Long-term treatment with sulindac in familial adenomatous polyposis: A prospective cohort study

examinationwe could show that malignanttumors in cotton rats were neuroendocrine(chromogranin A immunoreactive) and more specifically ECL cell derived (hietidine decarboxylase immunoreactive and Sevier-Mungerpositive). Moreover, a substantial part of gastric carcinomas from man and especially those classified as diffuse according to Lauren, expressed markers compatiblewith neuroendocrine(chromogranin A), and more specifically of ECL cell (Sevier-Munger) origin. Whereasthe number of positive tumor cells were low in most carcinomas studied by conventional immunohistochemical reaction, the number of positive cells increased markedly when applying the tyramide signal amplification for the chromngranin A immunoitetection. CONCLUSION:ECLceils give rise to gastric carcinomasnot only in rodents, but also in man. 1307 Evaluation Of Flash Echo Imaging For Assessment Of Blood Pertuzioe in Gastric Cancer Hideharu Okanohu, Jiro Hata, Ken Haruma, Mutsunori Hara, Kenjiro Nakamura, Koji Futagami, Shunji Matsumura, Shigeto Yoshida, Hiroaki Kusunoki, Shinji Tanaka, Masaharu Yoshihara, KazuakiChayama,Hiroshima Univ Sch of Medicine, Hiroshima Japan BACKGROUND:We have reported the usefulness of the Flash Echo Imaging (FEI) which is the intermittent harmonic imaging under the administration of microbubble contrast agent (Levovist), as the non-invasive method for the assessment of gastric blood flow in vivo (Gastroenterology A475, 2000). The AIM of this study was to confirm the reliability of FEI for the assessment of blood perfusion in gastric cancer by comparing with tumor vessel densities of the resectedspecimens. PATIENTSAND METHODS:Ten patients with advancedstage of gastric cancer (6 men, 4 women) were enrolled in this study. FEI was performed .beforegastrectomyas previously reported. On the tumor image of the strongest enhancement in each FEI series, 5 range of interest was settled to decide the mean echo intensity of the tumor. The mean tumor vessel densities were decided by counting microveseel on 5 fields (400x) of CD34-stainedspecimens. RESULTS:As shown in Fig.l, a significant positive linear correlation was noted between the intensity of FEI and microveseel count in CD34 stained specimens (r2 = 0.889, P
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Utilization Of IV Ranitidine And IV Pantoprazole in The Intensive Care Unit Of A University Teaching Centre David G. Morgan, Ajay Jain, McMaster Univ, Hamilton Canada;Catherine 8ednarowski, Hamilton Health Science Corp, Hamilton Canada Ajay Jaid, David Morgan~, Catherine Bednarowski2. Divisions of Gastroenterology~and Pharmacy~, McMaster Univers~ and Hamilton Health Sciences Corporation, Hamilton, Ontario, Canada Aim: in intensive care unit (leO) patients at a University teaching hospifal to: (1) compare the utilization of IV Ranitidine (R) before and alter the release of IV Pantoprazole (P) and; (2) evaluatethe utilization and dosing regime of P (bolus [8] vs continuous infusion [I]). Background: In the ICU, clinically significant stress-ulcer related bleeding results in significant morbidity and mortality. H2-reeeptorantagonists are commonly used for stressulcer prophylaxis. Who needsto be treated and with what is still debated.There is little data examiningthe utilization of proton-pump inhibitors in an ICU setting. Methods: Retrospective review identifying the number of ICU patients and the number of treatment days for R between May 1998 and April 1999 (Period 1) and; R and/or P between May 1999 and April 2000 (Period 2). Data was extractedfrom hospital computerizedpharmacy records. Results: R was administered in doses of 50rag 00, 50rag BID, or 50mg TID. P in its bolus form was given in doses of 40rag 00, 40rag BID, or 80rag 00; and as a continuous infusion in doses of 4mg/hr or 8rag/fir. There was a reduction in the utilization of R between Period 1 (612 days for 83 patients; 9.71 days/pt) and Pedod 2 (417 days for 56 patients; 7.44 days/pt). This difference was attributed to the use of P (285 days for 22 patients; 12.95 days/pt). During Period 2, the use of P compared with R was significantly greater (p = 0.027). Of the 285 day utilization of P, 240 days (22 patients; 10.91 days/pt) was administered as B; and 45 days (6 patients; 7.5 days/pt) as I (p = 0.05). Of the six patients that received continuous infusion P, all were used for presumed upper gastrointestinal bleeding.The approximatecost ($CDN) associated with the use of R was $3176.28 during Period 1, and during Period 2, $2164.23. The approximate total cost of P during Period 2 was $9658.50 (B - $6576.00). Conclusion: Sincethe releaseof IV Pantoprazole,the utilization of IV Ranitidinein ICU patients has been reduced. The majority of patients received P as a bolus. The number of days of use of I, P was greater than the suggested dosing for upper gastrointestinal bleeding (7.5 days vs 3.0 days). The implementation of educationaland managementguidelines in the use of R and P will result in more appropriate utilization and cost savings.

