Abstracts der ausgewählten Beiträge der Referenten

Inhaltsverzeichnis

Ösophagus/Magen/Duodenum....................................................................................3

Reflux.......................................................................................................................3Barrett...................................................................................................................... 7Helicobacter/Dyspepsie..........................................................................................20

Leber..........................................................................................................................28

Virushepatitis..........................................................................................................28NASH / ASH / Autoimmun......................................................................................40Portale Hypertension..............................................................................................43

Darmerkrankungen/Pankreas....................................................................................50

CED: Neue Substanzen.........................................................................................50Genetik und Immunologie......................................................................................59Pankreatitis / ERCP-Themen.................................................................................64IBS......................................................................................................................... 71

Onkologie / Ernährung...............................................................................................77

Koloskopie / Screening...........................................................................................77Onkologie GI-Trakt.................................................................................................88Onkologie hepatobiliär und Pankreas....................................................................95Ernährung............................................................................................................101

Thema direkt ansteuern: STRG + Anklicken

Ösophagus/Magen/DuodenumReflux W. Voderholzer

1. Abstracts von Originalarbeiten

Gastroenterology. 2005 Mar;128(3):532-40.

Nonresorbable copolymer implantation for gastroesophageal reflux disease: a randomized sham-controlled multicenter trial.

Deviere J, Costamagna G, Neuhaus H, Voderholzer W, Louis H, Tringali A, Marchese M, Fiedler T, Darb-Esfahani P, Schumacher B.

Service de Gastro-Enterologie et d'Hepato-Pancreatologie, Universite Libre de Bruxelles, Hopital Erasme, Brussels, Belgium. jdeviere@ulb.ac.be

BACKGROUND & AIMS: This aim was to determine whether endoscopic implantation of a biocompatible nonresorbable copolymer (Enteryx; Boston Scientific Corp, Natick, MA) is a more effective therapy for gastroesophageal reflux disease (GERD) than a sham procedure. METHODS: In a randomized, single-blind, prospective, multicenter clinical trial, 64 patients with GERD were enrolled whose symptoms were well controlled by proton pump inhibitor (PPI) therapy and rapidly recurred after cessation of PPI therapy. Thirty-two patients were assigned to Enteryx implantation and 32 to a sham procedure consisting of standard upper endoscopy. Patients in both groups with unsatisfactory symptom relief after 3 months were eligible for re-treatment by Enteryx implantation. The primary study end point was > or =50% reduction in PPI use. Secondary end points included > or =50% improvement in GERD score and the proportion of patients not undergoing re-treatment procedure. Follow-up evaluations were performed at 3 and 6 months. RESULTS: The percentage of Enteryx-treated patients achieving a > or =50% reduction in PPI use (81%) was greater than that of the sham group (53%), with a rate ratio of 1.52 (confidence interval [CI], 1.06-2.28; P=.023). A higher proportion of the Enteryx (68%) than sham group (41%) ceased PPI use completely (rate ratio, 1.67; CI, 1.03-2.80; P=.033). GERD health-related quality of life heartburn score improvement > or =50% was achieved by 67% of the Enteryx group versus 22% of the sham group (rate ratio, 3.05; CI, 1.55-6.33; P <.001). More Enteryx-treated (81%) than sham-treated (19%) patients did not undergo re-treatment (rate ratio, 4.33; CI, 2.23-9.29; P <.001). CONCLUSIONS: Enteryx implantation more effectively reduces PPI dependency and alleviates GERD symptoms than a sham procedure.

Am J Gastroenterol. 2004 Dec;99(12):2317-23.

Characteristics and clinical relevance of proximal esophageal pH monitoring.

Cool M, Poelmans J, Feenstra L, Tack J.

Department of Medicine, Division of Gastroenterology, University Hospitals Leuven, Belgium.

OBJECTIVE: It is well established that various ENT disorders and symptoms may be a manifestation of gastroesophageal reflux disease (GERD). Measuring proximal esophageal acid exposure might be useful in the evaluation of patients with suspected reflux-related ENT manifestations, but the limited available data are conflicting. The aim of the present study was to study the determinants of proximal esophageal acid exposure (PR) and to evaluate the clinical usefulness of ambulatory proximal pH monitoring. METHODS: Twenty healthy controls and 346 patients with suspected reflux disease underwent typical and atypical GERD symptom assessment, endoscopy, esophageal manometry and ambulatory combined dual esophageal pH, and Bilitec duodeno-gastro-esophageal reflux exposure (DGER) monitoring. The presence of pathological PR and its relation to symptom pattern and distal esophageal acid exposure (DR) and DGER exposure were analyzed. RESULTS: Fifty-seven patients (16%) had pathological PR. Demographic characteristics, symptom pattern, and manometric findings did not differ in patients with normal or pathological PR. Patients with pathological PR had significantly higher DR and DGER. The multivariate analysis identified only pathological DR as an independent risk factor for the presence of pathological PR (odds ratio 4.515, 95% CI 2.48-8.23, p < 0.0001). Only 20 patients (6%) had pathological proximal reflux without pathological distal acid reflux. CONCLUSION: The findings of the present article do not support routine proximal esophageal pH monitoring as a clinical tool: PR does not differentiate patients with typical or atypical GERD manifestations and depends mainly on DR.

2. DDW AbstractsDDW Abstract T1692-Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A531. Disclosures: Organization - Astra Zeneca, Sweeden, Relationship - Grant / Research Support Baclofen Reduces Weakly Acidic Reflux in Ambulant Patients With GERD D. Sifrim, J. Tack, J. Arts, P. Caenepeel, X. Zhang, J. Silny, H. Rydholm, J. Janssens Weakly acidic gastroesophageal reflux (pH drop between 7-4) might be associated with persisting symptoms in patients with GERD “on” PPI, and also with chronic cough in adults or cardio-respiratory events in infants. Treatment with PPI does not affect significantly weakly acidic reflux. By reducing TLESRs, baclofen decreases acid reflux in patients with GERD and bile reflux in patients refractory to PPI. Baclofen can also reduce postprandial weakly acidic reflux in patients with GERD studied in stationary recumbent position. However, most weakly acidic reflux occurs during daytime in upright ambulant conditions. We aimed to assess the effect of baclofen on total, acid and weakly acidic reflux in ambulant GERD patients. Methods: In a double blind, randomized, placebo controlled, cross-over designed study, 24h ambulatory ph-impedance monitoring, endoscopy and symptoms assessment were performed in 15 patients with GERD “off” PPI therapy [5 men, 55 years (27-73)] before and after 4 weeks of treatment with placebo or Baclofen 20 mg (t.i.d). At inclusion, patients had NERD (n=6), esophagitis gradeA (n=7) esophagitis gradeB (n=2). 8 patients had HH. Reflux was classified as acid (pH drop below 4), weakly acidic (nadir pH between 4 and 7) and weakly alkaline (impedance drops without pH change below 7). Results: Baclofen reduced the 24h total number of reflux events by 38%, acid reflux by 46% and weakly acidic reflux by 28%. The main effect was observed in upright position and during the postprandial periods (43%, 44% and 33% reduction, respectively, p< 0.05). Baclofen did not modify supine reflux. Baclofen reduced, but not significantly, 24h esophageal acid exposure (7.5±1.4 vs. 5.5±0.9) and did not affect the air-liquid composition or the proximal extent of reflux. Esophagitis was healed in 4/9 patients and scores for the most severe symptom were improved in 10/15 patients. Conclusion: The total number of reflux episodes (acid and weakly acidic) can be reduced by baclofen in ambulant patients with GERD “off” PPI. Outcome studies from adult patients with persisting symptoms “on” PPI or chronic cough as well as from infants with cardio-respiratory events are required to establish the clinical usefulness of pharmachological reduction of weakly acidic reflux in GERD. * p<0.05

total reflux acid weakly acidic

Weakly alkaline

all reflux pH>4

24hs 61±7 - 41±6*

30±5 - 18±3*

24±3 - 19±4

7±4 - 3±1 31±5 - 22±4

upright 57±7 - 34±4*

28±5 - 15±2*

23±3 - 16±3*

6±3 - 4±1 29±4 - 19±3*

DDW Abstract 630- Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A95. Disclosures: None Does Surgical Fundoplication Improve Chronic Laryngeal Symptoms and Signs Unresponsive To Aggressive Medical Therapy? a Prospective Cohort Study. J.M. Swoger, C. Millstein, J.E. Richter, D. Hicks, J. Ponsky, M. Vaezi  Objective: In patients with persistent laryngeal symptoms despite aggressive PPI therapy, gastroesophageal reflux disease (GERD) continues to be implicated. Continued reflux of intermittent or low volume acid or non-acid gastric contents is suggested as the potential cause. Such suggestions implicate surgical fundoplication as the ultimate therapy for these unresponsive patients. However, there are no prospective studies assessing this contention. Methods: 72 patients with suspected GERD related laryngeal symptoms/signs were initially treated with BID PPI’s for 4 months. All had baseline manometry, 24-hour pH, Bilitec, and laryngoscopy, with repeat pH monitoring on therapy at 4-months. 4-month symptomatic non-responders (<50% improvement) with continued laryngeal “inflammation” and normalized esophageal acid exposure were offered laparoscopic Nissen Fundoplication. Post surgery, all underwent symptom assessment at 1, 3, 6, and 12 months; manometry and 24-hour pH at 3-months; laryngoscopy at 6- and 12months, and BRAVO pH monitoring at 12-months. Primary outcome of the study was symptom improvement/resolution at 12-months post-surgery. The outcome was then compared to the cohort who refused surgical fundoplication and continued on PPI therapy. Results: 26/72 (36%) patients (study cohort) remained unresponsive to 4 months of aggressive PPI therapy. 10 patients (38%) agreed to undergo surgical fundoplication (mean age = 51.1, M= 4) and 16 patients (62%) did not (mean age = 50.6, M=4). The most common laryngeal symptoms were sore throat, hoarseness, and cough. Symptom severity (0-5) did not differ between groups (3.5 vs. 3.53). pH studies at 3-months and at 12-months were normal in all patients post fundoplication (mean % time pH < 4 = 0.27%, 0.34%; respectively). 1/10 (10%) of the surgical group reported improvement of their chronic laryngeal symptoms at 1 year compared to 1/16 of the control group (6.25%) (p= 1.0). Treatment of causes other than GERD (allergies or asthma) improved symptoms in 2/10 (20%) of the surgical group, and 10/16 (62%) non-surgical cohort (p= 0.1).Conclusions: 1) Surgical fundoplication does not improve laryngeal symptoms in patients unresponsive to aggressive PPI therapy. 2) In this group, the argument of intermittent, low volume or non-acid reflux as the cause of persistent laryngeal symptoms needs to be replaced with evaluation and therapy for other non-GERD causes.

Barrett T. Rösch

1. Originalarbeiten

Gastroenterology. 2004 Jul;127(1):310-30.

A critical review of the diagnosis and management of Barrett's esophagus: the AGA Chicago Workshop.

Sharma P, McQuaid K, Dent J, Fennerty MB, Sampliner R, Spechler S, Cameron A, Corley D, Falk G, Goldblum J, Hunter J, Jankowski J, Lundell L, Reid B, Shaheen NJ, Sonnenberg A, Wang K, Weinstein W; AGA Chicago Workshop.

University of Kansas School of Medicine and VA Medical Center, Kansas City, Missouri 64128-2295, USA. psharma@kumc.edu

BACKGROUND & AIMS: The diagnosis and management of Barrett's esophagus (BE) are controversial. We conducted a critical review of the literature in BE to provide guidance on clinically relevant issues. METHODS: A multidisciplinary group of 18 participants evaluated the strength and the grade of evidence for 42 statements pertaining to the diagnosis, screening, surveillance, and treatment of BE. Each member anonymously voted to accept or reject statements based on the strength of evidence and his own expert opinion. RESULTS: There was strong consensus on most statements for acceptance or rejection. Members rejected statements that screening for BE has been shown to improve mortality from adenocarcinoma or to be cost-effective. Contrary to published clinical guidelines, they did not feel that screening should be recommended for adults over age 50, regardless of age or duration of heartburn. Members were divided on whether surveillance prolongs survival, although the majority agreed that it detects curable neoplasia and can be cost-effective in selected patients. The majority did not feel that acid-reduction therapy reduces the risk of esophageal adenocarcinoma but did agree that nonsteroidal antiinflammatory drugs are associated with a cancer risk reduction and are of promising (but unproven) value. Participants rejected the notion that mucosal ablation with acid suppression prevents adenocarcinoma in BE but agreed that this may be an appropriate strategy in a subgroup of patients with high-grade dysplasia. CONCLUSIONS: Based on this review of BE, the opinions of workshop members on issues pertaining to screening and surveillance are at variance with published clinical guidelines.

Am J Gastroenterol. 2004 Nov;99(11):2107-14.

Identification of Barrett's esophagus in relatives by endoscopic screening.

Chak A, Faulx A, Kinnard M, Brock W, Willis J, Wiesner GL, Parrado AR, Goddard KA.

Division of Gastroenterology, Department of Medicine, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.

AIM: Familial aggregation of Barrett's esophagus and its associated cancers has been termed familial Barrett's esophagus (FBE). The aim of the study was to determine whether endoscopic screening would identify Barrett's esophagus (BE) in relatives of probands with BE or esophageal adenocarcinoma (EAC). METHODS: All living first-degree relatives of patients with long segment BE or EAC presenting to the endoscopy suite of two academic hospitals were sent validated questionnaires inquiring about gastroesophageal reflux symptoms and prior endoscopic evaluation. First-degree relatives of affected probands or affected relatives who reported no prior upper endoscopy were offered screening unsedated esophagoscopy. Relatives with chronic gastroesophageal reflux symptoms were also offered an alternative of conventional sedated upper endoscopy. The yield of screening endoscopy was measured. Screening endoscopy findings were then compared between family members of known FBE patients and those with "isolated" disease. RESULTS: One hundred and ninety-eight relatives from 69 families, 23 known FBE probands and 46 probands with apparently "isolated" disease, were enrolled. Forty relatives (29 FBE relatives and 11 relatives of probands with "isolated" disease) reported prior upper endoscopy. Screening upper endoscopies performed on 62 (25 FBE and 37 "isolated" disease relatives) of the remaining 158 relatives identified Barrett's epithelium in 13 (21%). Compared to probands with apparently "isolated" disease, Barrett's epithelium (EAC, BE, or SSBE) was identified significantly more often in siblings and offspring of FBE probands, p</= 0.05. Endoscopic screening of relatives of FBE probands identified a multigeneration multiplex FBE pedigree consistent with an autosomally dominant inherited trait. Endoscopic screening of relatives of probands with reported "isolated" diseased did not identify any new FBE pedigrees. CONCLUSIONS: Endoscopy identified EAC, long-segment BE, and short-segment BE in a substantial proportion of first-degree relatives of affected members of FBE families. A familial susceptibility to develop Barrett's epithelium appears to be present in a subset of patients with BE and EAC.

Gut. 2004 Oct;53(10):1402-7.

The Munich Barrett follow up study: suspicion of Barrett's oesophagus based on either endoscopy or histology only--what is the clinical significance?Meining A, Ott R, Becker I, Hahn S, Muhlen J, Werner M, Hofler H, Classen M, Heldwein W, Rosch T.Central Interdisciplinary, Endoscopy Unit, Department of Gastroenterology, Campus Virchow, Charite University Hospitals, Berlin, Germany. Thomas.Roesch@charite.de

BACKGROUND: The incidence of distal oesophageal adenocarcinoma is rising, with chronic reflux and Barrett's oesophagus being considered risk factors. Reliable detection of Barrett's oesophagus during upper endoscopy is therefore mandatory but requires both endoscopy and histology for confirmation. Appropriate management of patients with endoscopic suspicion but negative on histology, or vice versa, or of patients with no endoscopic suspicion but with a biopsy diagnosis of intestinal metaplasia at the gastro-oesophageal junction, has not yet been studied prospectively. PATIENTS AND METHODS: In a prospective multicentre study, 929 patients (51% male, mean age 50 years) referred for upper gastrointestinal endoscopy were included; 59% had reflux symptoms. The endoscopic aspect of the Z line and any suspicion of Barrett's oesophagus were noted, and biopsies were taken in all patients from the Z line (n = 4), gastric cardia (n = 2), and body and antrum (n = 2 each). Biopsies positive for specialised intestinal metaplasia (SIM) were reviewed by a reference pathologist for a final Barrett's oesophagus diagnosis. All patients with endoscopic and/or histological suspicion of Barrett's oesophagus were invited for a follow up endoscopy; the remaining cases (no endoscopic or histological suspicion of Barrett's oesophagus) were followed clinically. RESULTS: Of 235 patients positive for Barrett's oesophagus on endoscopy and/or histology, 63% agreed to undergo repeat endoscopy (mean follow up period 30.5 months). 46% of patients with an endoscopic Barrett's oesophagus diagnosis but no histological confirmation (group A) showed the same distribution, a further 42% did not have Barrett's oesophagus, and 11% had confirmed Barrett's oesophagus on both endoscopy and biopsy on follow up. In the group with a histological Barrett's oesophagus diagnosis but negative on initial endoscopy (group B), follow up showed the same in 26% whereas 46% had no Barrett's oesophagus, and confirmed Barrett's oesophagus (endoscopy plus histology) was diagnosed in 17%. Of the study population, 16 patients had Barrett's oesophagus on initial endoscopy confirmed by histology which remained constant in 70% at follow up (group C). Of the remaining patients without an initial Barrett's oesophagus diagnosis on either endoscopy or histology (group D) and only clinical follow up (mean follow up period 38 months), one confirmed Barrett's oesophagus case was found among 100 patients re-endoscoped outside of the study protocol. However, no single case of dysplasia or cancer of the distal oesophagus was detected in any patient during the study period. CONCLUSIONS: Even in a specialised gastroenterology setting, reproducibility of presumptive endoscopic or histological diagnoses of Barrett's oesophagus at follow up were poor. Only 10-20% of cases with either endoscopic or histological suspicion of Barrett's oesophagus had established Barrett's oesophagus after 2.5 years of follow up. The risk of dysplasia in this population was very low and hence meticulous follow up may not be required.

World J Gastroenterol. 2005 Feb 28;11(8):1182-6.

Long-term follow-up after complete ablation of Barrett's esophagus with argon plasma coagulation.

Madisch A, Miehlke S, Bayerdorffer E, Wiedemann B, Antos D, Sievert A, Vieth M, Stolte M, Schulz H.

Medical Department I, Technical University Hospital, Fetscherstr. 74, D-01307 Dresden, Germany. madisch@mk1.med.tu-dresden.de

AIM: To report the long-term outcome of patients after complete ablation of non-neoplastic Barrett's esophagus (BE) with respect to BE relapse and development of intraepithelial neoplasia or esophageal adenocarcinoma. METHODS: In 70 patients with histologically proven non-neoplastic BE, complete BE ablation was achieved by argon plasma coagulation (APC) and high-dose proton pump inhibitor therapy (120 mg omeprazole daily). Sixty-six patients (94.4%) underwent further surveillance endoscopy. At each surveillance endoscopy four-quadrant biopsies were taken from the neo-squamous epithelium at 2 cm intervals depending on the pre-treatment length of BE mucosa beginning at the neo-Z-line, and from any endoscopically suspicious lesion. RESULTS: The median follow-up of 66 patients was 51 mo (range 9-85 mo) giving a total of 280.5 patient years. A mean of 6 biopsies were taken during surveillance endoscopies. In 13 patients (19.7%) tongues or islands suspicious for BE were found during endoscopy. In 8 of these patients (12.1%) non-neoplastic BE relapse was confirmed histologically giving a histological relapse rate of 3% per year. In none of the patients, intraepithelial neoplasia nor an esophageal adenocarcinoma was detected. Logistic regression analysis identified endoscopic detection of islands or tongues as the only positive predictor of BE relapse (P = 0.0004). CONCLUSION: The long-term relapse rate of non-neoplastic BE following complete ablation with high-power APC is low (3% per year).

Endoscopy. 2004 Sep;36(9):782-7.

Circumferential endoscopic mucosal resection in Barrett's esophagus with high-grade intraepithelial neoplasia or mucosal cancer. Preliminary results in 21 patients.

Giovannini M, Bories E, Pesenti C, Moutardier V, Monges G, Danisi C, Lelong B, Delpero JR.

Endoscopic Unit, Institut Paoli-Calmettes, 232 Boulevard St-Marguerite, 13273 Marseilles Cedex 9, France.

BACKGROUND AND STUDY AIMS: Treatment by endoscopic mucosal resection (EMR) has been established for early lesions in Barrett's esophagus. However, the remaining Barrett's esophagus epithelium remains at risk of developing further lesions. The aim of this study was to evaluate the efficacy of circumferential endoscopic mucosectomy (circumferential EMR)s in removing not only the index lesion (high-grade intraepithelial neoplasia (HGIN) or mucosal cancer), but also the remaining Barrett's esophagus epithelium. PATIENTS AND METHODS: A total of 21 patients were included in the study (11 men, 10 women), who had Barrett's esophagus and either HGIN (n = 12) or mucosal cancer (n = 9). Of the patients, 17/21 were at high surgical risk and five had refused surgery. On the basis of preprocedure endosonography their lesions were classified as T1N0 (n = 19) or T0N0 (n = 2). The lesions and the Barrett's esophagus epithelium were removed by polypectomy after submucosal injection of 10-15 ml of saline; a double-channel endoscope was used in 15/21 cases. Circumferential EMR was performed in two sessions, the lesion and the surrounding half of the circumferential Barrett's esophagus mucosa being removed in the first session. In order to prevent the formation of esophageal stenosis, the second half of the Barrett's esophagus mucosa was resected 1 month later. RESULTS: Complications occurred in 4/21 patients (19 %), consisting of bleeding which was successfully managed by endoscopic hemostasis in all cases. No strictures were observed during follow-up (mean duration 18 months) and endoscopic resection was considered complete in 18/21 patients (86 %). For three patients, histological examination showed incomplete removal of tumor: one of these underwent surgery; two received chemoradiotherapy, and showed no evidence of residual tumor at 18 months' and 24 months' follow-up, respectively. Two patients in whom resection was initially classified as complete later presented with local recurrence and were treated again by EMR. Barrett's esophagus mucosa was completely replaced by squamous cell epithelium in 15/20 patients (75 %). CONCLUSIONS: Circumferential EMR is a noninvasive treatment of Barrett's esophagus with HGIN or mucosal cancer, with a low complication rate and good short-term clinical efficacy. Further studies should focus on long-term results and on technical improvements.

Gastrointest Endosc. 2003 Jun;57(7):854-9.

Circumferential EMR and complete removal of Barrett's epithelium: a new approach to management of Barrett's esophagus containing high-grade intraepithelial neoplasia and intramucosal carcinoma.

Seewald S, Akaraviputh T, Seitz U, Brand B, Groth S, Mendoza G, He X, Thonke F, Stolte M, Schroeder S, Soehendra N.

Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Germany.

BACKGROUND: There is no study of circumferential EMR in patients with Barrett's esophagus containing early stage malignant lesions. This study investigated the effectiveness and safety of circumferential EMR by using a simple snare technique without cap. METHOD: Patients with Barrett's esophagus containing multifocal high-grade intraepithelial neoplasia or intramucosal cancer, and patients with endoscopically nonidentifiable early stage malignant mucosal changes incidentally detected in random biopsy specimens were included in the study. A 30 x 50-mm polypectomy snare made of monofilament 0.4-mm steel wire was used without any additional device or submucosal injection. RESULTS: Twelve patients (10 men, 2 women; median age 63.5 years, range 43-88 years) underwent circumferential EMR; 5 had multifocal lesions, and 7 had no visible lesions. Segments of Barrett's epithelium were circumferential (median length 5 cm) and completely removed. The median number of EMR sessions was 2.5. The median number of snare resections per EMR session was 5. The medial total area of mucosa in resected specimens per session was 3.8 cm(2). Two patients developed strictures that were successfully treated by bougienage. Minor bleeding occurred during 4 of 31 EMR sessions. During a median follow-up of 9 months, no recurrence of Barrett's esophagus or malignancy was observed. CONCLUSIONS: Circumferential EMR with a simple snare technique is feasible, safe, and effective for complete removal of Barrett's epithelium with early stage malignant changes.

2. Kongreßabstracts DDW

DDW Abstract 644-Gastrointestsinal Endoscopy, 2005 Apr.;61(5):AB103

Does Barrett’s Esophagus Develop Over Time in Patients with Chronic GERD?

Lauren Gerson ; Julie Stoltey ; Nighat Ullah ; Peyman Sahbaie ; Harpreet Reeba

Background: Barrett’s esophagus (BE), a metaplastic change of the distal esophageal squamous mucosa to specialized intestinal metaplasia (IM), is present in approximately 8-20% of patients with chronic GERD undergoing upper endoscopy (EGD). Decision analytic models (Inadomi 2003) have assumed that 0.5% of GERD patients will develop new cases of BE per year. We performed a cohort study to determine the incidence of BE in patients with chronic GERD and normal index EGD.

Methods: We identified patients with GERD or BE between 1998-2004 by primary or secondary ICD-9 codes of 530.81 and/or 530.2.  Patients were eligible for study entry if 2 or more EGDs were performed at least 6 months apart. Patients were excluded if they underwent < 1 EGD, or 2 EGDs within < 6 months. BE was defined as the presence salmon-colored mucosa extending from the esophagogastric junction (EGJ) of at least 0.5 mm with IM on biopsy. We reviewed all primary endoscopy records and pathology reports in order to confirm IM and to distinguish SIM-EGJ from BE. In addition, we performed a retrospective analysis of BE patients who underwent index EGD at either institution.

Results:  We screened 5669 patients (10,047 data entries by ICD-9 code).  309 (6%) GERD patients and 125 (2%) BE patients who had at least 2 EGDs were enrolled. Five patients with erosive esophagitis on index EGD and BE detected on subsequent exam were excluded. The mean + SEM age of the GERD cohort was 60.6 + 0.85 (range 23-91), 30% were female, and 29% veterans. Most (238, 77%) of the patients were Caucasian, 25 (8%) were African-American, 18 (6%) Hispanic, and 28 (9%) Asian. The mean number of EGDs performed was 3.1 + 0.1 (range 2-15) over a mean number of 3.4 + 0.1 (range 0.5-12) years. Based upon a projected annual incidence of 0.5% new BE cases per year, we expected approximately 1.5 incident cases of BE per year, or a total of 5 new cases over the mean patient follow-up period. None of the patients with GERD and normal index EGD were found to develop BE. In addition, none of the 125 patients with BE were found to have normal distal esophageal biopsies on index EGD within a mean retrospective time period of 4.3 + 0.2 years.

Conclusions:  Patients with chronic GERD do not appear to develop Barrett’s esophagus over time if it is not present on the index endoscopy. Our results support the concept of “once in a lifetime” endoscopic screening for BE, however further prospective studies are indicated to confirm our results.

DDW Abstract S1762-Suppl. to Gastroenterol.2, 2005 April; 128(4):A251

High-Resolution Endoscopy Is More Important Than Chromoendoscopy or Narrow Band Imaging for Detecting Early Neoplasia in Barrett Esophagus: a Prospective Randomized Cross-Over Study

Mohammed Kara ; Femke Peters ; Wilda Rosmolen ; Kausilia Krishnadath ; Fiebo ten Kate ; Albert Bultje ; Paul Fockens ; Jacques Bergman

Background: High resolution endoscopy (HRE) used in combination with indigo carmine chromoendoscopy (ICC) or narrow band imaging (NBI) may improve the detection of high-grade dysplasia and early cancer (HGD/EC) in Barrett esophagus (BE). We conducted a randomized cross-over study to compare HRE-ICC with HRE-NBI for detecting HGD/EC in BE. Patients and Methods: We included BE patients who were referred for work-up of endoscopically inconspicuous HGD/EC (n=17), scheduled for follow-up after endoscopic treatment for HGD/EC (n=6), or scheduled for regular surveillance (n=5). All 28 patients underwent two procedures, HRE-ICC and HRE-NBI (6 weeks interval), in a randomized sequence. The two procedures were performed by two experienced endoscopists who were blinded to the findings of the other examination. A high-resolution zoom endoscope (Q240Z, Olympus) and a prototype NBI-system (Olympus, Tokyo, Japan) were used in all examinations .The BE was first inspected with HRE without using the zoom mode followed by detailed inspection (overview and zoom) with ICC or NBI. Two targeted biopsies were taken from detected lesions followed by 2-cm-interval-4-quadrant biopsies. Pathologists were blinded to the imaging technique used. Results: Using the combined histology results of the two procedures, 14 patients were diagnosed with HGD/EC. Both techniques identified 11 patients (79%) with HGD/EC by targeted biopsies and in all these patients HRE was sufficient to detect at least one lesion with HGD/EC.  ICC and NBI detected additional lesions with HGD/EC occult to HRE in 2 and 3 patients, respectively, without increasing the number of patients diagnosed with HGD/EC. Conclusion: In this group of high-risk BE patients, HRE performed by experienced endoscopists led to the identification of most patients with HGD/EC. In this setting, ICC and NBI are more suited for targeted detailed inspection and delineation of lesions than for primary detection of HGD/EC. HRE should be considered the imaging technique of choice in patients with BE.

Outcome measurement HRE-ICC HRE-NBI

Patients diagnosed with HGD/EC 13/14 (93%) 12/14 (86%)

Patients with HGD/EC in target biopsies 11/14 (79%) 11/14 (79%)

Patients with HGD/EC in lesions detected with HRE only

11/14 (79%) 11/14 (79%)

Patients diagnosed with HGD/EC from random biopsies only

2/14 (14%) 1/14 (7%)

 

DDW Abstract 1204-Gastrointestinal Endoscopy, 2005 Apr.;61(5):AB142

Ablative Therapy of Barrett's Esophagus (BE) By Endoscopic Argon Plasma Coagulation (APC)

Heinz Wolfgang Schimming ; Maik Bartikowsky ; Michael Vieth ; Manfred Stolte ; Ahmed Madisch ; Stephan Miehlke

Backround:Barrett’s esophagus is a premalignant condition. Medical or surgical treatment of GERD usually fails to induce complete regression of BE. The aim of this prospective randomised study was to evaluate the effectiveness of endoscopic APC in combination with high-dose omeprazole therapy for the ablation of BE.

