The cultivable bacterial flora of the esophagus in subjects with esophagitis.

BACKGROUND: The healthy human esophagus is colonized by bacteria similar to that of the oral mucosa. However, little is known about the microbiome of the esophagus in esophagitis or the possible role of bacteria in the inflammatory response. AIM: To survey bacterial diversity and compare the microbiome of the esophagus in subjects with gastro-esophageal reflux disease (GERD) and eosinophilic esophagitis (EoE). MATERIAL AND METHODS: Seventeen subjects diagnosed with GERD and 10 with EoE underwent endoscopic examination with brush sampling and biopsies from the oral cavity, upper and lower esophagus. The samples were cultivated on agar plates, and bacterial growth was identified to the genus or species level and semi-quantified. RESULTS: Significantly higher numbers of bacterial groups or species were found in specimens from the lower esophagus in subjects with EoE compared to subjects with GERD (median 4 (range 1-7) vs. 2 (range 0-6), p < .0014). Sixteen vs. 14 different bacterial groups or species were found in subjects with GERD and EoE, respectively, mostly in sparse or very sparse amounts. Alfa-streptococci (viridans streptococci) were the most common bacteria in both groups. Streptococci were present in all of the EoE-subjects but only in approximately 75% in lower esophagus of the GERD-subjects, regardless of the sampling method. CONCLUSION: Subjects with GERD had significantly less bacterial diversity in both oral and esophageal samples than EoE-subjects. Whether this discrepancy might be explained by an effect on the protective mucosal biofilm by the acidic content of the reflux in subjects with GERD remains unclear.

The diagnostic value of GerdQ in subjects with atypical symptoms of gastro-esophageal reflux disease.

BACKGROUND: Symptoms are essential in the clinical diagnosis of gastro-esophageal reflux disease (GERD). Questionnaires such as GerdQ have been developed as diagnostic aids. GerdQ has been thoroughly validated in well-characterized GERD patients, but has not yet been fully evaluated in a population that includes subjects with atypical symptoms. AIM: To evaluate GerdQ in a population with typical and/or atypical symptoms of GERD, defined by 24-h pH monitoring. The secondary aim was to investigate the outcome of GerdQ depending on the response to proton pump inhibitor (PPI) treatment. METHODS: The study included 646 subjects referred for 24-h pH monitoring due to a clinical suspicion of GERD. All subjects completed GerdQ before performing a 24-h pH monitoring. RESULTS: In total, 377 (58%) subjects were diagnosed with GERD based on symptoms and 24-h pH monitoring (GERDpH). Of these, 46% had atypical main symptoms. Overall, GerdQ (at cut-off 8) predicted GERDpH with a sensitivity and specificity of 62% and 74%, respectively. A high specificity but poor sensitivity for diagnosis of GERDpH was found for atypical main symptoms such as cough, dysphagia and globus. GerdQ had a relatively high sensitivity and specificity in predicting PPI response and a PPV of 99% at cut-off 8. CONCLUSIONS: GerdQ has a diagnostic value in an unselected population presenting with typical and/or atypical symptoms of GERD, but a low sensitivity for diagnosis of GERDpH was found in subjects with predominant symptoms such as cough, dysphagia and globus.

Epithelial Thickness is a Marker of Gastroesophageal Reflux Disease.