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Bolullmim To=in Injection and Surgical Crico-Myotomyfor Oro-Phawngeai OysPha8ia: Pvelimiiary Results of a Phase-II Study. Marie Costantini, Giovanni 7.aninotto, Rosario Marchese Ragona, Marco Ferraro, ChJara Briani, Lie Zanetti, Giorgio Rosa, GiusappePortale, Michela Costantino, Univ of Padua, Padua Italy

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1308 Application of Blood Levels of Gastrin-17, Pepsinooos I and H.pylori Antibodyfor NoneodoscopicDiagnosis of Atrophic Gastritis Pentti Sipponen, Tiina Maki, Paivi Ranta, Jorvi Hosp, Espoo Finland; Auli Linnala, 8iohit PIc, Helsinki Finland; Ilpo Keariainen,Titan Helske, Jorvi Hosp, Espoo Finland; Osmo Suovaniemi, 8iohit PIc, Helsinki Finland; Matti Harkonen, Helsinki Univ, Heisinki Finland Background: Endoscopy and biopsies are needed for diagnosis of atrophic gastritis in the antrum and corpus. Low serum levels of pepsinogen I (PGI) are used as a nonendoscopic test for atrophic corpus gastritis but nonendoscopic diagnosis of atrophic antrum gastritis has not been possible, so far. Objectives: The aim was to study whether the test panel composed of Elisa assays of serum PGI, gastrin-17 (G-17) after a prandial protein stimulus, and H.pylori antibodies (106) can be used as a tool for diagnosis of atrophic gastritis in the corpus and/or antrum. Methods: The study population consisted of 94 selectedpatients who underwent gastroscopy for dyspeptic symptoms in Jorvi Hospital. The results of the test panel were compared with the clinical and pathological diagnoses obtained from endoscopy and biopsies from the antrum and corpus (at least two from each compartment). PGI and 6-17 were determined by highly specific monoclonal antibodies based on immunoassaytest (Biohit PIc, Finland). Results:The new 6-17 test was highly specific and detectedonly amidated and glycine extendedG-17 without any cross,reactivity with other gasifies or relatedpopfides. As compared with histology, G-17 assay showed 92% and 88% sensitivity and specificity, respectively, in the diagnosis of advanced (moderate or severe) atrophic antrum gastritis. The correspondingvaluesfor PGI in atrophic corpus gastritis were 90% and 92%, respectively. The overall results obtained by the test panel and endoscopy agreed in 80% (75 of 94) of the cases. Of the 56 patients with endoscopic atrophic antrum or coq}us gastritis, 50 (89%) could be diagnosed with the present test panel. In the 38 cases without advancedatrophic antrum or corpus gastritis clinically, the test panel gave a positive result in three (8%) cases. Conclusions: The new blood test panel is a convenient and reliable tool in nonendoscopic diagnosis of gastritis and atrophic gastritis, and applicable for assessment of risk states of gastric cancer and peptic ulcer disease.

