Interrater Reliability of Functional Lumen Imaging Probe Panometry and High-Resolution Manometry for the Assessment of Esophageal Motility Disorders.

INTRODUCTION: High-resolution manometry (HRM) and functional lumen imaging probe (FLIP) are primary and/or complementary diagnostic tools for the evaluation of esophageal motility. We aimed to assess the interrater agreement and accuracy of HRM and FLIP interpretations. METHODS: Esophageal motility specialists from multiple institutions completed the interpretation of 40 consecutive HRM and 40 FLIP studies. Interrater agreement was assessed using intraclass correlation coefficient (ICC) for continuous variables and Fleiss' κ statistics for nominal variables. Accuracies of rater interpretation were assessed using the consensus of 3 experienced raters as the reference standard. RESULTS: Fifteen raters completed the HRM and FLIP studies. An excellent interrater agreement was seen in supine median integral relaxation pressure (ICC 0.96, 95% confidence interval 0.95-0.98), and a good agreement was seen with the assessment of esophagogastric junction (EGJ) outflow, peristalsis, and assignment of a Chicago Classification version 4.0 diagnosis using HRM (κ = 0.71, 0.75, and 0.70, respectively). An excellent interrater agreement for EGJ distensibility index and maximum diameter (0.91 [0.90-0.94], 0.92 [0.89-0.95]) was seen, and a moderate-to-good agreement was seen in the assignment of EGJ opening classification, contractile response pattern, and motility classification (κ = 0.68, 0.56, and 0.59, respectively) on FLIP. Rater accuracy for Chicago Classification version 4.0 diagnosis on HRM was 82% (95% confidence interval 78%-84%) and for motility diagnosis on FLIP Panometry was 78% (95% confidence interval 72%-81%). DISCUSSION: Our study demonstrates high levels of interrater agreement and accuracy in the interpretation of HRM and FLIP metrics and moderate-to-high levels for motility classification in FLIP, supporting the use of these approaches for primary or complementary evaluation of esophageal motility disorders.

AGA Clinical Practice Update on the Diagnosis and Management of Extraesophageal Gastroesophageal Reflux Disease: Expert Review.

DESCRIPTION: The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update is to review the available evidence and expert advice regarding the clinical management of patients with suspected extraesophageal gastroesophageal reflux disease. METHODS: This article provides practical advice based on the available published evidence including that identified from recently published reviews from leading investigators in the field, prospective and population studies, clinical trials, and recent clinical guidelines and technical reviews. This best practice document is not based on a formal systematic review. The best practice advice as presented in this document applies to patients with symptoms or conditions suspected to be related to extraesophageal reflux (EER). This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the CPUC and external peer review through standard procedures of Clinical Gastroenterology and Hepatology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. BEST PRACTICE ADVICE 1: Gastroenterologists should be aware of potential extraesophageal manifestations of gastroesophageal reflux disease (GERD) and should inquire about such disorders including laryngitis, chronic cough, asthma, and dental erosions in GERD patients to determine whether GERD may be a contributing factor to these conditions. BEST PRACTICE ADVICE 2: Development of a multidisciplinary approach to extraesophageal (EER) manifestations is an important consideration because the conditions are often multifactorial, requiring input from non-gastroenterology (GI) specialties. Results from diagnostic testing (ie, bronchoscopy, thoracic imaging, laryngoscopy, etc) from non-GI disciplines should be taken into consideration when gastroesophageal reflux (GER) is considered as a cause for extraesophageal symptoms. BEST PRACTICE ADVICE 3: Currently, there is no single diagnostic tool that can conclusively identify GER as the cause of EER symptoms. Determination of the contribution of GER to EER symptoms should be based on the global clinical impression derived from patients' symptoms, response to GER therapy, and results of endoscopy and reflux testing. BEST PRACTICE ADVICE 4: Consideration should be given toward diagnostic testing for reflux before initiation of proton pump inhibitor (PPI) therapy in patients with potential extraesophageal manifestations of GERD, but without typical GERD symptoms. Initial single-dose PPI trial, titrating up to twice daily in those with typical GERD symptoms, is reasonable. BEST PRACTICE ADVICE 5: Symptom improvement of EER manifestations while on PPI therapy may result from mechanisms of action other than acid suppression and should not be regarded as confirmation for GERD. BEST PRACTICE ADVICE 6: In patients with suspected extraesophageal manifestation of GERD who have failed one trial (up to 12 weeks) of PPI therapy, one should consider objective testing for pathologic GER, because additional trials of different PPIs are low yield. BEST PRACTICE ADVICE 7: Initial testing to evaluate for reflux should be tailored to patients' clinical presentation and can include upper endoscopy and ambulatory reflux monitoring studies of acid suppressive therapy. BEST PRACTICE ADVICE 8: Testing can be considered for those with an established objective diagnosis of GERD who do not respond to high doses of acid suppression. Testing can include pH-impedance monitoring while on acid suppression to evaluate the role of ongoing acid or non-acid reflux. BEST PRACTICE ADVICE 9: Alternative treatment methods to acid suppressive therapy (eg, lifestyle modifications, alginate-containing antacids, external upper esophageal sphincter compression device, cognitive-behavioral therapy, neuromodulators) may serve a role in management of EER symptoms. BEST PRACTICE ADVICE 10: Shared decision-making should be performed before referral for anti-reflux surgery for EER when the patient has clear, objectively defined evidence of GERD. However, a lack of response to PPI therapy predicts lack of response to anti-reflux surgery and should be incorporated into the decision process.

