Length of Barrett's oesophagus and cancer risk: implications from a large sample of patients with early oesophageal adenocarcinoma.

OBJECTIVE: Although it is well understood that the risk of oesophageal adenocarcinoma increases with Barrett length, transition risks for cancer associated with different Barrett lengths are unknown. We aimed to estimate annual cancer transition rates for patients with long-segment (≥3 cm), short-segment (≥1 to <3 cm) and ultra-short-segment (<1 cm) Barrett's oesophagus. DESIGN: We used three data sources to estimate the annual cancer transition rates for each Barrett length category: (1) the distribution of long, short and ultra-short Barrett's oesophagus among a large German cohort with newly diagnosed T1 oesophageal adenocarcinoma; (2) population-based German incidence of oesophageal adenocarcinoma; and (3) published estimates of the population prevalence of Barrett's oesophagus for each Barrett length category. RESULTS: Among 1017 patients with newly diagnosed T1 oesophageal adenocarcinoma, 573 (56%) had long-segment, 240 (24%) short-segment and 204 (20%) ultra-short-segment Barrett's oesophagus. The base-case estimates for the prevalence of Barrett's oesophagus among the general population were 1.5%, 5% and 14%, respectively. The annual cancer transition rates for patients with long, short and ultra-short Barrett's oesophagus were 0.22%, 0.03% and 0.01%, respectively. To detect one cancer, 450 patients with long-segment Barrett's oesophagus would need to undergo annual surveillance endoscopy; in short segment and ultra-short segment, the corresponding numbers of patients would be 3440 and 12,364. Similar results were obtained when applying US incidence data. CONCLUSIONS: The large number of patients, who need to undergo endoscopic surveillance to detect one cancer, raises questions about the value of surveillance endoscopy in patients with short segment or ultra-short segment of Barrett's oesophagus.

Long-term efficacy and safety of endoscopic resection for patients with mucosal adenocarcinoma of the esophagus.

BACKGROUND & AIMS: Barrett's esophagus-associated high-grade dysplasia is commonly treated by endoscopy. However, most guidelines offer no recommendations for endoscopic treatment of mucosal adenocarcinoma of the esophagus (mAC). We investigated the efficacy and safety of endoscopic resection in a large series of patients with mAC. METHODS: We collected data from 1000 consecutive patients (mean age, 69.1 ± 10.7 years; 861 men) with mAC (481 with short-segment and 519 with long-segment Barrett's esophagus) who presented at a tertiary care center from October 1996 to September 2010. Patients with low-grade and high-grade dysplasia and submucosal or more advanced cancer were excluded. All patients underwent endoscopic resection of mACs. Patients found to have submucosal cancer at their first endoscopy examination were excluded from the analysis. RESULTS: After a mean follow-up period of 56.6 ± 33.4 months, 963 patients (96.3%) had achieved a complete response; surgery was necessary in 12 patients (3.7%) after endoscopic therapy failed. Metachronous lesions or recurrence of cancer developed during the follow-up period in 140 patients (14.5%) but endoscopic re-treatment was successful in 115, resulting in a long-term complete remission rate of 93.8%; 111 died of concomitant disease and 2 of Barrett's esophagus-associated cancer. The calculated 10-year survival rate of patients who underwent endoscopic resection of mACs was 75%. Major complications developed in 15 patients (1.5%) but could be managed conservatively. CONCLUSIONS: Endoscopic therapy is highly effective and safe for patients with mAC, with excellent long-term results. In an almost 5-year follow-up of 1000 patients treated with endoscopic resection, there was no mortality and less than 2% had major complications. Endoscopic therapy should become the standard of care for patients with mAC.

The frequency of lymph node metastasis in early-stage adenocarcinoma of the esophagus with incipient submucosal invasion (pT1b sm1) depending on histological risk patterns.

