AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity.

BACKGROUND & AIMS: Pharmacological management of obesity improves outcomes and decreases the risk of obesity-related complications. This American Gastroenterological Association guideline is intended to support practitioners in decisions about pharmacological interventions for overweight and obesity. METHODS: A multidisciplinary panel of content experts and guideline methodologists used the Grading of Recommendations Assessment, Development and Evaluation framework to prioritize clinical questions, identify patient-centered outcomes, and conduct an evidence synthesis of the following agents: semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate extended-release (ER), naltrexone-bupropion ER, orlistat, phentermine, diethylpropion, and Gelesis100 oral superabsorbent hydrogel. The guideline panel used the evidence-to-decision framework to develop recommendations for the pharmacological management of obesity and provided implementation considerations for clinical practice. RESULTS: The guideline panel made 9 recommendations. The panel strongly recommended the use of pharmacotherapy in addition to lifestyle intervention in adults with overweight and obesity (body mass index ≥30 kg/m2, or ≥27 kg/m2 with weight-related complications) who have an inadequate response to lifestyle interventions. The panel suggested the use of semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate ER, and naltrexone-bupropion ER (based on moderate certainty evidence), and phentermine and diethylpropion (based on low certainty evidence), for long-term management of overweight and obesity. The guideline panel suggested against the use of orlistat. The panel identified the use of Gelesis100 oral superabsorbent hydrogel as a knowledge gap. CONCLUSIONS: In adults with overweight and obesity who have an inadequate response to lifestyle interventions alone, long-term pharmacological therapy is recommended, with multiple effective and safe treatment options.

Patients With Esophageal Adenocarcinoma With Prior Gastroesophageal Reflux Disease Symptoms Are Similar to Those Without Gastroesophageal Reflux Disease: A Cross-Sectional Study.

INTRODUCTION: A substantial proportion of patients with esophageal adenocarcinoma (EAC) do not report gastroesophageal reflux disease (GERD) symptoms. This study aimed to compare the risk factor profiles and cancer stage at presentation of patients with EAC with and without prior GERD. METHODS: In this retrospective cross-sectional study, patients with EAC were divided into 2 cohorts: (i) EAC with prior GERD: patients who reported typical GERD symptoms (heartburn or regurgitation) ≥1 year before cancer diagnosis and (ii) EAC without prior GERD: patients who did not report prior GERD symptoms or reported symptoms within 1 year of their cancer diagnosis. Baseline demographics, risk factors, and cancer stage at presentation were compared between the 2 cohorts. In addition, the distribution of patients based on numbers of BE/EAC-associated risk factors (1, 2, 3, 4, and 5 or more) was examined in the symptomatic and asymptomatic cohorts. RESULTS: Over 13 years, 388 patients with EAC with prior GERD and 245 patients with EAC without prior GERD were recruited. Both groups had similar baseline demographics and risk factors, but patients with EAC with prior GERD were more likely to have a history of BE. Asymptomatic patients had more advanced disease. Patients with 3 or more BE/EAC-related risk factors formed the largest proportion of patients in both the symptomatic and asymptomatic cohorts. DISCUSSION: Patients with EAC with and without prior GERD symptoms are phenotypically similar, suggesting that BE screening efforts to prevent or detect early EAC should not be restricted to just those with GERD.

A survey of physician training and credentialing in endoscopic submucosal dissection in the United States.