Variability in endoscopic assessment of Nissen fundoplication wrap integrity and hiatus herniation.

BACKGROUND: Upper endoscopy (EGD) is frequently performed in patients with esophageal complaints following anti-reflux surgery such as fundoplication. Endoscopic evaluation of fundoplication wrap integrity can be challenging. Our primary aim in this pilot study was to evaluate the accuracy and confidence of assessing Nissen fundoplication integrity and hiatus herniation among gastroenterology (GI) fellows, subspecialists, and foregut surgeons. METHODS: Five variations of post-Nissen fundoplication anatomy were included in a survey of 20 sets of EGD images that was completed by GI fellows, general GI attendings, esophagologists, and foregut surgeons. Accuracy, diagnostic confidence, and inter-rater agreement across providers were evaluated. RESULTS: There were 31 respondents in the final cohort. Confidence in pre-survey diagnostics significantly differed by provider type (mean confidence out of 5 was 1.8 for GI fellows, 2.7 for general GI attendings, 3.6 for esophagologists, and 3.6 for foregut surgeons, P = 0.01). The mean overall accuracy was 45.9%, which significantly differed by provider type with the lowest rate among GI fellows (37%) and highest among esophagologists (53%; P = 0.01). The accuracy was highest among esophagologists across all wrap integrity variations. Inter-rater agreement was low across wrap integrity variations (Krippendorf's alpha <0.30), indicating low to no agreement between providers. CONCLUSION: In this multi-center survey study, GI fellows had the lowest accuracy and confidence in assessing EGD images after Nissen fundoplication, whereas esophagologists had the highest. Diagnostic confidence varied considerably and inter-rater agreement was poor. These findings suggest experience may improve confidence, but highlight the need to improve the evaluation of fundoplication wraps.

Phenotyping patients with borderline elevated esophageal acid exposure.

Acid exposure time (AET) <4% on ambulatory reflux monitoring definitively rules out pathologic gastroesophageal acid reflux, while AET >6% indicates pathologic reflux per the Lyon Consensus, leaving AET of 4-6% as borderline. We aimed to elucidate the borderline AET population and identify metrics that could help differentiate this group. A total of 50 subjects in each group, AET <4, 4-6, and >6% on pH-impedance monitoring between 2015 and 2019, were retrospectively reviewed. In addition to demographic and clinical information, the extracted data included mean nocturnal baseline impedance (MNBI) on reflux study and high-resolution manometry (HRM) parameters and diagnosis. After excluding patients with prior foregut surgery, major esophageal motility disorder, or unreliable impedance testing, a total of 89 subjects were included in the analysis (25 with normal AET < 4%, 38 with borderline 4-6%, 26 with abnormal >6%). MNBI in borderline AET patients was significantly lower compared to normal AET (1607.7 vs. 2524.0 ohms, P < 0.01), and higher than abnormal AET (951.5 ohms, P < 0.01). Borderline subjects had a greater frequency of ineffective esophageal motility (IEM) diagnosis per Chicago classification v3.0 (42.1 vs. 8.0%, P = 0.01), but did not demonstrate any differences compared to abnormal subjects (34.6%, P = 0.56). Patients with borderline AET had an average MNBI that was in between normal AET and abnormal AET. Borderline AET patients also commonly demonstrate IEM on HRM, similar to those with abnormal AET. Our findings can be potentially useful in assigning higher clinical significance for patients found to have borderline AET with concomitant low MNBI and IEM on manometry.

