Functional lumen imaging probe topography identifies patients with normal acid exposure and esophageal hypervigilance amongst proton-pump inhibitor non-responders.

BACKGROUND: Multiple factors contribute to symptom generation and treatment response in proton-pump inhibitor non-responders (PPI-NRs). We aimed to test whether PPI-NRs with normal acid exposure have a higher degree of esophageal hypersensitivity and hypervigilance and can be identified using functional lumen imaging probe (FLIP) topography at the time of endoscopy. METHODS: Data from PPI-NRs whom underwent endoscopy, FLIP and wireless 96-h pH-metry were retrospectively analyzed. Patients were grouped according to acid exposure time (AET) as (a) 0 days abnormal (AET > 6%), (b) 1-2 days abnormal, or (c) 3-4 days abnormal. The esophageal hypervigilance and anxiety scale (EHAS) score and other symptom scores were compared between groups. The discriminatory ability of the esophagogastric junction (EGJ) distensibility index (DI) and max EGJ diameter in identifying patients with 0 days abnormal AET was tested via receiver-operating-characteristic (ROC) curve analysis. RESULTS: EHAS score was 38.6 in the 0 days abnormal AET group, 30.4 in the 1-2 days abnormal AET group (p = 0.073 when compared to 0 days abnormal) and 28.2 in the 3-4 days abnormal AET group (p = 0.031 when compared to 0 days abnormal). Area-under-the-curve (AUC) for the DI in association with 0 days AET > 6% was 0.629. A DI of < 2.8 mm2/mmHg had a sensitivity of 83.3%, and negative predictive value of 88% in classifying patients with 0 days abnormal acid exposure (p = 0.004). CONCLUSIONS: FLIP complements prolonged wireless pH-metry in distinguishing the subset of PPI-NRs with completely normal acid exposure and a higher burden of esophageal hypervigilance. Proper identification of patients along the functional heartburn spectrum can improve overall surgical outcomes.

The Upper Esophageal Sphincter Distensibility Index Measured Using Functional Lumen Imaging Probe Identifies Defective Barrier Function of the Upper Esophageal Sphincter.

Background/Aims: The mechanism via which supra-esophageal symptoms are generated is unclear. We assessed upper esophageal sphincter (UES) function in novel fashion using functional lumen imaging probe (FLIP) topography. We hypothesize that symptoms related to aspiration of esophageal contents may be associated with a more distensible UES. Methods: FLIP and reflux symptom index score data from patients undergoing diagnostic evaluation for an esophageal complaint over a 10-month period were analyzed retrospectively. UES distensibility on FLIP was studied at 40-70 mL volumes with in-depth analysis at 50 and 60 mL. Symptoms were compared between patients with low, middle, and high UES-distensibility index (UES-DI). Receiver-operating characteristic analysis was performed to determine associations between the UES-DI and individual reflux symptom index symptom item scores. Results: One hundred and eleven subjects were included. Overall, the associations between UES-DI and symptoms that could be related to supra-esophageal aspiration were strongest at the 50 mL FLIP volume. Choking item score was highest in the high UES-DI group (2.8) vs 1.4 (P < 0.001) in the middle UES-DI and 1.1 (P = 0.004) in the low UES-DI groups. Similarly, the cough item score was highest in the high UES-DI group (2.7) vs 1.5 (P = 0.009) and 0.9 (P = 0.002) groups. Conclusion: A higher UES-DI measures defective barrier function which could may be the main pathophysiology that generates supra-esophageal symptoms.

Safety and feasibility of same day discharge after per oral endoscopic pyloromyotomy in refractory gastroparesis: a pilot study.