BACKGROUND & AIMS: Histologic criteria have been refined for the diagnosis of gastroesophageal reflux disease (GERD). We aimed to evaluate these criteria for the assessment of GERD and to measure interassessor agreement. METHODS: We performed a post hoc analysis of data from the Diamond study (NCT 00291746), conducted in Europe and Canada on adults with frequent upper gastrointestinal symptoms who had not taken a proton pump inhibitor in the previous 2 months. GERD was diagnosed based on the presence of 1 or more of the following: reflux esophagitis, pathologic esophageal acid exposure, and/or positive symptom-acid association probability. Nonerosive reflux disease was defined as the presence of pathologic esophageal acid exposure and/or a positive symptom-acid association probability, but no reflux esophagitis. Biopsies collected from 336 patients from 0.5 cm and 2.0 cm above the Z line were evaluable; they were analyzed independently at pathology centers in Germany and Italy (biopsies from 258 and 195 patients, respectively). The primary outcomes were the accuracy of histologic criteria for the diagnosis of GERD, defined by endoscopy and pH monitoring, and interassessor agreement on histologic criteria. RESULTS: At the assessment site for basal cell layer thickness, total epithelial thickness was the best-performing criterion for diagnosis of investigation-defined GERD; it also identified nonerosive reflux disease, reflux esophagitis, and pathologic esophageal acid exposure at 0.5 cm and 2.0 cm above the Z line. Basal cell layer thickness and presence of dilated intercellular spaces did not identify patients with GERD. Among the criteria tested, the best agreement between assessments carried out at the 2 pathology centers was for total epithelial thickness at 0.5 cm and 2.0 cm above the Z line. CONCLUSIONS: Based on an analysis of 336 patients with frequent upper gastrointestinal symptoms, total epithelial thickness is a robust histologic marker for GERD.

Prucalopride is no more effective than placebo for children with functional constipation.

BACKGROUND & AIMS: Prucalopride is a selective, high-affinity agonist of the 5-hydroxytryptamine (serotonin) receptor 4 that enhances motility in the gastrointestinal tract. We performed a multicenter, randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of prucalopride in children (6 months to 18 years old) with functional constipation. METHODS: Children with functional constipation, based on the Rome III criteria, were given prucalopride (children ≤ 50 kg were given a 0.04 mg/kg oral solution; children >50 kg were given a 2-mg tablet) or placebo once daily for 8 weeks. The primary efficacy end point was the proportion of children with toileting skills who had a mean of ≥ 3 spontaneous bowel movements/week and ≤ 1 episode of fecal incontinence/2 weeks, from study weeks 5-8 (responders). Adverse events, clinical laboratory values, and electrocardiograms were monitored. RESULTS: Efficacy and safety were assessed in 213 children (106 prucalopride, 107 placebo). Twenty-five percent were younger than 4 years old, 50% were 4-11 years old, and 25% were 12-18 years old; 55.4% were girls. At screening, 62.3% of patients in the prucalopride group and 55.1% in the placebo group had a history of fecal incontinence; 60.4% and 55.1% in the prucalopride and placebo groups, respectively, had a mean of ≤ 1 spontaneous bowel movements/week. The proportion of responders was similar between groups (prucalopride, 17.0% and placebo, 17.8%). There were no statistically significant differences in the primary efficacy end point when patients were stratified by sex, age group, or country. The incidence of treatment-emergent adverse events was similar in the prucalopride (69.8%) and placebo (60.7%) groups. CONCLUSIONS: Prucalopride, although generally well tolerated, was not more effective than placebo in children with functional constipation. ClinicalTrials.gov Number: NCT01330381.

Dose-dependent effects of lesogaberan on reflux measures in patients with refractory gastroesophageal reflux disease: a randomized, placebo-controlled study.

BACKGROUND: The γ-aminobutyric acid type B-receptor agonist lesogaberan (AZD3355) has been developed for use in patients with gastroesophageal reflux disease (GERD) symptoms despite proton pump inhibitor (PPI) therapy (partial responders). This study aimed to explore the dose-response effect of lesogaberan on reflux episodes in partial responders. METHODS: In this randomized, single-centre, double-blind, crossover, placebo-controlled study, partial responders taking optimised PPI therapy were given 30, 90, 120 and 240 mg doses of lesogaberan. Each dose was given twice (12 h apart) during a 24-h period, during which impedance-pH measurements were taken. RESULTS: Twenty-five patients were included in the efficacy analysis and 27 in the safety analysis. The effect of lesogaberan on the mean number of reflux episodes was dose-dependent, and all doses significantly reduced the mean number of reflux episodes relative to placebo. Lesogaberan also dose-dependently reduced the mean number of acid reflux episodes (except the 30 mg dose) and weakly acid reflux episodes (all doses) significantly, relative to placebo. Regardless of dose, lesogaberan had a similar effect on the percentage of time with esophageal pH < 4 [mean reduction: 68.5% (30 mg), 54.2% (90 mg), 65.9% (120 mg), 72.1% (240 mg); p < 0.05 except 90 mg dose]. No adverse events led to discontinuation and no serious adverse events occurred during active treatment. CONCLUSIONS: Lesogaberan inhibited reflux in a dose-dependent manner in partial responders taking optimised PPI therapy, and these effects were significant versus placebo. All lesogaberan doses were well tolerated and were not associated with clinically relevant adverse events. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01043185.