BACKGROUND: A prerequisite for endoscopic treatment (ET) of not only mucosal, but also submucosal early adenocarcinoma of the esophagus (EAC) would be a rate of lymph node (LN) metastasis below the mortality rate of esophagectomy (2-5%). The aim of the present study was to evaluate the rate of LN metastasis in patients with pT1b sm1 EAC. METHODS: 1996-2010, 1,718 patients with suspicion of EAC were referred to the Department of Internal Medicine II at HSK Wiesbaden. In 123/1718 patients, the suspicion (endoscopic ultrasound, EUS) or definitive diagnosis of sm1 EAC (ER/surgery) was made. Rate of LN metastasis was analyzed separately for low-risk (LR; G1-2, L0, V0) and high-risk lesions (HR; G3, L1, V1; ≥ 1 risk factor). LN metastasis was only evaluated in patients who had a proven maximum invasion depth of sm1 (ER and/or surgery), and who in case of ET had a follow-up (FU) by EUS of at least 24 months. RESULTS: Of the 72/123 patients included into the study, 49 patients had LR (68%) and 23 HR lesions (32%). In endoscopically treated LR patients (37/49), mean EUS-FU was 60 ± 30 mo (range 25-146); in HR patients undergoing ET (6/23), it was 63 ± 17 mo (46-86; p = 0.4). Mean number of resected LN was 27 ± 16 (12-62) in operated LR patients and 27 ± 10 (12-47) in HR-patients. The rate of LN metastasis was 2% in the LR (1 patient) and 9% in the HR group (2 patients; p = 0.24). Mortality of esophagectomy was 3%. CONCLUSIONS: The rate of LN metastasis in pT1b sm1 early adenocarcinoma with histological LR pattern was lower than the mortality rate of esophagectomy. ER may therefore be used alternatively to surgery in this group of patients.

Prognostic risk factors of early esophageal adenocarcinomas.

OBJECTIVE: To define prognostic risk factors in patients with early adenocarcinomas of the esophagus (eACEs) who were treated by esophagectomy. BACKGROUND: Although endoscopic resection (ER) is more accepted for eACEs limited to the mucosa, the reported prevalence of lymph node metastases once the tumor infiltrates the submucosa seems to necessitate surgery in these cases. METHODS: We analyzed the results of 168 patients who had an esophageal resection because of an eACE. On the basis of specimen histologies and clinical follow-up (median, 64 months), we investigated the influence of lymph node metastases (N+), tumor infiltration depth, tumor differentiation (G1-3), and lymphatic or venous infiltration (L+ or V+) on overall and tumor-specific survival and recurrence rates. RESULTS: The 5-year survival rate was 79%. Lymph node infiltration was the only prognostic factor for the overall survival [hazard ratio (HR), 2.856; 1.314-6.207; P = 0.008], tumor-specific survival (HR, 8.336; 2.734-25.418; P < 0.001), and tumor recurrence (HR, 8.031; 3.041-21.206; P < 0.001) that was consistently present in all multivariate hazard Cox regression analyses. A total of 47% of the patients who had an N+ status developed tumor recurrences compared with 5.2% of those who had no lymph node involvement (P = <0.001). We found a significant correlation between N+ status and increasing depth of tumor infiltration (P = 0.004), lymphatic vessel infiltration (P = 0.002), tumor differentiation (G1 + G2 vs G3; P = 0.014) and vascular infiltration (P = 0.01). CONCLUSIONS: Lymph node status is the only independent risk factor for survival and recurrence rates. Tumor infiltration depth correlates with the rate of the lymph node metastases, but a clear watershed between deep mucosal and submucosal infiltration does not exist. As a consequence, careful staging procedures, including diagnostic ER, are mandatory to determine which patients can be treated by ER and which require an esophagectomy.

Second cancers and residual disease in patients treated for gastric mucosa-associated lymphoid tissue lymphoma by Helicobacter pylori eradication and followed for 10 years.

BACKGROUND & AIMS: Cure of Helicobacter pylori infection induces remission in most patients with gastric mucosa-associated lymphoid tissue lymphoma (GML) that is associated with these bacteria. We determined the long-term outcomes of these patients in a prospective multicenter trial and investigated whether they developed second cancers or had histologic residual disease. METHODS: We followed 120 patients with stage EI1 GML for a median of 122 months after H pylori eradication (range, 1-171 months). Remission was determined by histology analysis and development of second cancers was documented. RESULTS: Of the patients, 80% (96 of 120) achieved complete remission from GML, and 80% of those (77 of 96) remained disease free. Estimated mean survival time in the Kaplan-Meier analysis was 147 months (95% confidence interval: 138-156 months). Of the patients that achieved complete remission, 17% (16 of 96) had histologic residual disease after a median of 32 months (range, 3-68 months). Disease did not progress in any of these patients, and all but 1 achieved a second complete remission (median duration, 46 months). Standardized morbidity ratios revealed a significantly higher incidence of gastric cancer (8.567; 95% confidence interval, 3.566-20.582) or non-Hodgkin lymphoma (18.621; 95% confidence interval: 8.365-41.448) in the 96 patients that achieved a complete remission, compared with the general German population. CONCLUSIONS: Cure of H pylori infection leads to continuous complete remission in most patients with H pylori-associated GML. Patients are at risk for development of secondary cancers (ie, gastric cancer and non-Hodgkin lymphoma).