Chicago Classification Update (v4.0): Technical review on diagnostic criteria for hypercontractile esophagus.

Hypercontractile esophagus (HE), defined by the Chicago Classification version 3.0 (CCv3.0) as 20% or more hypercontractile peristalsis (Distal Contractile Integral >8000 mmHg·s·cm) on high-resolution manometry (HRM), is a heterogeneous disorder with variable clinical presentations and natural course, leading to management challenges. An update on the diagnostic criteria for clinically relevant HE was needed. Literature on HE was extensively reviewed by the HE subgroup of the Chicago Classification version 4.0 (CCv4.0) Working Group and statements relating to the diagnosis of HE were ranked according to the RAND UCLA Appropriateness methodology by the Working Group, and the quality of evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. An overall emphasis of the CCv4.0 is on clinically relevant esophageal dysmotility, and thus it is recommended that an HE diagnosis requires both conclusive manometric diagnosis and clinically relevant symptoms of dysphagia and non-cardiac chest pain. The Working Group also recognized the subtypes of HE, including single-peaked, multi-peaked contractions (Jackhammer esophagus), and hypercontractile lower esophageal sphincter. However, there are no compelling data currently for formally subdividing HE to these subgroups in clinical practice.

Esophageal motility disorders on high-resolution manometry: Chicago classification version 4.0©.

Chicago Classification v4.0 (CCv4.0) is the updated classification scheme for esophageal motility disorders using metrics from high-resolution manometry (HRM). Fifty-two diverse international experts separated into seven working subgroups utilized formal validated methodologies over two-years to develop CCv4.0. Key updates in CCv.4.0 consist of a more rigorous and expansive HRM protocol that incorporates supine and upright test positions as well as provocative testing, a refined definition of esophagogastric junction (EGJ) outflow obstruction (EGJOO), more stringent diagnostic criteria for ineffective esophageal motility and description of baseline EGJ metrics. Further, the CCv4.0 sought to define motility disorder diagnoses as conclusive and inconclusive based on associated symptoms, and findings on provocative testing as well as supportive testing with barium esophagram with tablet and/or functional lumen imaging probe. These changes attempt to minimize ambiguity in prior iterations of Chicago Classification and provide more standardized and rigorous criteria for patterns of disorders of peristalsis and obstruction at the EGJ.

Provider Variability in the Management Patterns of Increased Nonacid Reflux.

INTRODUCTION: Increased nonacid reflux is diagnosed in a subgroup of patients with gastroesophageal reflux disease who often present with reflux symptoms refractory to proton-pump inhibitor therapy. Despite the prevalence of this condition, the management approach for patients with increased nonacid reflux can often be varied and unclear. AIMS: Our primary aim was to investigate physician management patterns for patients who had received a diagnosis of increased nonacid reflux on impedance-pH studies. METHODS: Reflux studies in patients with increased nonacid reflux per Lyon Consensus criteria and management approaches were retrospectively reviewed. Reflux symptom survey, manometry findings, reflux symptom association (RSA) on reflux testing, immediate posttesting management information, and managing provider information were assessed. RESULTS: A total of 43 subjects in total were analyzed. Management plan after a diagnosis of increased nonacid reflux was decided by a gastroenterologist in over 95% of cases and varied greatly with no changes being the most common. Even among subjects with + RSA on reflux monitoring, no change in management was the most common action, although this occurred much less frequently compared to subjects with - RSA (28.6% vs. 78.6%, p < 0.01). When change in therapy occurred, medical treatment with baclofen was the most common choice (21.4%). Other management changes included medications for visceral hypersensitivity and antireflux surgery, although these changes occurred rarely. CONCLUSIONS: Abnormally increased nonacid reflux is frequently encountered on impedance-pH studies; however, management decisions vary significantly among gastroenterologists. When treatment change is implemented, they are variable and can include lifestyle modifications, medication trials, or antireflux surgery. Future development of standardized management algorithms for increased nonacid reflux is needed.

Clinical impact of routine esophagram after peroral endoscopic myotomy.