Acid-suppressive therapy with esomeprazole for relief of unexplained chest pain in primary care: a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: High-quality data regarding the efficacy of acid-suppressive treatment for unexplained chest pain are lacking. The aim of this study was to evaluate the efficacy of esomeprazole in primary-care treatment of patients with unexplained chest pain stratified for frequency of reflux/regurgitation symptoms. METHODS: Patients with a ≥ 2-week history of unexplained chest pain (unrelated to gastroesophageal reflux) who had at least moderate pain on ≥ 2 of the last 7 days were stratified by heartburn/regurgitation frequency (≤ 1 day/week (stratum 1) vs. ≥ 2 days/week (stratum 2)) and randomized to 4 weeks of double-blind treatment with twice-daily esomeprazole 40 mg or placebo. Chest pain relief during the last 7 days of treatment (≤ 1 day with minimal symptoms assessed daily using a 7-point scale) was analyzed by stratum in keeping with the predetermined analysis plan. RESULTS: Overall, 599 patients (esomeprazole: 297, placebo: 302) were randomized. In stratum 1, more esomeprazole than placebo recipients achieved chest pain relief (38.7% vs. 25.5%; P=0.018); no between-treatment difference was observed in stratum 2 (27.2% vs. 24.2%; P=0.54). However, esomeprazole was superior to placebo in a post-hoc analysis of the whole study population (combined strata; 33.1% vs. 24.9%; P=0.035). CONCLUSIONS: A 4-week course of high-dose esomeprazole provided statistically significant relief of unexplained chest pain in primary-care patients who experienced infrequent or no heartburn/regurgitation, but there was no such significant reduction in patients with more frequent reflux symptoms.

Cost and burden of gastroesophageal reflux disease among patients with persistent symptoms despite proton pump inhibitor therapy: an observational study in France.

BACKGROUND: Gastrointestinal reflux disease (GERD) is a common disorder that negatively impacts health-related quality of life (HRQL) and work productivity. Many patients have only a partial response to proton pump inhibitor (PPI) therapy and continue to experience GERD symptoms despite optimized treatment. This observational study aimed to provide information on symptoms, HRQL, resource usage, costs and treatment pathways associated with partial response to PPI therapy in French patients with GERD. METHODS: Patients with partial response to PPI therapy, defined as persistent GERD symptoms ≥3 days/week despite optimized treatment with a PPI, were recruited for this 12-month observational study. GERD symptoms, HRQL, work productivity and resource use were assessed by patient surveys. Costs were calculated based on lost work productivity and resource use. RESULTS: The patient population (n=262; mean age, 54 years; 40% men) carried a significant symptom burden, with 98% of patients having moderate-to-severe GERD symptoms and 65% of patients experiencing daily symptoms at baseline. HRQL and work productivity were significantly impaired, with a greater degree of impairment in patients with higher symptom burden. The mean total cost per patient over the 12-month follow-up period was €5237, of which €4674 (89%) was due to lost work productivity. CONCLUSIONS: Partial response to PPI therapy for GERD is associated with a high symptom burden, significant impairment of HRQL and work productivity, and substantial GERD-related costs.

Effect of food on the bioavailability of lesogaberan given as an oral solution or as modified-release capsules in healthy male volunteers.