Methods: Consecutive patients with BE were evaluated. The presence of CELLO was confirmed histologically by using alcian-blue and H&E staining; mucosal biopsies were obtained from each quadrant every 2cm and any abnormal-appearing area. BE were ablated by using an argon beamer device (ERBOTOM ICC200, Germany) as a contact-free thermal coagulation technique (gas flow 2l/min, power setting 90W). Ablation was performed longitudinally from the distal toward the proximal epithelial junction of up to 3cm in length in a single session of about 12 minutes‘ duration. This procedure was repeated every 3 weeks until there was visible complete reepithelialization with squamous epithelium, confirmed by histology using a standard biopsy protocol. During the entire treatment period acid suppression was obtained and patients were randomised to receive either 40mg omeprazole (arm A) or tid (arm B).

 Results: 103 patients agreed to participate in the study. In the 56 patients (37 men, 19 women), mean age 58,7 years (range 36 to 75 years), who completed treatment, the mean length of BE was 3,7cm (range 1 to 12cm). 3 patients had a low grade dysplasia, all other had CELLO without dysplasia. There were 32 patients with long segment BE, mean length 6cm (range 4 to 12cm) and 24 patients with short segment BE, mean length 1,9cm (range 1 to 3cm). The mean number of APC sessions was 2,8 (range 1 to 10), 2,2 (range 1 to 5) for short segment BE, 3,2 (range 1-10) for long segment BE, respectively 3,1 (arm A) vs. 2,6 sessions (arm B), p<0,05. Complete squamous reepithelialization was obtained in 53 patients (94,6%) but 1 patient (1,8%) who had a macroscopically non visible island of residual BE without dysplasia in histology. 1 patient developed a mild stricture of the lower esophagus (1,8%), that resolved after 2 sessions of bougie dilation, another patient a perforation of the cardia (1,8%), that was straightaway successful operated.There has been no relapse of BE under continuous acid suppression with 40mg omeprazole during a follow-up of 12 months

 Conclusion: APC in combination with high-dose omeprazole treatment is an effective technique for complete ablation of BE.

DDW Abstract 1179- Gastrointestinal Endoscopy, 2005 Apr.;61(5):AB136

A Prospective Multicenter Trial on Ablation of Non-Neoplastic Barrett’s Epithelium by Endoscopic Argon Plasma Coagulation in Combination with Esomeprazole (APBANEX)

Hendrik Manner ; Andrea May ; Stephan Miehlke ; Walter Kraemer ; Gabriele Niemann ; Bernd Wigginghaus ; Stephan Dertinger ; Wolfgang Schimming ; Ralf Kiesslich ; Manfred Stolte ; Christian Ell

BACKGROUND: In contrast to former clinical trials concerning the ablation of non-neoplastic Barrett’s epithelium (BE), Schulz et al. (Gastrointest Endosc, 2000) obtained a complete squamous regeneration after argon plasma coagulation (APC) in 98,6 % of treated patients. The aim of this prospective study was to evaluate for the first time the effectiveness of APC at a high power setting for the ablation of BE in a multicenter trial.

METHODS: In 8 study centers, 60 patients (mean age 57, range 27-77; 47 male, 13 female) with endoscopic and histologically proven non-neoplastic BE (length of BE 1-8 cm) were recruited for treatment by APC in combination with esomeprazole. After baseline documentation by video endoscopy (VE) plus chromoendoscopy with 0,5% methylene blue (MB) and four quadrant biopsies (4QB) including the gastroesophageal transition zone, BE was treated by repeated APC using a power setting of 90 W; the number of APC sessions was restricted depending on the length of BE. During the treatment period, all patients received esomeprazole 80 mg daily; 2 weeks after completion of treatment the esomeprazole dose was reduced to 20 mg on demand daily or adapted to the result of 24 h pH monitoring. Endoscopic examinations including VE, chromoendoscopy with MB, and 4QB depending on pretreatment length of BE were performed 3 weeks, 6 and 12 months after completion of treatment. The effect of ablation was classified either as complete remission (CR; complete macroscopic and microscopic regression of BE), partial remission (macroscopic regression more than 50% depending on pretreatment length of BE) or minor response (macroscopic regression of BE less than 50%).

RESULTS: 51/60 recruited patients were treated within the study. 3 patients were lost for follow-up (FU) after complications had occurred. In 37 of 48 patients (77%) CR was achieved after a mean FU of 14 months (range 12-32). To achieve complete ablation of BE (mean length 3,6 cm), a mean of 2,6 APC sessions (range 1-5) were used. Transient complications (chest pain, fever) were noted in 9/51 patients (17,6%). Major complications (stricture formation, bleeding, perforation) occurred in 5/51 patients (9,8%).

CONCLUSIONS: The fact that esophageal cancer incidence rate in non-neoplastic BE is low and the goal of ablation treatment namely complete ablation of BE is not reached in all patients together with the risk for morbidity due to ablation does not justify APC for ablation of non-neoplastic BE.

DDW Abstract 223- Gastrointestinal Endoscopy, 2005 Apr.;61(5):AB80

A Novel Multiband Mucosectomy Device Facilitates Circumferential Endoscopic Mucosal Resection in Barrett’s Esophagus with Early Malignant Changes

Stefan Seewald ; Salem Omar ; Stefan Groth ; Uwe Seitz ; Andreas de Weerth ; Yan Zhong ; Frank Thonke ; Soeren Schroeder ; Nib Soehendra

BACKGROUND: Various techniques are available for EMR in the upper and lower gastrointestinal tract. For early cancers of the esophagus, “suck and cut” technique using a transparent cap or variceal band ligator is the most commonly practiced method. To facilitate multiple or circumferential EMR (CEMR), a modified multiband variceal ligator (MBL) is introduced which allows sequential banding and snare resection without the need to withdraw the endoscope.

Method: To enable band delivery with a snare inserted in the therapeutic endoscope, the threading channel of the cranking device is enlarged from 2 mm to 3.3 mm. The six shooter MBL (Multiband Mucosectomy Device, CE0123, Cook Ireland Ltd., Limerick, Ireland) was used. Ten consecutive male patients (median age: 62 years, range 43-82) with Barrett’s esophagus (BE) containing high-grade intraepithelial neoplasia (HGIN) and/or intramucosal cancer (IMC) were treated. EMR was performed with pure coagulating current using a mini hexagonal polypectomy snare sized 1.5 x 2.5 cm. No submucosal saline injection was performed prior to resection.

Results: In 5 of 10 patients with circumferential BE of 2-9 cm in length (median: 4 cm), complete CEMR was performed in one session using 3-18 (median: 6) bands. Four patients with 3-10 cm (median: 4 cm) long-segment BE required 2-5 (median: 3) sessions using a total of 5-42 (median: 12) bands. Another patient having multifocal HGIN and/or IMC in 24 of a total of 49 specimens was finally recommended for surgery because of technical difficulties caused by mural thickening after 4 sessions. No serious procedure related complications were observed accept for 2 minor bleedings which were controlled endoscopically. Seven patients developed strictures after CEMR. All accept one patient was successfully managed by weekly bougienage after a median of 5 (range: 3-11) sessions. Deep wall tears developed in one patient during the fourth bougienage session for which limited distal esophageal resection was performed with uneventful outcome.

Conclusion: The novel technique of MBL-EMR is a safe and effective method which facilitates and simplifies circumferential removal of BE containing HGIN and/or IMC. However, the method is associated with a very high stricture rate if CEMR is performed in one single session. Complete removal of BE should be achieved by repeated partial EMR. Long-term follow-up is needed to observe for late recurrence and determining the clinical impact.

DDW Abstract S1196- Gastrointestinal Endoscopy, 2005 Apr.;61(5):AB140

Barrett Esophagus (BE) with High-Grade Dysplasia (HGD) and/or Early Cancer (EC): Stepwise Radical Endoscopic Resection (SRER) for Complete Removal of the BE Is Safe and Effective

Femke Peters ; Mohammed Kara ; Wilda Rosmolen ; Fiebo ten Kate ; Sheila Krishnadath

Background and Aim: Endoscopic resection in BE is usually used for removal of focal lesions with HGD/EC. Studies have shown that these ER’s are often irradical and up to 30% of patients develop metachronous lesions elsewhere in the BE during FU. Our aim was to prospectively evaluate the safety and efficacy of SRER in patients with HGD/EC in a BE.

Patients and methods: After work-up with high-resolution endoscopy (HRE), video-autofluorescence imaging (AFI), narrow-band imaging (NBI) and EUS, and review of all biopsies by an expert pathologist, pts with HGD/EC in a BE <5 cm, without signs of submucosal infiltration, lymphatic and hematogenous dissemination were included. Pts first underwent a diagnostic ER of the most suspicious lesion to evaluate infiltration depth, followed by SRER with intervals of 6 weeks. In all ER’s the cap-technique was used after submucosal lifting and at each SRER procedure resection of 50% of the original BE was attempted. Follow-up (FU) endoscopies (with lugol-staining and jumbo biopsies) were scheduled every 3 months, with EUS after 6 and 12 months.

Results:Between Jan ‘03 and Oct ‘04, 41 consecutive pts (33 m/8 f, mean age 65 (SD 8.2), median length BE 4 cm) were included. Thirty-five patients had visible abnormalities on HRE, AFI and/or NBI. Complete removal of BE was achieved in 26 pts after a median of 3 (2-3) SRER procedures. Therapy was discontinued in 2 patients due to unrelated comorbidity (18eukaemia, pulmonary cancer), 13 are still under treatment. Early complications occurred in 12/87 procedures (14%): 11 bleedings (all treated endoscopically without a drop in Hb or the need for blood transfusions) and 1 asymptomatic perforation treated conservatively. Symptomatic stenosis occurred in 5/26 (19%) pts, requiring a median of 3 dilatations. Histopathology of ER-specimens revealed: HGD in 16 and EC in 14 pts. In all specimens, deeper resection margins were free. Although revision of pre-treatment biopsies confirmed HGD/EC, 11 pts did not have HGD/EC in the ER-specimens (4 no dysplasia, 4 indefinite, 3 LGD).During a median FU of 7 months (5-12) none of the patients had signs of residual BE or buried Barrett in any of the biopsies and no signs of lymph node metastasis on EUS.

Conclusions: SRER is a safe and effective treatment for selected pts with HGD/EC in a BE. SRER provides optimal histopathological diagnosis and may reduce the number of recurrences, since all the mucosa at risk is effectively removed.

DDW Abstract S1152- Gastrointestinal Endoscopy, 2005 Apr.;61(5):AB140

Can Piecemeal Mucosectomy Completely Remove Barrett's Esophagus with High Grade Dysplasia or Adenocarcinoma?

Pierre Henri Deprez ; Tarik Aouattah ; Hubert Piessevaux ; Jacques Grodos ; Rene Fiasse ; Yves Horsmans ; Christine Sempoux

Aim: Prospective evaluation of piecemeal mucosectomy using the cap method (EMR-c) in patients presenting with Barrett’s esophagus and high grade dysplasia of superficial adenocarcinoma and aiming at complete removal of the neoplastic lesion and the intestinal metaplasia. Patients and methods: Inclusion criteria: long or short Barrett’s esophagus with high grade dysplasia or T1m N0 adenocarcinoma staged by radial or linear Pentax EUS scope (EG-3630-UR or EG-3830-UT) with the Hitachi EUB 6500 processor and 20MHz miniprobe. Resection was performed under general anesthesia, starting at the site of the tumour, after submucosal injection of 2-5 ml aliquots of saline for a total of 10-50 ml, than resecting the remaining Barrett’s mucosa from anal to oral direction. Circumferential resection was avoided if the height of Barrett’s metaplasia exceeded 1 cm. Oblique or straight transparent rigid cap was used and resection was completed if necessary by APC (0.6 L, 60 W) for residual bridging or short remaining tongs of metaplasia. Patients were discharged one or two days after mucosectomy under liquid diet and omeprazole 40mg bid was started before treatment and continued for 8 weeks minimum. Results: 20 patients (mean age 68y, range 47-85, 3 women/17 men) were included with HGD in 15 and mucosal adenocarcinoma in 5. Circonferential length of Barrett’s mucosa (C) was 19 mm (5-70) and highest limit (M) 26 mm (5-80). A total of 26 EMR-c sessions were performed (1.3; 1-5), removing 95 specimens (4.8; 1-13 per patient). Follow-up is now 13.3 months (3-38 months). Successful resection of HGD and adenocarcinoma was observed in all patients. Complete removal of intestinal metaplasia was observed in 65% of patients (13/20), with 2 patients still presenting low grade dysplasia. Remaining Barrett’s mucosa was however limited to sections of < 5 mm in 6/7 patients. Complications occurred in 4 patients: 3 minor bleeding episodes during EMR treated by endoscopic hemostasis (APC or hemoclip) and 1 oesophageal stricture requiring endoscopic dilatation. Conclusions: Although EMR-C piecemeal resection is acceptable for treatment of intraepithelial or mucosal adenocarcinoma complicating Barrett’s esophagus, it is only successful in 2/3 of patients when aiming at complete resection of intestinal metaplasia. Improvements in endoscopic techniques of esophageal mucosectomy and new appropriate devices to improve efficacy and safety are mandatory to obtain higher success rates.

Helicobacter/Dyspepsie P. MalfertheinerG. Treiber

DDW Abstract 43-Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-8

Development Of Premalignant Gastric Lesions in Area With High Gastric Cancer Incidence: Role Of H. Pylori Genotypes and Cytokine Gene Polymorphisms

Wai K Leung ; Martin CW Chan ; Ka-fai To ; Ellen PS Man ; Enders KW Ng ; San-ren Lin ; Joseph JY Sung

Cytokine gene polymorphisms and H. pylori (HP) virulent genotypes have been linked to gastric cancer development in western countries. We determined the role of cytokine polymorphisms of the host and bacterial virulent factors in the development of premalignant gastric lesions in region with high gastric cancer incidence.

Methods: DNA samples of 302 HP infected individuals who had participated in a chemoprevention trial were available for analysis (mean age = 52, male 46%). These subjects were living in Shandong province of China where the gastric cancer incidence is among the highest. None of these subjects had gastric cancer on baseline endoscopy. Polymorphisms in different loci of inflammatory cytokines IL-1B (-31, -511, IL1RN), IL-8 (-251), IL-10 (-1082, -819, -592), IL-18 (-607, -137) and TNFa (-308G/A) were determined by allelic discriminating TaqMan PCR or variable number of tandem repeats. Presence of HP virulence factors cagA, vacA (s and m region) and babA2 was determined by PCR. Baseline gastric biopsies were assessed for severity of gastritis and presence of glandular atrophy (GA) or intestinal metaplasia (IM) according to the updated Sydney Classification.

Results: GA and IM was found in 119 (39.4%) and 123 (40.7%) subjects, respectively. There was near linkage disequilibrium between IL1B -31C and -511T as well as between IL10 -819C and -592C in this study population. Carriers of IL1B -511T*/-31C* were associated with a modest increase in prevalence of IM (OR =1.9, 95% CI 1.1-3.5) and GA (OR = 2.0, 1.1-3.5). However, there was no association between presence of IM/GA and polymorphisms in IL-1RN or other inflammatory cytokines. Although most subjects from this region harbored the virulent HP strains (97.5% cagA+, 100% vacA s1, 83.5% babA2), carriage of vacA m1 strain was associated with a significantly increase in prevalence of IM (OR=1.7, 1.1-2.8) and GA (OR = 1.7, 1.0-2.7). The presence of both host (IL-1B-511T*) and HP (vacA m1) high-risk genotype further increased the risk of IM (OR= 5.7, 2.0-16) and GA (OR = 5.4, 1.9-15.3) when compared to individuals with CC genotype and vacA m2 strain.

Conclusion: The carriage of pro-inflammatory IL-1B polymorphism and HP vacA genotype was associated with the development of premalignant gastric lesions in regions with high gastric cancer incidence. Determination of these host and bacterial genotypes may help to identify individuals at high risk of developing gastric cancer. 

DDW Abstract 108- Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-19

The Interleukin-8-251 Promoter Polymorphism and Risk Of Gastric Cancer in Caucasian and Japanese Populations.

Emad M El-Omar ; Malcolm G Smith ; Georgina L Hold ; Charles Rabkin ; Wong-Ho Chow ; Joseph F Fraumeni ; N. Ashley G Mowat ; Takafumi Ando ; Hidemi Goto 

Background: Interleukin 8 is of critical importance in the inflammatory response to Helicobacter pylori. It is a powerful chemotactic factor that induces many of the early inflammatory responses to the infection. We have recently shown that a functional promoter polymorphism (IL-8–251 A/T) is associated with an increased risk of developing the pre-malignant changes of hypochlorhydria and gastric atrophy. We have also demonstrated that carriage of the IL-8–251 A allele is associated with higher IL-8 levels and a more pronounced inflammatory response in the gastric mucosa

Aim: To evaluate the effect of the IL-8–251 (A/T) polymorphism on the risk of developing gastric carcinoma, using case control studies from two populations of differing ethnic backgrounds.

Subjects and Methods: We used a 5’ nuclease assay to genotype the IL-8–251 A/T polymorphism in two gastric cancer case control studies: 1) a Caucasian gastric cancer case-control study consisting of 306 gastric cancer cases and 211 controls and 2) a Japanese gastric cancer case-control study consisting of 237 gastric cancer cases and 98 controls. Odds ratios and 95% confidence intervals (CI) were calculated and logistic regression was used to adjust for confounding variables.

Results: Carriage of the pro-inflammatory IL-8–251 A allele in the Caucasian case-control study was not associated with an increased risk of developing gastric carcinoma (OR = 1.006, 95% CI 0.7 – 1.5). No significant differences were observed when the cases were subdivided into cardia (OR = 0.811, 95% CI 0.5 – 1.3) and non-cardia gastric cancers (OR 1.173, 95% CI 0.8 – 1.8). Similarly in the Japanese population carriage of the A allele did not increase the risk of having gastric cancer (OR = 1.166, 95% CI 0.7 – 1.9).

Conclusion: Although carriage of the IL-8–251 A allele is associated with a more pronounced inflammatory response in the gastric mucosa of H. pylori infected subjects and an increased risk of developing pre-malignant changes, it does not appear to alter the risk of developing the eventual outcome of gastric cancer. This applies to populations of differing ethnicity. We postulate that this polymorphism is important at an early stage in the inflammatory response to H. pylori and may facilitate the action of other mediators in the development of gastric cancer.

 

DDW Abstract M1021- Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-293

Development Of Gastric Cancer From Helicobacter- Related Gastritis --Findings From a Ten Year Follow-Up Study

Kimihiko Yanaoka ; Chizu Mukoubayashi ; Hisanobu Deguchi ; Hirohito Magari ; Izumi Inoue ; Mikitaka Iguchi ; Hideyuki Tamai ; Kenji Arii ; Masashi Oka ; Yasuhito Shimizu

In high-risk area like Japan, the main route of stomach carcinogenesis is considered to begin with gastritis, proceeds to extensive atrophy together with intestinal metaplasia, then to dysplasia, and finally to cancer. However, there is a controversy whether the risk of gastric cancer increases as the progression of atrophyÐintestinal metaplasia resulting from the gastritis, or whether the high level of gastritis activity poses a high risk. In order to clarify this point, we conducted a longitudinal cohort study over a ten-year period. MATERIALS AND METODS: 4,655 healthy asymptomatic male subjects between ages 40 and 60 were evaluated in terms of Helicobacter pylori (HP)-related gastritis based on serum pepsinogen (PG) and serum HP antibody titer, with a follow-up study conducted over the ensuing ten years from 1994 to 2003 to track the incidence of gastric cancer and to examine the rate of gastric cancer occurrence accompanying the progression of atrophic gastritis. Atrophic gastritis was evaluated through endoscopic diagnosis, serum PG@testing and H. pylori (hereafter noted as HP) titer measurement, and the subjects were divided into four groups labeled A through D [A Group: HP (-) PG (-), B Group: HP (+) PG (-), C Group: HP (+) PG (+), D Group: HP (-) PG (+)]. RESULTS AND DISCUSSION: Gastric cancer developed in 63 cases during the ten-year follow-up period, 54 of which were early-stage gastric cancer. There were 23 cases in the group B, 37 in group C, three in group D, and no occurrences of gastric cancer in group A. The incidence rate of gastric cancer was null in group A, 0.09“ person-years in group B, 0.20“person-years in group C, and 1.25“person-years in group D. Histologically, there were 44 cases of intestinal type gastric cancer and 19 cases of diffuse type gastric cancer, with the background being such that 74% of the former were accompanied by extensive atrophic changes in the gastric mucosa, while 40% of the latter exhibited this background. There was no gastric cancer developed from healthy stomachs, while the risk for the cancer increased in a stepwise fashion as the progression of HP-related gastritis. Although these results clearly indicate that the progression of atrophic gastritis is the main route of stomach carcinogenesis in Japan, the fact cannot be overlooked that in the majority of cases of diffuse type gastric cancer, as well as one fourth of intestinal type gastric cancer develop from mild cases of HP-related gastritis.

 DDW Abstract W1571- Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-639

The Effect Of Second Look Endoscopy in Patients With Bleeding Peptic Ulcers

Seung Yup Lee ; Myung Kwon LEE ; Chang Min Cho ; Won Young Tak ; Young Oh Kweon ; Sung Kook Kim ; Yong Hwan Choi

Background: Recurrent bleeding is one of the most important risk factors for mortality in patients with peptic ulcer bleeding. Second look endoscopy has been suggested in order to reduce recurrent bleeding. But whether a clinical value of second look endoscopy with retreatment after initial hemostasis is controversial. We assessed whether a scheduled second look endoscopy with retreatment reduces the risks of recurrent bleeding, mortality rate in patients with peptic ulcer bleeding.

Methods: From February 2003 to June 2004, we have performed a prospective, randomized, controlled study of 143 patients with bleeding gastric or duodenal ulcers admitted to Kyungpook National University Hospital. Seventy patients in the study group were randomized to receive scheduled second look endoscopy in case of Forrest type I, IIa, or IIb ulcers beginning within 24 hours after initial hemostasis. Seventy three patients in the control group were observed closely. Endoscopic therapy was standardised to hypertonic saline epinephrine injection and subsquent hemoclipping.

Results: Nineteen of the 143 patients had recurrent bleeding after initial therapeutic endoscopy. The overal rebleeding rate was 13.3 %. Although duration of hospital stay was significantly lower in the study group than control group(5 days versus 7 days, p=0.035), rebleeding rate was similar for both groups(10% versus 16%, p=0.257). The two groups were similar in respect of blood units transfused, mortality within 30 days, volume of hypertonic saline epinephrine injection and number of hemoclips used. We analysed the probability of recurrent bleeding within 30 days, the results showed low probability of rebleeding tendency in the study group, but the difference was statistically insignificant(p=0.28).

Conclusions: According to above results, we can conclude that scheduled second look endoscopy with retreatment did not reduce the risk of recurrent bleeding in patients with peptic ulcer bleeding. Therefore a scheduled second look endoscopy does not seem to be recommended routinely in all patients following initial endoscopic treatment, but a larger group study in high risk patients seems to be needed.

DDW Abstract 835 - Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-133Eradication Of H. Pylori for the Prevention Of Recurrent Ulcer Bleeding in High-Risk Aspirin Users: a 4-Year Prospective Cohort StudyFrancis K.L. Chan ; Jessica Y.L. Ching ; B.Y. Suen ; Vincent W.S. Wong ; Lawrence C.T. Hung ; Aric J. Hui ; Justin C.Y. Wu ; W.K. Leung ; James Y.W. Lau ; Y.T. Lee ; Henry L.Y. Chan ; Joseph J.Y. Sung

Background We previously reported that among patients with H. pylori (HP) infection and a history of ulcer bleeding who received low-dose aspirin, eradication of HP was comparable to omeprazole in preventing recurrent ulcer bleeding in 6 months. Aim To determine the long-term incidence of recurrent ulcer bleeding in aspirin users with a hito-y of ulcer bleeding after eradication of HP. Methods We prospectively followed up three cohorts of aspirin users. The first cohort consisted of HP positive aspirin users with a re-ent episode of ulcer bleeding. After ulcer healing and HP eradication, they received aspi-in 80 mg od without anti-ulcer drugs (HP eradicated, prior GI bleed cohort). The second cohort consisted of aspirin-naive patients who had no previous ulcer bleeding. They re-ceived aspirin 80 mg od for vascular prophylaxis (Average-risk cohort). The third cohort consisted of HP negative aspirin users with a recent episode of ulcer bleeding. After ul-cer healing, they received enteric-coated aspirin 100 mg od without anti-ulcer drugs (HP negative, prior GI bleed cohort). Patients who used anti-ulcer drugs, steroid, anticoagu-lants, other anti-platelet agents or non-aspirin NSAIDs during the follow-up period were censored. The primary endpoint was the cumulative incidence of ulcer bleeding associa-ted with low-dose aspirin. Results There were 250 patients in the HP eradicated prior GI bleed cohort (median follow-up 41.3 months, range 0.5 – 48.0), 548 in the average-risk cohort (median follow-up 48.0 months, range 3.7 – 48.0), and 118 in the HP negative prior GI bleed cohort (median follow-up 22.0 months, range 0.5 – 48.0). The cumulative incidence rates of ulcer bleeding in 48 months were 4.5% in the HP eradicated prior GI bleed cohort, 2.0% in the average-risk cohort, and 18.4% in the HP negative prior GI bleed cohort (Figure). Conclusion Among aspirin users with HP infection and a history of ulcer bleeding, the long-term incidence of recurrent bleeding after HP eradication is comparable to that of average-risk aspirin users. In contrast, HP negative aspirin users with a history of ulcer bleeding have a high incidence of recurrent bleeding. l .

DDW Abstract 629- Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-95

Coxibs, NSAIDs, Aspirin, PPIs and the Risks Of Upper GI Bleeding in Common Clinical Practice

Angel Lanas ; Luis Alberto García-Rodríguez ; María-Teresa Arroyo ; Fernando Gomollón ; Eva Zapata ; Luis Bujanda ; Faust Feu ; Enrique Quintero ; Manuel Castro ; Santos Santolaria ; on behalf of investigators of AEG

Background and Aims: The overall safety profile of COX-2 selective inhibitors is under intense debate, since in addition to the potential/actual CV risk, even the benefits of these drugs on the GI tract have  been questioned. Aim: To determine the risk of  peptic ulcer upper GI bleeding (UGIB) associated with use of COX-2 selective, non-selective NSAIDs, aspirin or combination of these drugs.  Methods: Type of Study: case-control study with prospective data collection. Setting: A network of 40 hospitals integrated within the Spanish Association of Gastroenterology. Cases were consecutive patients with endoscopy-proven major UGIB. Controls  (2:1)  matched by age (5 years range), hospital and month of admission were patients who had been hospitalized with any primary diagnosis that was neither an indication nor a known contraindication of treatment with NSAIDS. A structured questionnaire with pictures of marketed drugs and careful review of prescriptions were used. Relative Risk (RR) of UGIB by logistic regression analysis is provided. Results: 2,777 cases and 5,532 controls were included; 47.9% of cases and 18.6% of controls had used either NSAIDs, coxibs, aspirin or combinations. The RR of UGIB associated with NA-NSAIDs was 5.0 (95% CI: 4.3-5.9). There was a dose-dependent risk associated with low-dose aspirin use (100 mg/day = 2.4;1.9-3.1), which was similar to that observed with clopidogrel (3.1; 2.2-4.4) or anticoagulants (3.0; 2.3-3.8). Coxib use was not associated with UGIB (1.3; 0.8-2.1) (celecoxib:1.0; 0.5-2.2; rofecoxib:1.6; 0.9-3.0), but the combination of coxib+low-dose aspirin  was associated with the same RR (9.5; 2.5-36.2) to that observed with NA-NSAID+low-dose aspirin (10.2; 6.2-16.7).  Among NA-NSAIDs, diclofenac (2.9; 2.2-3.8) had the lowest RR, but meloxicam was associated with a higher RR (7.9;3.6-17.2). Use of proton pump inhibitors or nitrates were associated with significant risk reduction of UGIB (range: 40-90%)  in NSAID/aspirin users. Unlike NSAID+PPI, the use of  PPI+coxib was associated with  prevention of UGIB (RR <1). Conclusion: Coxib treatment without the concomitant use of low-dose aspirin is not associated with a significant increase of the risk of UGIB. PPI co-therapy with NSAIDs, aspirin, and specially coxib reduce  ulcer bleeding risk. Antiplatelet non-aspirin therapy is associated with the same risk of UGIB to low-dose aspirin.

DDW Abstract 347- Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-50

Early Administration Of High-Dose Intravenous Omeprazole Prior To Endoscopy in Patients With Upper Gastrointestinal Bleeding; a Double Blind Placebo Controlled Randomized Trial

James YW Lau ; Wai Keung Leung ; Justin Cy Wu ; Francis KL Chan ; Vincent Wong ; Lawrence CT Hung ; Ka Yin Cheung ; MY Yung ; Vivian Wy Lee ; Philip WY Chiu ; Enders KW Ng ; Kenneth KC Lee ; Joseph JY Sung

Background: We previously showed that adjunctive use of high dose omeprazole infusion after endoscopic hemostasis prevented rebleeding and improved outcomes in patients with bleeding peptic ulcers. We hypothesize that early administration of high dose omeprazole before endoscopy hastens stigmata resolution and thereby reduces the need for endoscopic therapy. Methods: Consecutive patients admitted with overt signs of upper gastrointestinal bleeding were volume resuscitated. They were then randomized to receive omeprazole (80mg intravenous bolus followed by 8mg/hr) or its placebo prior to scheduled endoscopy. At endoscopy, actively bleeding ulcers or ulcers with non-bleeding visible vessels or clots were treated by epinephrine injection and heater probe thermo-coagulation. Omeprazole infusion was then continued for 72 hours after endoscopic hemostasis.  Results: Between March and November 2004, 369 patients were randomized (omeprazole 179, placebo 190). Of them, 220 were documented to have bleeding ulcers (omeprazole 110, placebo 112) Analysis was by intention-to-treat. The need for endoscopic treatment was significant reduced in those who received omeprazole (19/110 vs. 40/112, OR, 95%CI; 2.7, 1.4-4.9, P=.002).

