Long-Term Loss of Response in Proton Pump Inhibitor-Responsive Esophageal Eosinophilia Is Uncommon and Influenced by CYP2C19 Genotype and Rhinoconjunctivitis.

OBJECTIVES: Proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE) is diagnosed in at least one-third of patients with suspected eosinophilic esophagitis (EoE). We aimed to evaluate the durability and factors influencing long-term efficacy of PPI therapy. METHODS: Retrospective multicenter cohort study of patients with PPI-REE who had at least 12 months of follow-up. PPI therapy was tapered to the lowest dose, which maintained clinical remission. Primary outcomes were the proportion of patients with loss of histological response (<15 eos/HPF) and predictors of loss of response. CYP2C19 polymorphisms were determined from blood samples in a subset of patients. RESULTS: Seventy-five PPI-REE patients were included (mean follow-up 26 months (12-85)), of whom fifty-five (73%) had sustained histological remission on low-dose PPI therapy. Loss of response was significantly higher in those patients with a CYP2C19 rapid metabolizer genotype (36% vs. 6%, P = 0.01) and with rhinoconjunctivitis (40% vs. 13%, P = 0.007). On the multivariate analysis, a CYP2C19 rapid metabolizer genotype (odds ratio (OR) 12.5; 95% confidence interval (CI): 1.3-115.9) and rhinoconjunctivitis (OR 8.6; 95% CI: 1.5-48.7) were independent predictors of loss of response. Among relapsing patients, eosinophilia was limited to the distal esophagus in 14/20 (70%). Nine of ten relapsers, with distal eosinophilia, all showing a CYP2C19 rapid metabolizer genotype, regained histological remission after PPI dose intensification. CONCLUSIONS: Most PPI-REE patients remain in long-term remission on low-dose PPI therapy. CYP2C19 rapid metabolizer genotypes and rhinoconjunctivitis were independent predictors of loss of response to PPI, but patients frequently responded to PPI dose escalation.

[Changes in Wnt pathway inhibiting factors in nitrosamine-induced esophageal precancerosis lesions and effect of gexia zhuyu decoction].

OBJECTIVE: To discuss the changes in Wnt pathway inhibiting factors in esophageal precancerosis lesions induced by methyl benzyl nitrosamine (MBNA) and the effect of Gexia Zhuyu decoction. METHOD: Wistar rats were subcutaneously injected with MBNA (3.5 mg x kg(-1) for twice per week to establish the model. Since the 1st day after the model establishment, they were orally administered with Gexia Zhuyu decoction (16, 8 mg x kg(-1)). At the 10th week, esophageal tissues were collected to observe the pathological changes of esophageal mucosa, detect SFRP1, sFRP4, Axin1, Axin2 and GSK-3ß mRNA levels.by fluorescent quantitation PCR analysis and ß-catenin protein level by Western blotting. RESULT: Being induced by MBNA, rats in the model group showed slight atypical hyperplasia in the histopathological examination. Compared with the normal group, Gexia Zhuyu decoction dose high and low groups showed no significant pathomorphological and histological changes. The model group showed lower gene transcription levels of esophageal tissues sFRP1, sFRP4, Axin1 and Axin2 (P < 0.05 or P < 0.01) and higher ß-catenin protein expression level (P < 0.01) than the normal control group. The Gexia Zhuyu decoction low dose group showed higher gene transcription levels of esophageal tissues sFRP1, sFRP4, Axin1 and Axin2 (P < 0.05 or P < 0.01) and lower ß-catenin protein expression level (P < 0.01) than the normal control group. CONCLUSION: Up-regulated ß-catenin protein level and down-regulated Wnt pathway could enhance Wnt pathway activity of MBNA-induced esophageal precancerous lesions. Gexia Zhuyu decoction could down-regulate the ß-catenin protein level and up-regulate the transcription level of Wnt pathway inhibiting factors, but could not block MBNA-induced esophageal precancerosis lesions.

Effect of acid swallowing on esophageal contraction in patients with heartburn related to hypersensitivity.

BACKGROUND AND AIM: There are heterogeneous subgroups among those with heartburn, and data on these individuals are relatively scant. We aimed to evaluate the effect of acid challenge on the segmental contractions of esophageal smooth muscle in endoscopy-negative patients with normal esophageal acid exposure. METHODS: High-resolution esophageal manometry (HRM) was performed on 30 endoscopy-negative patients with heartburn accompanied by normal esophageal acid exposure using 10 water swallows followed by 10 acidic pomegranate juice swallows. Patients were classified into functional heartburn (FH) and hypersensitive esophagus (HE) groups based on the results of 24-hr impedance pH testing. HRM topographic plots were analyzed and maximal wave amplitude and pressure volumes were measured for proximal and distal smooth muscle segments. RESULTS: The pressure volume of the distal smooth muscle segment in the HE group measured during acidic swallows was higher than during water swallows (2224.1 ± 68.2 mmHg/cm per s versus 2105.6 ± 66.4 mmHg/cm per s, P = 0.027). A prominent shift in the pressure volume to the distal smooth muscle segment was observed in the HE group compared with the FH group (segmental ratio: 2.72 ± 0.08 versus 2.39 ± 0.07, P = 0.005). Manometric measurements during acidic swallows revealed that this shift was augmented in the HE group. The optimal ratio of pomegranate juice swallowing for discrimination of FH from HE was 2.82, with a sensitivity of 88.9% and a specificity of 100%. CONCLUSIONS: Hypercontractile response of distal smooth muscle segment to acid swallowing was more prominent in the HE group than the FH group.