Efficacy, safety, and long-term results of endoscopic treatment for early stage adenocarcinoma of the esophagus with low-risk sm1 invasion.

BACKGROUND & AIMS: Patients with early-stage mucosal (T1a) esophageal adenocarcinoma (EAC) are increasingly treated by endoscopic resection. EACs limited to the upper third of the submucosa (pT1b sm1) could also be treated by endoscopy. We assessed the efficacy, safety, and long-term effects of endoscopic therapy for these patients. METHODS: We analyzed data from 66 patients with sm1 low-risk lesions (macroscopically polypoid or flat, with a histologic pattern of sm1 invasion, good-to-moderate differentiation [G1/2], and no invasion into lymph vessels or veins) treated by endoscopic therapy at the HSK Hospital Wiesbaden from 1996 through 2010. The efficacy of endoscopic therapy was assessed on the basis of rates of complete endoluminal remission (CER), metachronous neoplasia, lymph node events, and long-term remission (LTR). Safety was assessed on the basis of rate of complications. RESULTS: Remissions were assessed in 61 of the 66 patients; 53 of the 61 achieved CER (87%). Of patients with small focal neoplasias ≤2 cm, 97% achieved CER (for those with tumors ≥2 cm, 77%; P = .026). Metachronous neoplasias were observed in 10 of 53 patients (19%; 9 of the 10 underwent repeat endoscopic resection). One patient developed a lymph node metastasis (1.9%). Fifty-one patients achieved LTR (84%); 90% of those with focal lesions ≤2 cm achieved LTR after a mean follow-up period of 47 ± 29.1 months (range, 8-120 months). No tumor-associated deaths were observed, and the estimated 5-year survival rate was 84%. The rate of major complications from endoscopic resection was 1.5%, and no patients died. CONCLUSIONS: Endoscopic therapy appears to be a good alternative to esophagectomy for patients with pT1b sm1 EAC, on the basis of macroscopic and histologic analyses. The risk of developing lymph node metastases after endoscopic resection for sm1 EAC is lower than the risk of surgery.

Progression of specialized intestinal metaplasia at the cardia to macroscopically evident Barrett's esophagus: an entity of concern in the ProGERD study.

OBJECTIVES AND AIMS: Histological Barrett's esophagus, defined as specialized intestinal metaplasia (SIM+) at the cardia without endoscopic suspicion of columnar epithelium, is found frequently in biopsies at the gastro-esophageal junction although its clinical relevance is unknown. The authors aim was to evaluate prospectively the progression of SIM+ to macroscopically evident Barrett's esophagus (BE/SIM+), and to identify risk factors for this progression. METHODS: Data were obtained from a sub-group of patients (no visible BE at presentation, but SIM+) included in the ProGERD study, a prospective evaluation of the clinical course of GERD under routine clinical care. They had esomeprazole 20-40 mg/day for 2-8 weeks. Symptom assessment was performed annually, and endoscopy with biopsy was planned at baseline, after healing treatment and after 2 and/or 5 years. RESULTS: 128 of 171 (74.8%) patients with unequivocal SIM at the z-line after healing were biopsied again after 2 and/or 5 years. At follow-up, 33 (25.8%) of these patients showed progression to BE/SIM+. Factors significantly associated with progression were smoking, a long history of GERD and severe esophagitis at baseline. Patients who had progressed to BE/SIM+ already at 2 years showed consistent findings at 5 years. CONCLUSION: More than 20% of GERD patients with SIM+ in this study were found to have BE/SIM+ within 2-5 years. This finding supports the hypothesis that SIM+ at the cardia could be the missing link explaining increased cancer risk in GERD patients without overt BE and merits further investigation in a prospective study.

Randomized trial on 14 versus 7 days of esomeprazole, moxifloxacin, and amoxicillin for second-line or rescue treatment of Helicobacter pylori infection.