BACKGROUND: Endoscopic submucosal dissection (ESD) is technically challenging, has a longer learning curve and a greater complication rate than most new endoscopic procedures. Formal training and credentialing guidelines for ESD are currently lacking in the United States (US). AIM: To survey ESD experts across the US to determine their learning process and obtain their opinion on how training and credentialing for ESD should develop. DESIGN: Anonymous electronic survey. SUBJECTS: ASGE members who are practicing US endoscopists. METHODS: The survey was developed by iterative revisions of questions administered to three investigators who have been performing ESD for > 5 years. The final survey was distributed electronically to US endoscopists who had previously attended ESD expert conferences. RESULTS: Thirty-five (58.3%) of 60 practicing ESD experts responded to the survey. A majority (91%) were in university-based, community, or tertiary care hospitals. All practitioners practiced on porcine explants and observed live ESD procedures as part of the training. Out of the participants, 75.8% received formal supervised hands-on training on porcine explants and/or humans before performing ESD independently. Fifty percent indicated that their facility had written guidelines specifically for ESD credentialing. Four out of 5 felt that credentialing requirements should include attending weekend ESD courses, observing live procedures, practicing on explants, and advanced endoscopic training in interventional endoscopy such as an additional year of fellowship. LIMITATIONS: Survey completion rate of 58.3%. CONCLUSION: ESD training should include practicing on explants, observation of live procedures, training in interventional endoscopy, and attending educational courses. Credentialing guidelines for ESD based on expert opinion need to be developed in the US.

The Effect of Endoscopic Surveillance in Patients With Barrett's Esophagus: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Guidelines recommend endoscopic surveillance of patients with Barrett's esophagus (BE) to identify those with dysplasia (a precursor of carcinoma) or early-stage esophageal adenocarcinoma (EAC) who can be treated endoscopically. However, it is unclear whether surveillance increases survival times of patients with BE. We performed a systematic review and meta-analysis to qualitatively and quantitatively examine evidence for the association of endoscopic surveillance in patients with BE with survival and other outcomes. METHODS: We searched publication databases for studies reporting the effects of endoscopic surveillance on mortality and other EAC-related outcomes. We reviewed randomized controlled trials, case-control studies, studies comparing patients with BE who received regular surveillance with those who did not receive regular surveillance, and studies comparing outcomes of patients with surveillance-detected EAC vs symptom-detected EACs. We performed a meta-analysis of surveillance studies to generate summary estimates using a random effects model. The primary aim was to examine the association of BE surveillance on EAC-related mortality. Secondary aims were to examine the association of BE surveillance with all-cause mortality and EAC stage at time of diagnosis. RESULTS: A single case-control study did not show any association between surveillance and EAC-related mortality. A meta-analysis of 4 cohort studies found that lower EAC-related and all-cause mortality were associated with regular surveillance (relative risk, 0.60; 95% CI, 0.50-0.71; hazard ratio, 0.75; 95% CI, 0.59-0.94). Meta-analysis of 12 cohort studies showed lower EAC-related and all-cause mortality among patients with surveillance-detected EAC vs symptom-detected EAC (relative risk, 0.73; 95% CI, 0.57-0.94; hazard ratio, 0.59; 95% CI, 0.45-0.76). Lead- and length-time bias adjustment substantially attenuated/eliminated the observed benefits. Surveillance was associated with detection of EAC at earlier stages. A randomized trial is underway to evaluate the effects of endoscopic surveillance on mortality in patients with BE. CONCLUSIONS: In a systematic review and meta-analysis of the effects of surveillance in patients with BE, surveillance as currently performed was associated with detection of earlier-stage EAC and may provide a small survival benefit. However, the effects of confounding biases on these estimates are not fully defined and may completely or partially explain the observed differences between surveyed and unsurveyed patients.

