusugami K. Nishimura H. Ando T. Yamaguchi T. Ohsuga M. Ina K. Enomoto A. Kimura Y. Yoshikai Y.
First Department of Internal Medicine, Nagoya University School of Medicine, Japan.
BACKGROUND & AIMS: Interleukin (IL)-15 has been found to share many immunoregulatory activities in lymphocytes with IL-2. The aim of this study was to investigate IL-15 activity in organ cultures, localization of IL-15 messenger RNA (mRNA), and proliferation of lamina propria mononuclear cells (LPMCs) in response to recombinant IL-15 using the mucosal tissues obtained from patients with inflammatory bowel disease (IBD). METHODS: The contents of IL-15, tumor necrosis factor alpha, and IL-2 in the culture supernatant of the rectal mucosal tissues were determined by an enzyme-linked immunosorbent assay. Expression of IL-15 mRNA was analyzed by in situ hybridization, and proliferative response of LPMCs to recombinant IL-15 was determined by [3H]thymidine incorporation into DNA. RESULTS: Significantly greater IL-15 activity was detected in active IBD, and this elevation was also observed in inactive ulcerative colitis. In contrast, greater tumor necrosis factor alpha activity was observed only in active IBD, and IL-2 was not detected in organ cultures. In situ hybridization showed IL-15 mRNA in macrophages and epithelial cells in active IBD specimens, and recombinant IL-15 induced a dose-dependent proliferative response in LPMCs. CONCLUSIONS: Mucosal IL-15 may be involved in the pathogenesis of IBD as one of the important mediators in activation of mucosal immune cells.

Clinical events after transjugular intrahepatic portosystemic shunt: correlation with hemodynamic findings.

Year 1998
Casado M. Bosch J. Garcia-Pagan JC. Bru C. Banares R. Bandi JC. Escorsell A. Rodriguez-Laiz JM. Gilabert R. Feu F. Schorlemer C. Echenagusia A. Rodes J.
Department of Medicine, Hospital Clinic i Provincial, Universitat de Barcelona.
BACKGROUND & AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) procedures are increasingly being used, but the relationship between the hemodynamic effects of TIPS and the clinical events on follow-up remains undefined. Hence, we have investigated the hemodynamic correlations of portal hypertension-related events after a TIPS procedure. METHODS: Prospective follow-up of 122 cirrhotic patients who had a TIPS procedure performed because of variceal hemorrhage was conducted. RESULTS: The portacaval pressure gradient (PPG) significantly decreased after the TIPS procedure (from 19.7 +/- 4.6 to 8.6 +/- 2.7 mm Hg; P > 0.001), but increased thereafter and at rebleeding (n = 25) was > 12 mm Hg in all patients (18.4 +/- 4.6 mm Hg). Twenty-six patients developed ascites; the PPG (measured in 19) was always > 12 mm Hg. Increasing the PPG to > 12 mm Hg occurred very frequently (83% at 1 year). Within 1 year, 77% of patients underwent balloon angioplasty or restenting. However, 80% had again a PPG of > 12 mm Hg 1 year after reintervention. Hepatic encephalopathy developed in 31% of patients at 1 year; 21 of 23 patients had a PPG of < 12 mm Hg. CONCLUSIONS: Total protection from the risk of recurrent complications of portal hypertension after a TIPS procedure requires that the PPG be decreased and maintained < 12 mm Hg. However, reintervention will be required in most patients within 1 year and again the second year. On the other hand, such portal decompression is associated with an increased risk of hepatic encephalopathy.

Targeted inhibition of hepatitis C virus-directed gene expression in human hepatoma cell lines.

