the efficacy, safety and tolerability of Antegren in patients with moderate to severely active CD. Methods: 244 patients with active CD (CDAI ->220 <450) were randomised to one of four treatment groups: a single 3mg/kg Antegren infusion; two 3mg/kg Antegren infusions at a 4-week interval; two 6mg/kg Antegren infusions at a 4-week interval; or placebo. The primary endpoint was remission (CDAI <150) 6 weeks after the start of treatment. Patients were followed up for 12 weeks following the first infusion and were additionally assessed for response (CDAI drop ->70 points) and changes in quality of life, as assessed by the Inflamma- tory Bowel Disease Questionnaire. Results: This is a study in progress, with all patients recruited, treated and data collected, though not fully analysed, at the time of submitting this abstract; all results will be available prior to May 2001. Funded by Elan Pharmaceuticals Inc., South San Fransisco, California, USA and Biogen, Boston, Massachusetts, USA.

683

Natural History of Helicobacter pylori infection from Infancy to Adullhood: A 21-year Follow-up Cohort Study Hoda M. Malaty, Baylor Coil of Medicine, Houston, TX; David Y. Graham, VA Medical Ctr, Houston, TX; Abdalla Elkasabany, Tulane Sch of Public Health, New Orleans, I_A; Sidd G. Reddy, Baylor Coil Of Medicine, Houston, TX; S R. Srinivasan, G S. Berenson, Tulana Sch of Public Health, New Orleans, LA

Aim:To examine H. pylori infection from infancy to young adulthood. Methods: A longitudinal cohort was selected retrospectively from a population followed over a 21-year period. 225 children (44% blacks, 51% females), first studied in 1975-76 at ages 1, 2, and 3 years were reexamined at intervals until 1995-96 as young adults. H. pylori status was assessed by presence of serum lUG H. pylori antibodies. Results: 8% of the cohort had H. pylori infection at ages 1-3. There was no association with age nor gender but there was a significant association with race (14% in blacks vs. 4% in whites, p = 0.008). By 18-20 years, the infection rate was 34% and remained significantly higher among blacks (p=O.O001) than whites, The seroconversion rates/year were 2% at ages 4-5, 2.3% at ages 7-9, 1.6% at ages 13-15, 1.3% at ages 18-20, and 0.8% at ages 21-23.40 (18%) of non-intestnd children at ages 1-3 became infected by ages 21-23. 45% of those who sero-convert became infected by ages 7-9, 27.5% at ages 13-15, 20% at ages 18-20, 7.5% at ages 21 to 23. The loss rate of infection (seroreversion rate) was the highest at ages 4-5 years, 2%/year vs. 1%/year at ages 21-23. Conclusions: Children were infected with H. pylod before age 2 and the infection persisted into young adulthood. The majority of the infections were acquired before the age 10. The highest rate of loss was before age 5. These findings suggest that treatment and preventive strategies must be aimed at children below the age of ten.

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The Natural History of H. pyleri (HP) Infection in Asymptomatin individuals: Should We Test and Treat Everyone? Ping Vaira, Dept of Internal Medicine and Gastroenterology, Bologna Italy; Massimo Rugge, Histopathology Unit, Padova Italy; Chiara Ricci, Dept of Internal Medicine, Bologna Italy; Valentina Russo, Hietopathology Unit, Padova Italy; Gioacchino Leandro, IRCCS, Castellana G Italy; Marcello Menegath, Dept of Internal Medicine, Bologna Italy; John Holton, Microbiology Unit, London United Kingdom; Luigi Gatta, Matin Miglioli, Dept of Internal Medicine, Bologna italy; Nimish Vakil, Univ of Wisconsin, Milwaukee, Wl