BACKGROUND: Gastroparesis is a debilitating medical condition with limited treatment options. Gastric per-oral pyloromyotomy (G-POEM) has emerged as a promising treatment option with remarkable short-term clinical success shown in multiple studies. While the post-procedure protocol is not standardized across many centers, the majority of the centers observes these patients in the hospital after the procedure for monitoring. In this single-center prospective study, we evaluated the safety and feasibility of same day discharge after the G-POEM procedure. METHODS: All the patients with refractory gastroparesis undergoing G-POEM from October 2019 to March 2020 were enrolled. A total of 25 patients were enrolled in the procedure. Based on the pre-defined criteria, patients were either discharged on the same day after the procedure or admitted to the hospital for further observation. The patient and procedure-related data were extracted from the chart review. Univariate analysis was performed (chi-squared test) on categorical variables after organizing categorical variables as numeric counts or percentages. The student t test was performed on continuous variables after reporting as mean and standard deviation. For analysis with a smaller sample size, Fisher exact and Mann-Whitney tests were used. RESULTS: A total of 25 patients were enrolled. The technical success of G-POEM was 100% and clinical success was 80% (20/25) at 1-month follow-up. Of the 25 patients, 9 patients (36%) were discharged on the same day according to the procedure from the recovery unit. Of the remaining 16 patients who were admitted to the hospital post-procedure, 10 (40%) were admitted due to procedure-related causes while other admissions were either pre-planned or due to social reasons. The average Charlson comorbidity index was lower in the same day discharge group ( P   <  0.05). The number of patients requiring double myotomy was higher in the same day discharge group ( P  < 0.05). The overall complication rate of G-POEM in the study cohort was 12% (3/25) with all complications being mild without any severe adverse events. CONCLUSION: G-POEM is a safe and effective method of treatment for refractory GP with higher clinical success in short-term follow-up. The same day discharge after G-POEM is safe and feasible in >50% of patients with close periprocedural monitoring.

Quantification of Interstitial Cells of Cajal in the Gastric Muscle of Patients with Gastroparesis at Per-Oral Endoscopic Pyloromyotomy: A Novel Approach for Future Research in Pathogenesis of Gastroparesis.

BACKGROUND: The role of Interstitial Cells of Cajal (ICC) in the pathogenesis of gastroparesis has been suggested by previous studies due to their involvement in the transmission of neuronal signaling to the smooth muscles of the GI tract. However, studies have been limited by the inability to obtain a gastric muscle sample, since routine endoscopy can only biopsy the mucosa. We present a new technique of muscle biopsy during per-oral endoscopic pyloromyotomy (GPOEM), a novel endoscopic procedure for treatment of gastroparesis. PATIENTS AND METHODS: All enrolled patients had diagnosed gastroparesis and had biopsies of the muscular layer at the antrum/pylorus during POEM. All GPOEM procedures took place from August 2019 to December 2019. Various demographic, disease-related, and procedure-related data were collected from chart review. ICC in the biopsy specimen was examined and quantitated. RESULTS: Through this method, we readily expose the gastric muscle of 21 patients through dissection of a gastric submucosal tunnel during GPOEM and provide reliable muscle sample for ICC quantification. Average number of ICC were higher in clinical responders (88 ICC ± 63 vs. 39 ICC ± 24, p = 0.02), defined as those who experienced significant improvement in nausea and vomiting symptoms after GPOEM. CONCLUSIONS: This study provides a reliable novel biopsy method for safely biopsy gastric muscle for quantitating the number of gastric ICC in patients with gastroparesis. The number of ICC may be related to the outcome of GPOEM therapy. However, further studies with larger number of patients are needed to confirm the results.

Simultaneous Examination of Eosinophil Infiltration in Esophageal Mucosa and Muscle in Patients with Achalasia: Direct Biopsy of the Esophageal Muscle at Per-oral Endoscopic Myotomy.

BACKGROUND: The relationship between eosinophilic esophagitis (EoE) and achalasia is not completely understood. There have been reports of eosinophilic infiltration of all esophageal layers in patients with achalasia. However, a routine endoscopic biopsy of the muscular layer is usually not feasible. We evaluate the safety and efficacy of muscle layer biopsy during per-oral endoscopic myotomy (POEM) as well as the prevalence of eosinophilic infiltration of the esophageal mucosa and muscular layer in patients with achalasia. PATIENTS AND METHODS: All enrolled patients had diagnosed achalasia and had simultaneous biopsies of the muscular layer at the middle esophagus and distal esophageal sphincter as well as the mucosal layer of the proximal and distal esophagus during POEM. All POEM procedures took place from August 2018 to December 2018 or September 2019 to November 2019. Various demographic, disease-related, and procedure-related data were collected from chart review. Eosinophilic infiltration in the biopsy specimen was examined. KEY RESULTS: Twenty consecutive patients (65% female, age range: 21-84) with a pre-procedure Eckardt score of >6 were enrolled during the study period, with the duration of their achalasia ranging from 1 to 32 years. Eighteen patients had clinical symptomatic improvement after POEM, as defined by an Eckardt score <3. Endoscopic examination did not reveal any signs of eosinophilic esophagitis. Pathologic examination of biopsies revealed eosinophilic infiltration in three of 20 patients (15%) in the distal esophageal mucosa (all <15 eosinophils/HPF) and none in the proximal esophageal mucosa. There was no eosinophilic infiltration in the distal esophageal sphincter and the middle esophageal muscle. No complication was noted due to muscle biopsy. CONCLUSIONS AND INFERENCES: Submucosal tunneling during POEM provides a safe access for direct esophageal muscle biopsy. This is the first report of the simultaneous biopsy of the esophageal mucosa and muscle in patients with achalasia. Contrary to all previously published studies, the association of esophageal eosinophilic infiltration and achalasia was not observed in this small sample study. Based on our findings, immune or autoimmune reaction rather than direct eosinophilic infiltration in the muscle is more likely the cause of achalasia.

