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The treatment of hepatocellular cancer (HCC) with transarterial chemoembolization (TACE) prior to orthotopic liver transplant (OLT) is of increasing importance due to the rise in HCC incidence and donor shortage. This single-center study examines 28 patients treated with TACE and 7 patients not treated with TACE, with HCC prior to OLT between 1999 and 2008. The overall 1- and 5-year survival of all transplanted patients with HCC was 94% (33 of 35) and 80% (28 of 35). There was no difference in survival (P = .99) between patients who underwent transplantation immediately (median 95 days) and patients who had significantly longer wait times (median 308 days) when treated with TACE. During extensive wait times for OLT, TACE can be used to keep patients with HCC on the waiting list by preventing tumor progression, with similar outcomes compared with those who underwent transplantation immediately.

The following on the natural history of Barrett's esophagus (BE) includes commentary on histological sequences of the development of Barrett mucosa; the transformation of esophageal cells from squamous to columnar phenotype; the stages of natural history of dysplasia; the difficulties of predicting progression of dysplasia to adenocarcinoma; the preferable biopsy protocols; the role of Helicobacter pylori infection and gastric atrophy in the risk of BE; the value of decrease of proton pump inhibitor efficacy following eradication of H. pylori; the place of antireflux surgery in the natural history of BE; the newest procedures for the endoscopic detection of early neoplasia; and the essential importance of a good understanding of the natural history for the best management of high-grade dysplasia., (© 2011 New York Academy of Sciences.)

Although the prevalence of Barrett's esophagus (BE) is rising no data exist for racial minorities on prevalence in the general population. Minorities have a lower prevalence than Caucasians, and yet age, smoking, abdominal obesity, and Helicobacter pylori are all risk factors. Metabolic changes induced by adipocytokines and the apparently strong association between obesity, central adiposity, and BE may lead to reconsideration of some aspects of the natural history of BE. There is lack of experimental evidence on acid sensitivity and BE, which is hyposensitive compared to esophageal reflux disease. Reactive nitrogen and oxygen species lead to impaired expression of tumor suppressor genes, which can lead to cancer development; thus, antioxidants may be protective. Gastroesophageal reflux disease may be considered an immune-mediated disease starting at the submucosal layer; the cytokine profile of the mucosal immune response may explain the different outcome of gastroesophageal reflux., (© 2011 New York Academy of Sciences.)

The following on endoscopic treatments of Barrett's esophagus includes commentaries on animal experiments on cryotherapy; indications for cryotherapy, choice of dosimetry, number of sessions, and role in Barrett's esophagus and adenocarcinoma; recent technical developments of RFA technology and long-term effects; the comparative effects of diverse ablation procedures and the rate of recurrence following treatment; and the indications for treatment of dysplasia and the role of radiofrequency ablation., (© 2011 New York Academy of Sciences.)

The following topics are explored in this collection of commentaries on treatments of adenocarcinomas related to Barrett's esophagus: the importance of intraoperative frozen sections of the margins for the detection of high dysplasia; the preferable way for sentinel node dissection; the current role of robotic surgery and of video-endoscopic approach; the value of the Siewert's classification of adenocarcinomas; the indications of two-step esophagectomy; the evaluation of pathological complete response; the role of PET scan in staging and response assessment; the role of p53 in the selection of adenocarcinomas patients; chemotherapy regimens for adenocarcinomas; the use of monoclonal antibodies in the control of cell proliferation; he attempt to define a stage-specific strategy, and the possible indications of selective therapy; and changes in mortality rates from esophageal cancer., (© 2011 New York Academy of Sciences.)

Sulindac, atorvastatin, or prebiotic dietary fiber may reduce colorectal cancer (CRC) risk. However, clinical trial data are currently limited. We conducted a randomized, phase II chemoprevention trial involving subjects 40 years or older, with previously resected colon cancer or multiple/advanced colorectal adenomas. Magnification chromoendoscopy (MCE) was performed to identify and characterize rectal aberrant crypt foci (ACF); eligibility criteria required five or more rectal ACFs at baseline. Intervention assignments were as follows: (a) atorvastatin 20 mg qd; (b) sulindac 150 mg bid; (c) oligofructose-enriched inulin (as ORAFTI®Synergy1) 6 gm bid; or (d) control (maltodextrin) 6 gm bid, for 6 months. Percent change in rectal ACF number (%ΔACF) within arm was the primary endpoint. Secondary endpoints included changes in proliferation (Ki67) and apoptosis (caspase-3), as measured from normal mucosa biopsy samples. Among 85 eligible randomized subjects, 76 (86%) completed the trial per protocol. The median (range) of rectal ACF was 9 (5-34) and 8 (0-37) at baseline and postintervention, respectively. The median (SD) for %ΔACF was 5.6 (-69% to 143%), -18.6 (-83% to 160%), -3.6 (-88% to 83%), and -10.0 (-100% to 117%) in the atorvastatin, sulindac, ORAFTI®Synergy1 and control arms, respectively. Neither within-arm (P = 0.12-0.59) nor between-arm (P = 0.30-0.92) comparisons of %ΔACF were statistically significant. The active and control interventions also seemed to have similar effects on mucosal proliferation and apoptosis (P > 0.05 for each comparison). Data from this multicenter, phase II trial do not provide convincing evidence of CRC risk reduction from 6-month interventions with atorvastatin, sulindac, or ORAFTI®Synergy1, although statistical power was limited by the relatively small sample size., (©2011 AACR.)

Objectives: The source of most cases of non-cardiac chest pain (NCCP) is thought to be the esophagus. We reasoned that if the origin of NCCP is truly esophageal and not cardiac, the characteristics and survival of individuals with NCCP should be similar to those of individuals with benign esophageal disease, such as gastroesophageal reflux disease (GERD). The aim of this study was to compare the characteristics, natural history, and long-term survival of two well-defined groups, NCCP patients and GERD patients., Methods: From 1984 to 1996, patients with NCCP were referred for endoscopy by the cardiology service after a coronary angiography done for chest pain was reported by the cardiologist as negative. Patients with GERD were referred for endoscopy for one of the usual symptoms of acid reflux. The baseline endoscopy and referrals occurred in the pre-proton pump inhibitor (PPI) era, before and during the availability of only the histamine receptor antagonists (HRAs). Thus, the endoscopic findings reflected the untreated natural state of the gastrointestinal mucosa. Endoscopic exams, esophageal biopsy, endoscopic anatomy mapping, and data verification were carried out in the endoscopy lab by one of three endoscopists using predefined criteria. All results were recorded both by hand and by entry into a database storage program. Patients were followed by their primary care providers in their usual outpatient general medicine clinics. The Veterans Affairs Decentralized Hospital Computer Program (VA DHCP) storage system provided access to mortality data as well as details of all prescriptions filled since 1985., Results: During the 12-year enrollment period, 1,218 patients in the GERD group and 161 in the NCCP group were referred for endoscopy. The follow-up period ranged from 1-22 years (mean 9.8 years). The groups were similar in age, gender, smoking and alcohol habits, and use of aspirin and NSAIDs (non-steroidal anti-inflammatory drugs) (P=NS), but there was a greater proportion of blacks in the NCCP group (P<0.003). In every parameter, NCCP patients had a significantly lower prevalence of GERD-related findings such as endoscopic esophagitis (P<0.0001), Barrett's metaplasia (P=0.02), the development of esophageal adenocarcinoma, and hiatal hernia presence (P=0.0001). In patients with hiatal hernia, the size of the hernia was similar in both groups (P=0.94). In the NCCP group compared with the GERD group, there was a significantly higher prevalence of cardiac factors, such as coronary artery disease (P=0.03), and there was a trend toward greater cardiac clinic enrollment (P=0.08) and cardiac medication usage (P=0.06). The amount and duration of anti-GERD therapy, such as HRAs and PPIs, were significantly less in the NCCP group (P=0.0001 for PPIs and P=0.0002 for HRAs). The diagnosis of NCCP disappeared from the electronic hospital record in 96% of patients within 2 years of follow-up. There was no significant difference in survival between the GERD and NCCP groups (hazard ratio=1.1; CI=0.8-1.5); however, longer duration of follow-up in those with a greater number of events may make a difference in survival., Conclusions: NCCP in most patients seems to be a short-lived event requiring extensive medical evaluation and having clinical characteristics significantly different from those associated with GERD. Patients with NCCP, confirmed by the absence of angiogram-documented coronary artery disease, who are referred for diagnostic endoscopy, have an excellent long-term benign prognosis, similar to patients with GERD.