Real-time 3-dimensional imaging of the esophagus and left atrium with a noncontact mapping system.

BACKGROUND: Recognizing the relative location of the esophagus to the left atrial posterior wall (LAPW) is required to avoid esophageal injury during atrial fibrillation ablation. METHODS AND RESULTS: The 24 patients undergoing circumferential pulmonary vein isolation (CPVI) each had the geometry of their left atrium (LA) and esophagus constructed by a noncontact mapping system with EnSite version 6.0J. The esophageal course relative to the LAPW was found to be to the left in 12, middle in 8, right in 2, and obliquely left-to-right in 2 patients, and in 13 patients (54%) it was located on or near either the left or right CPVI line. The mean distance between the esophagus and LAPW was shorter at the bottom line of the LAPW connecting both inferior pulmonary veins (3 +/- 3 mm) than at the LA roof line connecting both superior pulmonary veins (6 +/- 6 mm, P<0.01). CONCLUSIONS: The location of the esophagus relative to the LAPW varies with the patient, but a close location to either CPVI line was found in approximately 50% and a close location between the esophagus and LAPW was found in the inferior and middle locations in most patients.

Effect of s-methylmethionine sulphonium chloride on oesophagogastric ulcers in pigs.

OBJECTIVE: To assess the value of s-methylmethionine sulphonium chloride (SMMSC) (200 mg/kg) on nutritional performance of pigs and as prevention or therapy for oesophagogastric ulcers. DESIGN: Sixty pigs from a high health status herd with continuing oesophagogastric ulcer problems were endoscopically assessed for the presence or absence of oesophagogastric ulcers. Forty-eight pigs were then selected and allocated according to an initial oesophagogastric epithelial (ulcer score) classification to replicated treatment groups in a 2 x 2 factorial design. Weight gain and feed intake were measured over 49 d, after which pigs were killed and stomachs were collected, re-examined and scored for oesophagogastric ulceration. RESULTS: There was no difference over the 49 d in weight gain, feed intake and backfat in pigs with and without SMMSC supplementation between pigs with or without fully developed oesophagogastric ulcers at the start of the study. In pigs with an initially low ulcer score, feeding SMMSC did not prevent further oesophagogastric ulcer development. No significant effect of SMMSC was apparent when final mean oesophagogastric ulcer scores were compared in pigs with existing high ulcer score. However, further analysis of the changes in individual pig oesophagogastric ulcer scores during the experiment showed that the observed reductions in scores of the high ulcer group was significantly different from all other groups. CONCLUSION: This study has indicated that supplementation of pig diets with SMMSC cannot be justified unless the slight ulcer score improvement observed could be translated to some commercial production advantage such as a reduction in pig mortalities due to oesophagogastric ulcers. This study has further confirmed the benefit of endoscopy as a tool to enable objective assessment of oesophageal gastric health.

The negative effect of hyperbaric oxygen therapy at the acute phase of electrochemical esophageal burn induced by button battery ingestion.

OBJECTIVE: Ingestion of button battery, if lodges in esophagus, causes mucosal destruction in esophagus and may damage surrounding tissues due to electrochemical reactions which may lead to esophagus perforation, tracheosefageal fistula and other serious problems. We designed an experimental study to test the effect of hyperbaric oxygen therapy on battery induced electrochemical tissue damage in the esophagus of a rabbit model and possible change with duration of contact time. METHODS: Button batteries were inserted in esophagus of 40 rabbits which were divided into four groups. Groups 1 and 2 had 15 min of duration of contact time of battery in esophagus, while Groups 3 and 4 had 30 min. Groups 1 and 3 had hyperbaric oxygen therapy for 3 days; Groups 2 and 4 did not. At the end of 3rd day all animals were sacrified and samples were taken from the esophagus for determination of malondialdehyde levels and for histopathological examination to compare: mucosal destruction, muscular layer involvement, perforation and tracheal involvement between groups. RESULTS: Malondialdehyde levels, mucosal destruction, muscular layer involvement, perforation and tracheal involvement were significantly higher in groups which had 30 min of contact time compared to groups which had 15 min. The same assessments were significantly higher in Group 1 (15 min of contact time with hyperbaric oxygen therapy) compared to Group 2 (15 min of contact time without hyperbaric oxygen therapy). However, the difference between Group 3 (30 min of contact time with hyperbaric oxygen therapy) and Group 4 (30 min of contact time, no hyperbaric oxygen therapy) was not significant. CONCLUSION: Our study demonstrated that if contact time is 15 min HBO had an additive adverse effect to electrochemically burned esophagus by increasing free radicals and eventually tissue damage. However, if the contact time is 30 min its adverse effect is shielded by huge electrochemical destruction due to long contact time.