BACKGROUND: Triple therapy with a proton pump inhibitor, moxifloxacin, and amoxicillin has been proven effective in first-line treatment of Helicobacter pylori infection. AIM: To explore 1, the value of triple therapy with esomeprazole, moxifloxacin, and amoxicillin in second-line or rescue treatment of Caucasian patients and 2, the impact of treatment duration on eradication success. METHODS: H. pylori-infected patients with at least one previous treatment failure were randomized to oral esomeprazole 20 mg b.i.d., moxifloxacin 400 mg o.d., and amoxicillin 1000 mg b.i.d. for either 7 (EMA-7) or 14 days (EMA-14). Eradication was confirmed by 13C urea breath test. Antimicrobial susceptibility testing was performed in all patients at baseline and in patients who failed treatment. RESULTS: Eighty patients were randomized, and 60% had ≥ 2 previous treatment failures. Pretreatment resistance against clarithromycin and metronidazole was found in 70.5 and 61.5% of cases, respectively. The intention-to-treat eradication rate was significantly higher after EMA-14 compared with EMA-7 (95.0 vs 78.9%, p = .036). No independent risk factor for treatment failure could be identified. There were no serious adverse events. Five of the EMA-14 patients (12.5%) compared with none of the EMA-7 patients discontinued prematurely because of adverse events (p = .031). Post-treatment resistance against moxifloxacin was found in one of seven patients with isolated organisms (14.3%). CONCLUSION: Second-line/rescue H. pylori eradication therapy with esomeprazole, moxifloxacin, and amoxicillin is very effective and well tolerated. Fourteen days of treatment significantly increase the eradication rate but also the rate of adverse events.

Correlation of serum pepsinogens and gastrin-17 with atrophic gastritis in gastroesophageal reflux patients: a matched-pairs study.

BACKGROUND AND AIM: An algorithm (GastroPanel) for the non-invasive diagnosis of atrophic gastritis has been previously proposed, based on serum pepsinogen-I, gastrin-17, and Helicobacter pylori (H. pylori) antibodies. The aim of the present study was to evaluate whether serum markers correlate with and predict gastric atrophy in gastroesophageal reflux disease (GERD) patients. METHODS: The baseline data of the prospective ProGERD study, a study on the long-term course of GERD (n=6215 patients), served to select patients with atrophic gastritis diagnosed in biopsies from gastric antrum and corpus, and control cases without atrophy. A total of 208 pairs were matched for age, sex, GERD status (erosive vs non-erosive), presence of Barrett's esophagus, and histological H. pylori status were retrieved. Serum pepsinogen-I, gastrin-17, and H. pylori antibodies were determined using specific enzyme immunoassays. RESULTS: A significant negative correlation was found between the degree of corpus atrophy and the level of serum pepsinogen-I. A previously-reported negative correlation between the degree of antral atrophy and serum gastrin-17 could not be confirmed. The low sensitivity (0.32) and specificity (0.70) of the GastroPanel algorithm were mainly due to over diagnosis and under diagnosis of advanced atrophy in the antrum. CONCLUSION: The diagnostic validity of the GastroPanel algorithm to diagnose gastric atrophy non-invasively is not sufficient for general use in GERD patients.

Effects of Helicobacter pylori eradication on early stage gastric mucosa-associated lymphoid tissue lymphoma.

BACKGROUND & AIMS: Different remission rates of gastric low-grade, B-cell, mucosa-associated lymphoid tissue (MALT) lymphoma have been reported after Helicobacter pylori eradication. We assessed the long-term remission and relapse rates of early stage MALT lymphoma in patients treated only by H pylori eradication and identified factors that might predict outcome. METHODS: This systematic review analyzed data from 32 studies, including 1408 patients. RESULTS: The MALT lymphoma remission rate was 77.5% (95% confidence interval, 75.3-79.7), and was significantly higher in patients with stage I than stage II(1) lymphoma (78.4% vs 55.6%; P = .0003) and in Asian than in Western groups (84.1% vs 73.8%; P = .0001). Neoplasia confined to the submucosa regressed more frequently than that with deeper invasion (82.2% vs 54.5%; P = .0001); patients with lymphoma localized to the distal stomach experienced regression more frequently than those with lymphoma of the proximal stomach (91.8% vs 75.7%; P = .0037). The remission rate was higher among patients without the API2-MALT1 translocation than in those with this translocation (78% vs 22.2%; P = .0001). In an analysis of data from 994 patients, 7.2% experienced lymphoma relapse during 3253 patient-years of follow-up evaluation, with a yearly recurrence rate of 2.2%. Infection and lymphoma were cured by additional eradication therapy in all patients with H pylori recurrence (16.7%). Five (0.05%) of the patients initially cured of lymphoma developed high-grade lymphoma within 6 to 25 months of therapy. CONCLUSIONS: H pylori eradication is effective in treating approximately 75% of patients with early stage gastric lymphoma. Long-term follow-up evaluation of these patients is needed to detect early lymphoma relapse or progression.