Objective: Utilizing data obtained during a multicenter investigation, this paper illustrates how the use of covariates and careful modeling techniques can be useful in assessing whether a negative outcome from a small multicenter clinical trial could be due to imbalance in baseline characteristics. The Chemoprevention for Barrett's Esophagus Trial (CBET) was a phase IIb, multicenter, randomized, placebo-controlled trial of celecoxib in patients with Barrett's esophagus. The primary outcomes for the original study were the proportion of biopsy samples exhibiting dysplasia in the celecoxib and placebo groups. The secondary and tertiary outcomes included histologic change and measurements of biologically relevant markers, including COX-1 and -2 mRNA, prostanoid levels, and methylation of tumor suppressor genes p16, APC, and E-cadherin. The original study reported no significant differences in primary, secondary or tertiary outcomes. In this paper, we focus on the results of one of the secondary measures, quantitative endoscopy (QE)., Design: The study utilizes data from 56 patients in the CBET for whom baseline (BL) QE and one-year follow-up QE (F04) studies were performed. Of these, 29 were treated with celecoxib (200 mg twice daily for a minimum of 48 weeks) and 27 received the placebo. These patients are segmented as to the presence or absence of circumferential, tongues or islands of Barrett's., Measurements: The response of interest is total affected area at one year (Total F04); affected area at baseline (Total BL) is used as a covariate., Results: Controlling for complexity and clinic, there is a significant treatment effect. In addition, there is significant evidence that the area of Barrett's involvement decreased for patients in the treatment group., Conclusions: That there was a decrease for the celecoxib over the placebo group adds to the body of evidence that relates COX-2 specific inhibitors and cancer incidence.

The Chemoprevention for Barrett's Esophagus Trial (CBET) was a phase IIb, multicenter, randomized, placebo-controlled trial of celecoxib in patients with Barrett's esophagus. The overall outcome of the study was that there were no significant differences in primary, secondary, or tertiary outcomes. The purpose of the current study is to focus on results related to the method of measuring lesion size called quantitative endoscopy (QE). The design includes a review of a total number of studies and then restricts analyses to the four clinics that enrolled more than four patients each for whom a baseline and 1-year QE study was performed, comparing intra- and inter-patient and clinic differences in Barrett's esophagus. Measurements include the number of total QEs and adverse events, changes in areas from baseline to 1 year and other intervals, classification of Barrett's lesion type with respect to patients, clinics, and treatment. A total of 309 QE studies were completed with no adverse events. Differences in surface area measurements over time for a particular patient are smaller than the differences for randomly selected patients. The complexity mix (as defined by the mix of circumferential, tongues, and islands) of the Barrett's lesions varied with different clinics. In conclusion, QE is an efficient, safe, and accurate way to measure the area of Barrett's lesions variation between different clinical sites may be attributable to a subtle type of selection bias at the individual clinics rather than to regional differences.

Background & Aims: Outcomes of colon surveillance after colorectal cancer screening with colonoscopy are uncertain. We conducted a prospective study to measure incidence of advanced neoplasia in patients within 5.5 years of screening colonoscopy., Methods: Three thousand one hundred twenty-one asymptomatic subjects, age 50 to 75 years, had screening colonoscopy between 1994 and 1997 in the Department of Veterans Affairs. One thousand one hundred seventy-one subjects with neoplasia and 501 neoplasia-free controls were assigned to colonoscopic surveillance over 5 years. Cohorts were defined by baseline findings. Relative risks for advanced neoplasia within 5.5 years were calculated. Advanced neoplasia was defined as tubular adenoma greater than > or =10 mm, adenoma with villous histology, adenoma with high-grade dysplasia, or invasive cancer., Results: Eight hundred ninety-five (76.4%) patients with neoplasia and 298 subjects (59.5%) without neoplasia at baseline had colonoscopy within 5.5 years; 2.4% of patients with no neoplasia had interval advanced neoplasia. The relative risk in patients with baseline neoplasia was 1.92 (95% CI: 0.83-4.42) with 1 or 2 tubular adenomas <10 mm, 5.01 (95% CI: 2.10-11.96) with 3 or more tubular adenomas <10 mm, 6.40 (95% CI: 2.74-14.94) with tubular adenoma > or =10 mm, 6.05 (95% CI: 2.48-14.71) for villous adenoma, and 6.87 (95% CI: 2.61-18.07) for adenoma with high-grade dysplasia., Conclusions: There is a strong association between results of baseline screening colonoscopy and rate of serious incident lesions during 5.5 years of surveillance. Patients with 1 or 2 tubular adenomas less than 10 mm represent a low-risk group compared with other patients with colon neoplasia.

Introduction: Long-term gastric acid suppression has been suggested as a means to prevent complications of reflux esophagitis. We report on the 20-year follow-up of 2,306 patients with at least two endoscopic examinations who were taking no antisecretory medication before baseline endoscopy and whose long-term treatment was determined by reflux symptoms., Methods: From 1979 through 1998, endoscopy and biopsy were performed in the Hines Veterans Affairs Hospital endoscopy clinic by three endoscopists. Antireflux treatment was symptom-driven, and endoscopies were repeated mostly for symptomatic recurrence due to cessation of therapy., Results: Of 4,633 patients undergoing endoscopy for reflux symptoms, 2,306 had at least one follow-up endoscopy and biopsy. Over a mean follow-up period of 7.6 years (range, 1-20 years), the esophageal mucosa of 67% of patients remained unchanged, that of 21% improved, and that of 11% worsened. Esophageal stricture requiring dilation developed from a normal baseline mucosa in one of 1,313 patients (0.08%) and from an erosive baseline mucosa in 18 of 957 patients (1.9%). The overall incidence of stricture in patients with gastroesophageal reflux (GER) disease was <1/1,000 per year. Nonsteroidal anti-inflammatory drug (NSAID) consumption was associated with less mucosal improvement (odds ration [OR] = 0.67; confidence interval [CI] = 0.46-0.98). Use of histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) was associated with mucosal improvement (OR for PPIs = 1.49; CI = 1.14-2.17). Cohn's kappa was 42%, confirming the results that demonstrate stability of esophageal mucosal disease in the majority of patients., Conclusions: Symptom-driven treatment of GER disease after a thorough endoscopic examination to exclude premalignant or malignant esophageal mucosal disease is practical and safe for the vast majority of patients with uncomplicated GER symptoms.

Background & Aims: Common treatment practices in patients who continue to be symptomatic on proton pump inhibitor once-daily treatment include either increasing the dosage or the use of supplemental medication. This trial's purpose was to compare 2 therapeutic strategies, increasing the proton pump inhibitor dosage to twice daily versus switching to another proton pump inhibitor, in patients with persistent heartburn while receiving standard-dose proton pump inhibitor therapy., Methods: This multicenter, randomized, double-blind, double-dummy trial included patients with persistent heartburn symptoms while receiving therapy with lansoprazole 30 mg once daily. Patients were randomly assigned to treatment for 8 weeks with either single-dose esomeprazole (40 mg once daily) (n = 138) or lansoprazole 30 mg twice daily (n = 144). The primary efficacy variable was the percentage of heartburn-free days from day 8 to the end of treatment., Results: Single-dose esomeprazole was at least as effective as twice-daily lansoprazole for the primary end point of percentage of heartburn-free days during the study period (54.4% and 57.5%, respectively). Symptom scores improved from baseline in similar numbers of patients for heartburn (83.3% of patients in each group), acid regurgitation (76.8% vs 72.9%, P = .58), and epigastric pain (67.4% vs 61.1%, P = .32), and rescue antacid use was also similar (0.4 tablets/day vs 0.5 tablets/day, P = .50)., Conclusions: Switching patients with persistent heartburn on a standard-dose proton pump inhibitor to a different proton pump inhibitor was as effective as increasing the proton pump inhibitor dosage to twice daily for controlling heartburn symptoms.

