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.

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.

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.

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.

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.

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.

Systematic review: laparoscopic fundoplication for gastroesophageal reflux disease in partial responders to proton pump inhibitors.

AIM: To assess laparoscopic fundoplication (LF) in partial responders to proton pump inhibitors (PPIs) for gastroesophageal reflux disease (GERD). METHODS: We systematically searched PubMed and Embase (1966-Dec 2011) for articles reporting data on LF efficacy in partial responders. Due to a lack of randomized controlled trials, observational studies were included. Of 558 articles screened, 17 were eligible for inclusion. Prevalence data for individual symptoms were collated across studies according to mutually compatible time points (before and/or after LF). Where suitable, prevalence data were presented as percentage of patients reporting symptoms of any frequency or severity. RESULTS: Due to a lack of standardized reporting of symptoms, the proportion of patients experiencing symptoms was recorded across studies where possible. After LF, the proportion of partial responders with heartburn was reduced from 93.1% (5 studies) to 3.8% (5 studies), with similar results observed for regurgitation [from 78.4% (4 studies) to 1.9% (4 studies)]. However, 10 years after LF, 35.8% (2 studies) of partial responders reported heartburn and 29.1% (1 study) reported regurgitation. The proportion using acid-suppressive medication also increased, from 8.8% (4 studies) in the year after LF to 18.2% (2 studies) at 10 years. In the only study comparing partial responders to PPI therapy with complete responders, higher symptom scores and more frequent acid-suppressive medication use were seen in partial responders after LF. CONCLUSION: GERD symptoms improve after LF, but subsequently recur, and acid-suppressive medication use increases. LF may be less effective in partial responders than in complete responders.

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.

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.

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.

Translational gastrointestinal pharmacology in the 21st century: 'the lesogaberan story'.

The development of the novel γ-aminobutyric acid type-B receptor (GABAB) agonist lesogaberan is presented as an example of a partly successful translational strategy in the field of gastroenterology. Data on transient lower esophageal sphincter relaxations (TLESRs) and gastroesophageal reflux inhibition from preclinical models translated well to clinical studies in healthy volunteers and patients with gastroesophageal reflux disease (GERD). Animal models have also been used successfully to predict the effect of other target mechanisms on TLESRs in humans. However, while translation of physiology to symptomatology in patients with GERD was achieved, the effect size was too small to be of clinical significance. A deeper understanding of the cause of symptoms in different patient categories is therefore required.

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.

Pharmacokinetic profile of lesogaberan (AZD3355) in healthy subjects: a novel GABA(B)-receptor agonist reflux inhibitor.

BACKGROUND: Lesogaberan (AZD3355) is a novel reflux inhibitor developed as an add-on treatment to proton pump inhibitors (PPIs) for symptom relief in patients with gastroesophageal reflux disease who have a partial response to PPI therapy. OBJECTIVE: The aim of this study was to evaluate the pharmacokinetic profile of lesogaberan in healthy subjects after single oral and intravenous administration of (14)C-labeled lesogaberan and non-(14)C-labeled lesogaberan. STUDY DESIGN: This was an open-label, single-center, randomized, two-way crossover, phase I study. PARTICIPANTS: Ten healthy male subjects took part in the study. INTERVENTION: Volunteers were randomized to receive a single dose of either orally dosed (100 mg) or intravenously infused (20 mg) non-(14)C-labeled lesogaberan, and then orally (100 mg) or intravenously (20 mg) administered (14)C-labeled lesogaberan in a crossover design. Treatment periods were separated by a washout period of at least 7 days. MAIN OUTCOME MEASURES: Analyses of the rate and route of excretion, dose recovery, area under the plasma concentration versus time curve (AUC), AUC to the last quantifiable concentration, maximal plasma concentration (C(max)), time to C(max), the apparent elimination half-life, bioavailability, total clearance, renal clearance, fraction of the bioavailable dose excreted unchanged in the urine, cumulative amount of drug excreted unchanged in urine, and the apparent volume of distribution at steady state of lesogaberan. RESULTS: Lesogaberan was rapidly and extensively absorbed from the gastrointestinal tract and C(max) was achieved within 1-2 hours of oral dosing. The terminal half-life of lesogaberan was between 11 and 13 hours. Renal clearance accounted for approximately 22% of total body clearance. Based on the recovery of administered radioactivity, approximately 84% of the dose was excreted into the urine either as the parent compound or as water-soluble metabolite(s). There were no safety concerns raised during the study. CONCLUSION: Orally administered lesogaberan is rapidly absorbed with high bioavailability and the majority of the dose is excreted by the kidneys either as the parent compound or as metabolites. The major elimination pathway for lesogaberan in man is metabolism.