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BACKGROUND:Oropharyngealdysphagia (OPD) is a very disabilitating problem for patients with neurologicaldisorders. Its therapy is mainly basedon rehabilitativemeasuresand, often, non-oral feeding (gastrostomy, N-G tube) is the only possible treatment. Cricomyotomy has been used in selectedcases wh'h conflicting results and, recently, injection of Botulinum toxin (BUT) into the cricopharyngealmuscle has beensuggested.In order to evaluatethe indication, efficacy and adverse effects of these procedures on patients with OPD of neurological origin we started this phase II study. METHODS:From June 1999 to date we enrolled 9 patients with severe OPD (9 m, 1 f, median age 65 years, r.: 21-79) of different origin (4 stroke, 1 trauma, 1 post CNS surgery, 1 diabetic neuropathy, 1 post vascular surgery, 1 idiopathic). The mediantime from the insult was 7 months. Sevenpatientswere fed through a gastrostomy and 4 had a tracheostomy. The patients underwent careful neurological, rehabilitative and ENT evaluation,videofluorographyand high fidelity manometfy. In all, rehabilitativetreatment proved to be uneftective,and therefore underwent percutaneousinjections of BuT A (10 units) into the cricopharyngealmuscle, previously identifiedwith EMG.Six patients had one session, 3 had 2 consecutivesessions. RESULTS:No complications were recorded.A good result was obtained in 3 cases (flu 18, 10 & 8 mos.). The other 6 patients underwent surgical cricomyotomy: only one responded to this treatment with satisfactory outcome (f/u: 12 rags.), whereas the other 5 did not improve, in spite of complimentary continuous rehabilitative treatment. Only 1 patient with a central damage respondedto therapy, whereas all the noncentral patients had a satisfactory outcome (p<.05). The duration of symptoms and the sever~ of videofluorographic alteration of swallowing did not differ between patients with good or poor result, even if an intact oral phase of swallowing was more frequent in patients with good outcome (p = .08). Finally, severe manometric alterations were associated to a poor outcome (p<.05). CONCLUSIONS:BuT injections of cdcopharyngealmuscle may play a role in the treatment of patients with OPD of neurological origin. However,the treatment seems to be more effective in patientswithout CNS damageand severefunction involvement. Patients who do not respond to BuT treatment are unlike to respond to surgical myotomy. 1311 Long-Term Treatment with Sulindac in Familial AdenomatousPolyposis:A Prospective Cohort Study. Marcia R. Cruz-Correa, Linda M. Hylind, Ketharine E. Romans, Susan V. Booker, Francis M. Giardiello, Johns Hopkins Univ, Baltimore, MD Background: Treatment of patients with familial adenomatous polyposis (FAP) can consist on colectomy with ileorectal anastomosis (IRA). Sulindac, a non-steroidal anti-inflammatory drug, inducesregressionof colorectaladenomasin the retainedrectal segmentof FAP patients, although long-term effects of this therapy are not fully understood. Therefore, we evaluated the long-term effectivenessand toxicity of sulindac in maintaining patients with retained rectal segments free of rectal adenomas. Methods: Twelve FAP patients (5 females; mean age 37.1 yrs, range 21.5-53.8 yrs) with IRA received sulindac (mean 158 mg/day, range 69-238 mg) for a mean period of 63.4 +_ 31.3 months (range 14-98 months). Number, size, and histologic grade of polyps, side effects, and compliance were assessed every 4 months. The sign test and Wiicoxon sign-rank test were used to estimate the difference in polyp number and

histologic grade respectively,at one year and at last follow-up. Results:A significant regression of polyp number (baseline mean 28.9 _+ 26.2 SD) was observed in all patients at 12 months (6.8 _+ 10.g polyps)(p=O.039) and at a mean of 63.4 _+ 31.3 months (8.3 _+ 14.4 polyps) (p = 0.006). Preventionof recurrenceof higher-gradeadenomas(tubulovillous, villous adenomas) was also observed (p = 0.004). Compliancewith drug treatment was excellent:patients took 86% of schedule doses. The most common side effects were: rectal mucosal erosions in 6 (50%), and nausea/dyspepsiain 2 (17%) patients. Five of 12 patients (42%) were withdraw from the study after a mean follow-up time of 44 _+ 28 (range 14-89) months: 1 patient developedrectal cancer, 2 had progression of histology and/or number of polyps, 1 developedrectal refractory erosions, and 1 had poor compliance.There were no statistically significant differences in follow-up time, compliance,or mean sulindac dose betweenthe FAP patientswithdrawn and those not withdrawn from the trial. Conclusions:In the longest followup study to date,sulindacappearsto be effective in reducing numberand preventingrecurrence of higher-gradeadenomasin most FAP patients treated. Erosions at the IR anastomosis site can preclude adequatedose maintenance.Acknowledgements:Supported by grants from the Clayton Fund, Rangos Fund, Merck Company, NIH grant CA 53801 and NIH Training Grant (2"1"32DK07632-11).