Most asthmatics have GER, and the evidence is strong that GER plays an important role in some patients who have asthma. Despite sophisticated study methods and technologically advanced diagnostic tests, the results of published studies on mechanisms have failed to provide a diagnostic test with a degree of certainty great enough to identify which patients have GER-induced or GER-exacerbated asthma and which patients will respond to antireflux therapy. The difficulties involved in establishing a definite cause-and-effect relationship between GER and asthma are real. Even positive results on such direct tests as sputum inspection and scintigraphic monitoring, both of which establish reflux into the tracheobronchial tree, do not necessarily establish cause or effect and cannot be used to predict outcomes. Ambulatory esophageal pH testing can suggest, but cannot prove, the diagnosis of GER-induced asthma, and pH testing cannot be relied on safely to make clinical decisions. A trial of a proton pump inhibitor (PPI) is indicated to assess if asthma improves subjectively and objectively, but the dose must be high enough to prevent even silent esophageal acid exposure, and the duration must be long enough to allow for detection of even subtle trends in subjective and objective respiratory improvement. Antireflux surgery remains a therapeutic option and should not be withheld if GER is a reasonable suspect in asthma exacerbations. Although strong opinions have been voiced as to whether or not a good response to PPI therapy predicts a good response to antireflux surgery, the opinions, although logical, are based on personal experience and gut feelings; a good PPI response may not necessarily predict a good surgery response. Opinions suggesting that a poor response to PPI predicts a poor response to antireflux surgery also may seem logical but are not based on clinical data; a poor PPI response may not necessarily predict a poor antireflux surgery response. When the method is found that predicts which patients who have GER and asthma will respond to antireflux treatment, the results could be profound: fewer hospitalizations for respiratory complications, less pulmonary morbidity and mortality, less need for pulmonary medications, less time lost from work, fewer visits to physicians' offices, and less illness associated with corticosteroid therapy. For the present, however, clinical judgment and good sense still are our best friends. It is not unreasonable to urge patients to alter their lifestyle: the huge volume, calorie-dense, high-fat meals eaten before bedtime are not likely to prevent GER or add to their life expectancy.

Objectives: Certain pulmonary diseases are now recognized as possible complications of gastroesophageal reflux (GER) disease. To further clarify the relationship between GER and asthma, we determined the prevalence, nature, and patterns of reflux symptoms in consecutive asthmatics and a well-defined patient population control group., Methods: Two hundred and sixty-one asthmatic outpatients with well-documented asthma were interviewed in person using an extensive questionnaire. To avoid selection bias, we (a) used no selection criteria other than asthma, (b) interviewed every identified asthmatic from either the outpatient general medical clinic or pulmonary clinic (and excluded the gastroenterology clinic), and (c) excluded asthmatics referred because of gastrointestinal symptoms. A control group comprised 218 consecutive outpatients chosen from the same general medical clinics in which the asthmatics were enrolled. Interviews were conducted by one of two investigators., Results: The control and asthmatic groups were similar with regard to age, gender, ethnicity, and consumption of tobacco and alcohol. There were major significant differences between the asthmatics and controls with regard to the age of onset of pulmonary and reflux symptoms, prevalence of eating before bedtime, prevalence of reflux symptoms, the quality of reflux symptoms, and the factors that promote and relieve reflux symptoms. Heartburn, regurgitation, and dysphagia were present in 71%, 45%, and 22% of asthmatics compared with 51%, 30%, and 5% of controls (p < 0.001). Three times as many asthmatics as controls had heartburn occurring throughout the day and night (OR; 95% CI: 19.5; 4.5-85.7), and three times as many asthmatics as controls had sudden nocturnal awakening with reflux symptoms and reflux-associated pulmonary symptoms that occurred simultaneously with the reflux symptoms (p < 0.001). Within the asthma group, reflux symptoms were similar in those who required and those who did not require continuous bronchodilator therapy. In these asthmatics, however, those requiring continuous bronchodilator therapy (more severe asthma) developed pulmonary and GER symptoms at a significantly older age. Eating before bedtime was recognized by significantly more asthmatics than controls as a promoter of serious nocturnal GER symptoms (4.5; 2.7-7.7). In terms of patient awareness, one-third of the asthmatics with heartburn had previously considered a relationship between their reflux symptoms and their asthma., Conclusion: Compared to nonasthmatics, asthmatics have significantly more frequent and more severe day and night GER symptoms and significantly more of the pulmonary symptoms (nocturnal suffocation, cough, or wheezing) so often attributed to GER. The habit of eating before bedtime appears in asthmatics to have serious and life-threatening consequences.

Objective: In short term studies, asthma symptoms and pulmonary function have been reported to improve during and after medical treatment or surgical correction of gastroesophageal reflux (GER). In this study, we aimed to determine whether prolonged treatment of GER altered the long term natural history of asthma in asthmatics with GER., Methods: A total of 62 patients with both GER and asthma entered a randomized study of antireflux treatments for at least 2 yr: 24 controls (antacids as needed); 22 medical (ranitidine 150 mg t.i.d.); and 16 surgical (Nissen fundoplication). Asthma was defined as a previous diagnosis of asthma with discrete attacks of wheezing and 20% reversibility in airway disease. GER was defined as an abnormal ambulatory 24-h esophageal pH test and macroscopic or microscopic evidence of GER disease. Overall clinical status, asthma symptom scores, and pulmonary medication requirements were recorded monthly. Peak expiratory flow rates were recorded up to seven times per day for 1 wk of each month throughout the years. Pulmonary function, esophageal manometry, and endoscopy with biopsy were repeated yearly., Results: The 62 patients were followed for up to 19.1 yr. In the surgical group, but not in the medical or control groups, there was an immediate and sustained reduction in acute nocturnal exacerbations of wheezing, coughing, and dyspnea. By the end of 2 yr, improvement, marked improvement, or cure in the overall asthma status occurred in 74.9% of the surgical group, 9.1% of the medical group and 4.2% of the control group, whereas the overall status worsened in 47.8% of the control group, 36.4% of the medical group, and 12.5% of the surgical group (p < 0.001, surgical vs medical and control). The mean asthma symptom score of the surgical group improved 43%, compared with less than 10% in the medical and control groups (p = 0.0009). As determined by changes in peak expiratory flow rates, there was no statistically significant difference in pulmonary function during the 2-yr period or during regularly scheduled follow-up. There was no difference in medication requirements among the groups. There was no difference between the groups in overall survival., Conclusion: In patients with both GER and asthma, antireflux surgery (but not medical therapy with ranitidine 150 mg t.i.d.) has minimal effect on pulmonary function, pulmonary medication requirements, or survival, but significantly improves asthma symptoms and overall clinical status.

Eight patients with refractory GERD symptoms were controlled over a mean of 15.4 years only by the addition of a benzodiazepine to once-daily or twice-daily PPI therapy. In selected patients with refractory GERD, as defined by continued reflux symptoms despite twice-daily PPIs, the addition of a benzodiazepine to the PPI regimen may provide additional control of GERD symptoms.

