The Efficacy of Peroral Endoscopic Myotomy vs Pneumatic Dilation as Treatment for Patients With Achalasia Suffering From Persistent or Recurrent Symptoms After Laparoscopic Heller Myotomy: A Randomized Clinical Trial.

BACKGROUND & AIMS: For patients with achalasia experiencing persistent or recurrent symptoms after laparoscopic Heller myotomy (LHM), pneumatic dilation (PD) is the most frequently used treatment. Per-oral endoscopic myotomy (POEM) is increasingly being investigated as rescue therapy. This study aimed to determine the efficacy of POEM vs PD for patients with persistent or recurrent symptoms after LHM. METHODS: This randomized multicenter controlled trial included patients after LHM with an Eckardt score >3 and substantial stasis (≥2 cm) on timed barium esophagogram and randomized to POEM or PD. The primary outcome was treatment success, defined as an Eckardt score of ≤3 and without unscheduled re-treatment. Secondary outcomes included the presence of reflux esophagitis, high-resolution manometry, and timed barium esophagogram findings. Follow-up duration was 1 year after initial treatment. RESULTS: Ninety patients were included. POEM had a higher success rate (28 of 45 patients [62.2%]) than PD (12 of 45 patients [26.7%]; absolute difference, 35.6%; 95% CI, 16.4%-54.7%; P = .001; odds ratio, 0.22; 95% CI, 0.09-0.54; relative risk for success, 2.33; 95% CI, 1.37-3.99). Reflux esophagitis was not significantly different between POEM (12 of 35 [34.3%]) and PD (6 of 40 [15%]). Basal lower esophageal sphincter pressure and integrated relaxation pressure (IRP-4) were significantly lower in the POEM group (P = .034; P = .002). Barium column height after 2 and 5 minutes was significantly less in patients treated with POEM (P = .005; P = .015). CONCLUSIONS: Among patients with achalasia experiencing persistent or recurrent symptoms after LHM, POEM resulted in a significantly higher success rate than PD, with a numerically higher incidence of grade A-B reflux esophagitis. NETHERLANDS TRIAL REGISTRY: NL4361 (NTR4501), https://trialsearch.who.int/Trial2.aspx?TrialID = NTR4501.

Peroral endoscopic myotomy versus pneumatic dilation in treatment-naive patients with achalasia: 5-year follow-up of a randomised controlled trial.