 Table 1. Secondary outcomes in patients with bleeding peptic ulcers 

OmeprazoleN=110

PlaceboN=112

P

Endoscopic stigmata of bleeding

Spurter

Oozing

Non-bleeding visible vessel

Clots

Flat pigment and clean base

20

1

2

13

4

90

41

3

15

14

9

71

.003

Surgery 1 4 .15Mean VAS (10cm scale) for difficulty in therapy, SD

4.2, 2.2 5.1, 3.1 .30

Mean transfusion in units, SD 1.9, 2.2 2.2, 3.1 .43Mean hospital stay in days, SD 3.7, 3.8 4.7, 5.9 .12Recurrent bleeding in 30-day 5 5 .9930-day mortality from all causes 1 1 .99

Conclusion: Pre-emptive high dose omeprazole infusion prior to scheduled endoscopy hastens resolution of bleeding stigmata in ulcers and reduces need for therapy.

DDW Abstract 863- Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A138-139

Comparing Rates Of Dyspepsia With Coxibs Versus NSAID+ppi: a Systematic Review and Meta-Analysis Of Clinical Trial Data

Brennan M. R. Spiegel ; Mary Farid ; Gareth S. Dulai ; Ian M. Gralnek ; Fasiha Kanwal

Background: Although it is well established that both Coxibs and the NSAID+PPI combination reduce ulcer complications by 50% vs NSAID therapy alone, the impact of these therapies on dyspeptic symptoms is unclear. Because dyspeptic symptoms are far more prevalent than ulcer complications in NSAID users, economic models indicate that dyspepsia rates are the major determinant of cost-effectiveness in treating arthritis. We therefore performed a meta-analysis to compare rates of dyspeptic symptoms for two commonly used therapies in high-risk patients with arthritis: 1) Coxib alone, and 2) NSAID+PPI combination. 

Methods: We performed a structured search of MEDLINE and published abstracts to identify English-language randomized trials from 1990-2004 comparing either a Coxib vs NSAID or NSAID+PPI combination vs NSAID alone in chronic arthritis. Two reviewers independently selected studies that report incident dyspeptic symptoms, defined a priori as “epigastric pain,” “dyspepsia,” and “nausea.” The reviewers independently abstracted data and assigned a quality score for each study. We performed meta-analysis with a fixed effects model to compare the relative risk reduction (RRR) and Absolute Risk Reduction (ARR) of dyspeptic symptoms for Coxib vs NSAID and NSAID+PPI vs NSAID, and performed an Egger’s test to assess for publication bias. 

Results:  We identified 840 titles, of which 37 were selected for final review (kappa>0.9 for agreement). Meta-analysis of 32 studies (N=60,163 patients) comparing dyspeptic symptoms between Coxibs and NSAIDs revealed a 12% RRR for Coxibs (RR=0.88; 95% CI=0.85-0.90) with an ARR of 3.7%. Meta-analysis of 5 studies comparing dyspeptic symptom between the NSAID+PPI combination and NSAIDs alone revealed a 66% RRR for NSAID+PPI (RR=0.34; CI=0.22-0.54) with an ARR of 9%. There was no evidence of heterogeneity (p>0.05) or publication bias (p>0.05) in either analysis. Compared to the NSAID strategy, the number needed to treat in order to prevent a dyspeptic symptom was 27 for Coxibs and 11 for NSAID+PPI.

Conclusions: The NSAID+PPI strategy affords a greater risk reduction for dyspepsia than Coxibs alone when compared to the common baseline of NSAIDs alone. Because there are limited head-to-head data comparing Coxibs vs NSAID+PPI, these meta-analytic data provide the best indirect evidence that the NSAID+PPI strategy may be superior to Coxibs in minimizing incident dyspeptic symptoms during the treatment of chronic arthritis. 

 

LeberVirushepatitis T. Berg

1. Originalarbeiten

Hepatology. 2004 Oct;40(4):883-91.

Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine.

Di Marco V, Marzano A, Lampertico P, Andreone P, Santantonio T, Almasio PL, Rizzetto M, Craxi A; Italian Association for the Study of the Liver (AISF) Lamivudine Study Group, Italy.

Cattedra e U.O.C. di Gastroenterologia, Clinica Medica, Universita di Palermo, Palermo, Italy. vito.dimarco@tin.it

The effect of lamivudine treatment on the outcome of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis is unclear. In a retrospective multicenter study, we have analyzed the virological events observed during lamivudine therapy in patients with HBeAg-negative chronic hepatitis and evaluated the correlation between virological response and clinical outcomes. Among 656 patients (mean age 49.1 years) included in the database, 54% had chronic hepatitis, 30% had Child-Turcotte-Pugh (CTP) A cirrhosis, and 16% had CTP B/C cirrhosis. On therapy (median 22 months, range 1-66), a virological response was obtained in 616 patients (93.9%). The rate of maintained virological response was 39% after 4 years. During follow-up, 47 (7.2%) patients underwent liver transplantation, liver disease worsened in 31 (4.7%), hepatocellular carcinoma (HCC) developed in 31 (4.7%), and 24 patients (3.6%) died of liver-related causes. Patients who had cirrhosis and who maintained virological response were less likely than those with viral breakthrough to develop HCC (P <.001) and disease worsening (P <.001). Survival was better in CTP A patients with cirrhosis and maintained virological response (P =.01 by rank test). Multivariate analysis revealed that presence of cirrhosis and viral breakthrough were independently related to mortality and development of HCC. In conclusion, lamivudine is highly effective in reducing viral load in HBeAg-negative patients. After 4 years of therapy, 39% of patients maintain a virological and biochemical response. Loss of virological response may lead to clinical deterioration in patients with cirrhosis.

Hepatology. 2004 Dec;40(6):1421-5.

Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection.

van Bommel F, Wunsche T, Mauss S, Reinke P, Bergk A, Schurmann D, Wiedenmann B, Berg T.

Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charite, Universitatsmedizin Berlin, Campus Virchow, Berlin, Germany.

Adefovir dipivoxil was recently approved for the treatment of wild-type and lamivudine-resistant hepatitis B virus (HBV) infection. Tenofovir disoproxil fumarate, a congender of adefovir that is used in the treatment of HIV infected patients, has recently been shown to also be effective in patients with lamivudine-resistant HBV infection. We therefore compared the two substances in a study of 53 patients defined by high HBV DNA (>6 log10 copies/mL) levels and genotypic evidence of lamivudine resistance. Thirty-five patients received tenofovir for 72 to 130 weeks, and 18 received adefovir for 60 to 80 weeks. Changes in HBV DNA levels were followed for the complete period of 48 weeks. Early viral kinetics were compared on matched subgroups of 5 patients each. Individually, all tenofovir-treated patients showed a strong and early suppression of HBV DNA within a few weeks whether they were coinfected with HIV or were without comorbidity. In contrast, considerable individual variations in HBV DNA decline were observed in the adefovir group. Thus at week 48, only 44% of these patients had HBV DNA levels below 10(5) copies/mL in contrast to 100% of the tenofovir-treated patients (P = .001). No severe side effects were noticed in either group. No evidence of phenotypic viral resistance could be demonstrated in the tenofovir-treated patients in the long term (up to 130 weeks). In conclusion, tenofovir may become an effective alternative for the treatment of patients with lamivudine-resistant HBV infection.

2. Kongreßabstracts EASL und AASLD

Hepatology, Vol.40, No.4, Suppl., 1, 2004; Nr. 20

Peginterferon Alfa-24 (40KD) (PEGASYS®) monotherapy and in combination with lamivudine is more effective than lamivudine monotherapy in HBeAG-positive chronic hepatitis B: Results from a large, multinational study

George Lau, Queen Mary Hospital, Hong Kong, Hong Kong Special Administrative Region of China; Teerha Piratvisuth, Songklanakarin Hospital, Songkla, Thailand; Kang Xian Luo, Nangfang Hospital, Guangzhou, China; Patrick Marcellin, Hôpital Beaujon, Clichy, France; Satawat Thongasawat, Chiang Mai University, Chiang Mai, Thailand; Graham Cooksley, Royal Brisbane Hospital, Herston, Australia; Eward Gane, Middlemore Hospital, Otahuhu, New Zealand; Michael Fried, University of North Carolina, Chapel Hill, NC; Wan Cheng Chow, Singapore General Hospital, Singapore, Singapore; Sseung Woon Paik, Samsung Medical Centre, Seoul, Republic of Korea; Wen Yu Chang, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Republic of China; Thomas Berg, Charité Humboldt Universität zu Berlin, Berlin, Germany; Robert Flisiak, University of Bialystok, Bialystok, Poland; Friederike Zahm, Roche, Basel, Switzerland; Nigel Pluck, Roche, Welwyn, United Kingdom

Background: Recent data show that peginterferon alfa-2a (40KD) (Pegasys®) gives significantly higher post-therapy response rates than lamivudine in HBeAg-negative chronic hepatitis B (CHB). Combining peginterferon alfa-2a and lamivudine did not omprove response rates over peginterferon alfa-2a alone [Marcellin et al, J Hepatol 2004]. In this study, the efficacy and safety of peginterferon alfa-2a with and without lamivudine vs lamivudine alone has been evaluated in HBeAg-positive CHB. Methods: Randomized, partially double-blind multinational study. Patients with HBeAg-positive CHB (n=814) received (1:1:1):

1) Peginterferon alfa-2a (40KD) (PEGASYS®) 180 µg once weekly (qw) + placebo once daily (qd)

2) Peginterferon alfa-2a (40KD) (PEGASYS®) 180 µg qw + lamivudine 100 mg qd3) Lamivudine 100 mg qd.

Patients were treated for 48 weeks and assessed after 24 weeks of treatment-free follow-up. Results: Baseline characteristics were comparable in all treatment groups. The overall patients population was predominantly Asian (85-87%). After 24 weeks follow-up (week 72), the proportion of patients achieving predefined co-primary endpoints (HBeAg seroconversion or HBF DNA <100,000 copies/ml), and secondary endpoints (HBeAg loss and ALT normalization), was significantly higher with peginterferon alfa-2a monotherapy or combination therapy than with lamivudine monotherapy. HBsAg seroconversion at week 72 was reported in 16 patients receiving peginterferon alfa-2a (± lamivudine) compared with none receiving lamivudine monotherapy.

Withdrawals from treatment for safety reasons were low across all groups (<=3%). The majority of adverse events were mild in nature and incidense of serious adverse events was low in all treatment groups (2-6%). Adverse events were comparable between peginterfereon alfa-2a monotherapy and the combination therapy.Conclusions: Significantly higher post-therapy response rates were achieved with peginteferon alfa-2a (40KD) (PEGASYS®) monotherapy or combination therapy than with lamivudine monotherapy in patients with HBeAg-positive CHB. Combining peginterferon alfa-2a and lamivudine did not improve response rates over peginterferon alfa-2a alone. No unexpected adverse events were reported for peginterferon alfa-2a and the addition of lamivudine did not significantly alter the peginterferon alfa-2a safety profile.

PEGASYS® + placebo PEGASYS® + lami- lamivudine(n=271) vudine (n=271) (n=27)

Co-primary endpointsHBeAg seroconversion 32% (P<0.001)* 27% (P=0.023)* 19 %

HBV DNA < 100,000Copies/ml 32% (P=0.012)* 34% (P=0.003)* 22 %

Secondary endpointsHBeAg loss 34% (P<0.001)* 28% (P=0.043)* 21 %

ALT normalization 41% (P=0.002)* 39% (P=0.006)* 28 %* compared with lamivudine therapy

J. of Hepatology, Suppl. 2 Vol. 42, General Session 2: Hepatits B

PEGINTERFERON -2a (40 kDa) (PEGASYS®) VERSUS PEGINTERFERON -2a PLUS LAMIVUDINE VERSUS LAMIVUDINE IN HBeAg-POSITIVE CHRONIC HBV: EFFECT OF PREVIOUS TREATMENT AND DRUG EXPOSURE ON SUSTAINED RESPONSE

G.K.K. Lau1. T. Piratvisuth2, K-X. Luo3, P. Marcellin4, S. Thongsawat5, E. Gane6, M.W. Fried7, G. Cooksley8, P. Button9, Y-F. Liaw10.

1Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China; 2Department of Medicine, Songklanakarin Hospital, Sonkgla, Thailand; 3Department of Infectious Diseases, Nangfang Hospital, Guangzhou, China; 4Service d’Hépatologie, INSERM Unité 481 and Centre de Recherches Claude Bernard sur les Hépatites Virales, Hôpital Beaujon, Clichy, France; 5Department of Internal Medicine, Chiang Mai University, Chiang Mai, Thailand; 6Gastroenterology Department, Middlemore Hospital, Otahuhu, New Zealand; 7University of North Carolina Liver Program, University of North Carolina, Chapel Hill, NC, USA; 8Clinical Research Department, Royal Brisbane Hospital, Brisbane, Australia; 9Roche, Dee Why, Australia; 10Chang Gung Memorial Hospital, Linkou, Taiwan

Background: In chronic hepatitis C, previous treatment and extent of drug exposure seem to have an impact on response rates. In patients with chronic hepatits B (CHB) the effects of previous anti-HBV treatment and exposure to study drug on responses to pegylated interferon are less well investigated.

Objectives: To investigate the effect of previous treatment and drug exposure on efficacy and safety in a randomised, partially double-blind, multinational study.

Methods: HBeAg-positive patients (n=814) received (1:1:1) either peginterforn -2a (180 µg once weekly) + placebo, peginterferon -2a + lamivudine (100 mg once-daily) or lamivudine. Patients were treated for 48 weeks and assessed 24 weeks after the end of treatment (week 72). Treatment with any anti-HBV drug 6 months before study entry was not permitted. Analysis of drug exposure was performed only in the peginterferon -2a monotherapy arm.

HBeAg seroconversion rates at week 72 by previous treatmentPEGASYS + PEGASYS + LamivudinePlacebo lamivudine (n=272)(n=271) (n=271)

All patients (ITT) 32% 27% 19%P<0.001* p=0.023*

Pts without previous 66/214 (31%) 59/221 (27%) 42/208 (20%)Anti-HBV therapy** p=0.018* p=0.115*

Pts with previous exposure 13/30 (43%) 11/32 (34%) 4/32 (13%)to conventional IFN p=0.047* p=0.038*

Pts with previous exposure 10/31 (32%) 6/24 (25%) 7/42 (17%)To Lamivudine P=0.065* P=0.253*

*vs. lamivudine** Includes lamivudine and conventional or pegylated interferon

Results: The effects of previous treatment with either interferon and/or lamivudine on HBeAg seroconversion rates are shown in the table. Regardless of whether patients were pre-treated or not, HBeAg seroconversion rates at week 72 were higher with peginterferon -2a and combination therapy than with lamivudine. The rate of adherence to peginterferon -2a was high, with 78% of patients receiving ≥90% of the total drug dosage (≥776µg). HBeAg seroconversion rates were 28% in those receiving <90% of the total drug dosage and 33% in those receiving ≥of the total drug dosage.

Conclusions: Peginterferon -2a (40 kDa) (PEGASYS®) provided higher rates of HBeAg seroconversion than lamivudine, irrespective of whether the patients had or had not received previous anti-HBV therapy. Previous treatment with interferon or lamivudine did not substantially affect HBeAg seroconversion rates with peginterferon -2a in this study. Adherence to peginterferon -2a in this study was excellent.

J. of Hepatology, Suppl .2 Vol.42, 2005 General Session 2: Hepatits B, Abstract 35

ELEVATED SERUM LEVEL OF HEPATITIS B VIRUS DNA IS AN INDEPENDENT RISK FACTOR FOR HEPATOCELLULAR CARCINOMA: A LONG-TERM FOLLOW-UP STUDY IN TAIWAN

C.J. Chen1, H.I. Yang1, J.Su2, C.L. Jen1, E. Kuo3, S.L. You1, U.H. Iloeje2.1National Taiwan University, Taipei, Taiwan; 2Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, USA; 3Bristol-Myers Squibb, Taipei, Taiwan

Introduction: Reduction in circulating HBV DNA level is a marker of efficacy for anti-viral treatment of chronic hepatitis B. However, there has never been a long-term follow-up study to examine the dose-response relation between serum HBV DNA level and hepatocellular carcinoma (HCC). This study was carried out to elucidate independent and interactive effects of serum HBV DNA on the development of HCC adjusting for HBeAg status and serum ALT level.

Methods: A cohort of 3,851 subjects seropositive for HBV surface antigen (HbsAG) was recruited from seven townships in Taiwan between 1991 and 1992. Serum samples obtained at enrolment and follow-up examination were tested for HbsAg, HbeAg, HBV DNA by PCR, and serum ALT. The diagnosis of HCC was ascertained through data linkage with computerized profiles of the National Cancer Registry and Death Certification System in Taiwan. Multivariable adjusted relative risks (RRadj) were derived using Cox proportional hazard models.

Results: During 43,993 person-years of follow-up, 176 patients were newly diagnosed with HCC. After adjustment for gender, age, habits of cigarette smoking, and alcohol consumption, antibodies against hepatitis C virus, and HBeAg status, the risk of developing HCC was strongly associated with HBV DNA level in a dose-response relationship (P<0.001). The RRadj was 6.6 (95%CI: 3.8-11.6) for those who had an alevated HBV DNA level (>105 copies/ml). In people with ALT<1xULN, HBV DNA≥105 copies/ml had a higher risk of HCC compared to those with undetectable HBV DNA, RRadj 10.2 (95%CI:5.7-18.4). In people with high DNA at baseline, the HCC risk was higher with persistent elevation, compared to those clearing DNA on repeat sampling RRadj 6.4 (95%CI:4.4-9.5).

Conclusion: Persistently elevated serum level of HBV DNA is a strong risk predictor of HCC independent of HBeAg status, chronic HCV infection, and elevated serum ALT level. Reduction in HBV DNA level overtime was associated with a decreased HCC risk.

Hepatology, Vol. 40, No. 4, Suppl. 1, 2004; Nr. 1136

Entecavir is superior to lamivudine at reducing HBV DNA in patients with chronic hepatitis B regardless of baseline alanine aminotransferase levels.

M Rosmawati, University Malaya Medical Center, Kuala Lumpur, Malaysia; E Schiff, University of Miami, Miami, FL; RE Parana, Federal University of Bahia, Salvador, Brazil; W Sievert, MMC Clayton, Victoria, Australia; J Zhu, A Cross, D Dehertogh, D Apelian, Bristol-Myers Squibb Pharmaceutical Research Insitute, Wallingford, CT; the BEHoLD Study Group

Background: Entecavir (ETV) is a potent and selective inhibitor of hepatitis B virus (HBV) polymerase. Chronic hepatitis B patients with low serum alanine aminotransferase (ALT) levels typically show reduced or absent responses to interferon and lamivudine (LVD). Data from a Phase II dose-ranging trial in nucleoside-naïve patients suggested that this is not the case for ETV. This analysis assesses the influence of baseline ALT levels on the clinical efficacy of ETV 0,5 mg QD compared to LVD 100 mg QD in a Phase III trial in 709 nucleoside-naïve patients with chronic hepatitis B (ETV-022).Methods: Patients were HBeAg (+) with baseline HBV DNA ≥ 3 MEq/ml by bDNA assay and ALT ≥ 1,3 x ULN. Efficacy endpoints included proportions of patients with HBV DNA < 0,7 MEq/ml by bDNA, proportions with HBV DNA < 400 copies/mL by PCR, and HBV DNA reduction by PCR. Efficacy results for both treatment groups were analysed within subgroups with baseline ALT < 2,6 x ULN or ≥ 2.6 x ULN. Results: Baseline disease characteristics were comparable in the ETV and LVD groups. Mean baseline viral loads were ETV: 9.61 log10 c/mL; LVD: 9.69 log10 c/mL. The baseline ALT < 2.6 x ULN and ≥ 2.6 x ULN subgroups comprised 186 and 168 ETV patients, respectively, and 190 and 164 LVD patients, respectively. Virologic efficacy results at week 48 by treatment and baseline ALT subgroup are shown in the table. ETV was highly effective at reducing HBV DNA regardless of baseline ALT level, and was superior to LVD by all virologic assessments. In contrast, among LVD-treated patients, HBV DNA reduction and the proportion of patients with undetectable HBV DNA levels by bDNA or PCR assays was attenuated in the lower baseline ALT subgroup. Conclusions: These data confirm Phase II observations showing that in patients with chronic hepatitis B, entecavir 0.5 mg is highly effective and is superior to LVD at reducing HBV DNA regardless of baseline ALT levels.

Baseline ALT ETV LVD p-value*Log reduction from baseline in HBV DNA by PCR

% of patients with:HBV DNA < 0.7 MEq/mLby DNA

HBV DNA < 400 copies/mL by PCR

< 2.6 x ULN≥ 2.6 x ULN

< 2.6 x ULN≥ 2.6 x ULN

< 2.6 x ULN≥ 2.6 x ULN

- 6,79- 7.18

90 %92 %

59 %81 %

- 4.85 - 6,15

58 %74 %

28 %49 %

< 0.0001< 0.0001

< 0.0001< 0.0001

< 0.0001< 0.0001

J. of Hepatology No.2 Vol.42, 2005 General Session 2: Hepatits B, Abstract 36

INCIDENCE AND PREDICTORS OF EMERGENCE OF ADEFOVIR RESISTANT HBV DURING FOUR YEARS OF ADEFOVIR DIPIVOXIL (ADV) THERAPY FOR PATIENTS WITH CHRONIC HEPATITIS B (CHB)

S. Locarnini1, X. Qi2, S. Arterburn2, A. Snow2, C.L.Brosgart2, G. Currie2, M. Wulfsohn2, M.D. Miller2, S.Xiong2. 1VIDRL Melburne, Australia; 2Gilead Science Inc., Foster City, CA, USA

Background: Lamivudine-resistant (LAM-R) HBV emerged in 70% of CHB patients by 4 years of LAM therapy. Higher baseline HBV DNA, higher body mass index (BMI), and male were predictors for developing LAM-R (Lai_JID_2003;36:687).

Aims: To determine the incidence of ADV resistance (ADV-R) mutations after 192 weeks of ADV therapy and the predictors for ADV-R.

Methods: This analysis included 629, 293, 221, and 67 patients who received ADV through 48, 96, 144, and 192 weeks, respectively, from 5 studies. At baseline, patients had wild-type or LAM-R HBV. The majority of patients received ADV monotherapy. Most patients with LAM-R HBV received 3 years of ADV+LAM. ADV-R mutations were identified by sequencing HBV RT. The culmulative probability (CP) of ADV-R was calculating using the Life Table method. Logistic regression was used to identify predictors of ADV-R.

Results: 22 patients developed ADV-R mutations (N236T and/or A181V) by 4 years. The incidence per period was 0% (o/629) for 8-48 weeks, 2% (6/293) for 49-96 weeks, 5% (11/217) for 97-144 weeks, and 8% (5/62) for 145-192 weeks. The CP for developing ADV-R by week 192 was 15% for all patients (18% for patients in ADV monotherapy trials). No ADV-R mutations were identified in patients on LAM+ADV. The N236T mutation was observed 4 times more frequently than A181V. Dual mutations A181V(/T)+N236T were observed in 4 (18%) patients. Development of ADV-R mutations was associated with serum HBV DNA rebound (≥1 log) in most patients. Logistic regressions analyses of baseline HBV DNA, ALT, race, age, gender, BMI, liver histology, prior HBV therapy, and week 48 HBV DNA identified only higher serum HBV DNA at week 48 (median 4.2 log with ADV-R vs. 3 log without ADV-R) as a predictor of ADV-R.

Conclusions: The cumulative probability of developing adefovir resistance wa 18% b 192 weeks of ADV therapy in CHB patients. LAM+ADV combination therapy appears to lower the chance of developing ADV-R. Higher HBV DNA at week 48 during ADV therapy predicted emergence of ADV resistance. The chance of developing reistance was over 4-fold lower with ADV monotherapy compared to that reported for LAM monotherapy by 4 years.

Hepatology 2004; Vol. 40, No. 4, Suppl.1: 238A

Reduction of the relative relapse rate by prolongation of the duration of a therapy with Peginterferon alfa-2a plus Ribavirin in patients with genotype 1 infection up to 72 weeks

Berg T, v.Wagner M, Hinrichsen H, Heintges T, Buggisch P, Goeser T, Rasenack J, Pape G, Schmidt W, Kallinowski B, Klinker H, Spengler U, Alshuth U, Zeuzem S.

Background: The reasons for the relatively high virological relapse rates after antiviral combination therapy in patients with HCV genotype 1 are unknown. A prolongation of the duration of the therapy could represent a strategy for reducing relapse rates in this difficult-to-treat patient group.Patients and methods: In a German multicentre study 456 patients with histologically proven chronic HCV type 1-infection were treated with 180 µg peginterferon alfa-2a per week plus 800 mg ribavirin per day for either 48 weeks (n=231) or 72 weeks (n=225). The intention to-treat analysis didn't show a significant difference in the sustained virological response rate between the two treatment groups. In this study we examined the influence of the duration of therapy on the relative relapse rate in relation to viral kinetics.Results: Overall the relative relapse rate (related to the number of patients with negative HCV RNA at the end of therapy) was 23% (72/314). In patients treated for 48 or 72 weeks, the relapse rates were 27% (44/165) and 19% (28/149) (p=0.09), respectively. A significant reduction in the relative relapse rate was evident with the prolonged duration of therapy (72 weeks) in patients with a late virological response. 46% and 81% of patients with HCV RNA >1000 IU/ml after week 4 or 12, who were treated for 48 weeks, suffered a relapse, while the corresponding relapse rates after 72 weeks of treatment were 34% and 44%, respectively (p = 0.03; OR 2.1 95% CI: 1.04-4.1 and OR 5.4 95% CI: 1.14-25.6). No significant difference was evident for sustained virological response and relapse rates in patients who were HCV RNA negative (< 1000 IU/ml) at week 4 or 12.Conclusion: In patients with a late virological response (HCV RNA positive at week 12 and negative at week 24) a significant reduction of the relapse rate may be achieved by prolonging the duration of therapy up to 72 weeks.

Hepatology, Vol. 40, No. 4, Suppl. 1, 2004; Nr. 169

Reduction of the relative relapse rate by prolongation of the duration of a therapy with peginterferon alfa-2a plus ribavirin in patients with genotype 1 infection up to 72 weeks

Thomas Berg, Charité, Campus Virchow-Klinikum, Berlin, Germany; Michael von Wagner, Universitätskliniken des Saarlandes, Homburg/Saar, Germany; Holger Hinrichsen, Christian Albrechts-Universität Kiel, Kiel, Germany; Tobias Heintges, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany; Peter Buggisch, Universitätsklinik Eppendorf, Hamburg, Germany; Tobias Goeser, Universität zu Köln, Köln, Germany; Jens Rasenack, Medizinische Universitätsklinik Freiburg, Germany; Gerd R Pape, Klinikum Grosshadern, Ludwig-Maximilians Universität, München, Germany; Wolfgang E Schmidt, Medizinische Universitätsklinik, St. Josephhospital, Bochum, Germany; Birgit Kallinowski, Universitätsklinik, Heidelberg, Germany; Hartwig Klinker, Klinikum der Universität Würzburg, Würzburg, Germany; Ulrich Spengler, Medizinische Einrichtung der Rh. Fr. Wilhelm Universität, Bonn, Germany; Ulrich Alshuth, Hoffmann-La Roche, Grenzach, Germany; Stefan Zeuzen, Universitätskliniken des Saarlandes, Homburg/Saar, Germany; For the German Study Group PEGASYS + COPEGUS in HCV Genotype 1

Background: The reasons for the relatively high virological relapse rates after antiviral combination therapy in patients with HCV genotype 1 are unknown. A prolongation of the duration of the therapy coluld represent a strategy for reducing relapse rates in this difficult-to-treat patient group.Patients and Methods: In a German multicentre study 456 patients with histologically proven chronic HCV type 1-infection were treated with 180 µg peginterferon alfa-2a per week plus 800 mg ribavirin per day for either 48 weeks (n=231) or 72 weeks (n=225). The intention to-treat analysis didn’t show a significant difference in the sustained virological response rate between the two treatment groups. In this study we examined the influence of the duration of therapy on the relative relapse rate in relation to viral kinetics. Results: Overall the relative relapse rate (related to the number of patients with negative HCV RNA at the end of therapy), was 23% (72/314). In patients treated for 48 or 72 weeks, the relapse rates were 27% (44/165) and 19% (28/149) (p=0,09), respectively. A. significant reduction in the relative relapse rate was evident with the prolonged duration of therapy (72 weeks) in patients with a late virological response. 46% and 81% of patients with HCV RNA >1000 IU/ml after week 4 or 12, who were treated for 48 weeks, suffered a relapse, while the corresponding relapse rates after 72 weeks of treatment were 34% and 44%, respectively (p=0,03; OR 2.1 95% CI: 1.04-4.1 and OR 5.4 95% CI: 1.14-25.6). No significant difference was evident for sustained virological response and relapse rates in patients who were HCV RNA negative (< 1000 IU/ml) at week 4 or 12.

Conclusion: In patients with a late virological response (HCV RNA positive at week 12 and negative at week 24) a significant reduction of the relapse rate may be achieved by prolonging the duration of therapy up to 72 weeks. Hepatology, Vol. 40, No. 4. Suppl. 1, 2004; LB 02

Randomized multicenter study comparing 16 VS. 24 weeks of combination therapy with peginterferon alfa-2a plus ribavirin in patients chronically infected with HCV genotype 2 or 3.