Drug/Diet No drug/Tunaoil Sulindac/Tunaoil No drug/Cornoil Sullndac/Cornoil

Total ACF 180±23 153±15 144±19 121±13

Large ACF 50.8+8.0 39±4.9 31_+5.9 24±4.5

PGE2 2.9ng/rnl+.8 2.6ng/ml±.3 5.4ng/ml±.7 2.9ng/ml±.4

Confidenceintervals+/- 1 SEM

1314 R-Flurbiprotea Continues to Inhibit Colorectal Tumourigenesis in Azoxymethane Treated Rats When Given After Initiation Jonathan Ed Martin, Graeme P. Young, Robert James, Ying Hu, Flinders Medical Ctr, Bedford Park Australia

1312 Primary Chemopreveetion of Familial Adenomatous Polyposis: Stratification of Clinical Response to Sulindac by Mucosal Prostanoid Levels Vincent W. Yang, Robert A. Casero, Deborah E. Geiman, Walter C. Hubbard, Linda M. Hylind, Francis M. Giardiello, Johns Hopkins Univ, Baltimore, MD BACKGROUND:Previousstudies indicate that nonsteroidalantiinflammatory drugs (NSAIDs) cause regression of colorectal adenomas in patients afflicted by the autosomal dominant disorder, familial adenomatous polyposis (FAP). However, no studies have been conducted to assessthe effect of NSAIDsin preventingthe onset of polyposis in FAP.AIMS: To evaluate the efficacy of sulindac, an NSAiD, in preventing onset of polyposis and to identify suitable biomarkers with which to monitor its efficacy in FAP. METHODS:Forty one presymptomatic FAP patients were randomizedin a double-blind fashion to take placebo or sulindac daily for 4 years. The number and size of adenomas were evaluatedevery 4 months. Biopsies were obtainedfrom the normal-appearingrectal mucosaand analyzedfor prostanoidand polyamine content, and ornithine decarboxylase(ODC) activity at baseline, 4 months and then yearly. RESULTS:As seen in an accompanyingabstract, treatment with sulindac did not result in a statistically significant difference in the development of adenomas compared to placebo at the conclusion of the trial. The baseline mucosal prostanoid and polyamine levels, and ODC activities were not significantly different betweenplacebo- and sulindac-treatedgroups. Treatment with sulindac resulted in a statistically significant reduction in the mean levels of all 5 prostanoids measured [PGD2, PGE2, PGF2a,thromboxane (Tx) B2, and 6ketoPGFla] but not in polyaminelevels or ODC activities comparedto the placebogroup over the course of 4 years. Of 21 patients receiving sulindac, 9 developedadenomas (characterizedas nonresponders) and 12 did not (rssponders). When prostanoids were compared between the non-respondersand responders,the levelsof 3 (PGD2,TxB2and 6katoPGFla)of 5 prostanoids were significantly lower (p < 0.05) in the later group. The mean levels of PGE2and PGF2a were also lower in the responders but did not reach statistical significance (p = 0.12). No such difference was observedfor polyamine levels or ODC activity. CONCLUSIONS:Although sulindac did not prevent the onset of polyposis in this trial, there may exist a subset of patients in whom sulindac may be effective.This clinical responseis accompaniedby a greater reduction in the levels of several mucosal prostanoids but not in polyamines or ODC activity. Mucosal prostanoids in patients receiving sulindac-mediated chemoprevention may be an excellent biomarker in predicting the efficacy of the treatment.

1313

Background:The R enantiomer of the of non-steroidal anti-inflammatory drug (NSAID) flurbiprofen does not inhibit cyclooxygenase(COX). We have previously shown that it suppresses aberrantcrypt loci (ACF)in rats, in an azoxymathane(AOM) model of coloractaltumourigenesis (CRT) when given during initiation. However, NSAIDs have been shown to inhibit growth of neoplastic lesions in the colon when given after initiation. Becauseof the long delay between initiating events and colorsctal cancer, this characteristic may be crucial in their effectiveness in preventing CRT in humans. We aimed to study the effects of R-fluthiprofen on CRT in AOM rats when given after initiation. Methods:2 Groups of 15 rats were fed an AIN diet containing 20% fat. ADM was given at 15mg/kg in two doses 1 week apart. R-flurbiprofen was given at 30mg/kg/day by garage 6 days/week,starting 1 week after AOM. Animals were killed 8 weeks later. The colon was fixed and stained with 0.1% methylene blue to identify ACF. Colons were also stained with high iron diarnine/alcian blue to identify those ACF containing non-sulphated mucin, present in the more dysplastic and advancedlesions. Numbers of total and large (>3 crypts/focus) ACF were counted. Results were compared with our previous study where R-tiurbiprofen was commenced 1 week prior to carcinogen and rats were killed at the same time post carcinogen. PGE2production was measuredin cultured colonic explants by radio-immuno-assay. Results: There was a trend toward rats given Rflurbiprofen after carcinogen having fewer total ACF than controls (mean ACF count of 83.7 _+ 8% SEM of controls,p=.18). When given during initiation, in our previous study, Rflurfiiprofen reduced total ACF to 72.3 _+ 5% of controls (p<.g5). The difference in the reduction in ACFbetweenthe two studies was not significant. Large ACF (>3 crypts) staining for non-sulphated mucin were reduced by R-flurbiprofen given post-initiation to 60 -+8% of controls(p<.g5). PGE2 production was 2.5 -+ .4ng/ml for controls and 1.8 -+.4ng/mi for Rflurbiprofen (differencenot significant). R-flurbiprofen rats had less weight gain than controls, suggesting some toxicity (261g _+ 7.8 SEM compared with 302g _+13.4 controls, p<.01). Rats remained well during the study. Conclusions: R-fiurbiprofen continuss to suppress CRT as measured by the numbers of large ACF with dysplastic mucin when given after initiation. This study confirms that there are alternative pathways for suppressing CRT other than COX inhibition.