It is unknown which factors determine the severity of mucosal damage in gastroesophageal reflux disease (GERD). Our aim was to test whether the amount of esophageal acid exposure could predict the severity of esophageal injury in erosive reflux esophagitis. A total of 644 outpatients with symptomatic GERD underwent an esophagogastroduodenoscopy followed by esophageal manometry and 24-h pH monitoring. GERD was graded according to the endoscopic severity of mucosal damage as no erosions, single erosions, confluent erosions, esophageal ulcers, and strictures. A multiple linear regression was used to assess the joint influences of demographic characteristics, social habits, endoscopic anatomy, and various parameters of esophageal function tests on the severity of erosive reflux disease. No clear-cut association between the amount of acid reflux and the severity of erosive reflux esophagitis could be established. All individual parameters of esophageal pH monitoring, such as upright or supine acid contact time, frequency of all or only long reflux episodes, and an overall summary score of pH-metry, revealed no or only a weak correlation with the severity grade of erosive reflux esophagitis. Similarly, the pressure of the lower esophageal sphincter was only slightly more decreased in patients with extensive erosive esophagitis as compared to subjects without esophageal erosions. In the multiple linear regression, the presence of hiatus hernia was a stronger predictor of disease severity than any of the other parameters. In conclusion, factors other than exposure of the esophageal mucosa to acid must contribute to the development of erosive esophagitis.

Objective: The reasons for the development of dysplasia and adenocarcinoma in Barrett's mucosa are not well understood. The aims of this study were to characterize risk factors for the transition from Barrett's esophagus without dysplasia to Barrett's esophagus with high-grade dysplasia or esophageal adenocarcinoma., Methods: A group of 131 patients with high-grade dysplasia or esophageal adenocarcinoma were selected as case subjects. A first population of 2170 patients without gastroesophageal reflux disease (GERD) and a second population of 1189 patients with Barrett's esophagus served as two control groups. Logistic regression analyses were used to compare the risk factors associated with the occurrence of high-grade dysplasia or esophageal adenocarcinoma., Results: Patients with high-grade dysplasia or esophageal adenocarcinoma shared many characteristics with other forms of severe GERD, such as older age, male gender, and white ethnicity. The length of Barrett's esophagus and the size of hiatus hernia increased the risk for both conditions. Subjects with high-grade dysplasia and adenocarcinoma had more severe acid reflux than patients with other forms of GERD. Smoking and alcohol consumption did not affect the risk for developing high-grade dysplasia or adenocarcinoma in patients with Barrett's esophagus., Conclusions: High-grade dysplasia and esophageal adenocarcinoma seem to stem from an extreme and unfavorable constellation of all risk factors that are generally held responsible for the development of GERD and Barrett's esophagus.

Background: It has been suggested that patients with an inguinal hernia harbour an increased risk for colorectal cancer., Methods: In a prospective clinical trial, we compared the prevalence of colonic neoplasms in 100 cases with inguinal hernia and 100 controls without inguinal hernia. The number, size, histology type, and the location of all colorectal lesions found during a screening flexible sigmoidoscopy were recorded., Results: Not a single case of colorectal cancer was detected in the patients with inguinal hernia pending surgical repair. In the asymptomatic control subjects, one Dukes A and one Dukes B1 colon cancer were detected. Polypectomy was performed in 15% and 17% of the case and control subjects, respectively. During a 5-year period following the initial screening procedure, none of the case or control subjects was diagnosed with colon cancer., Conclusions: The decision for or against performing an endoscopic procedure in a patient with inguinal hernia should be guided by the general principles of screening for colorectal cancer. The mere presence of an inguinal hernia does not automatically increase the risk of colorectal cancer.

Objective: The fear that colorectal adenomas were missed on initial colonoscopy or that new adenomas have developed is often a rationale for repeating a colonoscopic examination. The aim of this study was to delineate risk factors associated with recurrence of colorectal adenomas after an initial baseline screening colonoscopy., Methods: The study population comprised 875 subjects who underwent a baseline screening colonoscopy followed by a second examination 1-5 yr later. Multiple logistic regression was used to assess the influence of potential risk factors on the occurrence or recurrence of colorectal adenomas, the strength of the influence being expressed as an OR with a 95% CI., Results: Colorectal adenomas were detected in 484 of all patients (55%) at baseline colonoscopy. Within a 1- to 5-yr time interval, 181 patients (37%) had recurrent adenomas (adenomas were removed during the first colonoscopy) and 73 patients (19%) had newly developed adenomas (adenomas were absent on the first colonoscopy). The occurrence of adenomas at baseline screening colonoscopy was the only factor associated with an increased risk for the recurrence of adenomas at follow-up (OR = 2.51, 95% CI = 1.77-3.55). Recurrence was associated with multiple baseline adenomas (4.45, 2.98-6.64) and baseline adenomas larger than 1 cm (2.62, 1.99-3.11). Recurrence was not associated with histology type or family history of colorectal cancer. There was a significant trend for adenomas to recur in the same proximal or distal segment as the baseline adenomas (p = 0.02)., Conclusions: Colon adenomas tend to recur with greater frequency if the adenomas removed at baseline were either large or multiple. Although patients with large adenomas or multiple adenomas at baseline screening colonoscopy are at a 2.6- to 4.5-fold risk for recurrence of adenomas, the rate of de novo adenoma formation in patients without baseline adenomas may be large enough to warrant repeat colonoscopy at some time in the future. The exact timing of the follow-up colonoscopy needs to be determined.

Aims: To evaluate the sensitivity and specificity of different symptoms in erosive reflux oesophagitis and Barrett's oesophagus., Methods: The presence of reflux symptoms was compared between a case population of 306 patients with endoscopically determined erosive reflux oesophagitis, 235 patients with biopsy-proven Barrett's oesophagus and a control population of 198 subjects without reflux disease., Results: Heartburn at any time and heartburn at night represented the only two symptoms to be simultaneously sensitive and specific. Symptoms that were induced by various foods, such as fat, tomato, chocolate, citrus or spices, tended to cluster in the same sub-group of patients. Similarly, heartburn induced by exercise, lying down or bending over tended to occur in the same sub-groups. The frequency of symptoms was influenced more by the presence of mucosal erosions than by the presence of Barrett's oesophagus. Reflux symptoms occurred more frequently in the presence rather than the absence of Barrett's oesophagus, and in long segment rather than short segment of Barrett's mucosa., Conclusions: Endoscopic inspection of the oesophageal mucosa remains the only certain method by which to reliably diagnose erosive reflux oesophagitis and Barrett's oesophagus.

One third of the general population may experience reflux symptoms, yet only a small fraction of patients with gastroesophageal reflux disease (GERD) have Barrett's esophagus. The aim of the present study was to compare the characteristics of GERD patients with and without Barrett's esophagus and identify potential risk factors for the appearance of Barrett's esophagus in reflux disease. Outpatients from a gastroenterology clinic who underwent upper gastrointestinal endoscopy, esophageal manometry, and 24-hr pH monitoring were recruited into a case-control study. A total of 256 case subjects with endoscopically and histologically proven Barrett's esophagus were compared to a control group of 229 subjects with nonerosive reflux disease. As compared to nonerosive reflux disease, Barrett's esophagus was strongly associated with more reflux episodes. Barrett's esophagus occurred more frequently among subjects with hiatus hernia and among subjects who consumed large amounts of alcohol or cigarettes. Frequent reflux episodes, hiatus hernia, smoking, and alcohol consumption were also risk factors for an increased length of Barrett's mucosa. Total esophageal mucosal acid contact time at pH < 4 was a significant risk factor for the length but not the presence of Barrett's esophagus. Intake of aspirin or NSAIDs was similar in patients with and without Barrett's esophagus. In conclusion, in comparison with nonerosive reflux disease, Barrett's esophagus is characterized by risk factors usually indicative of severe types of GERD. Mechanisms in addition to acid reflux must contribute to the development of Barrett's esophagus.

Patients experiencing gastroesophageal reflux may be predisposed to developing Barrett's esophagus, which is thought to be a precursor for the development of esophageal cancer. Currently, endoscopic surveillance is recommended for patients with Barrett's esophagus in the hope that esophageal cancer may be detected or even prevented. However, the frequency of endoscopic evaluations is a matter of debate. This article will examine whether regular endoscopic surveillance can prevent death of Barrett's cancer. The issues that are evaluated include the death rate from esophageal cancer, the need to scope all patients with reflux, the need to perform surveillance on all patients with Barrett's esophagus, survival data for Barrett's patients, and the incidence of nonsymptomatic Barrett's cancer.