Budesonide is effective in treating lymphocytic colitis: a randomized double-blind placebo-controlled study.

BACKGROUND & AIMS: Budesonide is effective in treating collagenous colitis, but no treatment is established for lymphocytic colitis. We performed a randomized, double-blind, placebo-controlled study to evaluate the effects of budesonide in patients with lymphocytic colitis. METHODS: Forty-two patients (median age, 61 years) with lymphocytic colitis and chronic diarrhea were randomly assigned to groups that were given oral doses of budesonide (9 mg/d) or placebo for 6 weeks. Nonresponders at week 6 were given open-label budesonide (9 mg/d) for 6 additional weeks. A complete colonoscopy and histologic and quality-of-life analyses were performed at baseline and at week 6. The primary end point was clinical remission at 6 weeks, with last observation carried forward (LOCF). All patients who left the study in clinical remission were followed for relapse. RESULTS: At week 6, 86% of patients given budesonide were in clinical remission (with LOCF) compared with 48% of patients given placebo (P = .010). Furthermore, open-label budesonide therapy induced clinical remission in 7 of 8 patients given placebo. Histologic remission was observed in 73% of patients given budesonide compared with 31% given placebo (P = .030). Only 1 patient discontinued budesonide therapy prematurely. During a mean follow-up period of 14 months, 15 patients (44.1%) experienced a clinical relapse (after a mean of 2 months); 8 of the relapsing patients were retreated with and responded again to budesonide. CONCLUSIONS: Budesonide effectively induces clinical remission in patients with lymphocytic colitis and significantly improves histology results after 6 weeks. Clinical relapses occur but can be treated again with budesonide.

Time-gated fluorescence spectroscopy improves endoscopic detection of low-grade dysplasia in ulcerative colitis.

BACKGROUND: Dysplasia in ulcerative colitis is frequently missed with 4-quadrant biopsies. An experimental setup recording delayed fluorescence spectra simultaneously with white light endoscopy was recently developed. OBJECTIVE: We compared detection of invisible flat intraepithelial neoplasia with protoporphyrin IX fluorescence and standard 4-quadrant biopsies. DESIGN: Prospective, crossover design without randomization of the order of procedures. SETTING: Gastroenterology Department, Humboldt University, Charité, Berlin, Germany. PATIENTS: Forty-two patients with extensive ulcerative colitis of more than 10 years' duration were included. INTERVENTIONS: Colonoscopy with 4-quadrant biopsies and targeted biopsies of macroscopic lesions and time-gated fluorescence-guided colonoscopy were performed 2 weeks apart by 2 blinded endoscopists. Three independent pathologists examined the biopsy specimens. MAIN OUTCOME MEASUREMENTS: The primary outcome criterion was detection rate of invisible flat intraepithelial neoplasia. RESULTS: Invisible flat intraepithelial neoplasia was detected in 3 (7%) patients by white light 4-quadrant biopsies and in 10 (24%) patients by fluorescence-guided endoscopy (P = .02). The sensitivity and specificity for differentiating patients with and without dysplasia were 100% and 81%, respectively. Dysplastic and nondysplastic mucosa could be discriminated with a sensitivity and specificity of 73% and 81%, respectively. LIMITATIONS: The trial was not randomized. CONCLUSION: The detection rate of intraepithelial neoplasia in patients with ulcerative colitis can be improved by fluorescence-guided colonoscopy.

Twelve-month endoscopic and histological analysis following proton-pump inhibitor-based triple therapy in Helicobacter pylori-positive patients with gastric ulcers.

OBJECTIVE: To evaluate endoscopic and histological findings after Helicobacter pylori eradication therapy in gastric ulcer (GU) patients after 12 months' follow-up. MATERIAL AND METHODS: A total of 401 GU patients were randomized to receive either twice-daily (b.i.d.) esomeprazole 20 mg+amoxicillin 1000 mg+clarithromycin 500 mg (EAC) for 1 week followed by placebo for 3 weeks, EAC followed by once-daily (o.d.) esomeprazole 20 mg for 3 weeks or esomeprazole 20 mg b.i.d. plus placebo antibiotics for 1 week followed by esomeprazole 20 mg o.d. for 3 weeks. Endoscopy with biopsy was performed at baseline, after treatment and at 6 and 12 months' follow-up (healed patients). RESULTS: Endoscopic abnormalities, particularly in the stomach, were common at baseline and remained similar during follow-up, regardless of ulcer status and treatment. Helicobacter gastritis was present (antrum or corpus) in approximately 20% of patients following eradication therapy (versus approximately 80% with esomeprazole alone); these effects were sustained during follow-up. Similar trends were observed for other histological variables (granulocyte and lymphoplasmocytic cell infiltration, replacement of gastric surface cells by regenerative epithelium, and mucous depletion). No changes in atrophy or intestinal metaplasia were observed. Eighteen gastric cancer cases were detected: 11 at baseline endoscopy, and seven during treatment and follow-up. CONCLUSIONS: Endoscopic abnormalities are common in GU patients and persist after proton-pump inhibitor-based triple therapy for H. pylori eradication, which is associated with large, sustained improvements in histological variables. Follow-up endoscopy and histology may be necessary, even in patients with apparently non-malignant GU, to improve the detection rate of gastric malignancy in populations with a high prevalence of gastric cancer.