Michael von Wagner, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Miriam Huber, Johann Wolfgang Goethe Universität, Frankfurt/Main, Germany; Thomas Berg, Charité, Campus Virchow-Klinikum, Berlin, Germany; Holger Hinrichsen, Christian-Albrecht-Universität, Kiel, Germany; Jens Rasenack, Medizinische Universitätsklinik, Freiburg, Germany; Tobias Heintges, Heinrich-Heine-Universität, Düsseldorf, Germany; Alexandra Bergk, Charité, Campus Virchow-Klinikum, Berlin, Germany; Christine Bernsmeier, Christian-Albrecht-Universität, Kiel, Germany; Stafan Zeuzem, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany

Background: Extending treatment duration with peginterfeeron alfa plus ribavirin form 24 to 48 weeks did not improve sustained virologic response rates in patients infected with HCV genotype 2 or 3 (Ann Intern Med 2004; 140:346-355, J Hepatol 2004; 40:993-999). Whether shorter treatment durations are possible for these patients without compromising sustained virologic response rates is unknown. Aim: To compare virologic response rates in patients with chronic HCV-2 or –3 infection treated for 16 vs. 24 weeks. Methods: Previously untreated patients (mean age 39 ± 10 yrs.) chronically infected with HCV genotype 2 (n=39) or 3 (n=114) were treated with 180 µg peginterferon alfa-2a once weekly in combination with ribavirin (800-1200 mg/day). HCV RNA was assessed after 4 weeks by quantitative RT-PCR assay (Cobas Amplicor Monitor). Patients with HCV RNA below the limit of detection of the assay (600 IU/mL) were randomised for a total treatment duration of 16 weeks (group A) or 24 weeks (group B). All patients with detectable HCV RNA levels at week 4 (group C) were treated for 24 weeks. End-of-treatment and sustained virologic response after a 24-week follow-up period were assessed by qualitative RT-PRC (Cobas Amplicor HCV, sensitivity 50 IU/mL). Results: Only 14/153 patients (9%) were allocated to group C. In contrast, 139/153 patients infected with HCV genotype 2 or 3 achieved HCV RNA levels below 600 IU/mL at week 4 of treatment and were randomised to groups A and B. Intent-to-treat virologic response rates are given in the Table: On-treatment dorp-out rates in groups A, B, C were 5.6%, 13.2%, 14.3%, respectively. Adverse events and laboratory abnormalities were similar to previous trials using peginterferon alfa-2a and ribavirin combination therapy. Conclusion: At week 4 of treatment with peginterferon alfa-2a plus ribavirin an early virologic response was observed in mor than 90% of patients chronically infected with HCV genotype 2 or 3. Combination therapy for 16 or 24 weeks achieved similar sustained virologic response rates in these early virologic response rate in patients without an early virologic response at week 4 (group C) implies that a treatment duration longer than 24 weeks may be necessary in this small subset of patients. TableVirologic All Group A Group B Group C

responseEnd of treatmentEnd of follow-up

135/153 (88.2%)111/153 (72.5%)

67/71 (94.4%)57/71 (78.9%)

58/68 (85.3%)51/68 (75.0%)

10/14 (71.0%)4/14 (28.6%)

NASH / ASH / Autoimmun M. Pirlich

Hepatology. 2004 May;39(5):1390-7.

A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis.

Naveau S, Chollet-Martin S, Dharancy S, Mathurin P, Jouet P, Piquet MA, Davion T, Oberti F, Broet P, Emilie D; Foie-Alcool group of the Association Francaise pour l'Etude du Foie.

Services d'Hepato-Gastroenterologie, Hopital Antoine Beclere, Clamart, Assistance Publique-Hopitaux de Paris, France. sylvie.naveau@abc.ap-hop-paris.fr

Tumor necrosis factor-alpha (TNF-alpha) may contribute to the progression of acute alcoholic hepatitis (AAH). The aim of this study was to evaluate the efficacy of an association of infliximab and prednisolone at reducing the 2-month mortality rate among patients with severe AAH. Patients with severe AAH (Maddrey score >/=32) were randomly assigned to group A receiving intravenous infusions of infliximab (10 mg/kg) in weeks 0, 2, and 4; or group B receiving a placebo at the same times. All patients received prednisolone (40 mg/day) for 28 days. Blood neutrophil functional capacities were monitored over 28 days. After randomization of 36 patients, seven patients from group A and three from group B died within 2 months. The probability of being dead at 2 months was higher (not significant [NS]) in group A (39% +/- 11%) than in group B (18% +/- 9%). The study was stopped by the follow-up committee and the sponsor (Assistance Publique-Hopitaux de Paris). The frequency of severe infections within 2 months was higher in group A than in group B (P <.002). This difference was potentially related to a significantly lower ex vivo stimulation capacity of neutrophils. There were no differences between the two groups in terms of Maddrey scores at any time point. In conclusion, three infusions of 10 mg/kg of infliximab in association with prednisolone may be harmful in patients with severe AAH because of the high prevalence of severe infections.

Hepatology. 2004 Mar;39(3):770-8 Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial.

Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, Lymp JF, Burgart L, Colin P.

Division of Gastroenterology and Hepatology, Mayo Clinic-W19A, 200 1st Street SW, Rochester, MN 55905, USA. lindor.keith@mayo.edu

No effective medical therapy is available for all patients with nonalcoholic steatohepatitis (NASH). Ursodeoxycholic acid (UDCA) has been suggested to be of benefit based on open label clinical studies. We randomized 166 patients with liver biopsy-proven NASH to receive between 13 and 15 mg/kg/d of UDCA or placebo for 2 years. End points included changes in liver test results and liver histology at 2 years of therapy. The treatment groups were comparable at entry with regard to age, gender, risk factors for NASH, serum liver biochemistries, and baseline liver histology. A total of 126 patients completed 2 years of therapy. Pre- and posttreatment liver biopsies were available in 107 patients for review at the end of the study. UDCA was well tolerated and body weight was stable during the study duration. Serum liver biochemistries were stable or improved in both the UDCA and placebo-treated groups. Changes in the degree of steatosis, necroinflammation, or fibrosis that occurred with therapy were not significantly different between the UDCA and placebo groups. In conclusion, 2 years of therapy with UDCA at a dose of 13 to 15 mg/kg/d, although safe and well tolerated, is not better than placebo for patients with NASH.

Hepatology. 2004 Jan;39(1):188-96.

A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis.

Promrat K, Lutchman G, Uwaifo GI, Freedman RJ, Soza A, Heller T, Doo E, Ghany M, Premkumar A, Park Y, Liang TJ, Yanovski JA, Kleiner DE, Hoofnagle JH.

Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease for which there is no known effective therapy. A proportion of patients with NASH progress to advanced fibrosis and cirrhosis. NASH is considered one of the clinical features of the metabolic syndrome in which insulin resistance plays a central role. This prospective study evaluates the role of insulin-sensitizing agent in treatment of NASH. Eighteen nondiabetic patients with biopsy-proven NASH were treated with pioglitazone (30 mg daily) for 48 weeks. Tests of insulin sensitivity and body composition as well as liver biopsies were performed before and at the end of treatment. By 48 weeks, serum alanine aminotransferase values fell to normal in 72% of patients. Hepatic fat content and size as determined by magnetic resonance imaging decreased, and glucose and free fatty acid sensitivity to insulin were uniformly improved. Histological features of steatosis, cellular injury, parenchymal inflammation, Mallory bodies, and fibrosis were significantly improved from baseline (all P < 0.05). Using strict criteria, histological improvement occurred in two-thirds of patients. Pioglitazone was well tolerated; the main side effects were weight gain (averaging 4%) and an increase in total body adiposity. In conclusion, these results indicate that treatment with an insulin-sensitizing agent can lead to improvement in biochemical and histological features of NASH and support the role of insulin resistance in the pathogenesis of this disease. The long-term safety and benefits of pioglitazone require further study.

Portale Hypertension M. Peck

Gastroenterology. 2004 Oct;127(4):1123-30

Recombinant factor VIIa for upper gastrointestinal bleeding in patients with cirrhosis: a randomized, double-blind trial.

Bosch J, Thabut D, Bendtsen F, D'Amico G, Albillos A, Gonzalez Abraldes J, Fabricius S, Erhardtsen E, de Franchis R; European Study Group on rFVIIa in UGI Haemorrhage.

Hospital Clinic, Liver Unit, Barcelona, Spain. jbosch@medicina.ub.es

BACKGROUND & AIMS: Upper gastrointestinal bleeding (UGIB) is a severe and frequent complication of cirrhosis. Recombinant coagulation factor VIIa (rFVIIa) has been shown to correct the prolonged prothrombin time in patients with cirrhosis and UGIB. This trial aimed to determine efficacy and safety of rFVIIa in cirrhotic patients with variceal and nonvariceal UGIB. METHODS: A total of 245 cirrhotic patients (Child-Pugh < 13; Child-Pugh A = 20%, B = 52%, C = 28%) with UGIB (variceal = 66%, nonvariceal = 29%, bleeding source unknown = 5%) were randomized equally to receive 8 doses of 100 microg/kg rFVIIa or placebo in addition to pharmacologic and endoscopic treatment. The primary end point was a composite including: (1) failure to control UGIB within 24 hours after first dose, or (2) failure to prevent rebleeding between 24 hours and day 5, or (3) death within 5 days. RESULTS: Baseline characteristics were similar between rFVIIa and placebo groups. rFVIIa showed no advantage over standard treatment in the whole trial population. Exploratory analyses, however, showed that rFVIIa significantly decreased the number of failures on the composite end point (P = 0.03) and the 24-hour bleeding control end point (P = 0.01) in the subgroup of Child-Pugh B and C variceal bleeders. There were no significant differences between rFVIIa and placebo groups in mortality (5- or 42-day) or incidence of adverse events including thromboembolic events. CONCLUSIONS: Although no overall effect of rFVIIa was observed, exploratory analyses in Child-Pugh B and C cirrhotic patients indicated that administration of rFVIIa significantly decreased the proportion of patients who failed to control variceal bleeding. Dosing with rFVIIa appeared safe. Further studies are needed to verify these findings.

Gastroenterology. 2004 Feb;126(2):469-75

Improved clinical outcome using polytetrafluoroethylene-coated stents for TIPS: results of a randomized study.

Bureau C, Garcia-Pagan JC, Otal P, Pomier-Layrargues G, Chabbert V, Cortez C, Perreault P, Peron JM, Abraldes JG, Bouchard L, Bilbao JI, Bosch J, Rousseau H, Vinel JP.

Service d'Hepato-Gastro-Enterologie, Federation Digestive, Centre Hospitalier Universitaire Purpan et U531 Institut National de la Sante et de la Recherche Medicale, Toulouse, France. bureau.c@chu-toulouse.fr

BACKGROUND & AIMS: A 50% dysfunction rate at 1 year is one of the main drawbacks of the transjugular intrahepatic portosystemic shunt procedure. Preliminary experimental and clinical studies suggest that the use of stents covered with polytetrafluoroethylene could tremendously decrease this risk. METHODS: Eighty patients with cirrhosis and uncontrolled bleeding (n = 23), recurrent bleeding (n = 25), or refractory ascites (n = 32) were randomized to be treated by transjugular intrahepatic portosystemic shunts with either a polytetrafluoroethylene-covered stent (group 1; 39 patients) or a usual uncovered prosthesis (group 2; 41 patients). Follow-up Doppler ultrasound was scheduled at day 7, at 1 month, and then every 3 months for 2 years. Angiography and portosystemic pressure gradient measurements were performed 6, 12, and 24 months after the transjugular intrahepatic portosystemic shunt procedure and whenever dysfunction was suspected. Dysfunction was defined as a >50% reduction of the lumen of the shunt at angiography or a portosystemic pressure gradient >12 mm Hg. RESULTS: After a median follow-up of 300 days, 5 patients (13%) in group 1 and 18 (44%) in group 2 experienced shunt dysfunction (P < 0.001). Clinical relapse occurred in 3 patients (8%) in group 1 and 12 (29%) in group 2 (P < 0.05). Actuarial rates of encephalopathy were 21% in group 1 and 41% in group 2 at 1 year (not significant). Estimated probabilities of survival were 71% and 60% at 1 year and 65% and 41% at 2 years in groups 1 and 2, respectively (not significant). CONCLUSIONS: The use of polytetrafluoroethylene-covered prostheses improves transjugular intrahepatic portosystemic shunt patency and decreases the number of clinical relapses and reinterventions without increasing the risk of encephalopathy.

Hepatology. 2004 Oct;40(4):793-801.

Influence of portal hypertension and its early decompression by TIPS placement on the outcome of variceal bleeding.

Monescillo A, Martinez-Lagares F, Ruiz-del-Arbol L, Sierra A, Guevara C, Jimenez E, Marrero JM, Buceta E, Sanchez J, Castellot A, Penate M, Cruz A, Pena E.

Digestive Disease Department, Hospital Universitario Insular de Gran Canaria, Canary Islands, Spain. monescillo@eresmas.com

Increased portal pressure during variceal bleeding may have an influence on the treatment failure rate, as well as on short- and long-term survival. However, the usefulness of hepatic hemodynamic measurement during the acute episode has not been prospectively validated, and no information exists about the outcome of hemodynamically defined high-risk patients treated with early portal decompression. Hepatic venous pressure gradient (HVPG) measurement was made within the first 24 hours after admission of 116 consecutive patients with cirrhosis with acute variceal bleeding treated with a single session of sclerotherapy injection during urgent endoscopy. Sixty-four patients had an HVPG less than 20 mm Hg (low-risk [LR] group), and 52 patients had an HVPG greater than or equal to 20 mm Hg (high-risk [HR] group). HR patients were randomly allocated into those receiving transjugular intrahepatic portosystemic shunt (TIPS; HR-TIPS group, n = 26) within the first 24 hours after admission and those not receiving TIPS (HR-non-TIPS group). The HR-non-TIPS group had more treatment failures (50% vs. 12%, P =.0001), transfusional requirements (3.7 +/- 2.7 vs. 2.2 +/- 2.3, P =.002), need for intensive care (16% vs. 3%, P <.05), and worse actuarial probability of survival than the LR group. Early TIPS placement reduced treatment failure (12%, P =.003), in-hospital and 1-year mortality (11% and 31%, respectively; P <.05). In conclusion, increased portal pressure estimated by early HVPG measurement is a main determinant of treatment failure and survival in variceal bleeding, and early TIPS placement reduces treatment failure and mortality in high risk patients defined by hemodynamic criteria.

Hepatology. 2005 Mar;41(3):572-8.

Variceal ligation plus nadolol compared with ligation for prophylaxis of variceal rebleeding: a multicenter trial.

de la Pena J, Brullet E, Sanchez-Hernandez E, Rivero M, Vergara M, Martin-Lorente JL, Garcia Suarez C.

Hospital Universitario Marques de Valdecilla, Santander, Spain. jpena@humv.es

beta-Blockers and endoscopic variceal ligation (EVL) have proven to be valuable methods in the prevention of variceal rebleeding. The aim of this study was to compare the efficacy of EVL combined with nadolol versus EVL alone as secondary prophylaxis for variceal bleeding. Patients admitted for acute variceal bleeding were treated during emergency endoscopy with EVL or sclerotherapy and received somatostatin for 5 days. At that point, patients were randomized to receive EVL plus nadolol or EVL alone. EVL sessions were repeated every 10 to 12 days until the varices were eradicated. Eighty patients with cirrhosis (alcoholic origin in 66%) were included (Child-Turcotte-Pugh A, 15%; B, 56%; C, 29%). The median follow-up period was 16 months (range, 1-24 months). The variceal bleeding recurrence rate was 14% in the EVL plus nadolol group and 38% in the EVL group (P = .006). Mortality was similar in both groups: five patients (11.6%) died in the combined therapy group and four patients (10.8%) died in the EVL group. There were no significant differences in the number of EVL sessions to eradicate varices: 3.2 +/- 1.3 in the combined therapy group versus 3.5 +/- 1.3 in the EVL alone group. The actuarial probability of variceal recurrence at 1 year was lower in the EVL plus nadolol group (54%) than in the EVL group (77%; P = .06). Adverse effects resulting from nadolol were observed in 11% of the patients. In conclusion, nadolol plus EVL reduces the incidence of variceal rebleeding compared with EVL alone. A combined treatment could lower the probability of variceal recurrence after eradication.

Gastroenterology. 2004 Aug;127(2):476-84.

A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis.

Merkel C, Marin R, Angeli P, Zanella P, Felder M, Bernardinello E, Cavallarin G, Bolognesi M, Donada C, Bellini B, Torboli P, Gatta A; Gruppo Triveneto per l'Ipertensione Portale.

Department of Clinical and Experimental Medicine, University of Padua, Padova, Italy. carlo.merkel@unipd.it

BACKGROUND & AIMS: Beta-blockers are extensively used to prevent variceal bleeding in patients with large esophageal varices. It is not established if beta-blockers delay the growth of small varices. METHODS: A total of 161 patients with cirrhosis and small esophageal varices (F1 according to the classification of Beppu et al.) without previous bleeding were enrolled. A total of 83 patients were randomized to nadolol (dose adjusted to decrease resting heart rate by 25%; mean dose given, 62 +/- 25 mg/day) and 78 to placebo. The principal end point was occurrence of large esophageal varices (F2 or F3 according to the classification of Beppu et al.). Endoscopic examination was performed after 12, 24, 36, 48, and 60 months of follow-up. Mean follow-up was 36 months. RESULTS: The 2 groups were well matched for demographic and clinical characteristics. During the study period, 9 patients randomized to nadolol and 29 randomized to placebo had growth of esophageal varices. At the end of follow-up, the cumulative risk was 20% versus 51% (P < 0.001) (absolute risk difference, 31%; 95% confidence interval, 17%-45%). When possible confounding factors were taken into account, treatment was a significant factor predicting growth of varices (odds ratio, 4.0; 95% confidence interval, 1.95-8.4). The cumulative probability of variceal bleeding was also lower in patients randomized to nadolol (P = 0.02). Survival was not different (P = 0.33). Adverse effects resulting in withdrawal of drug occurred in 9 in the nadolol group and one in the placebo group (P = 0.01). CONCLUSIONS: This study suggests that beta-blocker prophylaxis of variceal bleeding in patients with compensated cirrhosis should be started when small esophageal varices are present.

Hepatology. 2005 Mar;41(3):588-94.+#

Pantoprazole reduces the size of postbanding ulcers after variceal band ligation: a randomized, controlled trial.

Shaheen NJ, Stuart E, Schmitz SM, Mitchell KL, Fried MW, Zacks S, Russo MW, Galanko J, Shrestha R.

Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.

Elective esophageal variceal ligation (EVL) is performed to decrease the risk of variceal hemorrhage. Side effects of EVL include hemorrhage, chest pain, dysphagia, and odynophagia. Because gastric acid may exacerbate postbanding ulcers and delay healing, proton pump inhibition may decrease side effects associated with EVL. The aim of this study was to assess the efficacy of pantoprazole, a proton pump inhibitor, as an adjunct to elective EVL. We performed a double-blinded, randomized, placebo-controlled trial of pantoprazole after elective EVL. Subjects in the pantoprazole arm received 40 mg pantoprazole intravenously after EVL followed by 40 mg oral pantoprazole for 9 days. Control subjects received intravenous and oral placebo. Subjects underwent upper endoscopy 10 to 14 days after banding. Primary outcomes included the size and number of ulcers and the subjects' reports of dysphagia, chest pain, and heartburn. Forty-four subjects were randomized: 42 completed the protocol. At follow-up endoscopy, the mean number of ulcers was similar in the two groups. However, the ulcers in the pantoprazole group were on average half as large as in the placebo group (37 mm(2) vs. 82 mm(2), P < .01). Chest pain, dysphagia, and heartburn scores were not significantly different. Four subjects, all in the placebo group, had adverse outcomes, including 3 who bled from postbanding ulcers and 1 with sepsis. In conclusion, subjects receiving pantoprazole after elective EVL had significantly smaller postbanding ulcers on follow-up endoscopy than subjects receiving placebo. However, the total ulcer number and patient symptoms were not different between the groups.

BMJ. 2004 May 1;328(7447):1046. Epub 2004 Mar 30.

Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials.

Als-Nielsen B, Gluud LL, Gluud C.

Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Department 7102, H:S Rigshospitalet, DK-2100 Copenhagen, Denmark. bodil.a@ctu.rh.dk

OBJECTIVE: To assess the effects of non-absorbable disaccharides (lactulose and lactitol) in patients with hepatic encephalopathy. DATA SOURCES: Cochrane Hepato-Biliary Group controlled trials register, Cochrane Library, Medline, and Embase until March 2003; reference lists of relevant articles; authors and pharmaceutical companies. REVIEW METHODS: Randomised trials that compared non-absorbable disaccharides with placebo, no intervention, or antibiotics for hepatic encephalopathy were included. The primary outcome measures were no improvement of hepatic encephalopathy and all cause mortality. RESULTS: 22 trials were included. Compared with placebo or no intervention, non-absorbable disaccharides seemed to reduce the risk of no improvement in patients with hepatic encephalopathy (relative risk 0.62, 95% confidence interval 0.46 to 0.84, six trials). However, high quality trials found no significant effect (0.92, 0.42 to 2.04, two trials). Compared with placebo or no intervention, non-absorbable disaccharides had no significant effect on mortality (0.41, 0.02 to 8.68, four trials). Non-absorbable disaccharides were inferior to antibiotics in reducing the risk of no improvement (1.24, 1.02 to 1.50, 10 trials) and lowering blood ammonia concentration (weighted mean difference 2.35 micromol/l, 0.06 micromol/l to 13.45 micromol/l, 10 trials). There was no significant difference in mortality (0.90, 0.48 to 1.67, five trials). CONCLUSIONS: There is insufficient evidence to support or refute the use of non-absorbable disaccharides for hepatic encephalopathy. Antibiotics were superior to non-absorbable disaccharides in improving hepatic encephalopathy, but it is unclear whether this difference is clinically important. Non-absorbable disaccharides should not serve as comparator in randomised trials on hepatic encephalopathy.

Darmerkrankungen/PankreasCED: Neue Substanzen A. Dignaß

1. Originalarbeiten

Gastroenterology (im Druck, Juni-Ausgabe)

Infliximab as rescue therapy in severe to moderately severe ulcerative colitis. A randomised placebo controlled study.

Gunnar Järnerot, Erik Hertervig, Inga-Lill Friis-Liby, Lars Blomquist, Per Karlén, Christer Grännö, Mogens Vilien, Magnus Ström, Åke Danielsson,. Hans Verbaan, Per M Hellström, Anders Magnuson and Bengt Curman.

Background & Aims: In spite of treatment with corticosteroids, severe - moderately severe attacks of ulcerative colitis have a high colectomy rate. We intended to find another rescue therapy than cyclosporine A, which imposes a high risk of side-effects and cyclosporine related mortality.

Methods: This was a randomised double-blind trial of infliximab or placebo in severe - moderately severe ulcerative colitis not responding to conventional treatment. Patients were randomised to infliximab/placebo either on Day 4 after initiation of corticosteroid treatment if they fulfilled the index criteria for fulminant ulcerative colitis on Day 3 or on Day 6-8 if they on Day 5-7 fulfilled index criteria for a severe -moderately severe acute attack of ulcerative colitis. Results were analysed according to the intention - to - treat principle. The primary end point was colectomy or death 3 months after randomisation. Secondary end points were clinical and endoscopic remission at that time in patients not operated.

Results: 45 patients were included (24 infliximab, 21 placebo). No patient died. Seven patients in the infliximab and 14 in the placebo group had a colectomy (p=0.017. OR 4.9 (95%CI 1.4-17) within 3 months after randomisation. No serious side-effects occurred. Three patients in the placebo group required surgery for septic complications.

Conclusions: Infliximab in a dose of 4-5 mg/kg is an effective and safe rescue therapy in patients suffering from an acute severe or moderately severe attack of ulcerative colitis not responding to conventional treatment.

Gastroenterology. 2005 Mar;128(3):552-63.

Autologous hematopoietic stem cell transplantation in patients with refractory Crohn's disease.

Oyama Y, Craig RM, Traynor AE, Quigley K, Statkute L, Halverson A, Brush M, Verda L, Kowalska B, Krosnjar N, Kletzel M, Whitington PF, Burt RK.

Division of Immunotherapy, Department of Medicine, Northwestern University Medical Center, Chicago, Illinois 60611, USA. y-oyama@northwestern.edu

BACKGROUND & AIMS: Crohn's disease (CD) is an immunologically mediated inflammatory disease of the gastrointestinal tract. Due to a high morbidity and/or an increase in mortality in refractory cases, a new treatment approach is needed. In theory, maximum immune ablation by autologous hematopoietic stem cell transplantation (HSCT) can induce a remission. METHODS: We conducted a phase 1 HSCT study in 12 patients with refractory CD. Candidates were younger than 60 years of age with a Crohn's Disease Activity Index (CDAI) of 250-400 despite conventional therapies including infliximab. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony-stimulating factor and CD34 + enriched. The immune ablative (conditioning) regimen consisted of 200 mg/kg cyclophosphamide and 90 mg/kg equine antithymocyte globulin. RESULTS: The procedure was well tolerated with anticipated cytopenias, neutropenic fever, and disease-related fever, diarrhea, anorexia, nausea, and vomiting. The median days for neutrophil and platelet engraftment were 9.5 (range, 8-11) and 9 (range, 9-18), respectively. The initial median CDAI was 291 (range, 250-358). Symptoms and CDAI improved before hospital discharge, whereas radiographic and colonoscopy findings improved gradually over months to years following HSCT. Eleven of 12 patients entered a sustained remission defined by a CDAI < or =150. After a median follow-up of 18.5 months (range, 7-37 months), only one patient has developed a recurrence of active CD, which occurred 15 months after HSCT. CONCLUSIONS: Autologous HSCT may be performed safely and has a marked salutary effect on CD activity. A randomized study will be needed to confirm the efficacy of this therapy.

Gastroenterology. 2005 Apr;128(4):825-32

Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial.

Summers RW, Elliott DE, Urban JF Jr, Thompson RA, Weinstock JV.

James A. Clifton Center for Digestive Diseases, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA. robert-summers@uiowa.edu

BACKGROUND & AIMS: Ulcerative colitis is most common in Western industrialized countries. Inflammatory bowel disease is uncommon in developing countries where helminths are frequent. People with helminths have an altered immunological response to antigens. In animal models, helminths prevent or improve colitis by the induction of regulatory T cells and modulatory cytokines. This study determined the efficacy and safety of the helminth Trichuris suis in therapy of ulcerative colitis. METHODS: This was a randomized, double blind, placebo-controlled trial conducted at the University of Iowa and select private practices. Trichuris suis ova were obtained from the US Department of Agriculture. The trial included 54 patients with active colitis, defined by an Ulcerative Colitis Disease Activity Index of > or =4. Patients were recruited from physician participants and were randomly assigned to receive placebo or ova treatment. Patients received 2500 Trichuris suis ova or placebo orally at 2-week intervals for 12 weeks. RESULTS: The primary efficacy variable was improvement of the Disease Activity Index to > or =4. After 12 weeks of therapy, improvement according to the intent-to-treat principle occurred in 13 of 30 patients (43.3%) with ova treatment compared with 4 of 24 patients (16.7%) given placebo (P = .04). Improvement was also found with the Simple Index that was significant by week 6. The difference in the proportion of patients who achieved an Ulcerative Colitis Disease Activity Index of 0-1 was not significant. Treatment induced no side effects. CONCLUSIONS: Ova therapy seems safe and effective in patients with active colitis.

2. DDW Abstracts

DDW Abstract 689- Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-105

Disclosures: Organization - Centocor, Inc., Relationship - Employee

A Randomized Placebo-Controlled Trial Of Infliximab Therapy for Active Ulcerative Colitis: Act I Trial

P. Rutgeerts, B.G. Feagan, Dr., A. Olson, Dr., J. Johanns, Dr., S. Travers, Dr., D. Present, Dr., B.E. Sands, Dr., W. Sandborn, Dr. , A. Olson

Background: There is a need for an effective therapy for active ulcerative colitis (UC). Two randomized, placebo-controlled trials (ACT 1 and ACT 2) were designed to evaluate the safety and efficacy of infliximab (IFX) for active UC. Results from ACT 1, which evaluated patients treated with corticosteriods and/or 6-MP/AZA, are presented.Methods: Patients (n=364) with active UC despite use of corticosteroids/AZA/6-MP, with endoscopic evidence of moderate or severe UC (endoscopy score>=2) and a total Mayo score of 6-12 inclusive, were randomized to receive placebo, IFX 5 mg/kg or 10 mg/kg at wks 0, 2, and 6 then every 8 wks through wk 46. The primary endpoint was induction of clinical response, defined as a decrease in the Mayo score of >=30% and >=3 points, accompanied by a decrease in rectal bleeding score of >=1 or a rectal bleeding score of 0 or 1 at wk 8. Secondary endpoints included clinical remission, defined as a Mayo score <=2, with no individual subscores >1, and mucosal healing defined as an endoscopy subscore of 0 or 1.Results: Significantly higher proportions of patients receiving IFX 5 mg/kg (69.4%) and 10 mg/kg (61.5%) were in clinical response at wk 8 vs. placebo-treated patients (37.2%, p<0.001). At wk 30, 52.1% and 50.8% of IFX 5 and 10 mg/kg treated patients, respectively, achieved clinical response vs. 29.8% of placebo-treated patients (p<0.001 and p=0.002). At wk 8, 38.8% and 32.0% of IFX 5 and 10 mg/kg treated patients, respectively, were in clinical remission vs. 14.9% of placebo-treated patients (p<0.001 and p=0.002). These differences in remission rates persisted at wk 30 (33.9%, 5 mg/kg; 36.9%, 10 mg/kg vs. 15.7%, placebo; p=0.001 and p<0.001). Mucosal healing was achieved at wk 8 in 62% and 59% of patients receiving IFX 5 and 10 mg/kg, respectively vs. 33.9% of placebo-treated patients (p<0.001). This difference in mucosal healing was maintained at wk 30 (50.4%, 5 mg/kg; 49.2%, 10 mg/kg vs. 24.8%, placebo; p<0.001 for both). The proportion of patients who were able to discontinue corticosteroids while in clinical remission at wk 30 was greater in the combined IFX treatment group than in the placebo group (21.7% vs. 10.1%; p=0.039). IFX was generally well tolerated with a safety profile similar to that previously reported.Conclusion: IFX is effective in treating active UC by reducing signs and symptoms, inducing remission, attaining mucosal healing, and facilitating corticosteroid withdrawal while maintaining remission.