Evaluation of the pharmacokinetic interaction between lesogaberan (AZD3355) and esomeprazole in healthy subjects.

BACKGROUND: Transient lower esophageal sphincter relaxations (TLESRs) have been identified as a primary cause of reflux events in patients with gastroesophageal reflux disease (GERD). GABA(B) receptor agonists such as lesogaberan (AZD3355) have been shown to inhibit TLESRs in healthy subjects and patients with GERD, and, therefore, offer a novel therapeutic add-on strategy to acid suppression for the management of GERD. As lesogaberan is being developed as an add-on treatment for the management of patients with GERD who have a partial response to proton pump inhibitor (PPI) therapy, it is important to rule out any clinically important pharmacokinetic drug-drug interaction between lesogaberan and PPIs. OBJECTIVE: To evaluate the effect of esomeprazole on the pharmacokinetics and safety of lesogaberan and vice versa. STUDY DESIGN: This was an open-label, randomized, three-way crossover study. The study was open to healthy adult male and female subjects. The study subjects received treatment with, in random order, lesogaberan (150 mg twice daily [dose interval 12 hours]), esomeprazole (40 mg once daily), and a combination of both, during 7-day treatment periods. MAIN OUTCOME: The presence or absence of pharmacokinetic interactions between lesogaberan and esomeprazole was assessed by measuring the steady-state area under the plasma concentration-time curves during the dosing interval (AUC(τ)) and the maximum observed plasma concentration (C(max)) for lesogaberan and esomeprazole. RESULTS: Thirty male subjects (mean age 23.2 years, 97% Caucasian) were randomized to treatment and 28 subjects completed the study (one subject was lost to follow-up, and one subject discontinued due to an adverse event). The 95% confidence intervals of the geometric mean ratios for AUC(τ) and C(max) of lesogaberan and esomeprazole administered alone and concomitantly were within the recognized boundaries of bioequivalence (0.8-1.25). No new safety concerns were raised during this study. The number of patients with adverse events during treatment with lesogaberan alone (n = 17) and concomitantly with esomeprazole (n = 18) were comparable but higher than with esomeprazole alone (n = 10). Paresthesia (episodic, mild, and transient), pharyngitis, and flatulence were the most frequently reported adverse events. CONCLUSIONS: There was no observed pharmacokinetic interaction between lesogaberan and esomeprazole when concomitantly administered to healthy subjects, and concomitant therapy was well tolerated. TRIAL REGISTRATION NUMBER (clinicaltrials.gov): NCT00684190.

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.

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.

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.

Development of consensus guidelines for the histologic recognition of microscopic esophagitis in patients with gastroesophageal reflux disease: the Esohisto project.

No gold standard test exists for gastroesophageal reflux disease (GERD). Diagnostic difficulties are greatest when reflux symptoms occur without visible esophageal mucosal damage at conventional endoscopy. However, two thirds of such patients do have microscopic esophageal lesions. This study aimed to develop and standardize criteria for recognizing these microscopic esophageal lesions in GERD. Draft histologic criteria were developed and tested by an international group of 5 independent gastrointestinal pathologists using 167 biopsy specimens from GERD patients and healthy controls (phase I). Draft criteria were refined and reassessed using 250 photographs of biopsy specimens (phase II). Histologic lesions evaluated were basal cell hyperplasia, papillary elongation, intraepithelial eosinophil, neutrophil and mononuclear cell number, necrosis/erosion, healed erosion, and dilated intercellular spaces. Interobserver agreement and kappa values increased significantly from phase I to II. When tested in annotated photographs (phase II), mean pairwise agreements were 74%, 89%, 93%, 97%, 81%, 97%, 94%, and 74%, respectively. Mean pairwise kappa estimates (+/-SD) were 0.49 (0.16), 0.81 (0.05), 0.87 (0.05), 0.84 (0.09), 0.60 (0.09), 0.90 (0.04), 0.73 (0.14), and 0.61 (0.08), respectively. Estimated intraclass correlation coefficients for basal cell layer thickness and papillary length increased from 0.38 and 0.56 to 0.69 and 0.95, respectively, when revised criteria were used. The draft criteria achieved promising levels of agreement when assessed independently by 5 pathologists. Further steps include evaluation of lesions without indicating the area to be assessed and exploring the correlation of microscopic esophagitis with symptoms and esophageal acid exposure.

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.

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.