Background and Aims: The pulmonary symptoms of patients with lung disease may be ascribed to gastro-oesophageal reflux although a causal relationship between acid reflux and coughing or wheezing has not been proved. Does cough cause reflux or does reflux cause cough? The aim of this study was to evaluate 24 hour oesophageal pH tracings of asthmatics with gastro-oesophageal reflux to determine the temporal association between acid reflux and coughing or wheezing., Methods: The oesophageal tracings of 128 asthmatics from the outpatient clinics who underwent oesophagogastroduodenoscopy, oesophageal manometry, and 24 hour oesophageal pH monitoring were analysed. Three possible temporal relationships between the occurrence of acid reflux and the occurrence of coughs or wheezes were evaluated: (1) pulmonary symptoms preceding reflux; (2) reflux preceding pulmonary symptoms; and (3) unrelated occurrence of both events., Results: Of 128 asthmatics, 53 recorded five or more coughs and 19 recorded three or more wheezes during the 24 hour recording period. Mean acid contact time was similar in asthmatics with and without pulmonary symptoms (12.2 (1.2)% v 10.4 (0.6)%). Of all coughs and wheezes, 46% and 48%, respectively, were associated with acid reflux. For the individual asthmatic, the likelihood of reflux induced coughing increased as the number of coughs increased., Conclusions: Half of all coughs and wheezes in asthmatics are associated with acid reflux into the oesophagus. While an occasional coughing episode can lead to reflux, it is rather the reflux episode in the vast majority of instances that leads to cough.

Background & Aims: The contribution of duodeno-gastroesophageal reflux to the development of Barrett's esophagus has remained an interesting but controversial topic. The present study assessed the risk for Barrett's esophagus after partial gastrectomy., Methods: The data of outpatients from a medicine and gastroenterology clinic who underwent upper gastrointestinal endoscopy for any reason were analyzed in a case-control study. A case population of 650 patients with short- segment and 366 patients with long-segment Barrett's esophagus was compared in a multivariate logistic regression to a control population of 3047 subjects without Barrett's esophagus or other types of gastroesophageal reflux disease., Results: In the case population, 25 (4%) patients with short-segment and 15 (4%) patients with long-segment Barrett's esophagus presented with a history of gastric surgery compared with 162 (5%) patients in the control population, yielding an adjusted odds ratio of 0.89 with a 95% confidence interval of 0.54-1.46 for short-segment and an adjusted odds ratio of 0.71 (0.30-1.72) for long-segment Barrett's esophagus. Similar results were obtained in separate analyses of 64 patients with Billroth-1 gastrectomy, 105 patients with Billroth-2 gastrectomy, and 33 patients with vagotomy and pyloroplasty for both short- and long-segment Barrett's esophagus. Caucasian ethnicity, the presence of hiatus hernia, and alcohol consumption were all associated with elevated risks for Barrett's esophagus., Conclusions: Gastric surgery for benign peptic ulcer disease is not a risk factor for either short- or long-segment Barrett's esophagus. This lack of association between gastric surgery and Barrett's esophagus suggests that reflux of bile without acid is not sufficient to damage the esophageal mucosa.

Aims: To evaluate the frequency of reflux symptoms in patients with a diagnosed psychiatric disorder and to assess potential risk factors for symptom occurrence., Methods: The presence of reflux symptoms was compared between a case population of 94 psychiatric patients and a control population of 198 non-psychiatric patients., Results: Heartburn, exercise-induced heartburn, cough and dysphagia were all reported significantly more frequently by subjects with psychiatric disorders than by control subjects. The presence of any psychiatric diagnosis exerted an increased risk for both heartburn (odds ratio, 2.71; 95% confidence interval, 1.01-7.30) and exercise-induced heartburn (3.34; 1.12-9.96). The type of psychiatric disorder, the type of psychotropic medication and the lifestyle did not influence the presence of reflux symptoms., Conclusions: Reflux symptoms occur more frequently in patients with than without a diagnosed psychiatric disorder. The reflux symptoms are not associated with any specific type of medication and may reflect a generally reduced threshold for or distorted perception of symptoms.

Objective: This randomized, double-blind, multicenter study was conducted to confirm a previous finding that lansoprazole relieves heartburn faster than omeprazole in patients with erosive esophagitis., Methods: A total of 3510 patients with erosive esophagitis and at least one episode of moderate to very severe daytime and/or nighttime heartburn during the 3 days immediately before the screening visit were randomized to lansoprazole 30 mg once daily or omeprazole 20 mg once daily for 8 wk. Patients recorded the presence and severity of daytime and nighttime heartburn in daily diaries. On treatment days 1-4, patients were telephoned to confirm the completion of their daily diary. The primary efficacy parameters were the percentage of heartburn-free days and heartburn-free nights, as well as the average severity of daytime and nighttime heartburn., Results: During treatment day I and all evaluation time points including the entire 8-wk treatment period, significantly (p < 0.05) higher percentages of patients treated with lansoprazole than those treated with omeprazole did not experience a single episode of heartburn. Onset of heartburn relief was more rapid in lansoprazole-treated versus omeprazole-treated patients: on day 1, 33% versus 25% of lansoprazole- versus omeprazole-treated patients were heartburn-free. The percentages of heartburn-free days and heartburn-free nights were also significantly (p < 0.01) greater for patients treated with lansoprazole at all evaluation time points. Heartburn severity was significantly less among those treated with lansoprazole compared with omeprazole. Both treatments were safe and well tolerated., Conclusions: Over 8 wk, lansoprazole 30 mg once daily relieved heartburn symptoms faster and more effectively than omeprazole 20 mg once daily in patients with erosive esophagitis.

Objectives: Gallstones and hiatal hernia reportedly have been linked to similar dietary factors prevalent in western countries, and patients with cholelithiasis or previous cholecystectomy have been reported to have more duodenogastric reflux than healthy controls. Nonetheless, the contribution of duodenogastric reflux to the development of gastroesophageal reflux disease (GERD) remains controversial. The present study was aimed to assess the association between gallstone disease and GERD., Methods: Outpatients from general medical clinics who underwent upper GI endoscopy and abdominal ultrasonography were recruited into a case-control study. A case population of 790 patients with various grades of GERD was compared to a control population of 407 patients without GERD. In a multivariate logistic regression, the presence of GERD served as the outcome variable, whereas the presence of gallstones, hiatal hernia, social habits, and demographic characteristics served as predictor variables., Results: No associations were found between the presence of cholelithiasis or previous cholecystectomy and GERD or between the presence of cholelithiasis or previous cholecystectomy and hiatal hernia. The severity of GERD also remained unaffected by the presence of gallstones. The occurrence of GERD was influenced only by hiatal hernia (odds ratio [OR] = 3.15, 95% CI = 2.44-4.08), alcohol consumption (OR = 1.47, CI = 1.08-1.99), and not by cholelithiasis (OR = 1.02, CI = 0.68-1.51), or cholecystectomy (OR = 0.90, CI = 0.64-1.28). The frequency of GERD among hiatus hernia patients with gallstones (437/592 = 74%) was similar to the frequency of GERD among hiatus hernia patients without gallstones (168/220 = 76%, p = 0.516)., Conclusions: Neither cholelithiasis nor cholecystectomy poses a risk for the occurrence of GERD or hiatal hernia. Gallstone disease does not seem to influence the integrity of the esophageal mucosa through GERD.