DDW Abstract 688- Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-104

Disclosures: Organization - Schering-Plough, Centocor, Inc., Relationship - Grant / Research Support

Infliximab Induction and Maintenance Therapy for Ulcerative Colitis: the Act 2 Trial

W.J. Sandborn, D. Rachmilewitz, Dr., S.B. Hanauer, Dr., G.R. Lichtenstein, Dr., W.J. de Villiers, Dr., A. Olson, Dr., J. Johanns, Dr. , S. Travers, Dr. , J. Colombel, Dr.

Background: The efficacy of infliximab (IFX) for the treatment of ulcerative colitis (UC) was previously unknown. Two Phase 3 trials, ACT I and ACT 2, evaluated the safety and efficacy of IFX for treatment of active UC. Results from ACT 2 are presented.Methods: 364 patients with UC, refractory to at least one standard therapy including 5-ASA, corticosteroids, or immunosuppressants, were randomized to receive IFX 5 mg/kg, IFX 10 mg/kg, or placebo at wks 0, 2, 6, 14 and 22. The primary endpoint was induction of clinical response, defined as a decrease in the Mayo score of >=30% and >=3 points, accompanied by a decrease in the rectal bleeding score of >=1 or a rectal bleeding score of 0 or 1 at wk 8. Clinical remission, a secondary endpoint, was defined as a Mayo score <=2, with no individual subscores >1, and mucosal healing was defined as an endoscopy subscore of 0 or 1.Results: 64.5% of patients receiving IFX 5 mg/kg and 69.2% receiving 10 mg/kg were in clinical response at wk 8 vs 29.3% who received placebo (p<0.001 for both). At wk 30, 47.1% of patients receiving IFX 5 mg/kg and 60% receiving 10 mg/kg were in clinical response vs 26% of patients receiving placebo (p<0.001 for both). Clinical remission was achieved at wk 8 in 33.9% and 27.5% of IFX 5 and 10 mg/kg patients, respectively, compared to 5.7% of placebo-treated patients (p<0.001 for both). Differences in remission rates persisted at wk 30 (25.6%, 5 mg/kg; 35.8%, 10 mg/kg; 10.6%, placebo; p=0.003 and p<0.001). Mucosal healing was achieved at wk 8 in 60.3% and 61.7% of patients receiving IFX 5 mg/kg and 10 mg/kg, respectively, compared to 30.9% of placebo-treated patients (p<0.001 for both). Mucosal healing at wk 30 was achieved in 46.3% and 56.7% of patients receiving IFX 5 and 10 mg/kg, respectively, vs 30.1% of placebo-treated patients (p=0.009 and p<0.001). The proportion of patients who were able to discontinue corticosteroids while in clinical remission at wk 30 was significantly greater in both IFX groups compared with the placebo group (18.3%, 5 mg/kg; 27.3%, 10 mg/kg; 3.3%, placebo; p<0.001 and p=0.010, respectively). IFX was generally well tolerated with a safety profile similar to that previously reported.Conclusion: In patients with moderate-to-severe UC, IFX induces and maintains clinical response, clinical remission and mucosal healing, and permits the tapering of corticosteroids while maintaining remission.

DDW Abstract 489 - Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-74

Disclosures: None

Remission-Induction and Steroid-Sparing Efficacy By Oral Tacrolimus (FK506) Therapy Against Refractory Ulcerative Colitis

Authors: H. Ogata, T. Matsui, M. Nakamura , M. Iida, M. Takazoe, Y. Suzuki, T. Hibi

BACKGROUND: The effectiveness of immunosuppressive therapy with oral tacrolimus (FK506) for patients with refractory ulcerative colitis (UC) is not known except for pilot studies. AIMS: We conducted a randomized, placebo-controlled, double-blind study to determine the effective trough level, the efficacy and safety of oral tacrolimus therapy followed by an open-labeled trial subsequently performed to moderate/severe, refractory active UC. SUBJECTS and METHODS: Sixty patients with refractory UC were enrolled and randomized into either a placebo (PLC), low or high trough groups (LTG and HTG respectively) for a two-week treatment period. Patients in LTG and HTG were dose-adjusted with the levels of 5-10 ng/mL and 10-15 ng/mL respectively. Patients were evaluated with the response rate of Disease Activity Index (DAI) Score. The open-labeled trial was subsequently performed, and all patients were dose-adjusted with the levels of　5-15ng/mL. The DAI was re-evaluated and the doses of prednisolone were also calculated at 10 weeks after open-labeled trial started. RESULTS: Trough levels were well-controlled within their respective target levels under double-blind conditions. At 2 weeks after study entry, the response rates were 13/19 (68.4%) in HTG, 8/21 (38.1%) in LTG and 2/20 (10%) in PLC. Thus the HTG showed a significant improvement compared with PLC (P<0.001). All evaluation parameters (stool frequency, rectal bleeding, endoscopic findings and physician's global impression) were significantly improved in HTG compared with those in PLC or respective pre-values. The incidence of side effects, which consisted of minor side effects such as shaking of fingers and decreases in serum magnesium, in HTG was significantly higher than that in PLC. In the open-labeled trial, the response rate in former LTG and PLC was significantly improved (50.0% and 57.9%, respectively) including “Complete Responders”. Furthermore the mean doses of prednisolone were significantly decreased (7.8mg/day) compared with those in the study entry (19.7mg/day). CONCLUSION: Blood trough levels of tacrolimus by oral administration could be well-controlled, the high potency and rapid onset of oral tacrolimus therapy were demonstrated, and the steroid-tapering effect was also observed. Those results suggest that the oral administration of tacrolimus represents a safe and effective treatment option for patients with moderate/severe refractory active UC.

DDW Abstract S1349- Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-198

Disclosures: None

Tacrolimus (FK506) Rescue Therapy Is Safe and Effective in Patients With Severe and Refractory Inflammatory Bowel Disease – a Long Term Follow-Up

D. Baumgart, M.D., J.P. Pintoffl, A. Sturm, B. Wiedenmann, A.U. Dignass

BACKGROUND: Tacrolimus, a macrolide immunosuppressant inhibiting T cell activation, is currently approved for the prophylaxis of organ rejection in patients receiving allogeneic liver or kidney transplants. We have recently reported its low dose oral use in refractory inflammatory bowel disease (IBD). Here we report the outcome of a long term follow-up of 48 patients.METHODS: In this retrospective, observational single center study the charts of 48 (22 female, 26 male) adult (mean age: 41±13.1 SD years) IBD patients with steroid-dependent (n=16) or steroid-refractory (n=32) inflammatory bowel disease (Crohn’s disease, n=10; ulcerative colitis, n=36; pouchitis, n=2) were reviewed. Tacrolimus (0.1 mg/kg body weight per day) was administered orally in 46 patients and initially intravenously in 2 patients (0.01 mg/kg body weight per day), aiming for serum trough levels of 4–8 ng/mL. 37 of 48 (77.1%) patients were receiving concomitant azathioprine. No PCP prophylaxis was administered. The mean treatment duration was 24±4.7 SD months (range, 0.6–161 months). Patients were followed-up for a mean of 37±4.3 SD months (range, 2–161 months). Response was evaluated using a modified clinical activity index (M-CAI). Colectomy free survival was calculated using the Kaplan-Meier and Cox regression models.RESULTS: 44 patients (91.6%) experienced a clinical and laboratory response and 27 (56.2%) went into remission. Mean M-CAI values dropped from 13.5 at initiation to 2.7 at 42 months follow-up. Eight ulcerative colitis patients (16.7%) underwent colectomy between 2 and 41.3 months after tacrolimus initiation. Mean overall colectomy free survival was 119.9±12.3 SE months (limited to 166.3 months). Cumulative colectomy free survival was estimated at 0.6976±0.093 SE (see also chart). Steroids were reduced or discontinued in 36 of 40 patients (90%) taking steroids. Side-effects included a temporary rise of creatinine (n=4, 8.3%), tremor or paresthesias (n=4, 8.3%), hyperkalemia (n=1, 2.08%), hypertension (n=1, 2.08%) and an opportunistic infection (n=2, 4.17%).CONCLUSION: Oral low dose tacrolimus is safe and effective in refractory inflammatory bowel disease. Large randomized, controlled trials are warranted to further evaluate its role in the management of IBD.

DDW Abstract W1048- Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-583

Disclosures: None

Long-Term Outcome Of Treatment With Tacrolimus Therapy in Patients With Inflammatory Bowel Disease.

H. Nakase, H. Tamaki, S. Inoue, M. Matsuura, N. Uza, S. Ueno, A. Nishio, T. Chiba

Background: Tacrolimus has been shown to be effective in the treatment of inflammatory bowel disease (IBD). However, it remains unclear whether long term administration of tacrolimus to patients with IBD is effective and safe. Aim: To evaluate the efficacy and safety of long term administration of tacrolimus in patients with ulcerative colitis (UC) and Crohn’s disease (CD). Patients and Methods: Fourteen active CD patients ( 2 ileum, 10 ileum and colon, 2 colon ) who were refractory to conventional therapy (antibiotics, azathioprine, and infliximab) and 12 UC patients who were unable to taper off steroids, were enrolled in a prospective, uncontrolled, open-label study. Initially, tacrolimus was administered orally to aim for serum trough level of 10~15ng/ml. After patients achieved their clinical remission, tacrolimus was tapered to the serum trough level 5~10ng/ml. In CD patients, clinical improvement (decrease in CDAI of>/=70), and clinical remission (CDAI</=150) were assessed after treatment. In UC patients, UCAI was assessed as well. The treatment duration in CD and UC was 12 months and 11 months, respectively. Results: In CD patients, mean CDAI at study entry was 320; and mean dose of prednisolone (PSL) was 18mg. After 6wk of treatment, 12 patients (86%) achieved clinical improvement off steroid and 7 patients (50%) went into remission. After 16wk of treatment, 11 patients (78.5%) were still in clinical improvement and 8 patients (57%) went into remission. Overall, after 1 year, 10 patients (71%) went into remission and 4 patients had relapse, who were treated by the combination of tacrolimus and infliximab, thereafter. In UC patients, mean UCAI at study entry was 9.5±1.0; mean dose of PSL was 28mg. After starting tacrolimus, all patients could discontinue taking steroid. The mean UCAI was 3.2±0.6, 2.1±0.8, and 3.4±1.5 after 2wks, 12wks, and 24wks, respectively. Seven patients (58.3%) were still in remission after 11months of treatment. Four of 5 patients (41.7%) who had relapsed, received colectomy. The remaining one got clinical remission with leukocytapheresis therapy. Among UC and CD patients, two patients (7.6%) experienced the increase of serum creatinine level, but this side effect was managed with dose reduction. Conclusion: Long term use of tacrolimus is effective and safe for refractory IBD patients by carefully controlling its trough level. Randamized studies are required to compare tacrolimus with 6-MP in terms of efficacy and safety.

DDW Abstract 493- Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-75

Disclosures: Organization - Protein Design Laboratories, Relationship - Grant / Research Support

A Phase I-Ii Study: Multiple Dose Levels Of Visilizumab Are Well Tolerated and Produce Rapid and Sustained Improvement in Ulcerative Colitis Patients Refractory To Treatment With Iv Steroids (ivsr-Uc).

S.R. Targan, MD, B.A. Salzberg, MD, L. Mayer, MD, D. Hommes, MD, S. Hanauer, MD, U. Mahadevan, MD, W. Reinisch, MD, S.E. Plevy, MD, A.U. Dignass, MD, G. Van Assche, MD, A. Buchman, MD, G. Mechkov, MD, Z. Krastev, MD, J.N. Lowder

Purpose: An earlier Phase I study of visilizumab, a humanized anti-CD3 antibody, in IVSR-UC patients, showed tolerability and clinical activity of 10 or 15mg/kg doses administered on the first 2 consecutive days. The current open-label study was designed to evaluate the safety and determine the optimal clinical dose of visilizumab in a larger number of IVSR-UC patients. Methods: Patients with undetectable whole blood copies of EBV (EBVc/mL) were randomized to 5, 7.5, 10 or 12.5 mg/kg doses of visilizumab. Patients with detectable EBVc/mL (< 5000 copies/mL) were dose escalated through the dose levels. Efficacy was assessed with a Modified Truelove-Witts’ Severity Index (MTWSI); response defined as an index of < 10. Results: To date, a total of 53 (34 EBV- and 19 EBV+) patients have been enrolled. The mean baseline MTWSI was EBV-,12.6, and EBV+, 12.9. The majority of treatment-related AEs (in decreasing order of frequency) included general disorders, GI, nervous system, respiratory, musculoskeletal/connective tissue, skin, and psychiatric disorders. Mild to moderate cytokine release syndrome, unrelated to dose, occurred in the majority of patients. The 15 serious AEs were neither dose-dependent nor considered related to study medication. The incidence of serious infectious disorders was < 1%. No lymphoproliferative, malignant or life-threatening AEs were reported. Anti-visilizumab antibodies, the majority of which were neutralizing antibodies, occurred in 32% of patients. Decreases in MTWSI generally occurred by Day 8 and were maintained in many patients up to Day 90. At Day 30 there was no apparent dose-effect in mean difference from baseline in MTWSI.

Percent of IVSR-UC Patients with MTWSI < 10 (n=number of patients)Tx Day 8 15 22 30EBV-/+ - + - + - + - +

% 61.8 68.4 58.8 63.2 61.8 63.2 67.6 63.2There was no apparent increase in the incidence of infection in EBV+ patients or difference in clinical response. Complete results from Days 60 and 90 will be made available. Conclusion: All visilizumab doses studied were well tolerated and produced a rapid and sustained improvement in a majority of IVSR-UC patients.

Genetik und Immunologie R. Duchmann

Blood. 2004 Aug 1;104(3):895-903. Epub 2004 Apr 15.

Large-scale in vitro expansion of polyclonal human CD4(+)CD25high regulatory T cells.

Hoffmann P, Eder R, Kunz-Schughart LA, Andreesen R, Edinger M.

Department of Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany.

CD4(+)CD25+ regulatory T (Treg) cells are pivotal for the maintenance of self-tolerance, and their adoptive transfer gives protection from autoimmune diseases and pathogenic alloresponses after solid organ or bone marrow transplantation in murine model systems. In vitro, human CD4(+)CD25+ Treg cells display phenotypic and functional characteristics similar to those of murine CD4(+)CD25+ Treg cells: namely, hyporesponsiveness to T-cell receptor (TCR) stimulation and suppression of CD25- T cells. Thus far, the detailed characterization and potential clinical application of human CD4(+)CD25+ Treg cells have been hampered by their paucity in peripheral blood and the lack of appropriate expansion protocols. Here we describe the up to 40 000-fold expansion of highly purified human CD4(+)CD25high T cells in vitro through the use of artificial antigen-presenting cells for repeated stimulation via CD3 and CD28 in the presence of high-dose interleukin 2 (IL-2). Expanded CD4(+)CD25high T cells were polyclonal, maintained their phenotype, exceeded the suppressive activity of freshly isolated CD4(+)CD25high T cells, and maintained expression of the lymph node homing receptors L-selectin (CD62L) and CCR7. The ability to rapidly expand human CD4(+)CD25high Treg cells on a large scale will not only facilitate their further exploration but also accelerate their potential clinical application in T cell-mediated diseases and transplantation medicine.

Nat Genet. 2004 May;36(5):471-5. Epub 2004 Apr 11

Functional variants of OCTN cation transporter genes are associated with Crohn disease.

Peltekova VD, Wintle RF, Rubin LA, Amos CI, Huang Q, Gu X, Newman B, Van Oene M, Cescon D, Greenberg G, Griffiths AM, St George-Hyslop PH, Siminovitch KA.

Department of Medicine, University of Toronto, and Department of Immunology, Mount Sinai Hospital Samuel Lunenfeld Research Institute, Ontario, Canada.

Crohn disease is a chronic, inflammatory disease of the gastrointestinal tract. A locus of approximately 250 kb at 5q31 (IBD5) was previously associated with susceptibility to Crohn disease, as indicated by increased prevalence of a risk haplotype of 11 single-nucleotide polymorphisms among individuals with Crohn disease, but the pathogenic lesion in the region has not yet been identified. We report here that two variants in the organic cation transporter cluster at 5q31 (a missense substitution in SLC22A4 and a G-->C transversion in the SLC22A5 promoter) form a haplotype associated with susceptibility to Crohn disease. These variants alter transcription and transporter functions of the organic cation transporters and interact with variants in another gene associated with Crohn disease, CARD15, to increase risk of Crohn disease. These results suggest that SLC22A4, SLC22A5 and CARD15 act in a common pathogenic pathway to cause Crohn disease.

Gastroenterology. 2005 Feb;128(2):260-9.

A risk haplotype in the Solute Carrier Family 22A4/22A5 gene cluster influences phenotypic expression of Crohn's disease.

Newman B, Gu X, Wintle R, Cescon D, Yazdanpanah M, Liu X, Peltekova V, Van Oene M, Amos CI, Siminovitch KA.

Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

BACKGROUND AND AIMS: Previously, we identified 2 functionally relevant polymorphisms in the SLC22A4 / 22A5 genes at the IBD5 locus that alter gene/protein function and comprise a 2-allele haplotype ( SLC22A -TC) associated with increased risk for Crohn's disease (CD). Here we examine the contribution of this susceptibility haplotype alone and in combination with CARD15 variants to CD subphenotypes and to susceptibility to ulcerative colitis (UC). METHODS: Phenotype-genotype associations were evaluated in a Canadian cohort including 507 patients with CD, 216 patients with UC, and 352 ethnically matched controls genotyped for SLC22A4 C1672T, SLC22A5 G-207C, and the major CD-associated CARD15 variants. RESULTS: The SLC22A -TC haplotype was strongly associated ( P < .0001) with CD in the non-Jewish subgroup of this cohort, and the combination of SLC22A -TC homozygosity and one or more of the common CARD15 disease susceptibility alleles engendered a 7.5-fold increase in risk for CD ( P = 9 x 10 -8 ) and a 4.5-fold increase in risk for ileal disease ( P = .001). The risk haplotype showed only a suggestive association with CD in the Jewish subgroup and no association with UC in the cohort or in subgroups stratified by CARD15 genotypes. CONCLUSIONS: The SLC22A -TC haplotype acts together with CARD15 disease susceptibility alleles to increase risk for CD and ileal disease among CD patients but does not contribute to risk for UC in this Canadian cohort. The association of the SLC22A -TC haplotype and CARD15 alleles with ileal disease suggests that these variants have biologically intertwined effects in the pathogenesis of CD

Gastroenterology. 2005 May;128(5):1219-28.

Recombinant Probiotics for Treatment and Prevention of Enterotoxigenic Escherichia coli Diarrhea.

Paton AW, Jennings MP, Morona R, Wang H, Focareta A, Roddam LF, Paton JC.

Background & Aims: We have developed a therapeutic strategy for gastrointestinal infections that is based on molecular mimicry of host receptors for bacterial toxins on the surface of harmless gut bacteria. The aim of this study was to apply this to the development of a recombinant probiotic for treatment and prevention of diarrheal disease caused by enterotoxigenic Escherichia coli strains that produce heat-labile enterotoxin. Methods: This was achieved by expressing glycosyltransferase genes from Neisseria meningitidis or Campylobacter jejuni in a harmless Escherichia coli strain (CWG308), resulting in the production of a chimeric lipopolysaccharide capable of binding heat-labile enterotoxin with high avidity. Results: The strongest heat-labile enterotoxin binding was achieved with a construct (CWG308:pLNT) that expresses a mimic of lacto- N -neotetraose, which neutralized >/=93.8% of the heat-labile enterotoxin activity in culture lysates of diverse enterotoxigenic Escherichia coli strains of both human and porcine origin. When tested with purified heat-labile enterotoxin, it was capable of adsorbing approximately 5% of its own weight of toxin. Weaker toxin neutralization was achieved with a construct that mimicked the ganglioside GM2. Preabsorption with, or coadministration of, CWG308:pLNT also resulted in significant in vivo protection from heat-labile enterotoxin-induced fluid secretion in rabbit ligated ileal loops. Conclusions: Toxin-binding probiotics such as those described here have considerable potential for prophylaxis and treatment of enterotoxigenic Escherichia coli -induced travelers' diarrhea.

Nat Immunol. 2004 Aug;5(8):800-8. Epub 2004 Jun 27

NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses.

Watanabe T, Kitani A, Murray PJ, Strober W.

Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10 Room 11N238, 10 Center Drive, Bethesda, Maryland 20892, USA.

The mechanism by which mutations in CARD15, which encodes nucleotide-binding oligomerization domain 2 (NOD2), cause Crohn disease is poorly understood. Because signaling via mutated NOD2 proteins leads to defective activation of the transcription factor NF-kappa B, one proposal is that mutations cause deficient NF-kappa B-dependent T helper type 1 (T(H)1) responses and increased susceptibility to infection. However, this idea is inconsistent with the increased T(H)1 responses characteristic of Crohn disease. Here we used Card15(-/-) mice to show that intact NOD2 signaling inhibited Toll-like receptor 2-driven activation of NF-kappa B, particularly of the NF-kappa B subunit c-Rel. Moreover, NOD2 deficiency or the presence of a Crohn disease-like Card15 mutation increased Toll-like receptor 2-mediated activation of NF-kappa B-c-Rel, and T(H)1 responses were enhanced. Thus, CARD15 mutations may lead to disease by causing excessive T(H)1 responses.

Pankreatitis / ERCP-Themen S. Faiss

1. Originalarbeiten

Gastrointest Endosc. 2005 Mar;61(3):407-15.

High-dose allopurinol for prevention of post-ERCP pancreatitis: a prospective randomized double-blind controlled trial.

Katsinelos P, Kountouras J, Chatzis J, Christodoulou K, Paroutoglou G, Mimidis K, Beltsis A, Zavos C.

Department of Endoscopy and Motility Unit, Central Hospital, Thessaloniki, Greece.

BACKGROUND: Pancreatitis is the most common major complication of diagnostic and therapeutic ERCP. Allopurinol, a xanthine oxidase inhibitor that blocks generation of oxygen-derived free radicals, potentially may prevent post-ERCP pancreatitis. This study assessed the efficacy of high-dose oral allopurinol for prevention of post-ERCP pancreatitis. METHODS: A prospective, double-blind, placebo-controlled trial was conducted in 250 patients undergoing ERCP. Patients were randomized to receive allopurinol (600 mg) or placebo orally at 15 and 3 hours before the procedure. Patients were clinically evaluated, and serum amylase levels were determined before ERCP and at 6 and 24 hours thereafter. Standardized criteria were used to diagnose and to grade the severity of post-ERCP pancreatitis. RESULTS: A total of 243 patients were included in the analysis. The two groups were similar with regard to age; gender; underlying disease; indication for treatment; ERCP findings; and type of treatment, except for biliary sphincterotomy. Only 43 patients in the allopurinol group underwent biliary sphincterotomy vs. 87 in the placebo group ( p < 0.001). The frequency of acute pancreatitis was significantly lower in the allopurinol vs. the placebo group in the final multinomial regression analysis: allopurinol group, 4/125 (3.2%), with all 4 cases graded as mild, vs. placebo group, 21/118 (17.8%), of which 8/118 (6.8%) were graded as mild, 11/118 (9.3%) as moderate, and 2/118 (1.6%) as severe with fatal outcome ( p < 0.001). The protective effect of allopurinol was also apparent in the diagnostic ERCP and the biliary sphincterotomy subgroups when the frequency of post-ERCP pancreatitis was analyzed after stratification by procedure. The mean duration of hospitalization for pancreatitis was significantly shorter in the allopurinol compared with the placebo group (2.5 vs. 5.67 days; p < 0.001). CONCLUSIONS: Pretreatment with high-dose, orally administered allopurinol decreases the frequency of post-ERCP pancreatitis. Despite the promising results of this prospective, randomized trial, further studies are needed to verify these observations before allopurinol can be recommended for routine clinical use.

2. DDW-Abstracts

DDW Abstract 557-Gastrointestinal Endoscopy, 2005 Apr.;61(5): AB100

Does Prophylactic Allopurinol Administration Reduce the Risk and Severity of Post-ERCP Pancreatitis: Randomized Prospective Multicenter Study

Stuart Sherman ; Patrick Mosler ; Jeffrey Marks ; James L Watkins ; Joseph E Geenen ; Priya Jamidar ; Evan L Fogel ; Laura Lazzell-Pannell ; M'hamed Temkit ; Paul Tarnasky ; James Frakes ; Arif Aziz ; Pramod Malik ; Nicholas Nickl ; Adam Slivka ; John Goff ; Glen A. Lehman

BACKGROUND: Pancreatitis is the most common major complication of ERCP occurring in up to 30% of high-risk patients. Efforts have been made to identify pharmacological agents capable of reducing its incidence and severity. Numerous drugs have been evaluated during the last 30 years, but only a few have shown any potential efficacy, including somatostatin, gabexate mesilate, glyceryl trinitrate and diclofenac. The aim of this randomized, prospective, double-blind, multicenter trial was to determine whether prophylactic allopurinol, an inhibitior of oxygen-derived free radical production, would reduce the frequency and severity of post-ERCP pancreatitis.

METHODS: 701 patients were randomized to receive either allopurinol or placebo 4 hours and 1 hour prior to ERCP. A database was prospectively collected by a defined protocol on patients undergoing ERCP. Standardized criteria were used to diagnose and grade the severity of post-procedure pancreatitis (GI Endosc 1991; 37:383).

RESULTS: The groups were similar with regard to patient demographics and patient and procedure risk factors for pancreatitis. The overall incidence of pancreatitis was 12.55%. It occurred in 46 of 355 patients in the allopurinol group (12.96%), and in 42 of 346 patients in the control group (12.14%; p=0.52). The pancreatitis was graded mild in 7.89%, moderate in 4.51% and severe in 0.56% of the allopurinol group and mild in 6.94%, moderate in 4.62% and severe in 0.58% of the control group. There was no significant difference between the groups in the frequency or severity of pancreatitis. The study had at least a 90% power of detecting a true difference of 7% in post-ERCP-pancreatitis incidence between placebo (12%) and allopurinol treatment (5%).

CONCLUSION: Prophylactic oral allopurinol did not reduce the frequency or severity of post-ERCP pancreatitis. These results are in agreement with other smaller clinical studies, which did not show any benefit of allopurinol. Therefore, allopurinol cannot be recommended for post-ERCP pancreatitis prevention. Future studies evaluating the efficacy of low cost, safe, easy to administer agents aimed at prevention of post-ERCP pancreatitis are warranted. This study was supported by an ADHF/ASGE Endoscopic Research and Outcomes and Effectiveness Award.

DDW-Abstract T1217- Gastrointestinal Endoscopy, 2005 Apr.;61(5): AB195

Allopurinol to Prevent Post-ERCP Pancreatitis: Blind Interim Analysis of a Randomized Placebo-Controlled Trial

Joseph Romagnuolo ; Gurpal Sandha ; Caroline Kruger ; Gary May ; Marty Cole ; Syd Bass ; Eoin Lalor ; Vince Bain ; John McKaigney ; Richard Fedorak

Background:  Although ERCP is extremely useful in the management of biliopancreatic disease, it is associated with a risk of post-ERCP pancreatitis (PEP).  Animal studies suggest that allopurinol (xanthine oxidase inhibitor with high oral bioavailability and long-lasting active metabolites) may reduce PEP via decreased oxygen radicals.  A randomized pilot was promising.

Aim: To determine if allopurinol decreases the rate of PEP.

Methods: Patients referred for ERCP at 2 tertiary centers were randomized to allopurinol 300 mg or identical placebo orally 60 min (+/-20) prior to ERCP.  Randomization used computer-generated random numbers and blocking by center and by high-risk (manometry, pancreatic therapy) ERCP.  Demographics, indications and other potential confounders were recorded.  The primary outcome (PEP) was defined/graded according to a modified (incl. those seeking medical attention but not admitted (“ultra-mild”)) Cotton consensus definition.  Patients were contacted at 48 h and 30 days.  Secondary outcomes included severe PEP, length of stay, days lost from usual activities, and mortality. PEP rates in each group were compared with Chi-square.  Planned interim analysis was performed at 18 mos, blinded by treatment allocation (group A vs. B). Stochastic curtailment analysis (SCA) was performed to assess yield of further recruitment.

Results:  The interim analysis included 220 patients (112 A, 108 B); mean age 55 yrs (SD 18).  The mean procedure time was 50 min (SD 35); 59% had biliary sphincterotomy; 40% had a pancreatic injection; 20% had stones removed; 19% received a biliary stent; 5.9% a pancreatic stent. The PEP rates were 9.3% (A) and 8.9% (B) (p=0.9; dif=0.4% [95%CI: -7.3% to 7.9%].  For the non-high risk subgroup (n=198), the rates were 5.2% and 7.9% (NS).  There was no difference in severe PEP overall (1 vs 2 patients; p=0.6), nor in any subgroups.  The 2 SCAs, assuming subsequent recruitment at either 1) the same PEP rates as the sample size calculation (7%, 3.5%), or 2) the anticipated relative risk, but the observed baseline PEP rate, both indicated that a statistically significant result could still be achieved with target enrolment (p=0.04, p=0.004, respectively).  External monitoring committee felt the study should proceed.