Background: The natural history of asymptomatic HP infection in Caucasian subjects is uncertain. Consequently there is uncertainty about whether eradication is worthwhile in asymp- tomatic individuals. Aim: To determine the outcome of persistent HP infection in asymptomatic subjects compared to subjects with successful eradication over a 10 year time frame. Methods: In 1990-2, 359 healthy blood donors agreed to undergo endoscopy and biopsy of whom 274 elected to undergo eradication therapy. In 2000, after a mean of follow-up of 8.5 years from the initial endoscopy, 146 donors agreed to be re-endoscoped with biopsies taken from antrum, corpus and fundus, culture, urease test. Results: Overall 73/146 donors were found to be eradicated; the table shows the incidence of intestinal metaplasia (IM) Over the follow- up period evaluated ulcer disease developed in 9 (12%, 8 duodenal, 1 gastric) and 1 (1%) gastric of infected and eradicated donors respectively. The odds ratio for IM development was 3.56 (95% CI 1.67-7.59) for HP positive donors compared to HP negative ones. Cag A positive strains were present in 17 of 26 (85%) HP positive subjects with IM. The odds ratio for the development of IM was 3.06 (95% CI 1.15-8.12) for HP + / CagA + donors compared to the HP +/Cag A - ones. Conclusion: 1. Over a 8.5 years-follow-up period HP + ve asymptomatic donors have a 3.5 fold increased risk of developing IM compared to HP- donors. 2. CagA positive strains are associated with a 3 fold increased risk of IM compared to Cag A negative strains. 3. The risk for developing ulcer disease is 1.5%/year in asymptomatic subjects. 3.These results support the need for eradication even in asymptomatic subjects.

Intestinal No Intestinal p value Metaplasia Metaplasi a

HP+ (n=73) 26 (36%) 47 (64%) p= 0.002 Fisher's exact test

HP-(n=73) 9 (12%) 64 (88%)

685

Transmission of 14. pylori infection: Study in Families of Preschool-aged Children from Minas Gerais, Brazil. Dulciene M M Oueiroz, Gifone A, Rocha, Adriana Santos, Ana C. Bocewicz, Andreia M C Rocha, Univ Fed de Minas Gerais, Belo Horizonte Brazil; Andrea Gazzinelli, Ctr de Pesquisa Rene Rachou, Belo Horizonte Brazil; Jeffrey Bethony, Southwest Fdn for Biomed Research, San Antonio, TX; Rodrigo C. Oliveira, Ctr de Pesquisa Rene Rachou, Belo Horizonte Brazil

Background: Several studies have demonstrated that family has an important role in the transmission of H. pylori. However, these studies have been done in developing countries and most of them have been limited by the small sample size. Therefore, we evaluated the

role of the family in the transmission of the infection among preschool-aged children living =n a rural area of the State of M~nas Gerais, Brazil. The population uses water with no treatment and lives in dwellings with no sewer network. The annual income was less than US$ 2,500.00 for 95% of the families studied. Subjects and Methods: Firstly, we determined the prevalence of the infection in 261 children and 395 adults (2 months to 97 yrs old). H. pylori infection in children > 12 yrs old and adults was evaluated by ELISA (Cobas-Core, Roche). In children < 12 yrs old the infection was diagnosed by 13C urea breath test (100% sensitive and 98% specific for our population, even for children < 3 yrs old). Sixty-six children < 8 yrs old and their families (63 mothers, 60 fathers and 139 siblings) were studied in order to determine the role of the family in the transmission of the infection. The oldest child in each family was considered the index case. Then, all children < 15 yrs old (n=91) and their famities were also evaluated (86 mothers, 83 fathers and 170 siblings). Odds ratios and 95% CI were estimated by logistic regression, controlling for age, gender, number of children in household and Hp status of fathers, mothers and siblings. Results: The prevalence of the infection was 68,7% (95 CI: 68.0%-72.2%) and it increased with age (p<107). The annual change in seroprevalence was 5.7%, 5.0% and 1.0% for persons < 5 yrs, 6-10 yrs, and 11-50 yrs old, respectively. It decreased to < 0.3% in persons ages 51-60 yrs and became negative in those over 60 yrs old. In the group of preschool children 47.0% were Hp positive and positive mothers were a strong and independent risk factor for infection (OR = 21.3, Ch 2.6-176.1). Positive siblings were also significantly and positively associated with infection (OR = 1.9, CI: 12-3.1). When all children were analysed, a positive and independent association was also observed between H. pylori infection (OR = 1.2, CI: 1.1-1.3). In both groups no association was observed between positive fathers and risk for infection. Conclusion: Concordance of infection status among mothers and offsprings as well as among siblings but not fathers is consistent with person to person transmission of H. pylori infection.