Year 1998
Wu CH. Wu GY.
Department of Medicine, University of Connecticut School of Medicine, Farmington, USA. wu@nso.uchc.edu
BACKGROUND & AIMS: The 5'-nontranslated region (NTR) of hepatitis C virus (HCV) contains important elements that control HCV translation. The aim of this study was to determine whether antisense oligonucleotides against the NTR of the HCV genome can be targeted to inhibit HCV gene expression. METHODS: Antisense oligonucleotides directed against a sequence in the internal ribosomal binding site of the NTR (anti-III) and a portion of the NTR overlapping the core protein translational start site of HCV (anti-IV) were prepared. In transient transfections of a plasmid containing a luciferase gene immediately downstream from an HCV NTR insert, oligonucleotides anti-III and anti-IV in the form of asialoglycoprotein-polylysine complexes were administered to Huh7 cells, and luciferase activity generated by cytomegalovirus (CMV) HCVluc was measured. RESULTS: Anti-III inhibited luciferase activity by 75% and 99% at 0.01 mumol/L and 0.1 mumol/L, respectively. Similarly, anti-IV inhibited luciferase activity 88% and 99% at 0.01 mumol/L and 0.1 mumol/L, respectively. In cell lines stably transfected with CMV HCVluc plasmid, complexed anti-III inhibited luciferase activity in Huh7 cells by 20% at 10 mumol/L and 85% at 60 mumol/L, and was competable by an excess of asialoglycoprotein. CONCLUSIONS: Antisense oligonucleotides that bind to the NTR of HCV can be targeted by receptor-mediated endocytosis, and they specifically inhibit HCV-directed protein synthesis under intracellular conditions.

Successful treatment of retractile mesenteritis with oral progesterone.

Year 1998
Mazure R. Fernandez Marty P. Niveloni S. Pedreira S. Vazquez H. Smecuol E. Kogan Z. Boerr L. Maurino E. Bai JC.
Clinical Department, Hospital de Gastroenterologia, Buenos Aires, Argentina.
Retractile mesenteritis is a rare inflammatory mesenteric disorder that involves the intestine secondarily. The natural history of this process is diverse, but most patients require some empiric therapeutic measures. Up to now, pharmacological therapy has included corticosteroids, colchicine, and immunosuppressive drugs. Although these drugs are successful in most patients, some have been refractory to these therapies and, in others, the beneficial effects were counterbalanced by adverse reactions. Many patients require surgery, but most have poor results. This report describes a 42-year-old man with histologically proven retractile mesenteritis refractory to surgical intervention who had a good response to oral progesterone (10 mg/day for 6 months) with complete disappearance of tumor mass and clinical symptoms. No adverse effects were detected. Current knowledge about the mechanism by which progesterone affects fibrogenesis is scanty. It seems likely that progesterone down-regulates proliferation and metabolism of fibroblasts and fibrogenesis.

Oral contraceptive use and smoking are risk factors for relapse in Crohns disease. The Canadian Mesalamine for Remission of Crohns Disease Study Group.

Year 1998
Timmer A. Sutherland LR. Martin F.
Department of Community Health Sciences, Univeristy of Calgary, Alberta, Canada.
BACKGROUND & AIMS: Lifestyle factors have been shown to influence prognosis in Crohn's disease. The purpose of this study was to prospectively assess the effects of smoking and oral contraceptive use on clinical relapse rates. METHODS: Placebo-treated patients formed a prospective cohort, followed up for 48 weeks or until relapse. The influence of smoking and the use of oral contraceptives on relapse risk was examined by life-table analysis (log rank tests) and Cox proportional hazards modeling, taking into account demographic and disease characteristics. RESULTS: Of 152 patients, 61 (40%) had a relapse. Univariate analysis showed unfavorable outcomes for women (P = 0.05), current smokers (P = 0.005), and use of oral contraceptives (P = 0.001). Recent surgery was associated with a decreased risk of relapse (P = 0.02). The Cox model retained current smoking vs. never smoking (hazard ratio, 2.1; 95% confidence interval, 1.1-4.2), oral contraceptive use (hazard ratio, 3.0; 95% confidence interval, 1.5-5.9), and medical compared with surgical induction of remission (hazard ratio, 2.1; 95% confidence interval, 1.0-4.2) as predictors of relapse. Ex-smokers did not have an increased risk. Finally, sex, age, time in remission, disease location, and disease duration were not significant predictors. CONCLUSIONS: Oral contraceptive use and smoking are associated with an increased risk of relapse in patients with Crohn's disease.

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