Conclusion:  The interim (blind) analysis shows no reason for early trial termination.  The 95%CI for the PEP rate difference remains wide, and to date, allopurinol does not appear to significantly affect PEP rates.

DDW Abstract T1198- Gastrointestinal Endoscopy, 2005 Apr.;61(5): AB190

The Incidence of Pancreatitis After ERCP/Manometry Has Fallen with the Increasing Use of Temporary Pancreatic Stents Experience of 2861 Patients Over 10 Years

Peter Cotton ; Patrick D Mauldin ; Joseph Romagnuolo ; Robert H Hawes

There is increasing evidence that temporary pancreatic stenting reduces the incidence of post-ERCP pancreatitis (PEP) in patients at increased risk, such as those undergoing sphincter manometry. We have analysed the use of pancreatic stents and the pancreatitis rates for patients having manometry in our unit. Data were derived from the GITrac database, into which all procedures and their outcomes have been entered prospectively. Pancreatitis (and severity levels) was defined by established consensus criteria.

Over a period of 10 years, 2861 patients underwent biliary and/or pancreatic manometry. Most underwent both, as well as sphincteromy based on the results. The overall rate of PEP in 1481 patients without stents was 8.1%, which was significantly higher (p=0.002) than the incidence (5.3%; 95% CI: 4.2–6.6%) in 1380 patients with stents. The odds ratio for PEP with stents was 0.63 (95% CI: 0.5-0.9).  There was a trend to more episodes of moderate and severe pancreatitis in patients without stents (2.0%), compared to 1.3% in those with stents (p=NS). The progressive increase in the proportion of patients receiving stents correlated (Pearson coefficient -0.840) with a progressive decrease in the rate of pancreatitis (figure). The data were comparable in the 1790 patients who had not undergone prior endoscopic treatments. There were only 6 episodes (3.7%) of PEP in 162 cases undergoing manometry during the first 6 months of 2004.

Conclusion. These data confirm that sphincter manometry can be performed with a low risk of pancreatitis, using temporary pancreatic stents.

DDW Abstract T1219- Gastrointestinal Endoscopy, 2005 Apr.;61(5): AB195

Reduction of the Risk of Post-ERCP Acute Pancreatitis by Prophylactic Pancreatic Stent

Carmelo Sciume' ; Girolamo Geraci ; Franco Pisello ; Tiziana Facella ; Giuseppe Modica

Background: It is well known the high incidence variability of post-ERCP acute pancreatitis (1-40%), which may depend not only for the different definition of post-ERCP acute pancreatitis but also for different patients and procedures related factors acting synergistically. Impaired drainage of pancreatic juice after ERCP is the most relevant cause of post- ERCP acute pancreatitis. To evaluate the potential reduction of the incidence of ERCP-related acute pancreatitis, we used a prophylatic Wirsung stenting in high risk patients (SOD, difficult cannulation, reiterate Wirsung cannulation).

Materials and methods: 97 patients (14.1% of all 686 ERCP performed at the Service of Digestive Endoscopy, Section of General and Thoracic Surgery, Policlinico, University of Palermo) observed between 2000 and 2003, were randomized into Group A (56 patients) treated with “free-hand” pre-cut papillotomy and Group B (41 patients) with pre-cut papillotomy after pancreatic stent The results were prospectically analyzed. Stents were selected according to morphological Wirsung parameters. Stents were removed after 7-10 days.

Results: In our study, the difference between incidence of post-ERCP acute pancreatitis in the Group A (17.8%) was found dramatically different with respect to Group B (2.5%), (p < 0.05).

Conclusions: in our experience, the use of a temporary and prophylactic pancreatic stent significantly decreases the incidence of post-ERCP acute pancreatitis in high risk patients, as well as failed biliary and reiterate Wirsung cannulations and after sphincterotomy in SOD.

DDW Abstract T1222- Gastrointestinal Endoscopy, 2005 Apr.;61(5): AB196

A Prospective Comparative Stent Study for Prophylaxis of Post ERCP Pancreatitis: Comparison of 5 Fr Straight Stent vs 3 FR Pigtail Stent

Miriam Thomas ; Marc F. Catalano ; Joseph E. Geenen

Pancreatitis is the most frequent ERCP complication and pancreatic stenting is an effective method to prevent this complication particularly, in high risk pts. AIM: 1. To compare frequency of post ERCP pancreatitis in high-risk pts after placement of either a modified 5Fr straight ST versus a 3Fr pigtail ST. 2. To compare ST efficacy and safety and determine the rate of spontaneous outward migration of these ST. METHODS: 38 pts undergoing ERCP with high risk factors for developing post ERCP pancreatitis (SOD-12, ARP-13, abd pain-13 pts) were enrolled in this randomized, prospective, blinded study over a period of 1-yr with placement of 3Fr pigtail (15 pts) or 5Fr modified (no internal flap) (23 pts) straight ST. Pts had baseline amylase level drawn prior to as well as 6 & 24 hrs after procedure. Post ERCP pancreatitis was determined clinically & with enzyme levels >3ULN. Abd radiograph was obtained at 24-hrs & 7 days post ERCP to determine ST position. Pain scores from a scale of 1 to 10 were assessed pre ERCP at 6hrs, 24-hrs and 1 wk post ERCP. Phone contact was made at 24-hrs & 1 wk after the procedure to assess the clinical condition of the pt. 7 pts underwent repeat ERCP after ST placement & pancreatograms were compared. RESULTS:  Post ERCP pancreatitis rate with 3F & 5F ST were 33.3% (5/15) and 17.4% (4/23 pts) respectively (p= 0.26). Mild post ERCP pancreatitis with 3F & 5F ST was 60% (3/5) & 75% (3/4) while that of moderate pancreatitis was 40% (2/5) & 25% (1/4 pts) (p= 1.0) respectively. Spontaneous ST dislodgement at 24-hrs occurred in 7/13 pts with 3 Fr ST (53.8%) compared to 12/23 pts (52.2%) with 5Fr ST (p= 0.92). There was no significant difference between the rate of pancreatitis and ST dislodgment at 24-hrs. No pt required repeat procedures for ST removal as all spontaneously passed within a wk. Among pts who underwent repeat ERCP none had duct changes or complications attributable to ST placement. CONCLUSIONS: Post ERCP pancreatitis rate seemed to be lower with modified straight 5Fr ST. However, there was no significance when compared with the pigtail 3Fr ST. None of these patients needed repeat endoscopy for ST removal nor were there any ST induced duct changes in those who had repeat pancreatogram.

 

ST diameter

Pancreatitis rate Mild panc Mod panc Spont dislodge at 24 hrs

3 Fr 5/15 (33.3%) 3/5 (60%) 2/5 (40%) 7/13 (53.8%)5 Fr 4/23 (17.4%) 3/4  (75%) 1/4  (25%) 12/23 (52.2%)

 

 

DDW-Abstract 554- Gastrointestinal Endoscopy, 2005 Apr.;61(5): AB99

Endoscopic Versus Surgical Drainage of the Pancreatic Duct in Chronic Pancreatitis: A Prospective Randomised Trial

Djuna L. Cahen ; Dirk J. Gouma ; Yung Nio ; Myriam Delhaye ; Erik A.J. Rauws ; Marja A. Boermeester ; Olivier R. Busch ; Jaap Stoker ; Johan S. Laméris ; Marcel G.W. Dijkgraaf ; Kees Huibregtse ; Jacques Devière ; Marco J. Bruno

Objectives: Increased pancreatic pressure due to ductal outflow obstruction is considered to be one of the mechanisms of intractable pain in patients with chronic pancreatitis (CP). In symptomatic patients with a dilated pancreatic duct (PD), ductal decompression is therefore advocated. The aim of this prospective randomised trial was to provide a direct comparison between endoscopic and surgical drainage of the PD.

Methods: All symptomatic CP patients presented at the Academic Medical Hospital with a dominant obstruction of the PD (due to strictures and/or stones), without an inflammatory mass (size pancreatic head < 4 cm), were eligible for this study. Patients were randomised between endoscopic drainage by temporary stent insertion (preceded by extracorporeal shock wave lithotripsy (ESWL) in Brussels if indicated) and surgical drainage by pancreaticojejunostomy. Follow-up data were obtained during 2 years by scheduled visits to the outpatient clinic. Primary endpoint was the average Izbicki pain score, measured during the 2 years of follow-up. Secondary endpoints were clinical success rate (> 50 % decrease in pain score), morbidity, mortality and intervention rate.

Results: In October 2004 the study was discontinued after an interim analysis revealed a highly significant difference with respect to the primary endpoint. From January 2000, 39 patients have been included. In 87 % intraductal stones were present with a mean diameter of 10 mm. 19 patients were treated endoscopically with a median stent duration of 27 weeks (16 of which underwent ESWL) and 20 were operated upon.

During a median follow up for both groups of 24 months (range 6-24), the average Izbicki pain score was significantly less after surgical drainage (51 versus 25, p=0.001). Moreover, pain response after surgery was immediate (within 6 weeks) and consistent during the follow-up period. Furthermore, clinical success rates were 33 and 75 % for endoscopic and surgical drainage, respectively. One patient taking high dose NSAID’s died 4 days after ESWL from a perforated duodenal ulcer. Complication rates were similar for both groups but endoscopically treated patients underwent more therapeutic interventions (5 versus 1, p<0.001).

Conclusions: In this series of patients with advanced CP, surgical drainage of the PD was more effective than endoscopic treatment (ESWL and temporary stenting). Moreover, surgery resulted in more rapid pain relief and required significantly less interventions.

IBS H. Mönnikes

1. Originalarbeiten

Gastroenterology. 2004 Jun;126(7):1657-64.

Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome.

Coates MD, Mahoney CR, Linden DR, Sampson JE, Chen J, Blaszyk H, Crowell MD, Sharkey KA, Gershon MD, Mawe GM, Moses PL.

Department of Anatomy and Neurobiology, University of Vermont College of Medicine, Burlington, VT 05405, USA.

BACKGROUND & AIMS: Serotonin (5-HT) is a critical signaling molecule in the gut. 5-HT released from enterochromaffin cells initiates peristaltic, secretory, vasodilatory, vagal, and nociceptive reflexes. Despite being pathophysiologically divergent, ulcerative colitis (UC) and irritable bowel syndrome (IBS) are both associated with clinical symptoms that include alterations in the normal patterns of motility, secretion, and sensation. Our aim was to test whether enteric 5-HT signaling is defective in these disorders. METHODS: Rectal biopsy specimens were obtained from healthy controls and patients with UC, IBS with diarrhea (IBS-D), and IBS with constipation (IBS-C). Key elements of 5-HT signaling, including measures of 5-HT content, release, and reuptake, were analyzed with these samples. RESULTS: Mucosal 5-HT, tryptophan hydroxylase 1 messenger RNA, serotonin transporter messenger RNA, and serotonin transporter immunoreactivity were all significantly reduced in UC, IBS-C, and IBS-D. The enterochromaffin cell population was decreased in severe UC samples but was unchanged in IBS-C and IBS-D. When 5-HT release was investigated under basal and mechanical stimulation conditions, no changes were detected in any of the groups relative to controls. CONCLUSIONS: These data show that UC and IBS are associated with similar molecular changes in serotonergic signaling mechanisms. While UC and IBS have distinct pathophysiologic properties, these data suggest that shared defects in 5-HT signaling may underlie the altered motility, secretion, and sensation. These findings represent the first demonstration of significant molecular alterations specific to the gut in patients with IBS and support the assertion that disordered gastrointestinal function in IBS involves changes intrinsic to the bowel.

Gastroenterology 2005 Mar;128(3):541-51.

Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles.

O'Mahony L, McCarthy J, Kelly P, Hurley G, Luo F, Chen K, O'Sullivan GC, Kiely B, Collins JK, Shanahan F, Quigley EM.

Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.

BACKGROUND & AIMS: The aim of this study was to compare the response of symptoms and cytokine ratios in irritable bowel syndrome (IBS) with ingestion of probiotic preparations containing a lactobacillus or bifidobacterium strain. METHODS: Seventy-seven subjects with IBS were randomized to receive either Lactobacillus salivarius UCC4331 or Bifidobacterium infantis 35624, each in a dose of 1 x 10 10 live bacterial cells in a malted milk drink, or the malted milk drink alone as placebo for 8 weeks. The cardinal symptoms of IBS were recorded on a daily basis and assessed each week. Quality of life assessment, stool microbiologic studies, and blood sampling for estimation of peripheral blood mononuclear cell release of the cytokines interleukin (IL)-10 and IL-12 were performed at the beginning and at the end of the treatment phase. RESULTS: For all symptoms, with the exception of bowel movement frequency and consistency, those randomized to B infantis 35624 experienced a greater reduction in symptom scores; composite and individual scores for abdominal pain/discomfort, bloating/distention, and bowel movement difficulty were significantly lower than for placebo for those randomized to B infantis 35624 for most weeks of the treatment phase. At baseline, patients with IBS demonstrated an abnormal IL-10/IL-12 ratio, indicative of a proinflammatory, Th-1 state. This ratio was normalized by B infantis 35624 feeding alone. CONCLUSIONS: B infantis 35624 alleviates symptoms in IBS; this symptomatic response was associated with normalization of the ratio of an anti-inflammatory to a proinflammatory cytokine, suggesting an immune-modulating role for this organism, in this disorder.

Gut. 2005 May;54(5):601-7.

Amitriptyline reduces rectal pain related activation of the anterior cingulate cortex in patients with irritable bowel syndrome.

Morgan V, Pickens D, Gautam S, Kessler R, Mertz H.

Department of Radiology and Radiological Scienes, Vanderbilt University, Nashville, TN 37205, USA.

BACKGROUND AND AIMS: Irritable bowel syndrome (IBS) is a disorder of intestinal hypersensitivity and altered motility, exacerbated by stress. Functional magnetic resonance imaging (fMRI) during painful rectal distension in IBS has demonstrated greater activation of the anterior cingulate cortex (ACC), an area relevant to pain and emotions. Tricyclic antidepressants are effective for IBS. The aim of this study was to determine if low dose amitriptyline reduces ACC activation during painful rectal distension in IBS to confer clinical benefits. Secondary aims were to identify other brain regions altered by amitriptyline, and to determine if reductions in cerebral activation are greater during mental stress. METHODS: Nineteen women with painful IBS were randomised to amitriptyline 50 mg or placebo for one month and then crossed over to the alternate treatment after washout. Cerebral activation during rectal distension was compared between placebo and amitriptyline groups by fMRI. Distensions were performed alternately during auditory stress and relaxing music. RESULTS: Rectal pain induced significant activation of the perigenual ACC, right insula, and right prefrontal cortex. Amitriptyline was associated with reduced pain related cerebral activations in the perigenual ACC and the left posterior parietal cortex, but only during stress. CONCLUSIONS: The tricyclic antidepressant amitriptyline reduces brain activation during pain in the perigenual (limbic) anterior cingulated cortex and parietal association cortex. These reductions are only seen during stress. Amitriptyline is likely to work in the central nervous system rather than peripherally to blunt pain and other symptoms exacerbated by stress in IBS.

2. DDW Abstracts

DDW Abstract M1206- Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-330 Disclosures: None Symptomatic Overlap Between Irritable Bowel Syndrome and Microscopic Colitis D. Limsui, D. Pardi, E. Loftus, Jr., P. Kammer, W. Tremaine, M. Camilleri, W. Sandborn Purpose: Microscopic colitis is diagnosed by histologic criteria and irritable bowel syndrome (IBS) is diagnosed by symptom-based criteria. There has been no investigation into the overlap in diagnoses of microscopic colitis and IBS. Our aim was to assess the prevalence of clinical criteria for IBS in a population-based cohort of patients with microscopic colitis. Methods: The Rochester Epidemiology Project, a unique medical records linkage system providing data on all health care for the defined population of Olmsted County, MN was used to identify all county residents with a diagnosis of microscopic colitis between 1/1/85-12/31/01, as previously reported (Pardi, et al. Gastroenterology 2004:A124). The medical records of these individuals were reviewed to ascertain symptoms consistent with Rome, Rome II, and Manning criteria for IBS.  Results: 131 cases of microscopic colitis were identified. Median age was 68 (24-95); 71% were women. 73 (56%) and 69 (53%) met Rome II and Rome criteria for IBS, respectively. 54 (41%) had three or more Manning criteria. Patients meeting the criteria for IBS were younger and more likely to be female. 43 (33%) were initially diagnosed with IBS and later had a change in diagnosis to microscopic colitis. 88 (67%) had biopsy proven microscopic colitis during their initial evaluation, prior to consideration of a diagnosis of IBS. If the criteria for duration of symptoms were excluded, 92 (70%) would have met both Rome II and Rome criteria for IBS.  Conclusions: In this population-based cohort, approximately half of those with histologically confirmed microscopic colitis met clinical criteria for the diagnosis of IBS. Women and younger patients more often met clinical criteria for the diagnosis of IBS. The clinical symptom-based criteria for IBS are not specific enough to rule out the diagnosis of microscopic colitis. Therefore, patients with suspected diarrhea-predominate irritable bowel syndrome should undergo random biopsies of the colon to investigate for possible microscopic colitis.

DDW Abstract 788- Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-124 Disclosures: None The Impact Of Somatization on the Use Of Gastrointestinal Healthcare Resources in Irritable Bowel Syndrome B. Spiegel, F. Kanwal, B. Naliboff, E. Mayer Background: Although it is well documented that patients with irritable bowel syndrome (IBS) consume a disproportionate amount of health care resources compared to matched controls, the reasons for this disparity are unclear. One possibility is that resource utilization is partly driven by the presence of comorbid somatization – a process marked by multiple unexplained somatic complaints that is highly prevalent in IBS. We sought to determine whether higher levels of somatization are associated with higher levels of gastrointestinal (GI) resource utilization in IBS.  Methods: 1410 patients >18 years with IBS were evaluated at a university-based referral center. Subjects completed a symptom questionnaire, the SCL-90 psychometric checklist, and the SF-36 Health Survey. We measured two outcomes: (1) one-year aggregated direct GI health care costs (including physician visits and pre-specified tests, procedures, and surgeries) and, (2) one-year cumulative number of gastroenterology physician visits. Our primary regressor was somatization as measured by the somatization subscale of the SCL-90. We first developed a list of hypothesis-driven predictors of resource utilization within a conceptual framework, and then performed multivariate regression analyses to measure the adjusted influence of somatization on GI resource utilization.  Results: There was no difference in the adjusted probability of expending versus not expending any GI health care costs in the previous year in patients with high (+1 standard deviation) versus low (-1 standard deviation) somatization (RR=1.02; 95% CI=1.02, 1.03). Similarly, there was no difference in one-year GI physician visits between patients with high versus low somatization (group difference=0.35 visits, 0.33, 0.38). However, in the subset of patients expending at least $1.00 in GI costs in the previous year (47.7% of cohort), there was a significantly higher cost of care for subjects with high versus low somatization (group difference=$2053 per year; $1963, $2178).  Conclusions: IBS patients with high levels of somatization are not more likely to seek GI care compared to patients with low levels of somatization. However, once they are evaluated for care, patients with high somatization expend significantly more GI health care costs. This suggests that somatization is positively associated with health care costs in IBS, and that the association may be driven more by physicians than patients.

DDW Abstract T1160- Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-469 Disclosures: None Benefits Associated With Supplementation With An Encapsulated Probiotic Preparation in Subjects With Irritable Bowel Syndrome P.J. Whorwell, L. Altringer, J. Morel, Y. Bond, L. O'Mahony, B. Kiely, F. Shanahan, E. Quigley Background. We have previously demonstrated benefits in irritable bowel syndrome (IBS) with a milk-based probiotic preparation of a novel probiotic strain, Bifidobacterium infantis 35624. Aim. To evaluate benefits in IBS with an encapsulated preparation of the same probiotic strain. Methods. After a 2 week run-in phase, 291 female subjects with Rome II-positive IBS were randomized to placebo (n=73), or one of three doses of B. infantis 35624: 106 (n=74), 108 (n=74), or 1010 (n=70) CFU/capsule, given once daily for 4 weeks. IBS symptoms were monitored daily, by telephone, using an interactive voice response system (IVRS) and scored according to a 6-point Likert scale; stool frequency and form (using the Bristol Stool Scale) were also monitored daily. The primary efficacy variable was the abdominal pain score; secondary efficacy variables included other IBS symptoms, a composite symptom score, subject’s global assessment (SGA) of IBS symptom relief and quality of life. In all IBS symptom efficacy analyses, “centers” and “subjects within centers” were treated as random factors. All results were adjusted by baseline so dosage comparisons (placebo vs. 106 vs. 108 vs. 1010 ) were based on Least-square Means. Results. For the primary efficacy variable, abdominal pain/discomfort (-0.58±0.10 vs. -0.41±0.10 vs. -0.89±0.10 vs. -0.46±0.10) as well as for all secondary variables of composite score (-1.16±0.26 vs. -1.11±0.26 vs. -2.13±0.26 vs. -1.07±0.26), bloating/distension (-0.41±0.10 vs. -0.37±0.10 vs. -0.71±0.10 vs. -0.39±0.10), incomplete evacuation (-0.22±0.10 vs. -0.26±0.10 vs. -0.52±0.10 vs. -0.21±0.10), passage of gas (-0.26±0.09 vs. -0.21±0.09 vs. -0.51±0.09 vs. -0.27±0.09) and SGA for symptom relief (-0.20±0.26 vs. -0.20±0.25 vs. 0.74±0.27 vs. -0.74±0.28), bifidobacterium in a dose of 108 was significantly superior (P-value < 0.05) to placebo and all other bifidobacterium doses. The efficacy variable SGA for symptom relief was analyzed using a logistic model so its associated results are given on the logit scale. The corresponding success rates are 45% vs. 45% vs. 68% vs. 32%. No significant adverse events were recorded. Conclusion. B. infantis 35624, in a dose of 108 bacteria/day is effective in relieving all of the cardinal symptoms of irritable bowel syndrome. This study confirms benefits observed in previous studies, at a lower daily dose of probiotic in a capsule form, while demonstrating the complexity of achieving stable probiotic formulations.

Onkologie / ErnährungKoloskopie / Screening P. Bauerfeind

M. Fried

1. Originalarbeiten

Gastroenterology. 2004 Aug;127(2):452-6.

Colonoscopic miss rates for right-sided colon cancer: a population-based analysis.

Bressler B, Paszat LF, Vinden C, Li C, He J, Rabeneck L.

Department of Medicine, University of Toronto, Ontario, Canada.

BACKGROUND & AIMS: Colonoscopy contains an inherent miss rate for colorectal cancer. Although miss rates from academic centers or units known for their endoscopic expertise have been previously reported, the colorectal cancer miss rate of colonoscopy performed in usual clinical practice is unknown. We conducted a population-based study to estimate the proportion of right-sided colon cancers missed during colonoscopy in Ontario. METHODS: All persons > or =20 years old with a new diagnosis of right-sided colon cancer admitted to the hospital for surgical resection in Ontario from April 1, 1997, to March 31, 2001, were identified. Patients who had a colonoscopy within 3 years of their diagnosis were divided into 2 groups: detected cancers (those who had a colonoscopy up to 6 months before the diagnosis) and missed cancers (those who had a colonoscopy between 6 and 36 months before the diagnosis). Data were obtained from the Canadian Institute for Health Information Discharge Abstract Database, the Ontario Health Insurance Plan database, and the Registered Persons Database. RESULTS: Between April 1, 1997, and March 31, 2001, we identified 4920 persons with a new diagnosis of right-sided colon cancer, of whom 2654 (53.9%) had had at least 1 colonoscopy within 3 years of their admission for surgical resection. Most (96.0%) had had their most recent colonoscopy up to 6 months before admission (detected cancers). However, 105 patients (4.0%) had their most recent colonoscopy between 6 and 36 months before admission to the hospital (missed cancers). CONCLUSIONS: Among persons undergoing resection for right-sided colon cancer, the miss rate of colonoscopy for detecting cancer in usual clinical practice was 4.0%.

Dig Dis Sci. 2005 Jan;50(1):47-51.

Relationship of colonoscopy completion rates and endoscopist features.

Harewood GC.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA. harewood.gavin@mayo.edu

The success rate for reaching the cecum has been widely discussed as an indicator of technical expertise for colonoscopy. However, few studies have addressed the impact of endoscopist-specific parameters on cecal intubation rates. The aim of this study was to characterize the relationship between endoscopist-specific parameters (age, gender, experience level, annual procedure volume, insertion and withdrawal times) and cecal intubation rates for colonoscopy. Procedural data from all colonoscopies performed by gastroenterologists at the outpatient endoscopy unit of Rochester Methodist Hospital, Minnesota, between January and December 2003 were reviewed. Procedural data of 45 endoscopists who performed 17,100 colonoscopies over the study period were analyzed. The average cecal intubation rate was 93.9% (SD, 2.9%). Higher experience level (>9 years [median]) was significantly predictive of a cecal intubation rate >94% (OR = 3.43; 95% CI, 1.03-12.29; P = 0.04). Although higher procedure volume was not predictive of higher colonoscopy completion rates overall, when analysis was confined to the junior faculty members (<5 years' experience), completion rates for those endoscopists doing >200 per year (92.5%) was significantly higher than for those doing <200 per year (88.5%; P = 0.04). Our observations suggest that cecal intubation rates increase with increasing endoscopist experience. Moreover, among junior endoscopists, an annual volume of at least 200 procedures appears to be required to maintain adequate competence. Future prospective studies should provide data to support consensus guidelines recommending minimum annual procedure numbers required for maintenance of endoscopic competence among trained endoscopists.

New Engl J Med. 2005 May 19;352(20):2061-8.

Colonoscopic screening of average-risk women for colorectal neoplasia.

Schoenfeld P, Cash B, Flood A, Dobhan R, Eastone J, Coyle W, Kikendall JW, Kim HM, Weiss DG, Emory T, Schatzkin A, Lieberman D; CONCeRN Study Investigators.

Division of Gastroenterology, University of Michigan School of Medicine and Veterans Affairs Center for Excellence in Health Services Research, Ann Arbor 48105, USA. pschoenf@umich.edu

BACKGROUND: Veterans Affairs (VA) Cooperative Study 380 showed that some advanced colorectal neoplasias (i.e., adenomas at least 1 cm in diameter, villous adenomas, adenomas with high-grade dysplasia, or cancer) in men would be missed with the use of flexible sigmoidoscopy but detected by colonoscopy. In a tandem study, we examined the yield of screening colonoscopy in women. METHODS: To determine the prevalence and location of advanced neoplasia, we offered colonoscopy to consecutive asymptomatic women referred for colon-cancer screening. The diagnostic yield of flexible sigmoidoscopy was calculated by estimating the proportion of patients with advanced neoplasia whose lesions would have been identified if they had undergone flexible sigmoidoscopy alone. Lesions were considered detectable by flexible sigmoidoscopy if they were in the distal colon or if they were in the proximal colon in patients who had concurrent small adenomas in the distal colon, a finding that would have led to colonoscopy. The results were compared with the results from VA Cooperative Study 380 for age-matched men and women with negative fecal occult-blood tests and no family history of colon cancer. RESULTS: Colonoscopy was complete in 1463 women, 230 of whom (15.7 percent) had a family history of colon cancer. Colonoscopy revealed advanced neoplasia in 72 women (4.9 percent). If flexible sigmoidoscopy alone had been performed, advanced neoplasia would have been detected in 1.7 percent of these women (25 of 1463) and missed in 3.2 percent (47 of 1463). Only 35.2 percent of women with advanced neoplasia would have had their lesions identified if they had undergone flexible sigmoidoscopy alone, as compared with 66.3 percent of matched men from VA Cooperative Study 380 (P<0.001). CONCLUSIONS: Colonoscopy may be the preferred method of screening for colorectal cancer in women. Copyright 2005 Massachusetts Medical Society.

Ann Intern Med. 2003 Dec 16;139(12):959-65.

Using risk for advanced proximal colonic neoplasia to tailor endoscopic screening for colorectal cancer.

Imperiale TF, Wagner DR, Lin CY, Larkin GN, Rogge JD, Ransohoff DF.

Indiana University School of Medicine, Indiana University, Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana, USA.

BACKGROUND: Colonoscopic screening for colorectal cancer has been suggested because sigmoidoscopy misses nearly half of persons with advanced proximal neoplasia. OBJECTIVE: To create a clinical index to stratify risk for advanced proximal neoplasia and to identify a subgroup with very low risk in which screening sigmoidoscopy alone might suffice. DESIGN: Cross-sectional study. SETTING: A company-based program of screening colonoscopy for colorectal cancer. PATIENTS: Consecutive persons 50 years of age or older undergoing first-time screening colonoscopy between September 1995 and June 2001. MEASUREMENTS: A clinical index with 3 variables was created from information on the first 1994 persons. Points were assigned to categories of age, sex, and distal findings. Risk for advanced proximal neoplasia (defined as an adenoma 1 cm or larger or one with villous histology, severe dysplasia, or cancer) was measured for each score. The index was tested on the next 1031 persons from the same screening program. RESULTS: Of 1994 persons, 67 (3.4%) had advanced proximal neoplasia. A low-risk subgroup comprising 37% of the cohort had scores of 0 or 1 and a risk of 0.68% (95% CI, 0.22% to 1.57%). Among the validation group of 1031 persons, risk for advanced proximal neoplasia in the low-risk subgroup (comprising 47% of the cohort) was 0.4% (upper confidence limit of 1.49%). Application of this index detected 92% of persons with advanced proximal neoplasms and, if applied following screening sigmoidoscopy, could reduce the need for colonoscopy by 40%. The marginal benefit of colonoscopy among low-risk persons was small: To detect 7 additional persons with advanced proximal neoplasia, 1217 additional colonoscopies would be required. CONCLUSIONS: This clinical index stratifies the risk for advanced proximal neoplasia and identifies a subgroup at very low risk. If it is validated in other cohorts or groups, the index could be used to tailor endoscopic screening for colorectal cancer.