m

A Birth Cohort Study of the Sereepidemiologic Association of Hollcobactnr pylori Infection and Hepatitis A Virus in Rural Japan Hoda M. Malaty, Baylor Coil of Medicine, Houston, TX; Eiji Tanaka, Toshiko Kumagai, Hiroyoshi Ota, E T. Akamatsu, K Kiyosawa, Shinshu Univ Sch of Medicine, Matsumoto Japan; David Y. Graham, VA Medical Ctr, Houston, TX; Tsutomu Katsuyama, Shinshu Univ Sch of Medicine, Matsumoto Japan

Background: Recent studies have compared the seroepideimologic patterns of H. pylori and Hepatitis A vires (HAV) in attempts to establish the definitive mode of transmission of H. pylori infection. The aim of this study is to investigate the seroepidemiologic pattern of H. py/or/and Hepatitis A infection among the same individuals. Methods: We studied a cohort of Japanese children and adults residing in rural Japan whom monitored from 1986 to 1994. Each individual completed questionnaires and had repeated blood sampling./-/, py/ori status was assessed by the presence of anti-/-/, pylori lUG antibodies. Anti-HAV antibodies were assayed by ELISA. All subjects had at least two serum samples in successive years. We investigated the longitudinal changes of H. pylori infection over an 8-year follow-up period and we compared these changes to the HAV pattern. Results: The follow-up cohort consisted of 537 individuals; 73 children below the age of 20, and 464 adults. At study entry, the prevalence of Hpinfection was 87% among adults and 18% among children, and the prevalence of HAV was 81.5% among adults and 3% among children. Both infections increased parallel with age. The probability of coincidence of both infections in any single individual (i.e the concordance of the two infections) was 64%; 74% among adults and 7% among children. 76 individuals (14%) of the total population were seronegative for both infections. During the 8-year follow-up study, the seroconversion rates (e.g., the incidence of Hp infection) were 0.8% and 0.7% per year for children and adults, respectively, while there was no change in the seroprevalence of HAV. Of interest, 5 of the 7 individuals who acquired Hp infection during the follow-up period were seronegative for HAV. Conclusions: The discordance between H. pyloriand HAV seropositivity among the same individuals, especially children, is not consistent with a common source/route of transmission for both infections. Rather, the high rate of both infections among the same population is a marker for the level of sanitation and hygienic practices.

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The incidence of Hnlicobactor Pylori (lip) AcquisHion in Children of a Northern Manitoba Aboriginal Communily: Evidence for Parent-to-Child Transmission. Samir Sinha, Bruce Martin, Amin Kabani, Univ of Manitoba, Winnipeg Canada; Benjamin D. Gold, Emory Univ, Atlanta, GA; Qunsheng Song, Centers for Disease Control and Prevention, Atlanta, GA; Michael Sargent, Charles N. Bernetein, Univ of Manitoba, Winnipeg Canada

Background: We have previously reported that Wasagamack, an Aboriginal community in Northeastern Manitoba has a seroprevalence for Hp of 95% and that children ages 0-12 years have a stool antigen positivity rate of 56%. We aimed to determine the incidence rate of acquiring Hp among children who were negative by stool Ag testing in July, 1999. We further aimed to determine possible reservoirs of infection. Methods: There were 71 children who tested negative for Hp by ELISA stool antigen testing (provided by Meridien Diagnostics, and Oxoid). Fifteen children were not in the community, 4 had permanently moved and 2 died, leaving 50 (77%) available for restesting 1 year later, Stools were collected in 08/00 frozen and batch analyzed. In 07/99, there were 12 breastfeeding mothers on the community. Breast milk, urine, saliva and dental plaque were collected from these mothers. Water samples from water pails from 11 homes with children infected with Hp and from 12 homes with no infected children were collected and frozen. Berries and flies from the community were also collected and frozen. Samples were thawed, DNAs isolated and PCR performed using 2 sets of primers targeting at specific Hp genomic DNA. Results: Of 50 children 8(16%) became Hp positive. These included 5 who had no other siblings infected and 3 from families with infected siblings. All children infected had mothers positive for Hp. The ages of newly infected children were 1,1,2,3,7,B,9,13 yrs. No one age group had a greater likelihood of new infection. The only PCR positive results were from 1/11 water samples (from an infected home) and 2/12 saliva samples. Breast milk, urine, dental plaque, flies, berries were all negative. Conclusions These results indicate in a community with widespread Hp infection, overcrowded housing and

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primitive toileting, the incidence of childhood Hp acquisition was 16%/year. Since there was no apparent difference in infectivity rate depending on number of siblings infected it is probable that infection is being transmitted from mother to child. The positive PCR findings in the saliva may support this hypothesis. (Supported in part by Meddien Diagnostics and Astra Canada).