The novel Type B gamma-aminobutyric acid (GABAB)-receptor agonist lesogaberan (AZD3355) has been evaluated as an add-on to proton pump inhibitor treatment for gastroesophageal reflux disease, but the effect of food on the bioavailability of this compound has not been assessed. In this openlabel crossover study, healthy males received single 100 mg doses of lesogaberan (oral solution (A) or oral modified release (MR) capsules with a dissolution rate of 50% (B) or 100% (C) over 4 h) with and without food. Blood plasma concentrations of lesogaberan were assessed over 48 h. A log-transformed geometric mean Cmax and AUC ratio within the 90% confidence interval (CI) range (0.80 - 1.25) was defined as excluding a clinically relevant food effect. Overall, 57 subjects completed the study. Only the oral lesogaberan solution had a fed/fasting Cmax ratio outside the 90% CI range (Cmax ratio: 0.76). AUC ratios were within the 90% CI limits for all three lesogaberan formulations. The only substantial change in tmax associated with food intake was observed for the oral solution (1.0 h without food, 1.8 h with food). In conclusion, a clinically relevant food effect could be excluded for the lesogaberan MR formulations, but not for the oral lesogaberan solution.

Effects of lesogaberan on reflux and lower esophageal sphincter function in patients with gastroesophageal reflux disease.

BACKGROUND & AIMS: Transient lower esophageal sphincter relaxations (TLESRs) are a major mechanism behind reflux. This study assessed the effects of lesogaberan (AZD3355), a novel gamma-aminobutyric acid type B receptor agonist, on reflux and lower esophageal sphincter (LES) function when used as add-on treatment in patients with reflux symptoms despite proton pump inhibitor (PPI) treatment. METHODS: In this randomized, double-blind, placebo-controlled, crossover study, patients received lesogaberan (65 mg) or placebo twice on day 1 (morning/evening) and once on day 2 (morning), in addition to existing PPI treatment. Patients consumed a standardized meal 45-60 minutes after morning doses. Ambulatory impedance-pH monitoring was conducted for 24 hours after the first dose on day 1. Stationary manometry and impedance-pH monitoring was conducted for 4 hours after the third dose on day 2. RESULTS: Of 27 randomized patients, 21 were included in the per-protocol efficacy analysis. During the 24 hours after treatment start, lesogaberan reduced the mean number of reflux events by approximately 35% compared with placebo. During the 3 postprandial hours on day 2, lesogaberan reduced the geometric mean number of TLESRs by 25% and increased geometric mean LES pressure by 28% compared with placebo. The most common adverse events were headache (placebo: 11/27 patients; lesogaberan: 8/25 patients) and paresthesia (transient; placebo: 3/27 patients; lesogaberan: 5/25 patients). CONCLUSIONS: In patients with reflux symptoms despite PPI treatment, lesogaberan decreased the number of TLESRs and reflux episodes, and increased LES pressure compared with placebo. These findings support further evaluation of lesogaberan as an add-on treatment in patients partially responding to PPIs.

Refinement and reproducibility of histologic criteria for the assessment of microscopic lesions in patients with gastroesophageal reflux disease: the Esohisto Project.

BACKGROUND: Standardized criteria for assessing microscopic esophageal lesions are required to test their utility as markers of gastroesophageal reflux disease (GERD). AIMS: To finalize draft criteria for assessing microscopic esophageal lesions associated with gastroesophageal reflux and to test them for interobserver agreement. METHODS: An international group of gastrointestinal pathologists was convened to finalize, using a consensus-based approach, draft criteria for recognizing microscopic esophageal lesions. Finalized criteria were retested for interobserver variability by four of the pathologists using 120 digitized esophageal biopsy slides from patients with GERD. RESULTS: The finalized criteria included further clarification on lesion definitions and new guidance on how to select the area for assessing each lesion. This latter refinement was guided by the high interobserver agreement observed when draft criteria were previously applied to biopsies where the assessment area was preselected. When finalized criteria were applied in the current study to digitized biopsies without a preselected assessment area, the pairwise agreement was 73-97% for basal cell hyperplasia, papillary elongation, intraepithelial eosinophil, neutrophil and mononuclear cell numbers, and active/healed erosions, with slightly lower agreement (64%) for dilated intercellular spaces (DIS). When a combined severity score was applied, the level of agreement was 77%. The mean kappa ranged from fair to high (0.26-0.77) for individual lesions and was high for the combined score (0.64). CONCLUSIONS: These levels of agreement are comparable with or higher than those for other accepted histologic definitions. Further steps include clinical validation of these criteria by correlating microscopic lesions with clinical variables such as esophageal acid exposure.