Long-term Outcome of Per-oral Endoscopic Myotomy Performed in the Endoscopy Unit With Trainees.

INTRODUCTION: Per-oral endoscopic myotomy (POEM) has been widely adopted for the treatment of achalasia as it provides a precise, tailored myotomy in a minimally invasive endoscopic procedure. Several short-term studies and a few long-term studies have confirmed that POEM is a safe and effective treatment for achalasia. However, the long-term outcome of POEM performed by trainees is unknown. MATERIALS AND METHODS: We conducted a retrospective study of all patients who underwent POEM for achalasia at our tertiary care center during December 2012 and January 2019. All procedures performed with trainees were included. The primary outcome was the clinical response to POEM, defined as an Eckardt score of <3 after POEM. Trainees were trained in performing mucosotomy and submucosal dissection, creating a submucosal tunnel, identifying gastroesophageal junction, and performing myotomy and closure of mucosal incision in a step-by-step fashion. Trainees' performance was evaluated by the mentor based on several key points in each step. RESULTS: A total of 153 consecutive patients with a median age of 57±18 years were analyzed in this study. Of the total patients, 69 (45%) were male. The median length of follow-up after POEM was 32 months (range: 7 to 77 mo). A clinically significant response to POEM was achieved in 95% of patients at year 1, 84% at year 2, 80% at year 3, 79% at year 4, 78% at year 5, and 78% at year 6 and above. All trainees obtained competence within 6 cases for each step and could perform the procedure alone after 20 supervised cases. CONCLUSIONS: Overall, 78% of patients maintained positive clinical response at 6 years following POEM procedure. The recurrence rate of symptoms following POEM was 22% at a 6-year follow-up. This long-term outcome of POEM performed with trainees was comparable to those without trainees in other studies. To our knowledge, this is the longest follow-up and the largest number of patients after the POEM procedure performed with trainees.

Gas Leak and Mucosal Injury During Endoscopic Esophageal Myotomy After Previous Myotomy: A Single-Center Experience.

PURPOSE: Peroral endoscopic myotomy (POEM) after prior myotomy (PM-POEM) can be technically challenging with possible increased adverse events. We aimed to assess gas leak and mucosal injury incidence during PM-POEM, compared to an index POEM (iPOEM), and post-procedure extubation time. PATIENTS AND METHODS: A retrospective study comparing PM-POEM to iPOEM from March 2016 to August 2018. RESULTS: There were 21 subjects in the PM-POEM and 56 subjects in the iPOEM. The PM-POEM group was younger (average age 44.33 vs 57.57 years, p=0.0082). Gas leak incidence did not differ between groups (28.6% in PM-POEM vs 14.3% in iPOEM, p=0.148). For cases with imaging available postoperatively, there was a trend towards higher incidence of gas leak in the PM-POEM, but it was not statistically significant (60% vs 42.1%, p=0.359). The post-procedure extubation time was not different between PM-POEM and iPOEM (11.38 vs 9.46 minutes, p=0.93), but it was longer when gas leak occurred (15.92 vs 8.67 minutes, p=0.027). The odds of mucosal injury were four-fold higher (OR, 4.31; 95% CI, 1.32-14.08), and more clips were used to close mucosal injuries (0.62 vs 0.14 clips, p=0.0053) in the PM-POEM group. More procedures were deemed difficult or challenging in the PM-POEM (33.3% vs 7.1%, p=0.007). The number of clips used to close the mucosotomy was not different between groups (4.05 vs 3.84 clips, p=0.498). Although the myotomy was shorter in PM-POEM, it was not statistically significant (6.38 vs 7.14 cm, p=0.074). However, the procedure was longer in PM-POEM (61.28 vs 45.39 minutes, p=0.0017). There was no intervention or ICU admission required pertinent to the procedure. CONCLUSION: Performing PM-POEM can be more difficult with more mucosal injuries. Gas leak was associated with a slightly longer post-procedure extubation time, but clinical relevance is unclear given incidence of gas leak was unknown at time of extubation.