BACKGROUND: 2-year follow-up data from our randomised controlled trial showed that peroral endoscopic myotomy is associated with a significantly higher efficacy than pneumatic dilation as initial treatment of therapy-naive patients with achalasia. Here we report therapeutic success rates in patients treated with peroral endoscopic myotomy compared with pneumatic dilation at the 5-year follow-up. METHODS: We did a multicentre, randomised controlled trial in six hospitals in the Netherlands, Germany, Italy, Hong Kong, and the USA. Adults aged 18-80 years with newly diagnosed symptomatic achalasia (based on an Eckardt score >3) were eligible for inclusion. Patients were randomly assigned (1:1) to peroral endoscopic myotomy or pneumatic dilation using web-based randomisation with a random block size of 8 and stratification according to site. Randomisation concealment for treatment type was double blind until official study enrolment. Treatment was unmasked because of the different technical approach of each procedure. Patients in the pneumatic dilation group were dilated with a single series of 30-35 mm balloons. The need for subsequent dilations in the pneumatic dilation group, and the need for dilation after initial treatment in the peroral endoscopic myotomy group, was considered treatment failure. The primary outcome was therapeutic success (Eckardt score ≤3 in the absence of severe treatment-related complications and no need for retreatment). Analysis of the primary outcome was by modified intention to treat, including all patients randomly assigned to a group, excluding those patients who did not receive treatment or were lost to follow-up. Safety was assessed in all included patients. This study is registered at the Dutch Trial Registry, NTR3593, and is completed. FINDINGS: Between Sept 21, 2012, and July 20, 2015, 182 patients were assessed for eligibility, 133 of whom were included in the study and randomly assigned to peroral endoscopic myotomy (n=67) or pneumatic dilation (n=66). 5-year follow-up data were available for 62 patients in the peroral endoscopic myotomy group and 63 patients in the pneumatic dilation group. 50 (81%) patients in the peroral endoscopic myotomy group had treatment success at 5 years, compared with 25 (40%) in the pneumatic dilation group, an adjusted absolute difference of 41% (95% CI 25-57; p<0·0001). Reasons for failure were no initial effect of treatment (one patient in the peroral endoscopic myotomy group vs 12 patients in the pneumatic dilation group) and recurrent symptoms causing treatment failure (11 patients in the peroral endoscopic myotomy group [seven patients between 2 and 5 years] vs 25 patients in the pneumatic dilation group [nine patients between 2 and 5 years]); one patient in the pneumatic dilation group had treatment failure due to an adverse event. Proton-pump inhibitor use (mostly daily) was significantly higher after peroral endoscopic myotomy than after pneumatic dilation among patients still in clinical remission (23 [46%] of 50 patients vs three [13%] of 24 patients; p=0·008). 5-year follow-up endoscopy of patients still in clinical remission showed reflux oesophagitis in 14 (33%) of 42 patients in the peroral endoscopic myotomy group (12 [29%] grade A or B, two [5%] grade C or D) and two (13%) of 16 patients in the pneumatic dilation group (two [13%] grade A or B, none grade C or D; p=0·19). No intervention-related serious adverse events occurred between 2 and 5 years after treatment. The following non-intervention-related serious adverse events occurred between 2 and 5 years: a stroke (one [2%]) in the peroral endoscopic myotomy group; and death due to a melanoma (one [2%]) and dementia (one [2%]) in the pneumatic dilation group. INTERPRETATION: Based on this study, peroral endoscopic myotomy should be proposed as an initial treatment option for patients with achalasia. Although our study has shown that peroral endoscopic myotomy has greater long-term efficacy with a low risk of major treatment-related complications, this should not lead to abandonment of pneumatic dilation from clinical practice. Ideally, all treatment options should be discussed with treatment-naive patients with achalasia and a shared decision should be made. FUNDING: Fonds NutsOhra and European Society of Gastrointestinal Endoscopy.

General Well-being and Coping Strategies in Adult Eosinophilic Esophagitis Patients.

Background/Aims: Growing evidence suggests a negative effect of eosinophilic esophagitis (EoE) on patients' general health-related quality of life (HRQOL). However, the relevance and use of coping strategies and its relation to (disease specific) HRQOL as well as its determinants have not been studied well. Methods: Adult EoE patients were invited to complete standardized measures on general HRQOL (Short Form-36 Health Survey [SF-36]) and coping strategies (Utrechtse Coping Lijst [UCL]). Scores were compared to general population norms. The disease specific Adult Eosinophilic Esophagitis Quality of Life (EoE-QOL-A) measure was used to assess EoE-HRQOL. Socio-demographic-and clinical factors were also evaluated. Results: In total, 147 adult EoE patients (61% males), age 43 (interquartile range, 29-52) years were analyzed. Mental health-scores (SF-36) were significantly lower in EoE patients, whereas physical health-scores (SF-36) were similar in EoE patients (vs the general population; P = 0.010 and P = 0.240), respectively. The subdomain "disease anxiety" (EoE-QOL-A) was mostly affected, determinants were; female gender, younger age, severe clinical disease activity, higher number of food bolus extraction, and more recent EoE-diagnosis. Less effective coping styles (ie, passive/palliative reaction) were associated with a significant impact on each individual EoE-HRQOL-subdomain as well as lower scores of the Mental Health Component Scale in male EoE patients. Passive reaction in female EoE-patients correlated with impairment of the EoE-HRQOL-domains "emotional impact" and "disease anxiety." Active problem solving was significantly related to better perception of mental HRQOL (SF-36) in both males and females. Conclusions: EoE has a significant negative impact on mental HRQOL, with less effective coping strategies--specifically in males, being a relevant determinant. Thus, a pro-active approach towards coping mechanisms is needed in order to enhance HRQOL and manage patients' burden of EoE.