Development and validation of a laryngopharyngeal reflux questionnaire, the Pharyngeal Reflux Symptom Questionnaire.

OBJECTIVE: To develop and validate the Pharyngeal Reflux Symptom Questionnaire (PRSQ), a comprehensive, disease-specific, self-administered questionnaire for laryngopharyngeal reflux (LPR) disease. MATERIAL AND METHODS: The PRSQ was developed based on empirical evidence from a literature review and expert input from physicians and patients and tested in a pilot study. In this validation study, a total of 228 patients were included and classified according to the Reflux Symptom Index (RSI) cut-off score. Patients with an RSI score > 13 were defined as abnormal, i.e. having LPR disease (n = 102), and those with a score between 0 and 13 were defined as normal controls (n = 126). Psychometric properties of the PRSQ were evaluated by exploring the factor structure and by evaluating internal consistency and item convergent and discriminant validity. Convergent and discriminant validity were determined by using the Laryngopharyngeal Reflux-Health Related Quality of Life questionnaire (LPR-HRQL), the RSI and the Short Form-36. RESULTS: The PRSQ was well accepted by the patients. Compliance was satisfactory and missing item rates were low. After item reduction, due to items not being conceptually relevant or scaling errors and/or low factor loadings, a construct was achieved with no scaling errors and high internal consistency (Cronbach's alpha 0.79-0.93). The correlations between the PRSQ and similar dimensions in the RSI and LPR-HRQL were generally strong. Discriminant validity was satisfactory as the questionnaire discriminated between patients with and without LPR disease. CONCLUSION: The PRSQ showed good psychometric properties and may become a valuable instrument for assessing LPR disease.

Validation of the Swedish translation of LPR-HRQL.

BACKGROUND: The aim of this study was to adapt the Laryngopharyngeal Reflux Health- Related Quality of Life questionnaire (LPR-HRQL) to Swedish and evaluate its psychometric properties in patients with suspected laryngopharyngeal reflux (LPR). MATERIAL/METHODS: The psychometric validation included 228 patients with suspected LPR who had previously undergone a 2-level 24-hour pH examination and who answered a mail-distributed set of questionnaires. The patients were divided into 2 comparable groups according to the Reflux Symptom Index (RSI) cut-off score: 126 patients with RSI score between 0-13 (defined as normal) and 102 patients with RSI score >13 (defined as abnormal, i.e. having LPR disease). RESULTS: LPR-HRQL was adapted to Swedish using a formal forward-backward translation method with input from expert groups (patients and physicians). Psychometric properties of the Swedish version of LPR-HRQL were evaluated by using factor analysis to explore the factor structure. Convergent and discriminant validity was determined by using the questionnaires RSI and Short Form-36 (SF-36). The psychometric tests performed fulfilled the criteria for structural integrity, validity and reliability, mostly confirming the results obtained in the original LPR-HRQL version. CONCLUSIONS: The Swedish translated version of LPR-HRQL proved to be a statistically valid instrument with which to assess HRQL in patients with LPR disease, and will be further tested in prospective studies.

A more than 10-year prospective, follow-up study of esophageal and pharyngeal acid exposure, symptoms and laryngeal findings in healthy, asymptomatic volunteers.

OBJECTIVE: To evaluate the development of pharyngeal and esophageal acid exposure, symptoms, and laryngeal findings in previously healthy subjects. MATERIAL AND METHODS: Thirty-three subjects, previously included in a normative pH monitoring study, completed symptom questionnaires, a video laryngoscopic examination, and ambulatory 24-h pharyngeal and esophageal pH monitoring after a mean follow-up of 14 years. RESULTS: Twenty-four subjects (15 F, 9 M, mean age 57 years) completed the study. The number of subjects with pathological esophageal reflux increased from 5 (21%) at baseline to 8 (33%) at follow-up (p=0.23), whereas the proportion with pharyngeal acid exposure of at least 0.1% decreased from 42% to 13% (p=0.04). Heartburn and/or regurgitation developed in 11 of the 24 (46%) subjects and airway symptoms in 10 (42%) subjects. Laryngeal pathology was found in 9 of 23 subjects (39%). Airway symptoms were equally common among subjects with and those without laryngeal findings or with and without pharyngeal reflux. CONCLUSIONS: Esophageal acid exposure increases over time in previously symptom-free, healthy subjects. The increase in airway symptoms or laryngeal abnormalities is not directly related to increased acid exposure.