BACKGROUND AND AIMS: It is unclear whether the common practice of postoperative day (POD) 1 esophagram impacts clinical care or reliably identifies significant adverse events (AEs) related to peroral endoscopic myotomy (POEM). Therefore, we aimed to correlate the most clinically relevant esophagram findings with postoperative outcomes after POEM. METHODS: Patients were retrospectively reviewed and included if they underwent POEM at 1 of the 3 study institutions between 2014 and 2018. Patient outcomes were assessed in relation to relevant POD 1 esophagram findings such as esophageal dissection or leak. RESULTS: One hundred seventy post-POEM contrast esophagrams (139 fluoroscopy-based vs 31 CT-based) performed on POD 1 were included. Most esophagrams (n = 98) contained abnormal findings but only 5 showed esophageal leak or dissection. Confirmed postoperative AEs of leak or dissection occurred in 4 patients. In 2 patients, POD 1 esophagram appropriately identified the leak or dissection, but in the other 2 patients the initial esophagram was negative, and the AEs were not recognized before clinical deterioration. One patient had a false-positive leak and dissection noted on esophagram leading to an unremarkable endoscopy. CONCLUSIONS: Despite the low AE rate after POEM, follow-up esophagram on POD 1 frequently shows expected, unremarkable postprocedural findings and occasionally fails to diagnose serious AEs. This results in pitfalls in accuracy regarding agreement between esophagram versus clinical and endoscopic findings. Relying exclusively on esophagram for post-POEM clinical decision-making can lead to unnecessary additional testing or missed AEs.

Per-oral Endoscopic Myotomy Biopsies of Achalasia Patients Reveal Schwann Cell Depletion in the Muscularis Propria.

Achalasia is a neurodegenerative condition resulting in abnormal lower esophageal sphincter relaxation and impaired upstream esophageal body peristalsis.1 The pathophysiology and natural history of achalasia remain unclear, and evaluation of the histopathogenesis of achalasia has traditionally been challenging because the esophageal wall muscularis propria is not typically accessible via routine endoscopic biopsies.

Management of Eosinophilic Esophagitis: Dietary and Nondietary Approaches.

Eosinophilic esophagitis (EoE) is an allergen-driven chronic inflammatory condition, characterized by symptoms related to esophageal dysfunction and confirmed histologically by esophageal mucosal eosinophilia. Since its first description in the 1990s, the incidence and prevalence of EoE have been on the rise. It is known to affect all ages of various ethnic backgrounds and both sexes; however, it is most seen in White males. Children with EoE often present with abdominal pain, nausea, vomiting, and failure to thrive, whereas adults with EoE typically present with dysphagia and food impaction. Diagnosis of EoE requires histologic confirmation of elevated esophageal eosinophils in a symptomatic patient, and only after secondary causes have been excluded. Because EoE is a chronic and progressively fibrostenotic disease, treatment goals include resolution of symptoms, induction and maintenance of disease remission, and prevention and possibly reversal of fibrostenotic complications, while minimizing treatment-related adverse effects and improving quality of life. Treatment strategies include the "3 D's"-drugs, diet, and dilation. Standard drug therapies include proton-pump inhibitors and topical corticosteroids. Dietary therapies include elemental diet, allergy testing-directed elimination diet, and empiric elimination diets. Endoscopic esophageal dilation for EoE strictures can alleviate esophageal symptoms but has no effect on mucosal inflammation. Recent progress in EoE research has made possible evidence-based clinical guidelines. Ongoing pharmacologic trials show promise for novel biologic agents in the treatment of refractory EoE.

ACG Clinical Guidelines: Clinical Use of Esophageal Physiologic Testing.

Esophageal symptoms are common and may indicate the presence of gastroesophageal reflux disease (GERD), structural processes, motor dysfunction, behavioral conditions, or functional disorders. Esophageal physiologic tests are often performed when initial endoscopic evaluation is unrevealing, especially when symptoms persist despite empiric management. Commonly used esophageal physiologic tests include esophageal manometry, ambulatory reflux monitoring, and barium esophagram. Functional lumen imaging probe (FLIP) has recently been approved for the evaluation of esophageal pressure and dimensions using volumetric distension of a catheter-mounted balloon and as an adjunctive test for the evaluation of symptoms suggestive of motor dysfunction. Targeted utilization of esophageal physiologic tests can lead to definitive diagnosis of esophageal disorders but can also help rule out organic disorders while making a diagnosis of functional esophageal disorders. Esophageal physiologic tests can evaluate obstructive symptoms (dysphagia and regurgitation), typical and atypical GERD symptoms, and behavioral symptoms (belching and rumination). Certain parameters from esophageal physiologic tests can help guide the management of GERD and predict outcomes. In this ACG clinical guideline, we used the Grading of Recommendations Assessment, Development and Evaluation process to describe performance characteristics and clinical value of esophageal physiologic tests and provide recommendations for their utilization in routine clinical practice.