Identification of novel cyclooxygenase-2-dependent genes in Helicobacter pylori infection in vivo.

BACKGROUND: Helicobacter pylori is a crucial determining factor in the pathogenesis of benign and neoplastic gastric diseases. Cyclooxygenase-2 (Cox-2) is the inducible key enzyme of arachidonic acid metabolism and is a central mediator in inflammation and cancer. Expression of the Cox-2 gene is up-regulated in the gastric mucosa during H. pylori infection but the pathobiological consequences of this enhanced Cox-2 expression are not yet characterized. The aim of this study was to identify novel genes down-stream of Cox-2 in an in vivo model, thereby identifying potential targets for the study of the role of Cox- 2 in H. pylori pathogenesis and the initiation of pre- cancerous changes. RESULTS: Gene expression profiles in the gastric mucosa of mice treated with a specific Cox-2 inhibitor (NS398) or vehicle were analysed at different time points (6, 13 and 19 wk) after H. pylori infection. H. pylori infection affected the expression of 385 genes over the experimental period, including regulators of gastric physiology, proliferation, apoptosis and mucosal defence. Under conditions of Cox-2 inhibition, 160 target genes were regulated as a result of H. pylori infection. The Cox-2 dependent subset included those influencing gastric physiology (Gastrin, Galr1), epithelial barrier function (Tjp1, connexin45, Aqp5), inflammation (Icam1), apoptosis (Clu) and proliferation (Gdf3, Igf2). Treatment with NS398 alone caused differential expression of 140 genes, 97 of which were unique, indicating that these genes are regulated under conditions of basal Cox-2 expression. CONCLUSION: This study has identified a panel of novel Cox-2 dependent genes influenced under both normal and the inflammatory conditions induced by H. pylori infection. These data provide important new links between Cox-2 and inflammatory processes, epithelial repair and integrity.

Oral budesonide for maintenance treatment of collagenous colitis: a randomized, double-blind, placebo-controlled trial.

BACKGROUND & AIMS: Oral budesonide effectively induces clinical remission in patients with collagenous colitis, a debilitating illness characterized by chronic watery/loose diarrhea, but there is a high rate of relapse after treatment cessation. METHODS: This randomized, double-blind, placebo-controlled, multicenter study evaluated the efficacy and safety of long-term therapy with oral budesonide (Entocort CIR capsules) for maintenance of clinical remission of collagenous colitis. Patients were aged >18 years with histologically proven collagenous colitis and >3 watery/loose stools per day on >or=4 of the prior 7 days. Open-label oral budesonide 9 mg/d was administered to all patients for 6 weeks. Patients in clinical remission (3 stools per day on >or=4 consecutive days (and included patients withdrawn because of adverse events). RESULTS: Of 48 enrolled patients, 46 (96%) achieved clinical remission at week 6 and were randomized to maintenance budesonide or placebo. There were 21 relapses during maintenance therapy, and almost all occurred during the first 2 months. Budesonide therapy was associated with a significantly lower cumulative rate of relapse compared with placebo (6/23 [26%] and 15/23 [65%], respectively; P = .022), and high correlation between clinical remission and histologic improvement was observed. Budesonide was well tolerated with no serious adverse events. CONCLUSIONS: Oral budesonide 6 mg/d is efficacious and well tolerated for long-term maintenance of clinical remission in patients with collagenous colitis.

Long-term results of endoscopic resection in early gastric cancer: the Western experience.