Utility of gastric and duodenal biopsy sampling in adult eosinophilic esophagitis patients to rule out other gastrointestinal disorders.

RATIONALE: According to consensus guidelines, if eosinophilic esophagitis (EoE) is suspected, not only esophageal but also gastric and duodenal biopsy specimens should be sampled in order to exclude other generalized or eosinophilic gastrointestinal (GI) disorders, such as eosinophilic gastroenteritis or celiac disease. However, the diagnostic yield for this remains unclear. AIM: To assess the diagnostic yield of biopsy sampling from the stomach and duodenum in adult EoE patients to rule out generalized or eosinophilic GI disorders. METHODS: A retrospective chart-review was conducted in untreated adult EoE patients that underwent upper endoscopy with biopsies sampled from the esophagus, stomach and duodenum. Standardized (electronic) case-report forms were used to extract clinical, endoscopic and histologic data. RESULTS: In total, 93 adults (71% males, age 36.4 (interquartile range 28.4 - 49.1) years) with untreated EoE (≥15 eosinophils/high-power-field) were included. Symptoms of dysphagia and food impaction were reported in 93% and 58%, respectively of the patients. Typical endoscopic EoE-features were present in 77 (85%) patients. The yield of routinely sampled gastric and duodenal biopsy specimens in our cohort was 3.6% (95% confidence interval: 2.6-4.8%) (n/N = 1/93) for a relevant other generalized or eosinophilic GI diagnosis and 30% for other histological diagnosis such as non-specific or H. Pylori gastritis. In total, 62 (67%) patients presented with other GI symptoms and/or endoscopic abnormalities of the stomach and/or duodenum - which both may be suggestive for other relevant GI conditions. The diagnostic yield for a relevant generalized or eosinophilic GI disorder in this subgroup was, 4.8% (95%CI 3.4 - 6.7%) (n/N = 1/62). CONCLUSION: Gastric and duodenal biopsy specimens seem to have limited diagnostic value for the exclusion of generalized or eosinophilic GI disorders in adults with EoE.KEY POINTSEvidence is lacking on the diagnostic value of additional biopsies sampled form the stomach and duodenum to rule out other relevant generalized or eosinophilic gastrointestinal (GI) disorders.The yield of gastric and duodenal biopsies routinely sampled in our cohort was 3.6% for a relevant other generalized or eosinophilic GI diagnosis and 30% for other histological diagnosis such as non-specific or H. Pylori gastritis.The diagnostic yield for a relevant generalized or eosinophilic GI disorder in the subgroup of patients (67%) presenting with other GI symptoms and/or endoscopic abnormalities of the stomach and/or duodenum - which both may be suggestive for other relevant GI conditions was, 4.8%.Gastric and duodenal biopsy specimens seem to have limited diagnostic value for the exclusion of generalized or eosinophilic GI disorders in adults with EoE.

Effect of Peroral Endoscopic Myotomy vs Pneumatic Dilation on Symptom Severity and Treatment Outcomes Among Treatment-Naive Patients With Achalasia: A Randomized Clinical Trial.