Functional Lumen Imaging Probe Is Useful for the Quantification of Gastric Sleeve Stenosis and Prediction of Response to Endoscopic Dilation: a Pilot Study.

BACKGROUND: Stenosis after sleeve gastrectomy (SG) is common though diagnostic criteria and predictors of treatment response is unknown. Endoluminal functional impedance planimetry (EndoFLIP) is a diagnostic tool for measuring lumen geometry. We aimed to use EndoFLIP to characterize SG stenosis. METHODS: We enrolled SG stenosis patients undergoing serial pneumatic dilations between May 2018 and November 2018. Outcomes of interest included pre- and post-dilation EndoFLIP measurements and post-dilation symptom response. RESULTS: We included 10 patients who underwent a mean of 1.8 ± 0.7 dilations. Pre-dilation EndoFLIP characteristics were similar for responders and non-responders. Responders had larger mean post-dilation diameter (19.9 ± 2.9 mm vs 13.1 ± 1.3 mm, p = 0.007) and DI (21.3 ± 1.0 mm2/Hg vs 4.0 ± 5.4 mm2/Hg, p = 0.04) than non-responders. CONCLUSION: Our pilot study supports the use of EndoFLIP in the management of SG stenosis.

Expression Concordance of 325 Novel RNA Biomarkers between Data Generated by NanoString nCounter and Affymetrix GeneChip.

BACKGROUND: With the development of new drug combinations and targeted treatments for multiple types of cancer, the ability to stratify categories of patient populations and to develop companion diagnostics has become increasingly important. A panel of 325 RNA biomarkers was selected based on cancer-related biological processes of healthy cells and gene expression changes over time during nonmalignant epithelial cell organization. This "cancer in reverse" approach resulted in a panel of biomarkers relevant for at least 7 cancer types, providing gene expression profiles representing key cellular signaling pathways beyond mutations in "driver genes." Objective. To further investigate this biomarker panel, the objective of the current study is to (1) validate the assay reproducibility for the 325 RNA biomarkers and (2) compare gene expression profiles side by side using two technology platforms. METHODS AND RESULTS: We have mapped the 325 RNA transcripts and in a custom NanoString nCounter expression panel to be compared to all potential probe sets in the Affymetrix Human Genome U133 Plus 2.0. The experiments were conducted with 10 unique biological formalin-fixed paraffin-embedded (FFPE) breast tumor samples. Each site extracted RNA from four sections of 10-micron thick FFPE tissue over three different days by two different operators using an optimized standard operating procedure and quality control criteria. Samples were analyzed using mas5 in BioConductor and NanoStringNorm in R. Pearson correlation showed reproducibility between sites for all 60 samples with r = 0.995 for Affymetrix and r = 0.999 for NanoString. Correlation in multiple days and multiple users was for Affymetrix r = (0.962 - 0.999) and for NanoString r = (0.982 - 0.991). CONCLUSION: The 325 RNA biomarkers showed reproducibility in two technology platforms with moderate to high concordance. Future directions include performing clinical validation studies and generating rationale for patient selection in clinical trials using the technically validated assay.

High-Resolution Manometry Diagnosis of Ineffective Esophageal Motility Is Associated with Higher Reflux Burden.