688

Helicobacter pylori in North and South America before Columbus: Studies of human migration Yoshio Yamaoka, VAMC and Baylor Coil of Medicine, Houston, TX; Oscar Gutierrez, Univ Nacional de Colombia, Bogota Colombia; Jong G. Kim, Guru Hosp and Korea Univ Coil of Medicine, Seoul South Korea; Tadashi Kodama, Kei Kashima, Kyoto Prefectural Univ of Medicine, Kyoto Japan; Michael S, Osato, VAMC and Baylor Cell of Medicine, Houston, TX; Francisco C. Ramieriz, VA Medical Ctr, Phoenix, AZ; David Y. Graham, VAMC and Baylor Coil of Medicine, Houston, TX

Background: It is still unknown whether Helicobacterpylori existed in the New World before Columbus. We sought to determine whether the H. pylori genomic structure could be used to provide information on migration of people into the Americas. Methods: 1,076 H. pylori isolates were obtained from gastric biopsies from adult patients or healthy volunteers in the US, Canada, Colombia, Brazil, South Nrica, Italy, France, Pakistan, Kazakhstan, Thailand, Vietnam, Hong Kong, Taiwan, Japan and Korea. Native New World populations included strains from Alaska, strains from a remote group living in the Colombian Amazon and 3 strains from Native North Americans from Arizona. vacA (s and m region) and cagA (5' and 3' region) were analyzed by PCR and sequencing. Results: East Asian and non-Asian strains were readily separated by vacA and cagA structure. For example, East Asian strains were predominantly of the vacAslc (95%) and mlb genotype (%of ml strains). All East Asian and non-Asian cagA positive strains could be identified as East Asian type or non-Asian type. Kazakh and Pakistani strains were predominantly of the non-Asian type cagA with a talc vacA genotype. Native Colombian strains possessed vacA and cagA genes that were more closely related to East Asian structures than to non-Asian structures. Three (15%) cagA negative Alaskan strains possessed vacA gene structures similar to East Asian strains. Three Native Alaskan strains had cagA and vacA structures identical to Kazakh strains. Conclusions: The finding of archaic Asian feature of H. pylori among Native Americans suggests that H. pylori was present in the New World prior to Columbus. The differences between strains from different areas suggests that H. pylori crossed the Bering Strait to the New World at different times.

689

CPT-11/Cisplatin Neoadjuvant Therapy Downstages Locally Advanced Gastric Cancer Elliot Newman, Stuart G. Marcus, Milan Potmesil, Howard Hochster, Herman Yee, Sa~jeev Sewak, Mary Hayek, Franco M. Muggia, NYU Sch of Medicine, New York, NY

We examined the role of neoadjuvant therapy in downstaging locally advanced gastric can- cer.METHODS.Preoperative staging was performed with a combination of CT scan, endoscopic ultrasound and/or laparoscopy and laparoscopic ultrasound. Patients with T3 and/or N1 disease were eligible for entry. Neoadjuvant therapy consisted of 2 cycles CPT-11 (75mg/m2) with Cisplatin (25mg/m2)weekly X 4 every 6 weeks, followed by resection with D2 lymph node dissection. RESULTS: 16 patients were entered (3 T3NO, 13 T3N1).One progressed to stage IV disease and did not come to surgery. 15 underwent surgery after completing 76%/69% of the intended induction chemotherapy (CPT-11/cisplatin). 1 patient had stage 4 disease (liver) and underwent a palliative resection. All 14 remaining patients had an RO resection (2 total, 6 distal and 6 proximal gastrectomies) with an average of 39 (1-121) lymph nodes retrieved. There was one postoperative mortality (pulmonary embolus). One patient had an anastamotic leak,4 patients suffered superficial wound infections and three patients required reoperation (1 leak, 1 gastric atony, 1 unexplained acidosis). The median postoperative length of stay was 9 days (range 3 to 75).Complete TNM pathologic staging was possible in 12/14 patients (2 had inadequate nodal sampling) as summarized in table below. 8/12 patients were downstaged compared to their original preoperative staging. At a median follow up of 12 months, mean survival is 20 months (median not reached) with 4 distant and 1 regional recurrences. CONCLUSIONS: CPT-11 based neoadjuvant therapy downstages disease as evi- denced by the greater percentage of early stage tumors seen after RO resection in these patients compared to their preoperative staging. Further follow up is necessary to determine the ultimate impact of this combination therapy on overall survival.(Supported in part by Pharmacia Oncology and grants NCI/NIH CA16087 and GCRC MO1RROOO96)