OBJECTIVES: In the West, neither acute nor long-term results of endoscopic resection (ER) for early gastric cancer (EGC) have been reported in large studies. The aim of this study was to prospectively evaluate the efficacy and safety of ER in patients with EGC in a long-term follow-up (FU). METHODS: From May 1995 to October 2004, 179 patients were referred to our department for endoscopic therapy (ET) of gastric cancer (GC). Of these, 43 patients had intramucosal GC with a diameter of up to 30 mm and underwent ER with curative intent. All patients underwent a strict FU protocol at regular intervals. RESULTS: Of the 43 patients, 42 fulfilled our low-risk criteria for ET of EGC: gross tumor type I/II, intramucosal GC, diameter up to 30 mm, tumor differentiation G1/G2, and no infiltration into lymph vessels/veins. Two patients were not available for FU (remission status not evaluated). In another patient, gastric mucosa-associated lymphoid tissue lymphoma was detected simultaneously, and he was referred for surgery. 38 (97%) of the remaining 39 patients who underwent definitive ET (23 males (59%); mean age 69+/-10 years) achieved complete remission (CR) after a mean of 1.3+/-0.6 ER sessions. Minor complications (not Hb-relevant bleeding) occurred in 7 of the 39 patients (18%) and major complications (5 Hb-relevant bleeds, 1 covered perforation; all managed conservatively) in 6 patients (15%). During FUs (mean 57 months; range 5-137), recurrent or metachronous lesions were observed in 11 patients (29%). All lesions were successfully treated by repeated ET. No tumor-related deaths occurred during FU. CONCLUSIONS: Although ER for EGC in Western countries is effective, it is associated with a relevant risk of complications. In view of the possibility of recurrent or metachronous neoplasia, a strict FU protocol is mandatory.

Sequential H. pylori eradication and radiation therapy with reduced dose compared to standard dose for gastric MALT lymphoma stages IE & II1E: a prospective randomized trial.

BACKGROUND: In Helicobacter pylori (H. pylori) positive stage I gastric low-grade MALT lymphoma, eradication is the accepted first-line therapy. The role of eradication therapy in lymphoma > stage IE is still unclear. However, about 20% of patients show persistent lymphoma following successful eradication or primary H. pylori-negative lymphoma. A prospective study for salvage radiation therapy with standard 36 Gy in comparison to a reduced dose of 25.2 Gy is still missing. METHODS: A prospective, multicentre study investigated the efficacy of eradication in H. pylori-positive gastric low-grade MALT lymphoma stages IE and II1E (HELYX I). Refractory lymphoma or H. pylori-negative patients were treated in a prospective, randomised, multicentre, phase II study to receive either 25.2 Gy or 36 Gy radiotherapy (HELYX II). RESULTS: 102 patients (3 drop outs) were included in HELYX I: 75/99 (75.8%) showed complete remission after a median of 2.8 months. 18 (18.2%) had partial remission (PR) and 6 (6.0%) no change (NC). 29 patients (7 drop outs) were randomized in HELYX II (7 primarily H. pylori-negative, 15 patients from HELYX I with refractory disease after eradication). All patients achieved stable CR irrespective of radiation dose. Both presence of the t(11,18) translocation (OR 9.0, p = 0.01) and monoclonality of the tumour cells (OR 6.3, p = 0.006) were predictors for persistant lymphoma after eradication therapy. CONCLUSIONS: Most H. pylori-positive low grade gastric MALT lymphoma stage IE and II1E respond with stable CR after eradication therapy. In patients with refractory disease or H. pylori negative low grade gastric MALT lymphoma a dosage-reduced radiation therapy with 25.2 Gy is an effective standard dose in stage IE and II1E. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00154440.

Confocal laser endomicroscopy for in vivo diagnosis of early squamous cell carcinoma in the esophagus.

BACKGROUND & AIMS: Confocal laser endomicroscopy has been shown to allow direct histologic imaging of gastrointestinal tumors in vivo. This study was designed to assess the potential of endomicroscopy for predicting histology in vivo during routine endoscopy in patients with early squamous cell cancer. METHODS: Twenty-one consecutive patients with suspected early squamous cell cancer who had been referred for endoscopic therapy to a tertiary-care academic medical center were included in this prospective study. After staining with 0.5% Lugol's solution and injection of 500 mg fluorescein sodium, unstained mucosal areas were examined using confocal imaging. Images of each scanned lesion were acquired and stored digitally, and in vivo diagnosis was performed during ongoing endoscopy. Biopsy specimens were taken from every lesion. The confocal images were reviewed by 2 endoscopists, who were blinded to the histology and endoscopic appearance. RESULTS: Confocal images were acquired from 43 lesions in 21 patients. Twenty-seven of the 43 lesions (63%) were proven to be squamous cell cancer on histology. All squamous cell cancers were diagnosed correctly by endomicroscopy and 2 lesions were falsely diagnosed as neoplastic. The overall accuracy was 95%, and the sensitivity and specificity were 100% and 87%, respectively. Intraobserver agreement was almost perfect (kappa = 0.95) and interobserver agreement was substantial (kappa = 0.79). CONCLUSIONS: Confocal laser endomicroscopy is able to provide virtual histology of early squamous cell cancers with a high degree of accuracy and can facilitate rapid diagnosis during routine endoscopy.