N Engl J Med. 2004 Dec 23;351(26):2704-14.

Fecal DNA versus fecal occult blood for colorectal-cancer screening in an average-risk population.

Imperiale TF, Ransohoff DF, Itzkowitz SH, Turnbull BA, Ross ME; Colorectal Cancer Study Group.

Department of Medicine, Indiana University, and the Regenstrief Institute, Indianapolis, IN 46202, USA.

BACKGROUND: Although fecal occult-blood testing is the only available noninvasive screening method that reduces the risk of death from colorectal cancer, it has limited sensitivity. We compared an approach that identifies abnormal DNA in stool samples with the Hemoccult II fecal occult-blood test in average-risk, asymptomatic persons 50 years of age or older. METHODS: Eligible subjects submitted one stool specimen for DNA analysis, underwent standard Hemoccult II testing, and then underwent colonoscopy. Of 5486 subjects enrolled, 4404 completed all aspects of the study. A subgroup of 2507 subjects was analyzed, including all those with a diagnosis of invasive adenocarcinoma or advanced adenoma plus randomly chosen subjects with no polyps or minor polyps. The fecal DNA panel consisted of 21 mutations. RESULTS: The fecal DNA panel detected 16 of 31 invasive cancers, whereas Hemoccult II identified 4 of 31 (51.6 percent vs. 12.9 percent, P=0.003). The DNA panel detected 29 of 71 invasive cancers plus adenomas with high-grade dysplasia, whereas Hemoccult II identified 10 of 71 (40.8 percent vs. 14.1 percent, P<0.001). Among 418 subjects with advanced neoplasia (defined as a tubular adenoma at least 1 cm in diameter, a polyp with a villous histologic appearance, a polyp with high-grade dysplasia, or cancer), the DNA panel was positive in 76 (18.2 percent), whereas Hemoccult II was positive in 45 (10.8 percent). Specificity in subjects with negative findings on colonoscopy was 94.4 percent for the fecal DNA panel and 95.2 percent for Hemoccult II. CONCLUSIONS: Although the majority of neoplastic lesions identified by colonoscopy were not detected by either noninvasive test, the multitarget analysis of fecal DNA detected a greater proportion of important colorectal neoplasia than did Hemoccult II without compromising specificity. Copyright 2004 Massachusetts Medical Society.

Gastroenterology. 2004 May;126(5):1270-9

Fecal DNA testing compared with conventional colorectal cancer screening methods: a decision analysis.

Song K, Fendrick AM, Ladabaum U.

Department of Medicine, Division of Gastroenterology, University of California-San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0538, USA.

BACKGROUND & AIMS: Fecal DNA testing is an emerging tool to detect colorectal cancer (CRC). Our aims were to estimate the clinical and economic consequences of fecal DNA testing vs. conventional CRC screening. METHODS: Using a Markov model, we estimated CRC incidence, CRC mortality, and discounted cost/life-year gained for screening by fecal DNA testing (F-DNA), fecal occult blood testing (FOBT) and/or sigmoidoscopy, or colonoscopy (COLO) in persons at average CRC risk from age 50 to 80 years. RESULTS: Compared with no screening, F-DNA at a screening interval of 5 years decreased CRC incidence by 35% and CRC mortality by 54% and gained 4560 life-years per 100,000 persons at USD $47,700/life-year gained in the base case. However, F-DNA gained fewer life-years and was more costly than conventional screening. The average number of colonoscopies per person was 3.8 with COLO and 0.8 with F-DNA. In most 1-way sensitivity analyses and Monte Carlo simulation iterations, F-DNA remained reasonably cost-effective compared with no screening, but COLO and FOBT dominated F-DNA. Assuming fecal DNA testing sensitivities of 65% for CRC and 40% for large polyp, and 95% specificity, a screening interval of 2 years and a test cost of USD $195 would be required to make F-DNA comparable with COLO. CONCLUSIONS: Fecal DNA testing every 5 years appears effective and cost-effective compared with no screening, but inferior to other strategies such as FOBT and COLO. Fecal DNA testing could decrease the national CRC burden if it could improve adherence with screening, particularly where the capacity to perform screening colonoscopy is limited.

Gastroenterology. 2004 Nov;127(5):1300-11.

Computed tomographic colonography without cathartic preparation for the detection of colorectal polyps.

Iannaccone R, Laghi A, Catalano C, Mangiapane F, Lamazza A, Schillaci A, Sinibaldi G, Murakami T, Sammartino P, Hori M, Piacentini F, Nofroni I, Stipa V, Passariello R.

Department of Radiological Sciences, University of Rome, Rome, Italy. r_iannaccone@yahoo.it

BACKGROUND AND AIMS: We prospectively compared the performance of low-dose multidetector computed tomographic colonography (CTC) without cathartic preparation with that of colonoscopy for the detection of colorectal polyps. METHODS: A total of 203 patients underwent low-dose CTC without cathartic preparation followed by colonoscopy. Before CTC, fecal tagging was achieved by adding diatrizoate meglumine and diatrizoate sodium to regular meals. No subtraction of tagged feces was performed. Colonoscopy was performed 3-7 days after CTC. Three readers interpreted the CTC examinations separately and independently using a primary 2-dimensional approach using multiplanar reconstructions and 3-dimensional images for further characterization. Colonoscopy with segmental unblinding was used as reference standard. The sensitivity of CTC was calculated both on a per-polyp and a per-patient basis. For the latter, specificity, positive predictive values, and negative predictive values were also calculated. RESULTS: CTC had an average sensitivity of 95.5% (95% confidence interval [CI], 92.1%-99%) for the identification of colorectal polyps > or =8 mm. With regard to per-patient analysis, CTC yielded an average sensitivity of 89.9% (95% CI, 86%-93.7%), an average specificity of 92.2% (95% CI, 89.5%-94.9%), an average positive predictive value of 88% (95% CI, 83.3%-91.5%), and an average negative predictive value of 93.5% (95% CI, 90.9%-96%). Interobserver agreement was high on a per-polyp basis (kappa statistic range, .61-.74) and high to excellent on a per-patient basis (kappa statistic range, .79-.91). CONCLUSIONS: Low-dose multidetector CTC without cathartic preparation compares favorably with colonoscopy for the detection of colorectal polyps.

2. DDW-Abstracts

DDW-Abstract M1264- Gastrointestinal Endoscopy, 2005 Apr.;61(5): AB148

Use of Colonoscopy in Medicare Beneficiaries Increased Substantially Between 1999 and 2002 While the Use of Other Colorectal Cancer Diagnostic Tests Declined

Stacey J. Ackerman ; Kathryn P. Anastassopoulos ; Michael J. Lacey ; Stacey L. Amorosi ; Tyler G. Knight ; David A. Lieberman

Purpose: To examine trends in the use of colonoscopy, flexible sigmoidoscopy, double-contrast barium enema, and fecal occult blood test (FOBT) in Medicare beneficiaries from 1999 to 2002.

Background: In January 1998, Medicare began paying for colorectal cancer screening in average risk persons over age 50 using annual FOBT and/or flexible sigmoidoscopy every five years, or double-contrast barium enema every five to ten years. Screening colonoscopy for high risk persons once every ten years also was paid for. Payment was expanded to include average risk persons in July 2001.Methods:The Medicare 5% Carrier Standard Analytic File (SAF) for 1999 to 2002 was used to identify patient records with claims for colonoscopy, flexible sigmoidoscopy, double-contrast barium enema, and FOBT. The Carrier SAF is a representative 5% sample of final action claims for physician/supplier Part B services for all settings of care. The 5% Denominator SAF was used to obtain patient demographic information. Standard sampling methodology was used to extrapolate total volumes.Results:From 1999 to 2002, the number of Medicare beneficiaries increased by 4%. Beneficiaries in the study sample averaged 72 years of age, were 61% female, and 90% Caucasian. The number of procedures performed to evaluate colon health increased by 2% (from 7.77 to 7.92 million), and the number of colonoscopies increased by 52% (from 2.14 to 3.25 million). Conversely, there was a 59% decrease in sigmoidoscopy (810,000 to 334,000), 41% decrease in barium enema (522,000 to 306,000), and 6% decrease in FOBT (4.30 to 4.03 million). The percent of procedures with a primary diagnosis of polyp detection (ICD-9 211.3) remained constant for both colonoscopy (32% in 1999 and 33% in 2002) and sigmoidoscopy (7% in both 1999 and 2002).Conclusions:From 1999 to 2002, the number of procedures performed to evaluate colon health in Medicare beneficiaries remained steady, but the mix of procedures used changed. Colonoscopy use increased substantially while there was a marked decline in sigmoidoscopy and barium enema. Of note, the percent of colonoscopies with polyp detection remained unchanged despite a large increase in colonoscopy use. This may be explained by changes in screening patterns, patient mix, and increased public awareness. This study showed a dramatic shift in use of colon procedures over four years. Future study should monitor trends in colonoscopy use and patient outcomes, and the impact on system capacity.

DDW-Abstract Sp751- Gastrointestinal Endoscopy, 2005 Apr.;61(5): AB107

Predictors of Missed Colorectal Cancer During Colonoscopy: A Population-Based Analysis

Brian Bressler ; Lawrence Paszat ; Deanna Rothwell ; Zhongliang Chen ; Chris Vinden ; Linda Rabeneck

Background: In previous work we have shown that the miss rate for colorectal cancer (CRC) at colonoscopy (COL) is 2-6% depending on the site of CRC. However predictors of a missed CRC at COL are unknown.

Aim:  To identify predictors of missed CRC at COL.

Methods:  Using electronic data from the Canadian Institute for Health Information (CIHI) and the Ontario Health Insurance Program (OHIP), we identified all individuals ³ 20 years old, with a new diagnosis (dx) of right-sided CRC, transverse CRC, and rectal/sigmoid CRC, in the province of Ontario from 1/4/1997 to 31/3/2002.  We excluded those who did not have a COL within 3 years prior to their dx.  We divided each group into 2 categories. The detected cancers category consisted of individuals who had a COL within 6 months prior to dx.  The missed cancers category consisted of those who had a COL within 6-36 months prior to dx.  We combined the 3 groups and used a logistic regression model to examine patient (age, sex, history of previous abdominal/pelvic surgery, history of diverticulosis, site of CRC), procedure (performance date, polypectomy procedure), physician (specialty, experience), and setting (hospital, office-based) characteristics that might predict missed CRC.  We defined a physician’s experience based on the number of COLs s/he performed in the year preceding the most recent COL prior to the dx of CRC.

Results: We identified 25,877 patients with a new dx of right, transverse, or rectal/sigmoid CRC and excluded 13,038 who did not have a COL within 3 years of their CRC dx.  The remaining 12,839 patients comprised our study cohort, of whom 3,060 had right-sided CRC, 945 had transverse CRC, and 8,834 had rectal or sigmoid CRC.  The proportions of missed cancers were: 190 patients (6.2%) with right-sided CRC, 41 patients (4.3%) with transverse CRC, and 182 patients (2.1%) with rectal/sigmoid CRC. In multivariate analysis, patients who were older, female, had a history of previous abdominal/pelvic surgery, history of diverticulosis, those with right-sided or transverse CRC, those in whom an internist or family physician performed the COL, those in whom the physician was less experienced, and those who had an office-based COL were all independent predictors of a missed CRC

Conclusion:  In addition to patient characteristics, having a COL performed in an office setting, or by a less experienced endoscopist, or by an internist or family physician were independent predictors of missed CRC at COL.

DDW-Abstract 242- Gastrointestinal Endoscopy, 2005 Apr.;61(5): AB81

Cecal Intubation Rates and Endoscopist Features: Implications for Maintaining Endoscopic Competence

Gavin Harewood ; Beverly Ott

Introduction: Cecal intubation has been proposed as a benchmark for measuring technical competence for colonoscopy.  However, few studies have assessed the impact of endoscopist-specific parameters on cecal intubation rates.  This study aimed to characterize the relationship between endoscopist-specific parameters (experience level, annual procedure volume) and cecal intubation rates for colonoscopy. Methods: Procedural data from all routine colonoscopies performed by staff gastroenterologists at our outpatient endoscopy unit between January and December, 2003 were reviewed. Results: Procedural data of 45 staff endoscopists who performed 17,100 colonoscopies were analyzed.  Mean cecal intubation rate was 93.9% (SD, 2.9).   Higher experience level (> 9 years [median]) was predictive of cecal intubation rate >94%, OR = 3.43 (95% C.I., 1.03 – 12.29), p = 0.04.  Higher procedure volumes were not associated with higher colonoscopy completion rates.  However, when analysis was confined to junior faculty members with <5 years experience (18 endoscopists), completion rates for those endoscopists doing >200 per year (92.5%) was significantly higher than for those doing <200 per year (88.5%), p = 0.04 (figure).

Conclusions: Cecal intubation rates appear to increase with increasing endoscopist experience.  Among junior staff endoscopists, an annual volume of at least 200 procedures appears necessary to maintain competence.  Future studies should provide further data to support evidence-based guidelines recommending minimum annual procedure numbers required for maintaining endoscopic competence.

DDW-Abstract 424- Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-63

Stool DNA Screening for Colorectal Cancer: Prospective Multicenter Comparison With Hemoccult

David A Ahlquist ; Daniel J Sargent ; Theodore R Levin ; Douglas K Rex ; Dennis Ahnen ; Kandice L Knigge ; M. Peter Lance ; Charles L Loprinzi ; Lawrence J Burgart ; James E Allison ; Michael J Lawson ; Shauna L Hillman ; Mary E Devens

Stool DNA testing can detect colorectal neoplasms, but performance data on representative populations are needed. Aim: To compare the accuracy of PreGenPlus (PGP), a multi-target DNA-based stool assay, with that of Hemoccult (HO) for detection of screen-relevant neoplasia (cancer (CRC), high grade dysplasia (HGD), adenoma > 1cm) in an average-risk population.  Methods: The first 2502 evaluable subjects from a blinded multicenter NCI study (UO1 CA 89389) are analyzed.  Subjects are age 50-80, have had no structural colon exam within 10 yrs, and have < one 10 relative with CRC. Results are reported due to a change in the commercial PGP made prior to completion of the planned 4434 enrollment.  Subjects collect 3 whole stools and smear HO cards with same-day shipment to a central processing facility.  Stools received > 48 hours after defecation are disqualified.  PGP is performed on a single stool/subject at Exact Sciences and HO on 3 stools/subject at Mayo Clinic.  PGP is considered positive if any of 23 targeted markers is detected; HO is positive if either window on any of 3 cards reacts.  After stool collection, a verified complete colonoscopy is required for evaluability and serves as the gold standard.  All colorectal lesions are re-examined by a single pathologist.  Tissue from all available CRC/HGD are tested by PGP.  Results:  Median age was 59 and 46% were men. Of 146 subjects with screen-relevant neoplasia (SRN), PGP detected 30 (20%) and HO 17 (12%), p=0.03.  Of 23 subjects with CRC/HGD, PGP detected 8 (35%) and HO 9 (39%), p=0.76.  Specificities were 96% for PGP and 98% for HO, p<0.0001.  SRN detection by long DNA, a component marker on PGP panel, fell from 11% to 1.8% to 0% on stools received <24, 24-35, and >35 hours after defecation, respectively, p=0.04.  Other PGP markers were stable.  Among 17 CRC/HGD tissues tested, 11 expressed > 1 genetic alteration by PGP assay (65% tissue sensitivity) and corresponding stools were PGP positive in 5 (45%).  Median size of CRC/HGD was 24mm in PGP positives and 12mm in PGP negatives, p=0.03.  Conclusions:  In the screening setting: PGP detects more SRN than HO but at lower specificity. Both tests miss the majority of SRN. PGP insensitivity is affected by instability of long DNA in stool, non-expression of panel markers in SRN tissue, and incomplete marker recovery from stool.  Enrollment continues to allow assessment of a next generation assay with more informative markers and better DNA capture.    

Onkologie GI-Trakt H. Scherübl

1. Originalarbeiten

N Engl J Med. 2004 Jul 22;351(4):337-45.

Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.

Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E.

Royal Marsden Hospital, London, United Kingdom. david.cunningham@icr.ac.uk

BACKGROUND: The epidermal growth factor receptor (EGFR), which participates in signaling pathways that are deregulated in cancer cells, commonly appears on colorectal-cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We compared the efficacy of cetuximab in combination with irinotecan with that of cetuximab alone in metastatic colorectal cancer that was refractory to treatment with irinotecan. METHODS: We randomly assigned 329 patients whose disease had progressed during or within three months after treatment with an irinotecan-based regimen to receive either cetuximab and irinotecan (at the same dose and schedule as in a prestudy regimen [218 patients]) or cetuximab monotherapy (111 patients). In cases of disease progression, the addition of irinotecan to cetuximab monotherapy was permitted. The patients were evaluated radiologically for tumor response and were also evaluated for the time to tumor progression, survival, and side effects of treatment. RESULTS: The rate of response in the combination-therapy group was significantly higher than that in the monotherapy group (22.9 percent [95 percent confidence interval, 17.5 to 29.1 percent] vs. 10.8 percent [95 percent confidence interval, 5.7 to 18.1 percent], P=0.007). The median time to progression was significantly greater in the combination-therapy group (4.1 vs. 1.5 months, P<0.001 by the log-rank test). The median survival time was 8.6 months in the combination-therapy group and 6.9 months in the monotherapy group (P=0.48). Toxic effects were more frequent in the combination-therapy group, but their severity and incidence were similar to those that would be expected with irinotecan alone. CONCLUSIONS: Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer. Copyright 2004 Massachusetts Medical Society

J Clin Oncol. 2005 Apr 1;23(10):2310-7.

Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus.

Stahl M, Stuschke M, Lehmann N, Meyer HJ, Walz MK, Seeber S, Klump B, Budach W, Teichmann R, Schmitt M, Schmitt G, Franke C, Wilke H.

Department of Medical Oncology and Hematology, Kliniken Essen-Mitte, Henricistr 92, D-45136 Essen, Germany. m.stahl@kliniken-essen-mitte.de

PURPOSE: Combined chemoradiotherapy with and without surgery are widely accepted alternatives for the curative treatment of patients with locally advanced esophageal cancer. The value of adding surgery to chemotherapy and radiotherapy is unknown. PATIENTS AND METHODS: Patients with locally advanced squamous cell carcinoma (SCC) of the esophagus were randomly allocated to either induction chemotherapy followed by chemoradiotherapy (40 Gy) followed by surgery (arm A), or the same induction chemotherapy followed by chemoradiotherapy (at least 65 Gy) without surgery (arm B). Primary outcome was overall survival time. RESULTS: The median observation time was 6 years. The analysis of 172 eligible, randomized patients (86 patients per arm) showed overall survival to be equivalent between the two treatment groups (log-rank test for equivalence, P < .05). Local progression-free survival was better in the surgery group (2-year progression-free survival, 64.3%; 95% CI, 52.1% to 76.5%) than in the chemoradiotherapy group (2-year progression-free survival, 40.7%; 95% CI, 28.9% to 52.5%; hazard ratio [HR] for arm B v arm A, 2.1; 95% CI, 1.3 to 3.5; P = .003). Treatment-related mortality was significantly increased in the surgery group than in the chemoradiotherapy group (12.8% v 3.5%, respectively; P = .03). Cox regression analysis revealed clinical tumor response to induction chemotherapy to be the single independent prognostic factor for overall survival (HR, 0.30; 95% CI, 0.19 to 0.47; P < .0001). CONCLUSION: Adding surgery to chemoradiotherapy improves local tumor control but does not increase survival of patients with locally advanced esophageal SCC. Tumor response to induction chemotherapy identifies a favorable prognostic group within these high-risk patients, regardless of the treatment group.

N Engl J Med. 2005 May 26;352(21):2184-92.

Statins and the risk of colorectal cancer.

Poynter JN, Gruber SB, Higgins PD, Almog R, Bonner JD, Rennert HS, Low M, Greenson JK, Rennert G.

Department of Epidemiology, University of Michigan, Ann Arbor 48109-0638, USA.

BACKGROUND: Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and effective lipid-lowering agents. Statins inhibit the growth of colon-cancer cell lines, and secondary analyses of some, but not all, clinical trials suggest that they reduce the risk of colorectal cancer. METHODS: The Molecular Epidemiology of Colorectal Cancer study is a population-based case-control study of patients who received a diagnosis of colorectal cancer in northern Israel between 1998 and 2004 and controls matched according to age, sex, clinic, and ethnic group. We used a structured interview to determine the use of statins in the two groups and verified self-reported statin use by examining prescription records in a subgroup of patients for whom prescription records were available. RESULTS: In analyses including 1953 patients with colorectal cancer and 2015 controls, the use of statins for at least five years (vs. the nonuse of statins) was associated with a significantly reduced relative risk of colorectal cancer (odds ratio, 0.50; 95 percent confidence interval, 0.40 to 0.63). This association remained significant after adjustment for the use or nonuse of aspirin or other nonsteroidal antiinflammatory drugs; the presence or absence of physical activity, hypercholesterolemia, and a family history of colorectal cancer; ethnic group; and level of vegetable consumption (odds ratio, 0.53; 95 percent confidence interval, 0.38 to 0.74). The use of fibric-acid derivatives was not associated with a significantly reduced risk of colorectal cancer (odds ratio, 1.08; 95 percent confidence interval, 0.59 to 2.01). Self-reported statin use was confirmed for 276 of the 286 participants (96.5 percent) who reported using statins and whose records were available. CONCLUSIONS: The use of statins was associated with a 47 percent relative reduction in the risk of colorectal cancer after adjustment for other known risk factors. Because the absolute risk reduction is likely low, further investigation of the overall benefits of statins in preventing colorectal cancer is warranted. Copyright 2005 Massachusetts Medical Society.

2. Kongreßabstracts

DDW-Abstract 622- Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-93

Statins Reduce the Incidence Of Esophageal Cancer:a Study Of Half a Million Us Veterans.

Vikas Khurana ; Ramu Chalasani ; Gloria Caldito ; Charlton Fort

BACKGROUND: Statins are commonly used cholesterol-lowering agents that are noted to suppress tumor growth in several animal models, however clinical data for a chemoprotective role of statins in esophageal cancer is lacking.

DESIGN: The VISN 16 database, which contains clinical and demographic information about all veterans (>1.4 million patients) cared for in the South Central VA Health Care Network, was queried from Oct 1998 to June 2004. Retrospective case control design was used. Statistical analysis was performed using SAS software version 9.0 (Chicago, IL). Multiple logistic regression analysis was used with calculation of odds ratios and 95% confidence intervals. The data was adjusted for age, smoking, alcohol use and diabetes.

RESULTS: A total of 484,226 patients were studied. The mean age was 61.2 (SD+/-15.1) years and 91.7% were men, 164,645 (34%) were using statins. Esophageal cancer (ICD code of 150) was seen in 659 (0.14%). Statin users were less likely to develop esophageal cancer (Odds ratio 0.44: 95% CI 0.36-0.53). The data was controlled for age, smoking (p=0.1), alcohol use (p=0.67) and diabetes (p=0.52). Age (OR 1.03, 95% CI 1.02 -1.04, p <0.0001) and reflux (OR 2.42, 95% CI 2.05-2.85, p <0.0001) were significant covariates.

DISCUSSION: An internal consistency of the database is reflected by an increased risk associated with documented risk factors. Our data should be evaluated with caution, given the limitations of the population, the database and the fact that this is a case control study. Patients were placed in the statins users group if they were using statins prior to the diagnosis of esophageal cancer but the dose, duration and type of statin used was not factored into the analysis. Some factors known to increase the risk of esophageal cancer like Barrett’s esophagus was not incorporated into the study.

CONCLUSION: Statins are associated with a 56% reduced incidence of esophageal cancer after controlling for age, gender, smoking, alcohol use and diabetes.

DDW Abstract 605- Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-89-90

Multi-Center Prospective Randomized Trial Comparing Standard Esophagectomy Against Definitive Chemo-Irradiation for Treatment Of Squamous Esophageal Cancer: Early Results From the Chinese University Research Group for Esophageal Cancer (cure)

Philip Wai Yan Chiu ; Angus Chi Wai Chan ; Enders Kwok Wai Ng ; Sing Fai Leung ; Danny WH Lee ; JF Griffith ; Simon Kin Hung Wong ; Anthony Chi Ngan Li ; Wing Tai Siu ; Michael Ka Wah Li ; Peter Kwok Hung Kwong ; Hing Tat Leong ; Alex Auyeung ; Candice Lam ; Sydney Sheung Chee Chung

IntroductionSquamous cell carcinoma of the esophagus is well known to have a poor prognosis. From our preliminary study, combining chemotherapy with concomitant irradiation could achieve a significant tumor reduction and even complete regression. We conducted a prospective randomized trial to compare the efficacy and survival achieved by primary chemoirradiation to that by esophagectomy for patients with advanced squamous cell carcinoma of the esophagus. Methods: From July 2000 to 2004, 80 patients with potentially operable squamous cell carcinoma of mid or lower thoracic esophagus were randomized. Two or three-staged esophagectomy with 2-field dissection were performed. Patients treated with chemo-irradiation received continuous 5-fluorouracil infusion (200mg/m2/day) from day 1 to 42 and cis-platin (60mg/m2) on day 1 and 22. The tumor and regional lymphatics were concomitantly irradiated with a total of 60 Gy. Tumor response was assessed by endoscopy, EUS and CT scan. Salvage esophagectomy was performed for incomplete response or recurrence. The quality of life was assessed by EORTC OES-18 before, 6 weeks and 3 months after therapy. Results: 44 patients received standard esophagectomy, while 36 were treated with primary chemoirradiation. Median followup was 19 months. The operative mortality was 7.1%. The rate of postoperative complication was 38.1%. There was no difference in the early cumulative survival between the two groups (Log rank test p = 0.48). There were a higher proportion of patients complain of indigestion in the esophagectomy group (p = 0.001). Otherwise there is no different between the groups in other aspects of EORTC OES-18 before and 3 months after treatment.

Esophagectomy Chemoirradiation p-valueNo. of patients randomized 44 36 -No. of patients analyzable 42 33 -Median age 62 (47-76) 62 (42-74) 0.91Pre-treatment stagingT2 : T3 9 : 33 12 : 21 0.2N1 22 (52.4%) 12 (36.4%) 0.13Salvage esophagectomy - 5 (16.7%) -Recurrence 14 (32.6%) 14 (42.4%) 0.87Cumulative survival at 24 months 62.8% 63.6% 0.48ConclusionsFrom the early results of our prospective randomized trial, we found that both standard esophagectomy and definitive chemoirradiation achieved comparable intermediate-term survival.

ASCO meeting 2005, Abstract 4001

Perioperative chemotherapy in operable gastric and lower oesophageal cancer: final results of a randomised, controlled trial (the MAGIC trial, ISRCTN 93793971).

D. Cunningham, W. H. Allum, S. P. Stenning, S. Weeden, for the NCRI Upper GI Cancer Clinical Studies Group

Background: Epirubicin, Cisplatin and infused 5-FU (ECF) shows significant benefit in advanced oesophagogastric cancer, particularly locally advanced disease. This trial was designed to determine whether this effect translates into a survival advantage in operable disease. Methods: Patients with operable adenocarcinoma of the stomach, oesophagogastric junction or lower oesophagus were randomised to perioperative chemotherapy (CSC arm) or surgery alone (S arm). In the CSC arm, chemotherapy comprised three pre-operative and three post-operative cycles, 3 weeks apart, of E 50mg/m2 IV bolus, C 60mg/m2 infusion and 5-FU 200mg/m2/day continuous infusion. The trial was powered (2α=5%, 1-β=90%) to detect a 15% increase in 5-year survival (~250 events required), with pre-planned analysis with another European trial of the same design, collectively giving ~90% power to detect a 10% increase in survival. The latter trial closed early, therefore to increase power to detect a 10% increase from MAGIC alone, the final analysis was deferred until sufficient events had occurred to give at least 70% power (~320 deaths) to detect a hazard ratio (HR) of 0.75, equivalent to an absolute difference in survival of approximately 10% at 2 and 5 years. Results: Between 1994 and 2002, 503 patients (250 CSC, 253 S) were randomised; 74% gastric, 11% oesophago-gastric junction and 15% lower oesophagus. Initial analysis (ASCO 2003) demonstrated statistically significant differences in favour of CSC with respect to curative resection rate, resected tumour diameter and, for gastric and junctional patients, T stage. As of 12/2004, with median follow-up >3 years and 90% of patients followed to death or >2 years, 319 deaths have occurred, (149 CSC, 170 S). The survival HR is 0.75, 95% CI (0.60, 0.93), p=0.009; 5 year survival rates for CSC and S are 36% (30%, 43%) and 23% (17%, 29%) respectively. Progression-free survival was also significantly prolonged; HR 0.66 (0.53, 0.81), p=0.0001. Conclusions: Perioperative chemotherapy significantly improves resectability, progression-free and overall survival in operable gastric and lower oesophageal cancer

ASCO Meeting Abstract LBA3500

A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: Results of NSABP Protocol C-07

N. Wolmark, H. S. Wieand, J. P. Kuebler, L. Colangelo, R. E. Smith

Background: The primary aim of this two-arm randomized prospective study was to determine whether FULV + oxaliplatin (FLOX) would prolong 3-year disease-free survival (DFS) compared to FULV. Methods: Between February 2000 and November 2002, 2,407 patients with follow-up (1207 and 1200 in the respective arms) with stage II (28.6%) or III carcinoma of the colon were randomized to receive either FULV (5-FU, 500 mg/m2 iv bolus weekly x 6; LV, 500 mg/m2 iv weekly x 6, each 8 week cycle x 3) or FLOX (same FULV regimen with oxaliplatin 85 mg/m2 iv administered on weeks 1, 3, and 5 of each 8 week cycle x 3). The primary end point was DFS. Events were defined as first recurrence, second primary cancer, or death. Results: The median follow-up for patients who were still alive was 34 months. The hazard rate (FLOX vs. FULV) was 0.79 with 95% CI (0.67, 0.93), a 21% risk reduction in favor of FLOX. (See table below.) Grade 3 NCI-Sanofi neurosensory toxicity was noted in 8% of patients on FLOX and 1% of those receiving FULV. Hospitalization for diarrhea or dehydration associated with bowel wall thickening occurred in 56 patients on FLOX and 34 patients on FULV. There were 14 and 15 deaths while patients were on treatment for FULV and FLOX, respectively. Conclusion: The addition of oxaliplatin to weekly FULV significantly improved 3-year DFS in patients with Stage II and III colon cancer. Supported by Public Health Service grants U10-CA-12027 and U10-CA-69651 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. N. Wolmark and J. P. Kuebler have served on advisory boards and have received honoraria from Sanofi-Synthelabo, Inc.