Association of Serum Levels of Adipokines and Insulin With Risk of Barrett's Esophagus: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Metabolically active visceral fat may be associated with esophageal inflammation, metaplasia, and neoplasia. We performed a meta-analysis to evaluate the association of serum adipokines and insulin with Barrett's esophagus (BE). METHODS: We performed a systematic search of multiple electronic databases, through April 2015, to identify all studies reporting associations between leptin, adiponectin, insulin, insulin resistance, and risk of BE in adults. Comparing the highest study-specific category with the reference category for each hormone, we estimated the summary adjusted odds ratio (aOR) and 95% confidence intervals (CI), using a random effects model. RESULTS: We identified 9 observational studies (10 independent cohorts; 1432 patients with BE total, and 3550 control subjects). Meta-analysis revealed that high serum level of leptin was associated with 2-fold higher risk of BE (BE cases vs population control subjects in 5 studies: aOR, 2.23; 95% CI, 1.31-3.78; I(2), 59%). Total serum level of adiponectin was not associated with BE (BE cases vs population control subjects in 5 studies: aOR, 0.79; 95% CI, 0.46-1.34; I(2), 65%), although 1 study observed decreased risk of BE with increased level of low-molecular-weight adiponectin. High serum level of insulin was associated with increased risk of BE (BE cases vs population control subjects in 3 studies: aOR, 1.74; 95% CI, 1.14-2.65; I(2), 0), whereas insulin resistance was not associated with increased risk of BE (BE cases vs gastroesophageal reflux disease control subjects in 2 studies: aOR, 0.98; 95% CI, 0.42-2.30; I(2), 64%). CONCLUSIONS: Increased serum levels of leptin and insulin are associated with increased risk of BE, compared with population control subjects. In contrast, increased total serum levels of adiponectin and insulin do not seem to modify BE risk. Well-designed longitudinal studies of incident BE are needed to clarify existing associations of serum adipokines and insulin with BE.

Sex differences in esophageal cancer overall and by histological subtype.

Esophageal cancer is the seventh most common type of cancer in the world, the sixth leading cause of cancer-related death and its incidence is expected to rise 140% in the world in a period of 10 years until 2025. The overall incidence is higher in males, while data about prognosis and survival are not well established yet. The goal of this study was to carry out a comprehensive analysis of differences between sexes and other covariates in patients diagnosed with primary esophageal cancer. Data from 2005 to 2020 were obtained from the University Hospitals (UH) Seidman Cancer Center and from 2005 to 2018 from SEER. Patients were categorized according to histological subtype and divided according to sex. Pearson Chi-square test was used to compare variables of interest by sex and the influence of sex on survival was assessed by Kaplan Meier, log rank tests and Cox proportional hazards regression models. A total of 1205 patients were used for analysis. Sex differences in all types were found for age at diagnosis, histology, smoking status and prescriptions of NSAIDs and in SCC for age at diagnosis and alcoholism. Survival analysis didn't showed differences between males and females on univariable and multivariable models. Males have a higher incidence of Esophageal Cancer and its two main subtypes but none of the comprehensive set of variables analyzed showed to be strongly or unique correlated with this sex difference in incidence nor are they associated with a sex difference in survival.

Identifying DNA methylation biomarkers for non-endoscopic detection of Barrett's esophagus.

We report a biomarker-based non-endoscopic method for detecting Barrett's esophagus (BE) based on detecting methylated DNAs retrieved via a swallowable balloon-based esophageal sampling device. BE is the precursor of, and a major recognized risk factor for, developing esophageal adenocarcinoma. Endoscopy, the current standard for BE detection, is not cost-effective for population screening. We performed genome-wide screening to ascertain regions targeted for recurrent aberrant cytosine methylation in BE, identifying high-frequency methylation within the CCNA1 locus. We tested CCNA1 DNA methylation as a BE biomarker in cytology brushings of the distal esophagus from 173 individuals with or without BE. CCNA1 DNA methylation demonstrated an area under the curve of 0.95 for discriminating BE-related metaplasia and neoplasia cases versus normal individuals, performing identically to methylation of VIM DNA, an established BE biomarker. When combined, the resulting two biomarker panel was 95% sensitive and 91% specific. These results were replicated in an independent validation cohort of 149 individuals who were assayed using the same cutoff values for test positivity established in the training population. To progress toward non-endoscopic esophageal screening, we engineered a well-tolerated, swallowable, encapsulated balloon device able to selectively sample the distal esophagus within 5 min. In balloon samples from 86 individuals, tests of CCNA1 plus VIM DNA methylation detected BE metaplasia with 90.3% sensitivity and 91.7% specificity. Combining the balloon sampling device with molecular assays of CCNA1 plus VIM DNA methylation enables an efficient, well-tolerated, sensitive, and specific method of screening at-risk populations for BE.