Postoperative TNM Staging

TNM IA IB II Ilia IIIB N n 2 4 2 2 1 1

690

Colonization-Dependent Expression Of inducible Nitric Oxide Synlhase By The Gastrointestinal Epithelium Michael Edward Mitchell, Richard C. Lyons, Ellen I. Closs, Mary Park, Cunningham M. James, Brigham and Women's Hosp, Boston, MA

Disruption of the gastrointestinal tract with bacterial contamination is responsible for a host of surgical conditions. The mechanisms responsible for bacterial resistance of the GI tract have not been fully elucidated. In other tissues, the bactericidal activity of activated macrophages is dependent in part upon expression of inducible nitric oxide synthase (iNOS), the enzyme that catalyzes the synthesis of nitric oxide (NO) from k-arginine and molecular oxygen. Several reports have identified iNOS expression in GI-derived epithelial cell lines, however, a systematic in vivo study of iNOS expression in the GI tract has not been performed. It is our hypothesis that iNOS plays a role in the GI mucosal barrier to bacterial and parasitic invasion. METHODS: To test this hypothesis, we examined the in vivo expression of iNOS in the GI tract of normal

baib/c, germ-free, and ~/-interferon - / - mice using RNAse protection and a sensitive in situ hybridization assay. RESULTS: iNOS expression was strongly localized to the epithelium of the GI tract. Increasing steady state levels of iNOS RNA were observed in each more distal segment of the GI tract of normal mice from the stomach (1X), duodenum (4.1X), jejunum (6.3X), caecum (9.1X), to the colon (10.5X), paralleling the degree of bacterial colonization. Consistent with our hypothesis, iNOS mRNA and enzyme activity were not detected in the GI tract of germ-free mice, but rapidly appeared after removal from the germ-free environment or injection with E. Coil LPS. Moreover, the pattern of iNOS expression in the GI tract of ~/- interferon - / - mice was not detectably changed compared to + /+ littermates. LPS- dependent induction of iNOS expression and production of NO in GI epithelial cells was confirmed usin9 the colon carcinoma-derived cell line, CMT-93. in addition to the GI epithelium, LPS-induced accumulation of iNOS mRNA was also observed in the epithelium covering the renal papilla and preferentially in the periportal region of hepatic Iobules. SUMMARY: iNOS is expressed by the GI epithelium of normal mice and the degree of expression throughout the GI tract parallels the degree of bacterial colonization. Furthermore, iNOS expression is absent in germ-free mice but is reinstated when these mice are removed from their germ- free environment or treated with LPS. These results are consistent with the hypothesis that nitric oxide produced by these tissues in response to bacterial colonization contributes to the barrier that prevents bacterial and parasitic invasion.

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Long-Term Survival After Esophagectomy For Barrett's Adenocarcinoma In Endoscopically Surveyed And Non-Surveyed Patients Mark K. Ferguson, Amy Durkin, Univ of Chicago, Chicago, IL