Importance: Case series suggest favorable results of peroral endoscopic myotomy (POEM) for treatment of patients with achalasia. Data comparing POEM with pneumatic dilation, the standard treatment for patients with achalasia, are lacking. Objective: To compare the effects of POEM vs pneumatic dilation as initial treatment of treatment-naive patients with achalasia. Design, Setting, and Participants: This randomized multicenter clinical trial was conducted at 6 hospitals in the Netherlands, Germany, Italy, Hong Kong, and the United States. Adult patients with newly diagnosed achalasia and an Eckardt score greater than 3 who had not undergone previous treatment were included. The study was conducted between September 2012 and July 2015, the duration of follow-up was 2 years after the initial treatment, and the final date of follow-up was November 22, 2017. Interventions: Randomization to receive POEM (n = 67) or pneumatic dilation with a 30-mm and a 35-mm balloon (n = 66), with stratification according to hospital. Main Outcomes and Measures: The primary outcome was treatment success (defined as an Eckardt score ≤3 and the absence of severe complications or re-treatment) at the 2-year follow-up. A total of 14 secondary end points were examined among patients without treatment failure, including integrated relaxation pressure of the lower esophageal sphincter via high-resolution manometry, barium column height on timed barium esophagogram, and presence of reflux esophagitis. Results: Of the 133 randomized patients, 130 (mean age, 48.6 years; 73 [56%] men) underwent treatment (64 in the POEM group and 66 in the pneumatic dilation group) and 126 (95%) completed the study. The primary outcome of treatment success occurred in 58 of 63 patients (92%) in the POEM group vs 34 of 63 (54%) in the pneumatic dilation group, a difference of 38% ([95% CI, 22%-52%]; P < .001). Of the 14 prespecified secondary end points, no significant difference between groups was demonstrated in 10 end points. There was no significant between-group difference in median integrated relaxation pressure (9.9 mm Hg in the POEM group vs 12.6 mm Hg in the pneumatic dilation group; difference, 2.7 mm Hg [95% CI, -2.1 to 7.5]; P = .07) or median barium column height (2.3 cm in the POEM group vs 0 cm in the pneumatic dilation group; difference, 2.3 cm [95% CI, 1.0-3.6]; P = .05). Reflux esophagitis occurred more often in the POEM group than in the pneumatic dilation group (22 of 54 [41%] vs 2 of 29 [7%]; difference, 34% [95% CI, 12%-49%]; P = .002). Two serious adverse events, including 1 perforation, occurred after pneumatic dilation, while no serious adverse events occurred after POEM. Conclusions and Relevance: Among treatment-naive patients with achalasia, treatment with POEM compared with pneumatic dilation resulted in a significantly higher treatment success rate at 2 years. These findings support consideration of POEM as an initial treatment option for patients with achalasia. Trial Registration: Netherlands Trial Register number: NTR3593.

The role of mast cell stabilization in treatment of postoperative ileus: a pilot study.

OBJECTIVES: Although postoperative ileus (POI) is considered multifactorial, intestinal inflammation resulting from manipulation-induced mast cell activation is recognized as an important pathophysiological mechanism. Therefore, mast cell stabilization may represent a new therapeutic approach to shortening POI. The aim of this paper was to study the effect of ketotifen, a mast cell stabilizer, on postoperative gastrointestinal transit in patients who underwent abdominal surgery. METHODS: In this pilot study, 60 patients undergoing major abdominal surgery for gynecological malignancy with standardized anesthesia were randomized to treatment with ketotifen (4 or 12 mg) or placebo. Patients were treated for 6 days, starting 3 days before surgery. Gastric emptying of liquids, selected as a primary outcome parameter, was measured 24 h after surgery using scintigraphy. Secondary end points were (scintigraphically assessed) colonic transit, represented as geometrical center of activity (segment 1(cecum) to 7(stool)) and clinical parameters. RESULTS: Gastric retention 1 h after liquid intake was significantly reduced by 12 mg (median 3% (1-7), P=0.01), but not by 4 mg ketotifen (18% (3-45), P=0.6) compared with placebo (16% (5-75)). Twenty-four hour colonic transit in placebo was 0.8 (0.0-1.1) vs. 1.2 (0.2-1.4) colon segments in the 12 mg ketotifen group (P=0.07). Abdominal cramps were significantly relieved in patients treated with 12 mg ketotifen, whereas other clinical parameters were not affected. CONCLUSIONS: Ketotifen significantly improves gastric emptying after abdominal surgery and warrants further exploration of mast cell stabilizers as putative therapy for POI.