Background: The risk factors that precipitate the occurrence of oesophageal mucosal injury in patients on continuous nonsteroidal anti-inflammatory drug (NSAID) therapy are unknown., Methods: Outpatients who regularly consumed NSAIDs for osteoarthritis were recruited from a rheumatology clinic into a prospective case-control study. All patients answered a structured interview and underwent upper gastrointestinal endoscopy., Results: Of 450 eligible patients, 195 (43%) consented to be interviewed and undergo upper gastrointestinal endoscopy. Oesophagitis was diagnosed in 41 of these 195 patients (21%). The occurrence of gastric or duodenal ulcer in individual patients did not predict the concomitant damage of the oesophageal mucosa. Young age (odds ratio: 1.79 per decade of life; 95% confidence interval: 1.11-2.86) and hiatus hernia (odds ratio: 3.72; 95% confidence interval: 1.63-8.49) both increased the risk of developing oesophagitis. When questioned, all oesophagitis patients revealed at least one gastrointestinal symptom, heartburn being named most frequently (odds ratio: 4.78; 95% confidence interval: 2.04-11.17). The type of anti-inflammatory medication, the use of alcohol and the use of nicotine were not associated with any significant risk for erosive oesophagitis., Conclusions: Patients on chronic NSAID therapy for rheumatological disease suffer frequently from erosive oesophagitis. While the risk may be higher in patients with a pre-existing tendency for gastro-oesophageal reflux, any concomitant history of NSAID-induced peptic ulcer disease does not add to the risk. Erosive oesophagitis should be considered especially in patients on NSAIDs who complain of heartburn.

Background & Aims: Surgical resection of the esophagus is frequently recommended for Barrett's high-grade dysplasia (HGD) without cancer., Methods: During a 20-year period, patients were diagnosed and observed through an organized surveillance program at the Hines Veterans Affairs Hospital. The program was supported by Hines VA and organized and managed by 2 endoscopists using preestablished endoscopic criteria., Results: Barrett's esophagus was diagnosed in 1099 patients, and 36,251 esophageal mucosal specimens were reviewed. Seventy-nine of 1099 patients (7.2%) initially had HGD (34 prevalent) or subsequently developed HGD (45 incident) without evidence of cancer. Of the 75 HGD patients who remained without detectable cancer after the 1 year of intensive searching, 12 developed cancer (16%) during a mean 7.3-year surveillance period: 11 of the 12 who were compliant were considered cured with surgical or ablation therapy. Cancer did not develop in the remaining 63 HGD patients during the surveillance period., Conclusions: HGD without cancer in Barrett's esophagus follows a relatively benign course in the majority of patients. In the patients who eventually progress to cancer during regular surveillance, surgical resection is curative. Surveillance endoscopies with biopsy is a valid and safe follow-up strategy for Barrett's patients who have HGD without cancer.

Background: Heterotopic gastric-type mucosa occurs as a flat island or islands of red mucosa in the proximal third of the esophagus where it gives rise to the "cervical inlet patch" (CIP). The aim of the present study was to delineate the clinical epidemiology of the CIP, especially its possible relationship to Barrett's esophagus., Methods: A case-control study compared 53 case subjects with CIP and 4882 control subjects without CIP. In a multivariate logistic regression, the presence of CIP was chosen as the outcome variable, whereas demographic characteristics, social habits, and presence of other endoscopic diagnoses served as predictor variables., Results: The prevalence of CIP was 1.1%. Its presence was associated with hiatal hernia (odds ratio 2.26: 95% CI [1.12, 4.56]) gastric ulcer (2.93: 95% CI [1.34, 6.40]) and Barrett's esophagus (4.41: 95% CI [2.31, 8.41])., Conclusions: The coincidence of the cervical inlet patch and Barrett's esophagus could suggest a shared embryonic etiology.

Objective: The most effective combination therapy to eradicate Helicobacter pylori has not yet been found. The perfect combination would be effective, relatively free of side effects, and easy to comply with. We studied a 14-day course of three medications taken twice daily by H. pylori-infected patients who were enrolled in the outpatient Veterans Affairs (VA) clinics. The two major objectives were 1) to determine the effectiveness of the combination therapy and 2) to determine the compliance of patients in a VA population., Methods: Fifty-two male patients were identified with H. pylori infection by positive CLO (Rapid Urease Test) test, positive Giemsa stain, or positive serology. Active infection was confirmed by a positive 13C urea breath test (UBT). Patients were treated for 14 days with open-label triple-combination therapy of ranitidine bismuth citrate (RBC; 400 mg b.i.d.), amoxicillin (1000 mg b.i.d.), and clarithromycin (500 mg b.i.d.). Successful eradication of H. pylori was confirmed by repeat UBT at 6-8 wk after the final dose of therapy., Results: Of the 52 enrolled patients, 49 (94.2%) met the criteria for successful completion of the study (per protocol analysis based on compliance with at least 80% of medication and performance of both UBTs). Of the three patients who did not successfully complete, one was cured (after 6 days of treatment), and two remained infected (after 3 days and 9 days of treatment). Of the 49 completed patients, 45 (91.8%) were cured, and four remained infected. Overall, regardless of compliance (intent-to-treat analysis), 46 of the 52 (88.4%) patients had documented cure of H. pylori infection as determined by the posttreatment UBT. By 3 yr after H. pylori eradication, two of 15 (13.3%) patients who were not on baseline medications had developed the need for antisecretory therapy, but 18 of 31 (58.1%) who were on baseline medications were able to stop therapy. Thus, at 3 yr, successful H. pylori eradication decreased the need for antisecretory therapy from 67.4% of the H. pylori-infected population to 43% of the H. pylori-eradicated population. The effect of H. pylori eradication in improving symptoms at 3 yr was statistically significant in both the ulcer population and the nonulcer population. Adverse events were mild, and included diarrhea (26 patients), bad taste in mouth (24 patients), nausea/upset stomach (nine patients), and headache (two patients). The diarrhea was self-limiting in 25 of the 26 patients. Only two patients discontinued medication because of adverse events., Conclusion: The RBC/amoxicillin/clarithromycin combination was, in our VA population, an easily complied with, highly effective, and safe triple therapy with a 90% H. pylori eradication rate. Successful eradication of H. pylori leads to a dramatic decrease in upper-gut symptoms and decreased need for antisecretory therapy.

Background: Gastro-oesophageal reflux is worse after meals, and antacids are usually consumed after dietary indiscretion., Aim: To investigate whether walking or gum chewing affect meal-induced gastro-oesophageal reflux., Methods: The study population comprised 12 case subjects with gastro-oesophageal reflux disease and 24 healthy controls. Each subject was studied using pH-metry for 5 h on 3 separate days. After baseline recording of pH for 1 h, all subjects were fed a standard breakfast over a 20-min period. On one of the days, oesophageal pH was recorded after the 20-min eating period for an additional 4 h in the sitting position. On another day, postprandial oesophageal pH was recorded for the first hour whilst walking, and for 3 subsequent hours whilst sitting. During a third day, oesophageal pH was recorded for the first postprandial hour whilst gum-chewing, followed by 3 h of sitting., Results: Food intake promoted gastro-oesophageal reflux in case subjects with GERD as well as in healthy controls, although postprandial reflux was more pronounced amongst the refluxers than amongst the controls. Chewing gum for 1 h after the meal reduced the acid contact time in both groups, with a more profound effect in refluxers than in controls. Whilst the beneficial effect of 1-h of gum-chewing lasted for up to 3 h in both groups, the beneficial effect of 1-h of walking was apparent only in refluxers, only to a mild degree, and only for a short duration., Conclusions: Chewing gum after a meal helps to reduce postprandial oesophageal acid exposure.

Objectives: It is presently not fully understood which risk factors contribute to the occurrence of reflux esophagitis and how such factors might influence the severity of the disease. The aim of this study was to delineate the clinical epidemiology of erosive reflux esophagitis., Methods: Outpatients from a medicine and gastroenterology clinic who underwent upper GI endoscopy were recruited into a case-control study. A total of 1,533 patients with and 3,428 patients without endoscopically diagnosed reflux esophagitis were categorized as case and control subjects, respectively. Using multivariate logistic regressions for statistical analysis, the presence of esophageal erosions, ulcers or strictures, served as three separate outcome variables. Demographic characteristics, intake of nonsteroidal anti-inflammatory drugs (NSAIDs), consumption of alcohol and cigarettes, and the presence of hiatus hernia or peptic ulcer served as predictor variables., Results: Erosive reflux esophagitis tended to occur more frequently in Caucasian male patients. Hiatus hernia was associated with a strong risk for developing esophageal erosions, ulcers, and strictures. Although statistical significance was demonstrated only for esophageal erosions, in all grades of reflux esophagitis alike, gastric and duodenal ulcer exerted a protective influence. Consumption of NSAIDs increased the risk for esophageal ulcers only. Smoking and alcohol were not associated with an increased risk of developing any type of erosive reflux esophagitis., Conclusions: The results stress the critical role played by hiatus hernia in all grades of erosive reflux esophagitis. NSAIDs may act through a mechanism of topically induced esophageal injury. Our data also suggest that the presence of either gastric or duodenal ulcer exerts a protective influence against the development of reflux disease.