A randomized, double-blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients.

The efficacy, safety, and tolerability of voriconazole and fluconazole were compared in 391 immunocompromised patients with mycology- and biopsy-proven esophageal candidiasis. Primary efficacy analysis (256 patients) of esophageal treatment as assessed by esophagoscopy revealed success rates of 98.3% with voriconazole and 95.1% with fluconazole. The 95% confidence interval for the difference in success rates ranged from -1.0% to 7.5%. The overall safety and tolerability of both antifungals were acceptable. Fewer patients discontinued voriconazole treatment because of insufficient clinical response (4 patients [2.0%] vs. 5 patients [2.6%]). More patients discontinued voriconazole than fluconazole treatment because of laboratory test abnormalities (7 patients [3.5%] vs. 2 patients [1.0%]) or treatment-related adverse events (5 patients [2.5%] vs. 1 patient [0.5%]). The most frequent adverse events (23%) with voriconazole were mild, transient visual disturbances. Voriconazole (200 mg, b.i.d.) was shown to be at least as effective as fluconazole in the treatment of biopsy-proven esophageal candidiasis in immunocompromised patients.

[A chronobiological study of the function of the epithelial proliferative system of the murine esophagus after its infection with typhoid and the use of lomefloxacin]. / Khronobiologicheskoe issledovanie sostoianiia proliferativnoi sistemy épiteliia pishchevoda myshei posle zarazheniia ikh briushnotifoznoi infektsiei i primeneniia lomefloksatsina.

The rhythmical character of the function of the proliferative system of the oesophagus epithelium of mice changed after infection by Salmonella typhi and after injection of lomefloxacin to intact and infected mice. The degree of the changes depended on the exposure time. The proliferative system of the oesophagus epithelium was more resistant to the infection in the night-time than the day-time and equally resistant to the effect of lomefloxacin in both the day-time and the night-time. The proliferative system of the oesophagus epithelium of the infected mice exposed to lomefloxacin in the day-time proved to be in a noncompensated state and in the night-time it proved to be in the hyperfunctional state.

Assessment of apoptosis in oesophageal carcinoma preoperatively treated by chemotherapy and radiotherapy.

Apoptosis, programmed cell death, was immunohistochemically determined in 55 samples of oesophageal squamous cell carcinoma using the BM1 Mab. Sections from patients not treated (group 1, n = 12) or preoperatively treated by chemotherapy (group 2, n = 11), radiation (group 3, n = 13) or both (group 4, n = 8), and 11 additional cases of high-grade dysplasia or early cancer were examined. Most of the apoptotic cells were BM1-positive and checked by TUNEL proved to be nick end positive. They accounted for 7 (11%), 19 (29%), 21 (32%) and 26 (38%) cells per field in those 4 groups respectively. Chemotherapy and/or radiation significantly increased the number of apoptotic cells as compared to controls (p = 0.029 and p = 0.029, respectively). To assess the implications of the oncogene expression in the apoptotic pathway, additional section stained with bcl2 and p53 were negative for bcl2 and were positive for p53 in 16 samples (37%). Overall, positive cases for p53 mutation showed a significantly decreased incidence of apoptotic cells (p = 0.03). These results suggest that in situ assessment of apoptotic response better correlates to the apoptosis induced by radiation than that by chemotherapy, that abnormalities of the p53 protein decrease the apoptotic response in oesophageal carcinoma, and that immunohistochemical analysis of p53 protein helps to determine the sensitivity to these anticancer agents.

Clinical efficacy of nifedipine and other calcium antagonists in patients with primary esophageal motor dysfunctions.

In this paper the pharmacodynamic effects of calcium channel blockers (verapamil, nifedipine, diltiazem, fendiline, nitrendipine, nimodipine, and nisoldipine) on esophageal motility in man and their clinical effects in patients with various forms of primary esophageal motility disorders are critically analysed and summarized. The evaluation of efficacy and safety is mainly focused on nifedipine (Bay a 1040, Adalat; CAS 21829-25-4), since it has been best documented clinical pharmacologically and therapeutically in this field. Nifedipine and--with varying potency--the other calcium antagonists reduce effectively the increased lower esophageal sphincter pressure (LESP) and abnormally high and prolonged peristaltic and nonperistaltic contractions in the esophageal body in patients with achalasia, diffuse esophageal spasm (DES), and other disorders which may cause angina-like chest pain and/or dysphagia. Pharmacodynamic effects on esophageal motility are closely correlated with the plasma concentration of nifedipine in healthy volunteers and in patients. However, a final judgement on the therapeutic value of these compounds in esophageal motor abnormalities cannot be given due to conflicting results from clinical studies with fairly small numbers of patients and varying study designs. Among the different calcium antagonists investigated nifedipine represents the best investigated and the most suitable compound for the treatment of primary hypertensive esophageal motor disorders.