Diagnosis and treatment of irritable bowel syndrome with predominant constipation in the primary-care setting: focus on linaclotide.

Irritable bowel syndrome (IBS) is a complex functional gastrointestinal disorder that is exceedingly common in clinical practice. IBS with predominant constipation (IBS-C) is a subtype of IBS that accounts for more than a third of the IBS diagnosed. Diagnosis of IBS requires a careful personalized approach, a comprehensive clinical history, limited but relevant investigations, and continued follow-up. Major IBS societies and guidelines recommend offering a positive diagnosis of IBS based on presenting symptomatology. Abdominal pain that may or may not be relieved by defecation is the cardinal symptom of IBS; distension and bloating are other common symptoms. Careful attention should be paid to alarm symptoms before a diagnosis of IBS is made. Pharmacotherapy with linaclotide is recommended for moderate-severe IBS-C, based on high-quality evidence from randomized controlled trials. Diarrhea is the major side effect of linaclotide, and limited cost-effectiveness data currently exist.

Treatment Selection Choices Should Not Be Based on Benefits or Costs Alone: A Head-to-Head Randomized Controlled Trial of Antiviral Drugs for Hepatitis C.

BACKGROUND: Clinicians often face dilemmas with decisions related to formulary choices when two similar drugs are simultaneously available in the market. We studied the comparative safety, effectiveness, and treatment costs of the two first generation direct-acting antiviral agents (DAA), boceprevir and telaprevir as uncertainty existed regarding the drug of choice between these two seemingly equally Hepatitis-C treatment options. METHODS: We randomly assigned 50 patients in an open-label, pragmatic randomized controlled trial (RCT) at a VA Medical Center to either boceprevir or telaprevir in combination with peginterferon and ribavirin, stratified by the presence of cirrhosis and prior treatment experience. Tolerability was assessed at each visit and reasons for discontinuation of treatment and severity of adverse events due to PI treatment were adjudicated using a blinded adjudication committee. The primary outcome was difference in tolerability between boceprevir vs. telaprevir. Secondary outcomes included viral response rates and cost-per cure achieved. RESULTS: Higher rates of treatment discontinuations and/or severe DAA associated adverse events were seen in 10/25 (40%) patients randomized to telaprevir compared to 2/25 (8%) patients randomized to boceprevir (RR: 5; 95% CI: 1.2, 20; p<0.01). Cure rates did not appear to be significantly different between groups (telaprevir vs. boceprevir: RR 1.23; 95% CI: 0.76, 1.99; p = 0.39). On an intention-to-treat basis, total cost per cure was $44,329 for boceprevir vs. $57,115 for telaprevir. The significant side effect profile of telaprevir combined with the availability of highly efficacious second generation DAAs led to the early discontinuation of the trial. CONCLUSION: Telaprevir is associated with a significantly higher rate of severe adverse events leading to treatment discontinuations, hospitalizations or severe anemia and a substantially higher cost per SVR when compared to boceprevir. Real-time, point of care, pragmatic randomized controlled trials are necessary for guidance beyond just acquisition costs and to make evidence-based formulary selections when multiple effective treatments are available. (Clinicaltrials.gov registration: NCT02113631).

Role of Obesity in the Pathogenesis and Progression of Barrett's Esophagus.

Central obesity is involved in the pathogenesis and progression of Barrett's esophagus to esophageal adenocarcinoma. Involved are likely both mechanical and nonmechanical effects. Mechanical effects of increased abdominal fat cause disruption of the gastroesophageal reflux barrier leading to increased reflux events. Nonmechanical effects may be mediated by inflammation, via classically activated macrophages, pro-inflammatory cytokines, and adipokines such as Leptin, all of which likely potentiate reflux-mediated inflammation. Insulin resistance, associated with central obesity, is also associated with both Barrett's pathogenesis and progression to adenocarcinoma. Molecular pathways activated in obesity, inflammation and insulin resistance overlap with those involved in Barrett's pathogenesis and progression.