Utilizing functional lumen imaging probe in directing treatment for post-fundoplication dysphagia.

BACKGROUND: Esophagogastric junction obstruction (EGJO) post-fundoplication (PF) is difficult to identify with currently available tests. We aimed to assess the diagnostic accuracy of EGJ opening on functional lumen imaging probe (FLIP) and dilation outcome in FLIP-detected EGJO in PF dysphagia. METHODS: We prospectively collected data on PF patients referred to Esophageal Clinic over 18 months. EGJO diagnosis was made by (a) endoscopist's description of a narrow EGJ/wrap area, (b) appearance of wrap obstruction or contrast/tablet retention on esophagram, or (c) EGJ-distensibility index (DI) < 2.8 mm2/mmHg on real-time FLIP. In patients with EGJO and dysphagia, EGJ dilation was performed to 20 mm, 30 mm, or 35 mm in a stepwise fashion. Outcome was assessed as % dysphagia improvement during phone call or on brief esophageal dysphagia questionnaire (BEDQ) score. RESULTS: Twenty-six patients were included, of whom 17 (65%) had a low EGJ-DI. No patients had a hiatal hernia greater than 3 cm. Dysphagia was the primary symptom in 17/26 (65%). In 85% (κ = 0.677) of cases, EGJ assessment (tight vs. open) was congruent between the combination of endoscopy (n = 26) and esophagram (n = 21) vs. EGJ-DI (n = 26) on FLIP. Follow-up data were available in 11 patients who had dilation based on a low EGJ-DI (4 with 20 mm balloon and 7 with ≥ 30 mm balloon). Overall, the mean % improvement in dysphagia was 60% (95% CI 37.7-82.3%, p = 0.0001). Nine out of 11 patients, including 6 out of 7 undergoing pneumatic dilation, had improvement ≥ 50% in dysphagia (mean % improvement 72.2%; 95% CI 56.1-88.4%, p = 0.0001). CONCLUSIONS AND INFERENCES: Functional lumen imaging probe is an accurate modality for evaluating for EGJ obstruction PF. FLIP may be used to select patients who may benefit from larger diameter dilation.

Delayed Tension Symptomatic Pneumoperitoneum After POEM Requiring Needle Decompression.

INTRODUCTION: Per-oral endoscopic myotomy (POEM) is an effective modality for the management of achalasia. Tension pneumoperitoneum is a significant complication that causes hemodynamic instability, generally within the periprocedural period. METHODS: Here, we report 2 cases of delayed tension pneumoperitoneum that was recognized and treated several hours after uncomplicated POEM. RESULTS: These cases illustrate the importance of continued vigilance for this complication outside of the immediate periprocedural period as well as the utility of computed tomography-guided aspiration in managing it. DISCUSSION: When discharging patients after POEM, caregivers should be aware of this rare complication and alert patients to return for immediate care when it happens.

Compromised responses to dietary methionine restriction in adipose tissue but not liver of ob/ob mice.

OBJECTIVE: Dietary methionine restriction (MR) reduces adiposity and hepatic lipids and increases overall insulin sensitivity in part by reducing lipogenic gene expression in liver, inducing browning of white adipose tissue (WAT), and enhancing the lipogenic and oxidative capacity of the remodeled WAT. METHODS: Ob/ob mice have compromised ß-adrenergic receptor expression in adipose tissue and were used to test whether MR could ameliorate obesity, insulin resistance, and disordered lipid metabolism. RESULTS: In contrast to responses in wild-type mice, MR failed to slow accumulation of adiposity, increase lipogenic and thermogenic gene expression in adipose tissue, reduce serum insulin, or increase serum adiponectin in ob/ob mice. However, MR produced comparable reductions in hepatic lipids and lipogenic gene expression in both genotypes. In addition, MR was fully effective in increasing insulin sensitivity in adiponectin(-/-) mice. CONCLUSIONS: These findings show that diet-induced changes in hepatic lipid metabolism are independent of weight loss and remodeling of WAT and are not required for insulin sensitization. In contrast, the failure of ob/ob mice to mount a normal thermogenic response to MR suggests that the compromised responsiveness of adipose tissue to SNS input is an important component of the inability of the diet to correct their obesity and insulin resistance.