BACKGROUND: There is growing controversy over the cost-effectiveness of surveillance endoscopy for patients with Barrett's esophagus. METHODS: A retrospective review was performed of patients surviving resection for Barrett's adenocarcinoma to assess the influence of endoscopic surveillance on long-term survival. From 1980 to 2000, 69 patients (65 men, 4 women) aged 61.4 years (range 35-84) survived resection for Barrett's adenocarcinoma. Fifteen were initially diagnosed with benign Barrett's esophagus and were followed in an endoscopic surveillance program. The remaining 54 patients had the initial diagnosis of Barrett's esophagus made at the time of their cancer diagnosis. RESULTS: Patients in surveil- lance programs were younger (56 vs 63 yrs; p =0.06), experienced less preoperative weight loss (4.9 vs 12.0 Ibs; p=O.1), had better dysphagia scores (1.6 vs 2.3; p=O.O08), had a similar incidence of GERD symptoms (82% vs 69%), and did not undergo preoperative chemotherapy or radiotherapy. In contrast, 33% and 17% of non-surveillance patients had preoperative chemotherapy or radiation therapy, respectively. The surveillance group under- went transthoracic (73%) or transhiatal (27%) resection, while these resections were per- formed in 75% and 25%, respectively, of the non-surveillance group. Follow-up was complete in 67 (97%). Pathologic stage was 0 or I in 11/15 (73%) surveillance patients compared to 13/54 (24%) non-surveillance patients (p<O.O01). Median survival for surveillance patients was 104 mos compared to 13 mos for non-surveillance patients (p<O.O01). Weight loss (hazard ratio [HR] for 5 Ib loss = 1.19; 95% confidence interval [CI] = 1.02-1.39; p =0.34) and surveillance (HR = 3.08; CI = 0.90-10.54; p = 0.07) were predictors of survival (stratified by stage). CONCLUSIONS: Surveillance endoscopy permits early diagnosis of adenocarcinoma in Barrett's patients and contributes substantially to long-term survival. An initial screening endoscopy for patients with substantial GERD symptoms may be useful in decreasing the mortality from Barrett's adenocarcinoma by determining which patients should be entered into a surveillance program.

692

Rome II Diagnostic Criteria for Dyssynergic Defecation (Anismus)-Is H Valid? Satish Sc Rag, Ranjit S. Mudipalli, Kiersten Anderson, Mary Stessman, Univ of Iowa Hospitals and Clinics, Iowa City, IA

Background: About 50% of patients with chronic constipation have dyssynergic defecation. The Rome II criteda proposed that in addition to symptoms, patients must exhibit manometric, EMG, or radiologic evidence for inappropriate contraction or failure to relax the pelvic floor muscles; evidence for adequate propulsive forces and for incomplete evacuation. AIM: To examine the diagnostic yield of Rome li by performing anorectal manometry (ARM), balloon defecation (BO), colon transit study (CTS) and defecography in patients with difficult defecation. Methods: Sixty patients (M/F:17/43),who fulfilled Rome II criteria for constipation were evalu- ated and categorized as follows: ARM. A 6 sensor probe was placed to measure anal and rectal pressures during straining and to assess inappropriate rise or inadequate anal relaxation and propulsive forces; BD:ability to expel 50 cc water filled balloon-abnormal = -> 3min; CTS: 1 capsule(24 markers), 1 x-ray technique-abnormal = - 5 markers at 120 hrs; Defecogmphy. abnormal= retention of -> 50% contrast +_ poor rectal stripping. Results: ARM showed adequate propulsive force with inappropriate anal contraction in 27(45%) and failure to relax in 12(20%) patients. BD,CTS or defecography was abnormal in 38 (63%), 37(61%) and 18 (30%) patients respectively. Rome II criteria was fulfilled by 34/60(66%) patients; 34 had abnormal ARM, 27 abnormal BD, 23 abnormal CTS & 8 abnormal defecography. Of the remaining 26•60 patients, 13 had two abnormal tests (BD, CTS or defecography), 6 had three abnormal tests. Also, 20/26 had impaired propulsive force with inappropriate anal contraction, 5/26 had inappropriate contraction or failure to relax and 1 normal ARM. Conclusions: Rome ~l criteria underestimated this condition. It excluded 13/60(22%) patients with two or more abnormal defecation tests. Also an impaired propulsion was seen in 20•60 (33%) patients,many with other abnormal tests; a group also excluded. Because 75% of such patients improve with biofeedback (Dig Dis Sci 1977;2197-05), their exclusion seriously limits potential benefits. Hence, this group should be included in the diagnostic criteria for dyssynergic defecation. Incomplete evacuation is better assessed by either BD or CTS; defecography adds very little to the diagnostic yield. Our data suggests that abnormal manometry (including impaired propulsion) with either abnormal BO or CTS provides the best diagnostic yeild.

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