Gastroesophageal reflux (GER) and asthma occur together frequently. The relationship has been recognized for more than 2,000 years but has not been appreciated until recently. Attempts to determine the number of asthmatics that currently have GER (prevalence) have shown a higher-than-expected prevalence. Of the approximately 200 published studies on the relationship between GER and asthma, the true prevalence of GER in asthmatics, however, can be estimated from fewer than 20 of the studies. These studies, which comprise highly selected referred populations, are unlikely to reflect the overall population of patients with asthma. Nevertheless, the estimated prevalence of GER in asthmatics is between 60-80% in adults and 50-60% in children. No attempts have been made to determine the incidence of GER in asthmatics. To identify asthmatics who develop GER over time would be a formidable task, requiring decades of close follow-up of asthmatics who do not now have GER. Despite the lack of data on the incidence of GER, data on the prevalence raise an important issue: If the prevalence of GER in adult asthmatics is similar to the prevalence of GER in child asthmatics, what is the true incidence of GER? There are two potential answers: (1) all of the child asthmatics with GER grow up to become the adult asthmatics with GER (GER incidence = 0%); and (2) some child asthmatics with GER outgrow either the GER or the asthma; some adults with asthma develop GER while others with GER develop asthma (low, medium, or high incidence depending on the numbers). It is not unreasonable to suspect that some child asthmatics with GER become adult asthmatics with GER, and that children with GER who apparently "outgrow" their asthma surface later as adults with both asthma and GER. Because most children leave their pediatricians after adolescence, the information required to demonstrate continued asthma or GER is lost. As a result, the medical community sees two completely different populations, each with very similar conditions: childhood asthma with GER and adult asthma with GER. If the high prevalence of GER in asthmatics is clinically relevant, it should be readily explainable. We suggest that the GER/asthma relationship consists of a self-propagating situation whereby reflux aggravates asthma, which in turn induces further reflux. In the early course of the disease, asthma may not be apparent, as aspiration-induced pulmonary symptoms may occur very infrequently-perhaps once or twice a year. With time, however, aspiration may become more frequent, and the pulmonary tree may become hypersensitive. The individual may be diagnosed as having asthma. The pulmonary tree becomes increasingly hypersensitive, to a variety of stimuli. In such a scenario, the initial contribution of acid aspiration is no longer apparent, as the primary focus is on the asthma. In any individual patient, the emphasis may be placed on the GER if reflux symptoms predominate or on asthma if pulmonary symptoms predominate. The result is confusion over whether a patient with GER has asthma or whether a patient with asthma has GER. The unending debate about whether GER is a cause of the asthma or a result of the asthma becomes the focus of attention. At such a point, the question of whether GER exists in asthmatics or whether pulmonary symptoms exist in refluxers is irrelevant. For the individual patient, gastric contents refluxed into the pulmonary tree is an undesirable event, whether cause or effect, and it is up to the physician to determine how such events can be stopped.

The relationship between gastroesophageal reflux (GER) and asthma has troubled physicians for centuries and has been a source of debate among pulmonologists, allergists, and gastroenterologists for decades. Attempting to tie together the pieces of the puzzle, numerous investigators have struggled to show that in patients with asthma, GER symptoms occur too frequently, gastric acid dwells for too long in the esophageal lumen, and refluxed gastric acid injures the esophageal mucosa more than expected. Unfortunately, all of the work done by these fine investigators has failed to demonstrate a "cause and effect" relationship. Although they have succeeded in convincing us that GER occurs more frequently in asthmatics than in nonasthmatics, they still must continue until we all know how to predict which patients have gastroesophageal-induced or gastroesophageal-exacerbated asthma.

"It is not the death of GERD that I seek, but that it turns from its evil ways and follows the path of righteousness." The reflux world is fully aware of what GERD is and what GERD does. What the world does not know, however, is the answer to the most important yet least asked question surrounding GERD's raison-d'etre: Why is GERD here and why do we have it? What GERD is: abnormal gastric reflux into the esophagus that causes any type of mischief. What GERD does: causes discomfort and/or pain with or without destroying the mucosa; causes stricture or stenosis, preventing food from being swallowed; sets the stage for the development of esophageal adenocarcinoma; invades the surrounding lands to harass the peaceful oropharyngeal, laryngeal and broncho-pulmonary territories; reminds us that we are not only human, but that we are dust and ashes. Why GERD is here: We propose three separate and distinct etiologies of GERD, and we offer the following three hypotheses to explain why, after 1.5 million years of standing erect, we have evolved into a species (specifically Homosapiens sapiens) that is destined to live with the scourge of GERD. Hypothesis 1: congenital. The antireflux barrier, comprising the smooth-muscled lower esophageal sphincter, the skeletal-muscled right crural diaphragm and the phreno-esophageal ligament does not completely develop due to a developmental anomaly or incomplete gestation. Hypothesis 2: acute trauma: The antireflux barrier in adults suffering acute traumatic injury to the abdomen or chest is permanently disrupted by unexpected forces, such as motor vehicle accidents (with steering wheel crush impact), blows to the abdomen (from activities such as boxing, etc.), heavy lifting or moving (e.g., pianos, refrigerators) or stress positions (e.g., hand stands on parallel gym bars). The trauma creates a hiatal hernia that renders the antireflux mechanism useless and incapable of preventing GERD. Hypothesis 3: chronic trauma: The antireflux barrier in children and adults is gradually weakened over time as a result of chronic straining to defecate and straining in an unphysiologic position, both of which stem from our modern day habits of eating a low-fiber diet and living on the high-seated toilet. We suggest that the chronic traumatic hiatal hernia is (a) the cause of more than 90 percent of the GERD that stalks the Western world; (b) is a direct result of abandoning the popular and worldwide practice of squatting to socialize, eat and defecate; and (c) is our just reward for adopting the "civilized" high sitting position on chairs and modern toilets.

Background: The combination of ranitidine bismuth citrate (RBC) and clarithromycin (CLR) was compared with each treatment alone for the eradication of H. pylori and healing of duodenal ulcers in patients infected with H. pylori., Methods: This two-phase, randomized, double-blind, placebo-controlled, multicenter study evaluated 203 patients with an active duodenal ulcer treated with either (1) RBC 400 mg BID for 4 weeks plus CLR 500 mg TID for the first 2 weeks; (2) RBC 400 mg BID for 4 weeks plus placebo TID for the first 2 weeks; (3) placebo BID for 4 weeks plus CLR 500 mg TID for the first 2 weeks; or (4) placebo BID for 4 weeks plus placebo TID for the first 2 weeks. Patients with healed ulcers after treatment entered a 24-week observation phase for the assessment of H. pylori and ulcer relapse., Results: Four-week ulcer healing rates were higher with RBC + CLR (71%) and RBC alone (66%) compared with placebo (15%; p < 0.05) and CLR alone (49%). H. pylori eradication rates were significantly higher with RBC + CLR (86%) compared with RBC alone (0%, p < .001) or CLR alone (24%, p < .001). Ulcer recurrence rates after 6 months were lower in patients eradicated of H. pylori infection (17%) compared with patients who remained infected (43%). All treatments were well tolerated., Conclusions: Ranitidine bismuth citrate plus clarithromycin is a simple, convenient, and well-tolerated dual therapy regimen that is effective in eradicating H. pylori and healing duodenal ulcers in patients infected with H. pylori. The eradication of H. pylori in patients with healed ulcers significantly reduces the rate of ulcer relapse.