Early Barrett's carcinoma with "low-risk" submucosal invasion: long-term results of endoscopic resection with a curative intent.

BACKGROUND: Endoscopic therapy (ET) has become a less risky alternative to open surgery in mucosal Barrett's cancer (BC) because of the very low risk of lymph node (LN) metastasis. Recently published surgical series demonstrated that even in case of minimal submucosal invasion of BC, the risk for LN metastasis is very low. In consequence, also these patients might be eligible for curative ET. The aim of this study was to prospectively evaluate the efficacy and safety of endoscopic resection (ER) in these patients. METHODS: From September 1996 to September 2003, the suspicion or definite diagnosis of submucosal BC was made in 80 patients referred to our department. Of those, 21 patients (20 male [95.2%], mean age 62 +/- 9 yr, range 47-78) fulfilled the definition of "low-risk" submucosal cancer: invasion of the upper submucosal third (sm1), absence of infiltration into lymph vessels/veins, histological grade G1/2, and macroscopic type I/II. ET was carried out using ER with the suck-and-cut technique with or without an additive ablation of non-neoplastic remnants of Barrett's esophagus. RESULTS: One of the 21 patients was referred to surgery directly after the detection of sm1 invasion at the beginning of the study. One patient died (not tumor-related) before completion of ET. Using definitive ET, complete remission (CR) was achieved in 18 of 19 patients (95%) after a mean of 5.3 months (range 1-18) and a mean of 2.9 resections (range 1-9). Only one minor complication (bleeding without drop in hemoglobin level >2 g/dL) occurred (5% of patients). During a mean follow-up (FU) of 62 months (range 45-89), recurrent or metachronous carcinomas were found in 5 patients (28%). Repeat ET was carried out successfully using ER (4 patients) and argon plasma coagulation (1 patient). In one of the 19 patients (5%), tumor freedom had not been achieved after a total of 2 ER. This patient died of a heart attack before surgery could be performed. The calculated 5-yr survival rate of all 21 patients was 66%. No tumor-related death occurred. CONCLUSIONS: As in mucosal BC, ER is associated with favorable outcomes even in case of "low-risk" submucosal BC. Further and larger clinical trials are required before a general recommendation for ER as the treatment of choice in "low-risk" submucosal BC can be given.

One-week once-daily triple therapy with esomeprazole, moxifloxacin, and rifabutin for eradication of persistent Helicobacter pylori resistant to both metronidazole and clarithromycin.

AIM: To investigate a 1-week once-daily triple therapy with esomeprazole, moxifloxacin, and rifabutin for rescue therapy of Helicobacter pylori infection. METHODS: Consecutive patients (n = 103) with at least one previous treatment failure and H. pylori infection resistant to both metronidazole and clarithromycin were treated with esomeprazole 40 mg, moxifloxacin 400 mg, and rifabutin 300 mg, given once daily for 7 days. Eradication was confirmed by histology and culture. CYP2C19 status was determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Intention-to-treat and per-protocol eradication rates were 77.7% (68.4-85.3) and 83.3% (74.4-90.2). Five patients discontinued prematurely (4.8%). Eradication was achieved in 93.1% of poor/intermediate metabolizers and in 78.8% of homozygous extensive metabolizers (p = .14). Eradication rates in patients with one, two, three, and four or more previous failures were 78.3%, 89.6%, 68.6%, and 88.9%, respectively (p = .21). The regimen was effective in seven of nine patients who previously failed quadruple therapy. Post-treatment resistance to moxifloxacin and rifabutin was detected in two (12.5%) and five (31%) patients after treatment failure. CONCLUSION: Once-daily triple therapy with esomeprazole, moxifloxacin, and rifabutin is a promising, safe, and convenient regimen for rescue therapy of H. pylori infection that may serve as a valuable alternative to quadruple therapy, particularly for patients with intolerance to amoxicillin.