Reducing Adverse Effects During Drug Development: The Example of Lesogaberan and Paresthesia.

PURPOSE: Lesogaberan, a γ-aminobutyric acid (GABA)B receptor agonist, was developed for the treatment of gastroesophageal reflux disease in patients with a partial response to proton pump inhibitor therapy. A high prevalence of paresthesia was observed in healthy individuals after dosing with lesogaberan in early-phase clinical trials. The aim of this review was to gain further insight into paresthesia caused by lesogaberan by summarizing the relevant preclinical and clinical data. METHODS: This study was a narrative review of the literature and unpublished data. FINDINGS: The occurrence of paresthesia may depend on the route or rate of drug administration; several studies were conducted to test this hypothesis, and formulations were developed to minimize the occurrence of paresthesia. Phase I clinical studies showed that, in healthy individuals, paresthesia occurred soon after administration of lesogaberan in a dose-dependent manner regardless of the route of administration. The occurrence of paresthesia could be decreased by fractionating the dose or reducing the rate of administration. These findings suggest that the initial rate of absorption plays an important part in the development of paresthesia. Modified-release formulations minimize the occurrence of paresthesia while retaining the anti-reflux activity of the drug, as measured by esophageal pH and the number of transient lower esophageal sphincter relaxations. IMPLICATIONS: The development of lesogaberan was halted because the effect on gastroesophageal reflux disease symptoms observed in Phase II studies was not considered clinically meaningful in the target patient population. Nevertheless, it is an example of successful formulation development designed to minimize the occurrence of a compound's adverse effect while retaining its pharmacodynamic action.

Health economic evaluation of stent or endoluminal brachytherapy as a palliative strategy in patients with incurable cancer of the oesophagus or gastro-oesophageal junction: results of a randomized clinical trial.

OBJECTIVE: To relieve dysphagia is the main goal in palliative treatment of patients with incurable cancer of the oesophagus or the gastro-oesophageal junction. The aim of this prospective, randomized multicentre study was to compare stent placement and brachytherapy regarding health economy and clinical outcomes. METHODS: Patients with incurable cancer of the oesophagus or gastro-oesophageal junction were randomized to receive a self-expandable metallic stent or 3 x 7 Gy brachytherapy. At clinical follow-up visits, dysphagia was scored and health care consumptions were recorded. Costs were based on hospital debits. Total lifetime healthcare consumption costs and costs for the initial treatments were calculated and a sensitivity analysis was conducted. RESULTS: Thirty patients were randomized to each treatment group. There was no difference in survival or complication rates between the two treatment strategies. There was a significant difference in the change of dysphagia scores between the time of inclusion and the 1-month follow-up visit, in favour of the stented group (P = 0.03). This difference had disappeared at 3 months. Median total lifetime costs were 17,690 for the stented group compared with 33 171 for the brachytherapy group (P = 0.005). This difference was due to higher costs for the initial treatment (4615 versus 23 857, P < 0.0001). Sensitivity analyses showed that the charges for a brachytherapy session had to be reduced from 6092 to 4222 (31%) to make this therapeutic concept cost-competitive. CONCLUSION: Stenting is currently more cost-effective compared with fractionated 3 x 7 Gy brachytherapy for patients with incurable cancer of the oesophagus and gastro-oesophageal junction.

Long-term efficacy of total (Nissen-Rossetti) and posterior partial (Toupet) fundoplication: results of a randomized clinical trial.