The medical literature has been deluged with articles on the relation between gastroesophageal reflux (GER) and asthma. In an effort to piece together the complex puzzle, investigators from all disciplines have gathered their patients with wheezing and heartburn and studied the epidemiology, the possible cause or effect mechanisms and the therapeutic response to GER treatment. Indeed, since humans first began to hunker down and work together to discuss interesting observations, the world has begun to breathe easier. Epidemiological evidence for a GER/asthma association suggests that about three-fourths of asthmatics, independent of the use of bronchodilators, have acid GER, increased frequency of reflux episodes, or heartburn; and 40% have reflux esophagitis. Physiological studies suggest that 2 separate mechanisms are involved in the GER/asthma relationship: (1) a vagally mediated pathway and (2) microaspiration. In any given patient, however, there is no acceptable diagnostic method available to confirm the presence or absence of GER-induced asthma. Clinical trials, using antireflux medical therapy and antireflux surgery have begun to provide some clues about GER-related pulmonary symptoms. The trials of medical therapy using acid suppressing drugs (e.g. histamine-2 receptor antagonists) have ranged from no benefit to modest improvement of only nocturnal asthma symptoms. Studies with proton-pump inhibitors are underway. In uncontrolled surgical studies, antireflux surgery has resulted in partial or complete remission of asthma symptoms in a large proportion of patients. Despite the uncontrolled nature of these studies, many patients have had dramatic subjective improvement in pulmonary symptoms. It appears for now that clinical trials are the only available means to assess whether medical or surgical treatment of GER in patients with both GER and asthma improves the symptoms of asthma and decreases the need for pulmonary medications. One conclusion is certain: We no longer can ignore the important co-existent nature of these 2 afflictions.

Gastric ulcer disease remains a cause of hemorrhage, perforation, outlet obstruction, and death. Recent advances in the understanding of peptic ulcer disease indicate that infection with Helicobacter pylori and ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs) are the cause of almost all gastric and duodenal ulcers. Our therapy, therefore, is in a state of transition: the old acid-suppressive temporary therapy that allows frequent ulcer recurrences and complications is being replaced by curative therapies. The old therapy, by reducing gastric acid secretion or enhancing gastric mucosal defenses, inhibited the cofactors needed for ulcer development. Acid suppression relieved symptoms and healed ulcers, while defense enhancers, such as prostaglandin analogs healed and prevented acute NSAID-induced gastric ulcers. These benefits were maintained, however, only as long as acid-reducing agents or mucosal defense enhancers were continued. On the other hand, curative therapies (such as eradicating H. pylori infection and/or stopping the use of NSAIDs) eliminate the causes of ulcer. Curative combination regimens consisting of antibiotics, ranitidine bismuth citrate, bismuth, and proton pump inhibitors have been approved by the Food and Drug Administration. These new regimens can cure benign gastric ulcer. Unfortunately, we cannot always determine which gastric ulcers are benign, and concern about gastric cancer remains. All gastric ulcers therefore still require biopsy and histological examination. With new treatment regimens, the time may be rapidly approaching when ulcer disease will be "history."

Introduction: Relapse of erosive oesophagitis occurs in almost all patients if treatment is stopped after initial healing., Aim: To assess the potential of different therapeutic regimens of omeprazole to prevent relapse of erosive reflux oesophagitis after initial healing with omeprazole., Patients and Methods: Patients whose active erosive reflux oesophagitis (grade > or = 2) had healed (grade 0 or 1) after 4-8 weeks of open-label omeprazole 40 mg daily (phase I) were eligible to join a multi-centre, 6-month double-blind, placebo-controlled maintenance study (phase II), which included endoscopy, symptom assessments, serum gastrin measurements, and gastric fundic biopsies. During phase I, endoscopy was performed at weeks 0, 4, and 8. At the end of phase I, 429 of 472 patients (91%) were healed, and there were significant reductions in heartburn, dysphagia and acid regurgitation. Of the 429 patients who healed, 406 joined phase II and were randomized to one of three groups: 20 mg omeprazole daily (n = 138), 20 mg omeprazole for 3 consecutive days each week (n = 137), or placebo (n = 131). During phase II, endoscopy was performed at months 1, 3, and 6 or at symptomatic relapse., Results: The percentages of patients still in endoscopic remission at 6 months were 11% for placebo, 34% for omeprazole 3-days-a-week, and 70% for omeprazole daily. Both omeprazole regimens were superior to placebo in preventing recurrence of symptoms (P < 0.001); however, omeprazole 20 mg daily was superior to omeprazole 20 mg 3-days-a-week (P < 0.001). Compared to baseline, omeprazole therapy resulted in no significant differences among treatment groups in the distribution of gastric endocrine cells., Conclusions: These results show that after healing of erosive oesophagitis with 4-8 weeks of omeprazole, relapse of oesophagitis and recurrence of reflux symptoms can be prevented in 70% of patients with a maintenance regimen of 20 mg daily, but that intermittent dosing comprising 3 consecutive days each week significantly compromises efficacy.

Purpose: We conducted a randomized, double-blind, multicenter clinical trial to determine whether lansoprazole was superior to continued therapy with histamine H2-receptor antagonist therapy in healing erosive reflux esophagitis., Methods: Investigators from nine medical centers enrolled 159 patients with endoscopically documented esophageal erosions and/or ulcers that had failed to heal with 12 or more wk of at least standard dosages of histamine H2-receptor antagonist therapy. Patients received ranitidine 150 mg b.i.d. for 8 wk or lansoprazole 30 mg for 4 wk followed by either lansoprazole 30 mg or lansoprazole 60 mg for another 4 wk of treatment. Patients underwent endoscopy at screening and at weeks 2, 4, and 8., Results: At 2, 4, and 8 wk of therapy, healing rates were significantly higher in the lansoprazole group compared with the ranitidine group (p < 0.001). By 8 wk, 84% of the lansoprazole group were healed as opposed to only 32% of the ranitidine group. Lansoprazole was superior to ranitidine in providing relief of upper abdominal burning and daytime heartburn (p < 0.001) and reducing the need for antacids (p < 0.001). Lansoprazole patients had less interference with sleep and less day time drowsiness than ranitidine patients (p = 0.05). The percentages of patients with adverse events were similar in both groups. Fasting serum gastrin levels at weeks 4 and 8 were significantly higher in the lansoprazole group compared with the ranitidine group., Conclusion: Eight weeks of lansoprazole therapy is safe, superior to continued ranitidine therapy, and effective in healing more than 80% of patients with erosive reflux esophagitis previously resistant to histamine H2-receptor antagonist therapy.

Background: Barrett's oesophagus is thought to be a complication of severe gastro-oesophageal reflux., Aim: To determine whether the proton pump inhibitor, lansoprazole, is effective in healing erosive reflux oesophagitis in patients with Barrett's oesophagus., Methods: An 8-week, randomized, double-blind study was conducted using patients with both erosive reflux oesophagitis and Barrett's oesophagus. Erosive reflux oesophagitis was defined as grades 2-4 oesophagitis; Barrett's oesophagus, as specialized columnar epithelium obtained by biopsy from the tubular oesophagus; and healing, as a return to grade 0 or 1 oesophageal mucosa (complete re-epithelialization). One-hundred and five (105) patients from one centre were randomized to receive either lansoprazole 30 mg daily or ranitidine 150 mg twice daily. Unhealed or symptomatic lansoprazole patients at week 4 were randomized to receive the same 30 mg dose daily or an increased dose of 60 mg daily. Endoscopy was performed at baseline and at weeks 2, 4, 6 and 8., Results: The treatment groups were similar in regards to baseline characteristics, erosive reflux oesophagitis grades and length of Barrett's oesophagus. At each 2-week interval, lansoprazole patients had significantly greater healing rates and less day and night heartburn and regurgitation than ranitidine patients. There were no significant differences between treatment groups in antacid use, quality of life parameters, or rate of reported adverse events. Median values for fasting serum gastrin levels remained within the normal range for both groups., Conclusion: In patients with both Barrett's oesophagus and erosive reflux oesophagitis, lansoprazole is significantly more effective than ranitidine in relieving reflux symptoms and healing erosive reflux oesophagitis.