  N Events3yr % DFS

FULV 1207 332 71.6

FLOX 1200 272 76.5

P = 0.004

Onkologie hepatobiliär und Pankreas G. Schachschal

1. Originalarbeiten

Hepatology. 2005 Apr;41(4):707-16.

Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort.

Marrero JA, Fontana RJ, Barrat A, Askari F, Conjeevaram HS, Su GL, Lok AS.

Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109-0362, USA. jmarrero@umich.edu

Currently there is no consensus as to which staging system is best in predicting the survival of patients with hepatocellular carcinoma (HCC). The aims of this study were to identify independent predictors of survival and to compare 7 available prognostic staging systems in patients with HCC. A total of 239 consecutive patients with cirrhosis and HCC seen between January 1, 2000, and December 31, 2003, were included. Demographic, laboratory, and tumor characteristics and performance status were determined at diagnosis and before therapy. Predictors of survival were identified using the Kaplan-Meir test and the Cox model. Sixty-two percent of patients had hepatitis C, 56% had more than 1 tumor nodule, 24% had portal vein thrombosis, and 29% did not receive any cancer treatment. At the time of censorship, 153 (63%) patients had died. The 1- and 3-year survival of the entire cohort was 58% and 29%, respectively. The independent predictors of survival were performance status (P < .0001), MELD score greater than 10 (P = .001), portal vein thrombosis (P = .0001), and tumor diameter greater than 4 cm (P = .001). Treatment of HCC was related to overall survival. The Barcelona Clinic Liver Cancer (BCLC) staging system had the best independent predictive power for survival when compared with the other 6 prognostic systems. In conclusion, performance status, tumor extent, liver function, and treatment were independent predictors of survival mostly in patients with cirrhosis and HCC. The BCLC staging system includes aspects of all of these elements and provided the best prognostic stratification for our cohort of patients with HCC.

Gastroenterology (im Druck, Juni-Ausgabe)

A Randomized Controlled Trial of Radiofrequency Ablation with Ethanol Injection for Small Hepatocellular Carcinoma : Rf Ablation vs. Ethanol Injection for HCC

S. SHIINA, T. TERATANI, S. OBI, S. SATO, S. TATEISHI, T. FUJISHIMA, T. ISHIKAWA, Y. KOIKE, H. YOSHIDA, T. KAWABE, and M. OMATA

Department of Gastroenterology, University of Tokyo, Tokyo, Japan

Background & Aims: Percutaneous radiofrequency ablation is a recently introduced treatment for hepatocellular carcinoma, while ethanol injection is now a standard therapy. We compared their long-term outcomes. Methods: Two hundreds and thirty-two patients with hepatocellular carcinoma who had three or fewer lesions, each 3 cm or less in diameter, and liver function of Child-Pugh class A or B were entered onto a randomized controlled trial. The primary endpoint was survival, and the secondary endpoints were overall recurrence and local tumor progression. Results: One hundred and eighteen patients were assigned to radiofrequency ablation and 114 to ethanol injection. The number of treatment sessions was smaller (2.1 times vs 6.4 times, p < 0.0001) and the length of hospitalization was shorter (10.8 days vs 26.1 days, p < 0.0001) in radiofrequency ablation than in ethanol injection. Four-year survival rate was 74% (95% CI 65 – 84%) in radiofrequency ablation and 57% (95% CI 45 – 71%) in ethanol injection. Radiofrequency ablation had a 46% smaller risk of death (adjusted relative risk 0.54 [95% CI 0.33 - 0.89], p = 0.02), a 43% smaller risk of overall recurrence (adjusted relative risk 0.57 [95% CI 0.41 - 0.80], p = 0.0009) and an 88% smaller isk of local tumor progression (relative risk 0.12 [95% CI 0.03 - 0.55], p = 0.006) than ethanol injection. The incidence of adverse events was not different between the two therapies. Conclusions: Judging from higher survival but similar adverse events, radiofrequency ablation is superior to ethanol injection in the treatment of small hepatocellular carcinoma.

Z Gastroenterol. 2005 May;43(5):439-43.

Is 18F-FDG-PET Suitable for Therapy Monitoring after Palliative Photodynamic Therapy of Non-Resectable Hilar Cholangiocarcinoma?]

Muller D, Wiedmann M, Kluge R, Berr F, Mossner J, Sabri O, Caca K.

Klinik und Poliklinik fur Nuklearmedizin, Universitat Leipzig.

BACKGROUND: If existing biliary drainage is insufficient, photodynamic therapy (PDT, laser treatment after application of a photosensitizer) is an already established adjunct to palliative therapy for progressing hilar cholangiocarcinoma (Klatskin tumours), since it prolongs survival and improves quality of life. Experimental studies of other tumour entities showed that (18)F-FDG-PET ( (18)F-fluorodeosxyglucose-positron emission tomography) may play a role in monitoring tumour response to PDT. Furthermore, previous studies have revealed a high accuracy of this method for the detection of hilar cholangiocarcinoma. Therefore, the aim of the present study was to investigate the feasibility of (18)F-FDG-PET as a follow-up screening method in patients with hilar cholangiocarcinoma who underwent PDT. PATIENTS AND METHODS: 10 patients were examined by (18)F-FDG-PET before and 4 - 6 weeks after PDT. The following parameters were evaluated: maximum and mean SUV in the tumour, the ratio of maximum SUV in the tumour and mean SUV in the liver, the vital tumour volume, as well as bilirubin and CA 19 - 9 levels. RESULTS: All tumours were detected by (18)F-FDG-PET. Within a period of 4 - 6 weeks after PDT the cholestasis parameter bilirubin decreased significantly. However, SUV-associated parameters did not show a significant change after treatment while the estimated vital tumour volume even increased. DISCUSSION: PDT does not effect a relevant reduction of tumour mass in non-resectable hilar cholangiocarcinoma. However, PDT leads to a significant reduction of cholestasis. If (18)F-FDG-PET is suitable for monitoring the effect of new palliative therapeutic approaches, like brachytherapy, the use of modern chemotherapeuticals, COX-2 and receptor-tyrosine kinase inhibitors, perhaps also in combination with PDT, has to be further investigated.

Endoscopy. 2005 May;37(5):425-33.

Prospective study of the effectiveness of percutaneous transhepatic photodynamic therapy for advanced bile duct cancer and the role of intraductal ultrasonography in response assessment.

Shim CS, Cheon YK, Cha SW, Bhandari S, Moon JH, Cho YD, Kim YS, Lee LS, Lee MS, Kim BS.

Institute for Digestive Research and Digestive Disease Center, Soon Chun Hyang University College of Medicine, Seoul, Korea. schidr@hosp.sch.ac.kr

BACKGROUND AND STUDY AIMS: We evaluated the therapeutic effects of percutaneous transhepatic photodynamic therapy (PDT) in patients with advanced bile duct cancer. The utility of intraductal ultrasonography (IDUS) for the assessment of responses and for regular follow up after PDT was also examined. METHODS: Percutaneous transhepatic biliary drainage (PTBD) was initiated before PDT. Following dilation and maturation of the PTBD tract, percutaneous PDT was performed. Intraluminal photoactivation was carried out using percutaneous cholangioscopy 2 days after intravenous application of a hematoporphyrin derivative. All patients were additionally provided with percutaneous bile duct drainage catheters after PDT. IDUS was conducted monthly to measure the thickness of the tumor mass before and after PDT. RESULTS: 24 patients with advanced cholangiocarcinomas (Bismuth IIIa, n = 4; IIIb, n = 10; IV, n = 10) were treated with PDT. At 3 months after PDT, the mean thickness of the tumor mass had decreased from 8.7 +/- 3.7 mm to 5.8 +/- 2.0 mm (P < 0.01). At 4 months after PDT, the thickness of the mass had increased to 7.0 +/- 3.7 mm. Quality of life indices improved dramatically and remained stable 1 month after PDT; the Karnofsky index increased from 39.1 +/- 11.36 to 58.2 +/- 22.72 points (P = 0.003). The 30-day mortality rate was 0 %, and the median survival time was 558 +/- 178.8 days (current range 62 - 810 days). CONCLUSIONS: PDT using percutaneous cholangioscopy is safe and effective for advanced hilar cholangiocarcinoma, and seems to prolong survival. IDUS is useful for evaluating changes in the thickness of the tumor mass after PDT.

2. DDW-Abstracts

DDW Abstract 245 Disclosures: None MELD Score Predicts Mortality in Cirrhotic Patients Undergoing Hepatic Resection for Hepatocellular Carcinoma S.H. Teh, S.S. Cha, J.D. Christein, J.H. Donohue, M.L. Kendrick, F.G. Que, M.B. Farnell, W.R. Kim, P.S. Kamath, D.M. Nagorney BACKGROUND: Hepatic resection for hepatocellular carcinoma (HCC) in patients with cirrhosis is generally recommended for those who are Child-Pugh Class A. The Model for End-Stage Liver Disease (MELD) has been shown to accurately predict survival in patients with cirrhosis. Whether MELD can be used to select patients with cirrhosis for hepatic resection is unknown. AIMS: To determine the risk factors for mortality in cirrhotic patients undergoing hepatic resection. METHODS: A retrospective chart review of all patients with HCC and cirrhosis who underwent surgical resection between January 1993 and December 2003 was undertaken to determine risk for mortality. RESULTS: There were 82 patients, 62 male, 20 female (mean age 62.1 years); 45 patients had a MELD score ³ 9 (range 9-15). Child-Pugh score ranged between 5-9 points. The mean size of the tumor was 5.2 cm. Fifty-nine patients had minor (£ 3 segments) hepatic resection (MELD £ 8, n= 29; MELD ³ 9, n= 30 ), and 23 patients had major (³ 4 segments) hepatic resections (MELD £ 8, n= 8 ; MELD ³ 9, n= 15 ). Hospital mortality and 30-day mortality were 12% and 16% respectively, predominantly due to liver failure. Multivariate analysis demonstrated that factors significantly associated with increasing mortality were: MELD score ³ 9 (p< 0.0001); presence of symptoms (p=0.0001); tumor larger than 5 cm (p=0.01), and high grade (p=0.03), but not Child-Pugh class (p=0.6), vascular invasion or multilobar disease. Overall, MELD score £ 8 was associated with 0% 30-day mortality as compared with 29% for those with MELD score of ³ 9 (p=0.002) (Table). For MELD ³ 9, 30-day mortality (p=0.6) and long-term survival was similar between minor and major hepatic resection. CONCLUSION: MELD is a strong predictor of both perioperative mortality and long-term survival in cirrhotic patients undergoing hepatic resection. In patients with cirrhosis, hepatic resection (minor or major) for HCC is recommended if the MELD score is £ 8. In patients with MELD score ³ 9, other treatment modalities should be considered.

 Table 1: Overall Survival by MELD Score

Survival (%)

MELD £ 8

(n=37)

MELD ³ 9

(n=45)P value

30 days 100 71 0.002

1 year 89 48 0.002

3 years 63 36  

5 years 51 24  

 

DDW Abstract M1667-Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-761-2 Disclosures: None Radiofrequency Ablation for Hepatocellular Carcinoma: Long-Term Results S. Shiina, T. Teratani, R. Tateishi, T. Fujishima, Y. Kondo, N. Yamashiki, N. Mine, R. Masuzaki, M. Yanase, T. Ishikawa, S. Obi, H. Yoshida, T. Kawabe, M. Omata Background: Radiofrequency ablation (RFA) has been reported to be efficacious for hepatocellular carcinoma (HCC). However, there have not been many reports on its long-term results. The aim of this study was to evaluate survival and recurrence after RFA for HCC. Subjects and Methods Indications of RFA were as follows; 1) unresectable lesions or refusal of surgery, 2) no extrahepatic metastasis or vascular invasion, 3) absence of refractory ascites, 4) PT > 50 % and Plt > 50,000, 4) T. Bil < 3.0 mg/dl, 5) obtainment of informed consent. We put no restrictions on lesion location. The subjects of this study were 434 consecutive patients with HCC who received RFA as the initial treatment between 1999 and 2004. There were 283 males and 151 females. The age was 66.3 + 8.5 (mean + S.D.) years. Lesion number was 1.9 + 1.5 (1-12). Maximum lesion size was 2.8 + 1.3 (0.9-9.7) cm. Liver function was in Child-Pugh A in 296 cases, in B in 134, and in C in 4. We performed RFA percutaneously with a cooled-tip electrode. As a general rule, we ablated not only the tumor but also some amount of the surrounding tissue. One to three days after RFA, CT was performed to determine the efficacy. If there were any possible undestroyed portions, RFA was repeated until the entire tumor necrosis. All patients had CT and US every 4 months to find any recurrence. We examined 20 factors (age, sex, tumor size, tumor number, AFP, AFP-L3 & DCP before RFA, AFP, AFP-L3 & DCP after RFA, histological grade of tumor differentiation, Alb, T. Bil, ALT, PT, Plt, Child-Pugh liver dysfunction, presence of cirrhosis, HBs-Ag, HCV-Ab) to predict survival and recurrence. Results Survival rates after RFA were 95% at 1-year, 88% at 2-years, 78% at 3-years, 68% at 4-years, and 56% at 5-years. Alb, T. Bil and tumor size were significant predictive factors for survival. Overall recurrence after RFA was 19% at 1-year, 43% at 2-years, 60% at 3-years, 66% at 4-years, and 76% at 5-years. Tumor size, tumor number and AFP were significant predictive factors for overall recurrence. Local recurrence after RFA was 1.1% at 1-year, 2.2% at 2-, 3-, 4-, and 5-years. Complications were encountered in 16 cases. However, there was no mortality related to RFA. Conclusion RFA achieved considerably good survival. RFA may be a valuable therapy for HCC.  

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Ernährung J. Ockenga

1. Originalarbeiten

JAMA. 2005 Jan 5;293(1):43-53.

Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial.

Dansinger ML, Gleason JA, Griffith JL, Selker HP, Schaefer EJ.

Division of Endocrinology, Diabetes, and Metabolism, Atherosclerosis Research Laboratory, Tufts-New England Medical Center, Boston, Mass 02111, USA. mdansinger@tufts-nemc.org

CONTEXT: The scarcity of data addressing the health effects of popular diets is an important public health concern, especially since patients and physicians are interested in using popular diets as individualized eating strategies for disease prevention. OBJECTIVE: To assess adherence rates and the effectiveness of 4 popular diets (Atkins, Zone, Weight Watchers, and Ornish) for weight loss and cardiac risk factor reduction. DESIGN, SETTING, AND PARTICIPANTS: A single-center randomized trial at an academic medical center in Boston, Mass, of overweight or obese (body mass index: mean, 35; range, 27-42) adults aged 22 to 72 years with known hypertension, dyslipidemia, or fasting hyperglycemia. Participants were enrolled starting July 18, 2000, and randomized to 4 popular diet groups until January 24, 2002. INTERVENTION: A total of 160 participants were randomly assigned to either Atkins (carbohydrate restriction, n=40), Zone (macronutrient balance, n=40), Weight Watchers (calorie restriction, n=40), or Ornish (fat restriction, n=40) diet groups. After 2 months of maximum effort, participants selected their own levels of dietary adherence. MAIN OUTCOME MEASURES: One-year changes in baseline weight and cardiac risk factors, and self-selected dietary adherence rates per self-report. RESULTS: Assuming no change from baseline for participants who discontinued the study, mean (SD) weight loss at 1 year was 2.1 (4.8) kg for Atkins (21 [53%] of 40 participants completed, P = .009), 3.2 (6.0) kg for Zone (26 [65%] of 40 completed, P = .002), 3.0 (4.9) kg for Weight Watchers (26 [65%] of 40 completed, P < .001), and 3.3 (7.3) kg for Ornish (20 [50%] of 40 completed, P = .007). Greater effects were observed in study completers. Each diet significantly reduced the low-density lipoprotein/high-density lipoprotein (HDL) cholesterol ratio by approximately 10% (all P<.05), with no significant effects on blood pressure or glucose at 1 year. Amount of weight loss was associated with self-reported dietary adherence level (r = 0.60; P<.001) but not with diet type (r = 0.07; P = .40). For each diet, decreasing levels of total/HDL cholesterol, C-reactive protein, and insulin were significantly associated with weight loss (mean r = 0.36, 0.37, and 0.39, respectively) with no significant difference between diets (P = .48, P = .57, P = .31, respectively). CONCLUSIONS: Each popular diet modestly reduced body weight and several cardiac risk factors at 1 year. Overall dietary adherence rates were low, although increased adherence was associated with greater weight loss and cardiac risk factor reductions for each diet group.

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Cochrane Database Syst Rev. 2004 Oct 18;(4):CD004183.

Antioxidant supplements for preventing gastrointestinal cancers.

Bjelakovic G, Nikolova D, Simonetti RG, Gluud C.

Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Dept. 7102, H:S Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK 2100 Copenhagen, Denmark. g.bjelakovic@ctu.rh.dk

BACKGROUND: Oxidative stress may cause gastrointestinal cancers. The evidence on whether antioxidant supplements are effective in preventing gastrointestinal cancers is contradictory. OBJECTIVES: To assess the beneficial and harmful effects of antioxidant supplements in preventing gastrointestinal cancers. SEARCH STRATEGY: We identified trials through the trials registers of the four Cochrane Review Groups on gastrointestinal diseases, The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 1, 2003), MEDLINE, EMBASE, LILACS, and SCI-EXPANDED from inception to February 2003, and The Chinese Biomedical Database (March 2003). We scanned reference lists and contacted pharmaceutical companies. SELECTION CRITERIA: Randomised trials comparing antioxidant supplements to placebo/no intervention examining the incidence of gastrointestinal cancers. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion and extracted data. The outcome measures were incidence of gastrointestinal cancers, overall mortality, and adverse events. Outcomes were reported as relative risks (RR) with 95% confidence interval (CI) based on fixed and random effects meta-analyses. MAIN RESULTS: We identified 14 randomised trials (170,525 participants), assessing beta-carotene (9 trials), vitamin A (4 trials), vitamin C (4 trials), vitamin E (5 trials), and selenium (6 trials). Trial quality was generally high. Heterogeneity was low to moderate. Neither the fixed effect (RR 0.96, 95% CI 0.88 to 1.04) nor random effects meta-analyses (RR 0.90, 95% CI 0.77 to 1.05) showed significant effects of supplementation with antioxidants on the incidences of gastrointestinal cancers. Among the seven high-quality trials reporting on mortality (131,727 participants), the fixed effect (RR 1.06, 95% CI 1.02 to 1.10) unlike the random effects meta-analysis (RR 1.06, 95% CI 0.98 to 1.15) showed that antioxidant supplements significantly increased mortality. Two low-quality trials (32,302 participants) found no significant effect of antioxidant supplementation on mortality. The difference between the mortality estimates in high- and low-quality trials was significant by test of interaction (z = 2.10, P = 0.04). Beta-carotene and vitamin A (RR 1.29, 95% CI 1.14 to 1.45) and beta-carotene and vitamin E (RR 1.10, 95% CI 1.01 to 1.20) significantly increased mortality, while beta-carotene alone only tended to do so (RR 1.05, 95% CI 0.99 to 1.11). Increased yellowing of the skin and belching were non-serious adverse effects of beta-carotene. In four trials (three with unclear/inadequate methodology), selenium showed significant beneficial effect on gastrointestinal cancer incidences. REVIEWERS' CONCLUSIONS: We could not find evidence that antioxidant supplements prevent gastrointestinal cancers. On the contrary, they seem to increase overall mortality. The potential cancer preventive effect of selenium should be studied in adequately conducted randomised trials.

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Lancet. 2005 Feb 26;365(9461):764-72.

Effect of timing and method of enteral tube feeding for dysphagic stroke patients (FOOD): a multicentre randomised controlled trial.

Dennis MS, Lewis SC, Warlow C; FOOD Trial Collaboration.

Department of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, UK. martin.dennis@ed.ac.uk

BACKGROUND: Undernutrition is common in patients admitted with stroke. We aimed to establish whether the timing and route of enteral tube feeding after stroke affected patients' outcomes at 6 months. METHODS: The FOOD trials consist of three pragmatic multicentre randomised controlled trials, two of which included dysphagic stroke patients. In one trial, patients enrolled within 7 days of admission were randomly allocated to early enteral tube feeding or no tube feeding for more than 7 days (early versus avoid). In the other, patients were allocated percutaneous endoscopic gastrostomy (PEG) or nasogastric feeding. The primary outcome was death or poor outcome at 6 months. Analysis was by intention to treat. FINDINGS: Between Nov 1, 1996, and July 31, 2003, 859 patients were enrolled by 83 hospitals in 15 countries into the early versus avoid trial. Early tube feeding was associated with an absolute reduction in risk of death of 5.8% (95% CI -0.8 to 12.5, p=0.09) and a reduction in death or poor outcome of 1.2% (-4.2 to 6.6, p=0.7). In the PEG versus nasogastric tube trial, 321 patients were enrolled by 47 hospitals in 11 countries. PEG feeding was associated with an absolute increase in risk of death of 1.0% (-10.0 to 11.9, p=0.9) and an increased risk of death or poor outcome of 7.8% (0.0 to 15.5, p=0.05). INTERPRETATION: Early tube feeding might reduce case fatality, but at the expense of increasing the proportion surviving with poor outcome. Our data do not support a policy of early initiation of PEG feeding in dysphagic stroke patients.

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Am J Gastroenterol. 2005 Feb;100(2):432-9

A randomized study of early nasogastric versus nasojejunal feeding in severe acute pancreatitis.

Eatock FC, Chong P, Menezes N, Murray L, McKay CJ, Carter CR, Imrie CW.

Lister Department of Surgery and Department of Nutrition and Dietetics, Glasgow Royal Infirmary, Alexandra Parade, Glasgow G31 2ER, Scotland.

BACKGROUND: After 50 yr in which nasoenteric feeding was considered contraindicated in acute pancreatitis (AP), several clinical studies have shown that early nasojejunal (NJ) feeding can be achieved in most patients. A pilot study of early nasogastric (NG) feeding in patients with objectively graded severe AP proved that this approach was also feasible. A randomized study comparing NG versus NJ feeding has been performed. METHODS: A total of 50 consecutive patients with objectively graded severe AP were randomized to receive either NG or NJ feeding via a fine bore feeding tube. The end points were markers of the acute phase response APACHE II scores and C-reactive protein (CRP) measurements, and pain patterns by visual analogue score (VAS) and analgesic requirements. Complications were monitored and comparisons made of both total hospital and intensive-care stays. RESULTS: A total of 27 patients were randomized to NG feeding and 23 to NJ. One of those in the NJ group had a false diagnosis, thereby reducing the number to 22. Demographics were similar between the groups and no significant differences were found between the groups in APACHE II score, CRP measurement, VAS, or analgesic requirement. Clinical differences between the two groups were not significant. Overall mortality was 24.5% with five deaths in the NG group and seven in the NJ group. CONCLUSIONS: The simpler, cheaper, and more easily used NG feeding is as good as NJ feeding in patients with objectively graded severe AP. This appears to be a useful and practical therapeutic approach to enteral feeding in the early management of patients with severe AP.

Editorial hierzu:

Am J Gastroenterol. 2005 Feb;100(2):440-1.What route to feed patients with severe acute pancreatitis: vein, jejunum, or stomach?

Raimondo M, Scolapio JS.

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Eur J Gastroenterol Hepatol. 2004 Nov;16(12):1375-80.

Combining steroids with enteral nutrition: a better therapeutic strategy for severe alcoholic hepatitis? Results of a pilot study.

Alvarez MA, Cabre E, Lorenzo-Zuniga V, Montoliu S, Planas R, Gassull MA.

Department of Gastroenterology, University Hospital Germans Trias i Pujol, Badalona, Catalonia, Spain.

BACKGROUND: Results of a previous randomized controlled trial comparing the outcome of patients with severe alcoholic hepatitis treated with total enteral nutrition (TEN) or corticosteroids suggest that these treatments act through different mechanisms and may be complementary. We report a pilot study of combined treatment with TEN and a shorter course of steroids in patients with severe alcoholic hepatitis. METHODS: Thirteen patients with severe alcoholic hepatitis were treated with systemic steroids and TEN. Steroid therapy started with 40 mg oral prednisolone daily, and was progressively tapered as soon as both serum bilirubin and prothrombin time decreased below 50% of their baseline values. TEN (2000 kcal, or 8374 kJ, daily) was administered throughout the hospital stay. Patients were followed for at least 12 months or until death. RESULTS: Tapering of prednisolone dose could be started after a mean (SD) of 15.4 (3.8) days, whereas TEN was maintained for 22 (3.8) days. TEN was tolerated in 10 of the 13 patients. The major adverse event attributable to therapy was hyperglycemia requiring insulin therapy, which occurred in 12 of 13 patients. Only two patients (15%) died during the treatment period. Another patient died within the first 2 months of follow-up. In no case was the death due to infectious complications, despite two-thirds of patients developing infections during the treatment period. Infections during follow-up occurred only in three patients. CONCLUSION: This pilot study suggests that TEN associated with a short course of steroids could be a good therapeutic strategy for severe alcoholic hepatitis. This possibility deserves investigation in a randomized controlled trial.

Paper zum vorigen:Hepatology. 2000 Jul;32(1):36-42.

Short- and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial.

Cabr inverted question marke E, Rodr inverted question markiguez-Iglesias P, Caballer inverted question markia J, Quer JC, S inverted question markanchez-Lombrana JL, Par inverted question markes A, Papo M, Planas R, Gassull MA.

Steroids are recommended in severe alcohol-induced hepatitis, but some data suggest that artificial nutrition could also be effective. We conducted a randomized trial comparing the short- and long-term effects of total enteral nutrition or steroids in these patients. A total of 71 patients (80% cirrhotic) were randomized to receive 40 mg/d prednisolone (n = 36) or enteral tube feeding (2,000 kcal/d) for 28 days (n = 35), and were followed for 1 year or until death. Side effects of treatment occurred in 5 patients on steroids and 10 on enteral nutrition (not significant). Eight enterally fed

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patients were prematurely withdrawn from the trial. Mortality during treatment was similar in both groups (9 of 36 vs. 11 of 35, intention-to-treat) but occurred earlier with enteral feeding (median 7 vs. 23 days; P =.025). Mortality during follow-up was higher with steroids (10 of 27 vs. 2 of 24 intention-to-treat; P =. 04). Seven steroid patients died within the first 1.5 months of follow-up. In contrast to total enteral nutrition (TEN), infections accounted for 9 of 10 follow-up deaths in the steroid group. In conclusion, enteral feeding does not seem to be worse than steroids in the short-term treatment of severe alcohol-induced hepatitis, although death occurs earlier with enteral nutrition. However, steroid therapy is associated with a higher mortality rate in the immediate weeks after treatment, mainly because of infections. A possible synergistic effect of both treatments should be investigated.

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2. DDW Abstracts

DDW Abstract 54-Suppl. to Gastroenterol.2, 2005 Apr.;128(4):A-778 Disclosures: None Enteral Nutrition Improves Functional Parameters in Liver Cirrhosis K. Norman, H. Kirchner, U. Friedrich, H. Lochs, J. Ockenga, M. Pirlich Introduction: Malnutrition is a frequent problem in liver cirrhosis, occurring in up to 60% of all patients. It has devastating consequences affecting morbidity and mortality. Both physical and metabolic functions are severely compromised.Aim: We investigated whether short term enteral nutrition is useful in improving physical and metabolic parameters in patients with advanced liver cirrhosis.Methods: We randomized 25 patients with decompensated liver cirrhosis (Child Pugh score B or C) to receive either high protein enteral nutrition (35 kcal/kg bodyweight and 1.5 g protein/kg bodyweight) via nasogastric tube (n=13) or standard hospital diet for 2 weeks (n=12). Patients with malignant or terminal disease were not included. The patients were assessed before and after nutritional intervention. Nutritional status on admission was characterized by the Subjective Global Assessment. Liver function was determined by prothrombin time, bilirubin and albumin. Muscle function was assessed by hand grip strength dynamometry. Body composition was measured by bioelectrical impedance analysis. Results: 20 (77 %) patients were classified as malnourished and 23 (92%) had hand grip strength values below 85 % of gender and age related norm. Intervention and control patients did not differ regarding age, nutritional status, muscle function, and severity of disease.Enteral nutrition significantly improved muscle function in the intervention group (from 25.2 +/- 10.9 kg to 29.9 +/- 9.2 kg, p=0.035), whereas it did not change significantly in the control group (from 27.1 +/- 12.1 kg to 30.5 +/- 12.5 kg, n.s.). Simultaneously, prothrombin time increased significantly in the intervention group (from 52.4 +/- 17.8 % to 61.2 +/- 21.8 %, p<0.05) but no significant improvement occurred in controls (from 53.1 +/- 14.3 % to 58.0 +/- 15.2%, n.s.). Bilirubin, albumin and body composition did not change significantly during the study period, although there was a slight increase in body cell mass in the intervention group, which however did not reach statistical significance. Conclusion: The majority of our patients with advanced liver cirrhosis were classified malnourished according to the SGA (77%). Short term enteral nutrition initiated on admission to hospital however succeeded in improving both muscle function and prothrombin time. Intensive nutritional therapy should therefore be part of the therapeutic concept in these patients.

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