Can FLIP guide therapy in idiopathic esophagogastric junction outflow obstruction?

Background Esophagogastric junction outflow obstruction (EGJOO) has a variable disease course. Currently, barium swallow (BaS) and manometric parameters are used to characterize clinically significant EGJOO. The esophagogastric junction distensibility index (EGJ-DI) measured via functional lumen imaging probe (FLIP) can provide complementary information. Our aim was to assess symptom response in patients with EGJOO and an abnormal EGJ-DI after botulinum toxin (BT) treatment. Methods A prospective cohort study of adults with idiopathic EGJOO was performed from September 2019 to March 2021. Patients with dysphagia underwent upper endoscopy with FLIP. If the EGJ-DI was abnormally low, BT was injected. Data examined included demographics, medical history, endoscopic and FLIP findings, BaS, manometry, and Eckardt score (ES). ES improvement was assessed via paired samples t-test. Pearson’s chi-square tests were used to assess for associations. Results Of the 20 patients, 75% had an abnormal EGJ-DI and underwent BT injections. Mean ES for patients with abnormal EGJ-DIs significantly improved from baseline to 1, 3, and 6 month follow-up (P-values: 0.01, 0.05, and 0.02, respectively). There was a significant association between an abnormal EGJ-DI with delayed bolus transit and presence of rapid drink challenge panesophageal pressurization on manometry: P = 0.03 and P = 0.03. Conclusion This prospective study revealed that an abnormal EGJ-DI can guide BT as assessed via symptomatic response. Additionally, abnormal EGJ-DI measurements were significantly associated with other parameters used previously to determine clinically relevant EGJOO. Larger follow-up studies are warranted to further elucidate guidance for therapy in EGJOO.

Randomized, Single-Blind, Multicenter Phase II Study of Two Doses of Imetelstat in Relapsed or Refractory Myelofibrosis

PURPOSE Patients with myelofibrosis who are relapsed or refractory (R/R) to Janus-associated kinase inhibitors (JAKis) have poor clinical outcomes including dismal overall survival (OS) that ranges between 13 and 16 months. Imetelstat, a telomerase inhibitor, was evaluated in patients with intermediate-2 or high-risk myelofibrosis R/R to JAKi in a phase II multicenter study (ClinicalTrials.gov identifier: NCT02426086 ). PATIENTS AND METHODS Patients were randomly assigned to receive either imetelstat 9.4 mg/kg or 4.7 mg/kg intravenous once every 3 weeks. Spleen response (≥ 35% spleen volume reduction) and symptom response (≥ 50% reduction in total symptom score) rates at week 24 were coprimary end points. Secondary end points included OS and safety. RESULTS Study enrollment was closed early, and patients treated with 4.7 mg/kg were permitted to continue treatment with 9.4 mg/kg. At week 24, spleen and symptom response rates were 10.2% and 32.2% in the 9.4-mg/kg arm and 0% and 6.3% in the 4.7-mg/kg arm. Treatment with imetelstat 9.4 mg/kg led to a median OS of 29.9 months and bone marrow fibrosis improvement in 40.5% and variant allele frequency reduction of driver mutations in 42.1% of evaluable patients. Fibrosis improvement and variant allele frequency reduction correlated with OS. Target inhibition was demonstrated by reduction of telomerase activity and human telomerase reverse transcriptase level and correlated with spleen response, symptom response, and OS. Most common adverse events on both arms were grade 3 or 4 reversible cytopenias. CONCLUSION In this phase II study of two imetelstat doses, 9.4 mg/kg once every 3 weeks demonstrated clinical benefits in symptom response rate, with an acceptable safety profile for this poor-risk JAKi R/R population. Biomarker and bone marrow fibrosis assessments suggested selective effects on the malignant clone. A confirmatory phase III study is currently underway.

Comparing Efficacy and Safety of Empirical vs. Guided Therapy for Non-cardiac Chest Pain: A Pragmatic Randomized Trial

Background: Non-cardiac chest pain is common with two-thirds due to gastroesophageal reflux disease (GERD).Objective: To evaluate the effectiveness and safety of guided vs. empirical therapy in non-cardiac chest pain.Methods: Adults with normal angiogram or stress test were randomized into either a guided or empirical group. In the guided group, after the ambulatory pH-impedance test, if GERD then dexlansoprazole 30 mg/day for 8 weeks, but if functional or hypersensitive chest pain, then theophylline SR 250 mg/day for 4 weeks. In the empirical group, dexlansoprazole 60 mg/day was given for 2 weeks. The primary outcome was global chest pain visual analog score (VAS) and secondary outcomes were Quality of Life in Reflux and Dyspepsia (QOLRAD), GERD questionnaire (GERDQ), and pH parameters, all determined at baseline, 2nd and 8th weeks.Results: Of 200 screened patients, 132 were excluded, and of 68 randomized per-protocol, 33 were in the guided group and 35 in the empirical group. For between-group analysis, mean global pain scores were better with guided vs. empirical group at 8th week (P = 0.005) but not GERDQ or QOLRAD or any of pH measures (all P > 0.05). For within-group analysis, mean QOLRAD improved earliest at 8th week vs. baseline (P = 0.006) in the guided group and 2nd week vs. baseline (P = 0.011) in the empirical group but no differences were seen in other secondary outcomes (P > 0.05). No serious adverse events were reported.Conclusions: Guided approach may be preferred over short-term empirical therapy in symptom response, however QOLRAD, acid-related symptoms, or pH measures are not significantly different (trial registration ID no. NCT03319121).

Transoral incisionless fundoplication demonstrates durability at up to 9 years

Goals: To assess the long-term results of transoral incisionless fundoplication (TIF 2). Background: TIF with the EsophyX2 is an accepted procedure to treat gastroesophageal reflux disease (GERD). Long-term data have been limited. We report clinical outcomes of 151 patients followed up to 9 years. Study: A single institution prospective registry of patients undergoing TIF 2 between 11/2008 and 7/2015. Outcomes were assessed by complications, re-interventions, and a mixed effect model of clinical response over time. Results: A total of 151 patients (87 women), mean age 62 years (30–91), mean body mass index (BMI) 26.6 (20–36.1), 93% on daily proton pump inhibitor (PPI), underwent TIF 2 without hiatal hernia repair; 131 of the 151 patients (86%) were available for follow-up at a median of 4.92 years (0.7–9.7 years). Of 120 patients ⩾5 years post-TIF, 62 (51%) were followed for a median 6.8 years. Median GERD-health-related quality of life (HRQL) scores decreased from 21 (interquartile range (IQR) 9.5–30) off PPI and 14 (4–24) on PPI at baseline to 4 (2–8) at 4.92 years and remained at 5 (2–9) in the 62 patients 5–9 years post-TIF. Sixty-four per cent had successful (>50%) reductions in GERD-HRQL scores at 4.92 years and 68% of patients followed ⩾5 years. Median regurgitation decreased from 15 (8–20) off PPI and 11 (5–20) on PPI at baseline to 0 (0–4) at 4.92 years, remaining at 1 (0–3) in 62 patients 5–9 years post-TIF. Mixed model analyses confirmed significant and stable improvements in GERD-HRQL and regurgitation scores at all annual follow-up time points after TIF. Daily PPI use decreased from 93% to 32% at 4.92, and 22% at ⩾5 years post-TIF. Revision to laparoscopic fundoplication in 33(22%) showed comparable outcomes. Two patients recovered uneventfully after laparoscopic surgery for localized perforation. Conclusions: TIF 2 provides durable relief of GERD symptoms at up to 9 years with 69–80% of patients having a successful outcome by symptom response and PPI use.