The efficacy of fundoplication operations in the long-term management of gastroesophageal reflux disease (GERD) has been documented. However, only a few prospective controlled series support the long-term (>10 years) efficacy of these procedures, and further data are required to also determine whether the type of fundoplication affects the frequency of postfundoplication complaints. The aim of this study was to conduct a randomized, controlled clinical trial to assess the long-term symptomatic outcome of a partial posterior fundoplication as compared to a total fundic wrap. During the years 1983 to 1991, a total of 137 patients with chronic gastroesophageal reflux disease were enrolled in the study; 72 were randomized to semifundoplication (Toupet) and 65 to total fundoplication (Nissen-Rossetti). A standardized symptom questionnaire was used for follow-up of these patients. A total of 110 patients completed a median follow-up of 11.5 years; 54 had a total wrap and 56 underwent a partial posterior fundoplication. During this period, seven patients required reoperation (Nissen-Rossetti in 5 and Toupet in 2), 11 patients died, and nine patients were lost to follow-up or did not comply with the follow-up program. Control of heartburn (no symptoms or mild, intermittent symptoms) was achieved in 88% and 92% in the total and partial fundoplication groups, respectively, and the corresponding figures for control of acid regurgitation were 90% and 94%. We observed no difference in dysphagia scoring between the two groups, although odynophagia was somewhat more frequently reported in those undergoing a total fundoplication. On the other hand, a significant difference was observed in the prevalence of rectal flatus and postprandial fullness, which were recorded significantly more often in those undergoing a total fundoplication (P < 0.001 and P < 0.03, respectively). Posterior partial fundoplication seems to maintain the same high level of reflux control as total fundoplication. Earlier observations demonstrating the advantages of a partial fundoplication, which included fewer complaints associated with gas-bloat, continue to be valid after more than 10 years of follow-up.

Mechanical consequences of short gastric vessel division at the time of laparoscopic total fundoplication.

Laparoscopic Nissen fundoplication is currently the most commonly practiced antireflux operation. Some adverse consequences of the operation remain in the form of mechanical side effects, labeled postfundoplication complaints, of which dysphagia and gas bloat seem to predominate. Measures have been suggested to counteract some of these and one frequently advocated has been division of the short gastric vessels to create a short-floppy wrap. The advantages of this are still debated, particularly in the long-term perspective. The aim of the present study was to evaluate the mechanical consequences of dividing all short gastric vessels at the time of a laparoscopic total fundoplication. Ninety-nine patients with chronic gastroesophageal reflux disease (GERD) were originally allocated on a random basis to have either all short gastric vessels divided or left intact at the time of a laparoscopic total fundoplication. A subsample of these patients, again selected at random, were recruited for a comprehensive manometric investigation 1 year after the operation. In this cohort, 12 patients had all short gastrics divided and in 12 patients, the wrap was done with intact vessels by use of the anterior portion of the fundus. Manometry was carried out by the use of a sleeve sensor to straddle the lower esophageal sphincter (LES), and gastric distension (750 ml air) was used to trigger transient LES relaxations (TLESR). The basal LES tone was similar in the two groups (14.2 +/- 2.4 and 18.8 +/- 4.3, mean +/- SE), respectively. Accordingly, all other relevant manometric variables were equal when the two groups were compared, except for the total number of TLESRs (triggered by gastric distension by air) that were significantly higher (p < 0.02) in patients having their short gastric vessels intact. Consequently, numerically more common cavities were recorded in the latter group. Very similar outcomes in terms of motor function of the LES and esophageal body were observed after a total fundoplication irrespective of whether a complete division of all gastric vessels had been carried out or not. However, after gastric distension with air, more TLESRs were recorded in the latter group suggesting a better maintained ability to vent air from the stomach.

The effect of mosapride on oesophageal motor function and acid reflux in patients with gastro-oesophageal reflux disease.