1315 Both EpHhelial And Stromal Cells Expression Of Cyclo-Oxygenase-2 Protein Are Associated With Dysplasia In Colorectal Adenemas. Robert Benamouzig,Elisabeth Longchampt, Laire Olazabal,HeleneYoon, Antoine Martin, Thierry Coste, Hosp Avicenne, Bobigny France; Daniel Couturier, Stanislas Chaussade, Apacc Study Group, Hosp Cochin, Paris France Cyclo-oxygenase-2(COX-2)protein expressionis observedin coloractalneoplasms.The extent and distribution of COX-2 expression in epithelial and/or stmmal cells as well as the exact nature of these stromal cells remains debated.The purpose of this study was (1) to quantify COX-2 protein in colorectal adenomasepithelial and stromal cells and (2) to characterizethe nature of these COX-2 positive stromal cells. Material and Methods: 344 adenomas were obtainedfrom the 184 first consecutivepatients (age 60_+9years) included in a large prospective multi-center randomizedstudy aimed to evaluatethe effect of long term daily use of low dose aspirin in reducing the occurrence of new adenomatous polyps. All patients have had colonoscopyto the caecum with adequatepreparation resulting in clearanceof either a single adenoma >10 mm in size or 3 adenomas of any size. All biopsy specimens were blindly assessedfor architectural pattern and dysplasiaby 2 independentpathologists. Immunohistochemistry was carried out on formalin-fixed paraffin-embeddedsections with specific antiCOX-2, anti-P53, anti-b-catenin and anti-P21 antibodies. Staining intensity were scored 0-3 by two blinded independentobservers. Results: An high to moderate expressionof COX-2 in epithelial and superficial stromal cells was observed in 33 and 55% of the adenomas(score 2 and 3), respectively.COX-2epithelial cells staining was heterogeneousboth betweencrypts and inside a crypt. Epithelial and superficial stromal cells COX-2 expression were correlated (p
Lack of Interaction of Sulindac and n-3 Fatty Acids in Their Effects on Colo-Rectal Tumeurigenesis Jonathan Ed Martin, Graeme P. Young, Robert James, Ying Ru, Richard Le Leu, Rinders Medical Ctr, Bedford Park Australia Background: Non-steroidal anti-inflammatory drugs(NSAIDs) and omega 3 polyunsaturated fatty acids(n-3 PUFAs), in fish oil, are protective against colorsctal tumourigeneais (CRT). NSAIDsinhibit cyclooxygenase(COX)as do n-3 PUFAs.n-6 PUFAs,found in corn oil, enhance COX activity. Using the azoxymethane(AOM) model of CRT in rats we aimed to study the interaction of the effect of these agents on CRT and the importance of COX inhibition in that interaction. Methods: Groups of 15 Sprague-Dawleyrats were put on an AIN diet curtaining 20 % fat and drug by gavage. The diet contained 20% corn oil or 6% tuna oil/14 % olive oil. Sulindac was given at 20mg/kg/day. At 1 and 2 weeks, AOM was given at a dose of 15mg/kg. Animals were killed 12 weekslater. PGE2production was measuredby radioimmunoassay in media from standardisedcultured colonic explants. Colons were fixed and stained with 0.1% methylene blue and examined for ACF. ACF with > 3 crypts were recorded as large ACF. Results: Tuna oil and sulindac suppressedproduction of PGE2(p
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