OBJECTIVE: To evaluate the efficiency of the 5-HT4 agonist and 5-HT3 antagonist mosapride, as compared with cisapride, on oesophageal acid reflux variables and oesophageal motor function in patients with chronic gastro-oesophageal reflux disease (GORD). METHOD: Forty-one patients with proven GORD were included in a double-blind, randomised, double-dummy, three-way crossover study. All patients received mosapride 60 mg twice daily, mosapride 30 mg three times daily, and cisapride 20 mg twice daily for seven days in a randomised order, separated by a washout period of at least five days. Twenty-three patients underwent four combined ambulatory 24-h motility and pH recordings within two weeks before the start of treatment and on day seven of each treatment period. The remaining 18 patients underwent three ambulatory 24-h pH recordings only, i.e. on treatment day seven of each treatment period. RESULTS: Mosapride had no significant effect on the total number of contractions in the oesophagus, or on the effectiveness, or possible effectiveness, of the propagations. Significant but numerically small effects on peristaltic durations and amplitudes were noted during both mosapride and cisapride treatment as compared with baseline values. The effect on acid reflux for both mosapride and cisapride was most pronounced for the duration of the longest reflux episode. The fraction of time with pH less than 4 was reduced by mosapride 30 mg three times daily in the supine position and by cisapride both totally and in the supine position. The number of reflux episodes was reduced significantly only by cisapride. Oesophageal clearance was reduced significantly by cisapride only in the supine position. CONCLUSION: Mosapride had small but statistically significant effects, comparable to those of cisapride, on acid reflux variables and oesophageal motor function in patients with GORD.

The effect of cisapride on oesophageal motility and lower sphincter function in patients with gastro-oesophageal reflux disease.

OBJECTIVES: To evaluate the efficiency by which the 5-HT4 agonist cisapride affects important motor functions involved in the control of gastro-oesophageal reflux. METHOD: Thirty patients with proven gastro-oesophageal reflux disease (endoscopy and 24 h pH-metry) were included in a randomized, double-blind, placebo controlled study with a cross-over design. Cisapride, 20 mg b.i.d., during 4 weeks was compared with placebo. At baseline, as well as after 4 and 8 weeks all patients underwent symptom assessments, sleeve manometry with concomitant oesophageal pH-monitoring and an acid clearance test. RESULTS: Despite adequate plasma levels cisapride had no significant effect on swallow induced peristaltic amplitude, duration, propagation speed, the elicitation of secondary peristalsis nor on acid clearance. Neither the basal tone of the lower oesophageal sphincter nor the number of transient lower oesophageal sphincter relaxations induced by gas distension of the stomach was affected by the administered dose of cisapride. CONCLUSION: Although cisapride has been alleged to improve symptoms as well as the oesophagitis in patients with gastro-oesophageal reflux disease, we found the compound (20 mg b.i.d.) devoid of effects on important motor mechanisms involved in the pathogenesis of the disease.

Hypopharyngeal acid exposure: an independent risk factor for laryngeal cancer?

OBJECTIVES/HYPOTHESIS: Gastroesophageal reflux disease has in recent years been linked to a variety of extraesophageal conditions including laryngeal cancer. However, whether a causal relationship exists is still under debate. The present study aimed to compare the occurrence and severity of gastroesophago-hypopharyngeal reflux in patients with laryngeal cancer with those of healthy volunteers. STUDY DESIGN: Prospective, controlled study. METHODS Forty-one consecutive patients with newly diagnosed laryngeal cancer were examined by esophageal manometry and an ambulatory, 24-hour, double-probe pH monitoring. Their results were compared with those of 40 healthy volunteers. RESULTS: Hypopharyngeal acid exposure was registered mainly in the upright body position. A pathological acid exposure, as compared with the upper levels of normality among the healthy volunteers, was found in the hypopharynx in six (16%) patients with laryngeal cancer and in the distal esophagus in 10 (25%) patients. Pathological acid exposure in either location was found in 15 (37%) patients and in both locations in 1 (3%) patient. However, the mean acid exposure time and the mean value of the number of reflux events did not differ significantly between cancer patients and control subjects at either location. The exclusion of meal periods from the analysis did not alter these observations. Nonsmoking cancer patients (n = 5) and nonsmoking control subjects (n = 36) had similar acid exposure both in the hypopharynx and in the distal esophagus. CONCLUSION: The present results do not support gastroesophago-hypopharyngeal reflux as being an independent risk factor for laryngeal cancer.