INTRODUCTION: Ineffective esophageal motility (IEM) is the most commonly diagnosed abnormality on high-resolution manometry (HRM). However, the clinical significance of IEM and associated reflux burden remains unclear. AIM: Our primary aim was to compare reflux patterns between IEM versus normal motility on HRM. METHODS: HRM and reflux studies in patients with IEM and normal motility were retrospectively reviewed. Esophageal pressure topography parameters, reflux variables, and patient-reported outcome questionnaires were explored. RESULTS: A total of 239 patients with IEM were explored. Of these, 146 underwent reflux monitoring. Additionally, 100 patients with normal HRM all of whom had undergone reflux monitoring were included. IEM patients were more likely to have an abnormal number of reflux events compared to normal (22.7% vs. 9.0%, p < 0.01). Including only off-proton pump inhibitor (PPI) testing, IEM patients had higher mean total acid exposure time (AET) and total reflux events compared to normal motility (p = 0.02). Within IEM patients, higher AET modestly correlated with increased percentage of impaired swallows. Increased reflux events modestly correlated with higher impaired swallows and decreased lower esophageal sphincter (LES) resting pressure. Reflux burden increased with higher esophagogastric junction (EGJ) subtype, driven mostly by subtype III, although there was no difference in the distribution of EGJ subtypes between the IEM and normal HRM cohorts. CONCLUSIONS: Patients with HRM diagnosis of IEM may be more prone to acid reflux while off-PPI and non-acid reflux while on-PPI. Reflux burden appears to be worse in IEM patients who have lower resting LES pressure, higher EGJ subtype, or higher percentage of impaired swallows.

Management of eosinophilic esophagitis is often discordant with guidelines and not patient-centered: results of a survey of gastroenterologists.

Published guidelines for the management of eosinophilic esophagitis (EoE) recommend an initial trial of proton pump inhibitors (PPI), histologic assessment for response to therapy, and tailoring treatments to patient needs and provider resources. Effectiveness studies directly comparing therapies are lacking, leaving a situation ripe for shared decision making. We aimed to assess gastroenterologists' adherence to guidelines and how they respond to EoE patients' preferences regarding management. We administered a web-based survey to practicing US gastroenterologists, assessing knowledge, and practice patterns in the management of EoE, including comfort with alternative treatments to steroids. Ninety-two providers responded, including 55% in private practice. Nearly half (47%) reported spending ≤10 minutes on initial education and counseling and 48% recommended PPI monotherapy prior to other strategies. Of those who did not start with PPI monotherapy, 55% chose topical steroids ± PPI and 26% dietary elimination ± PPI. Despite this, 90% felt comfortable allowing a patient to start dietary elimination instead of steroids, but less comfortable with dilation alone (39%) or no treatment (30%). Upon symptomatic resolution, 72% of academic providers recommended endoscopy with biopsies to demonstrate histologic response to treatment, compared to 27% in private practice. There are substantial variations in adherence to guidelines regarding PPI use and assessing response to therapy. Gastroenterologists prefer topical steroids over other treatment modalities and most spend little time educating and counseling, which may limit informed decision making. Strategies aimed at decreasing these variations in management and promoting shared decision making in EoE are needed.

Cytidine monophosphate N-acetylneuraminic acid synthetase enhances invasion of human triple-negative breast cancer cells.

BACKGROUND: Cancer cells have altered bioenergetics, which contributes to their ability to proliferate, survive in unusual microenvironments, and invade other tissues. Changes in glucose metabolism can have pleomorphic effects on tumor cells. METHODS: To investigate potential mechanisms responsible for the increased malignancy associated with altered glucose metabolism, we used an unbiased nuclear magnetic resonance spectroscopy screening method to identify glucose metabolites differentially produced in a highly malignant human triple-negative breast cancer (TNBC) cell line (BPLER) and a less malignant isogenic TNBC cell line (HMLER). RESULTS: N-acetylneuraminic acid (Neu5Ac), the predominant sialic acid derivative in mammalian cells, which forms the terminal sugar on mucinous cell surface glycoproteins, was the major glucose metabolite that differed. Neu5Ac was ~7-fold more abundant in BPLER than HMLER. Loss of Neu5Ac by enzymatic removal or siRNA knockdown of cytidine monophosphate N-acetylneuraminic acid synthetase (CMAS), which activates cellular sialic acids for glycoprotein conjugation, had no significant effect on cell proliferation, but decreased the ability of BPLER to invade through a basement membrane. Conversely, overexpressing CMAS in HMLER increased invasivity. TNBCs in The Cancer Genome Atlas also had significantly more CMAS copy number variations and higher mRNA expression than non-TNBC, which have a better prognosis. CMAS knockdown in BPLER ex vivo blocked xenograft formation in mice. CONCLUSION: Neu5Ac is selectively highly enriched in aggressive TNBC, and CMAS, the enzyme required for sialylation, may play an important role in TNBC tumor formation and invasivity.

The Proton Pump Inhibitor Nonresponder: a Behavioral Approach to Improvement and Wellness.

PURPOSE OF REVIEW: Gastroesophageal reflux disease (GERD) is a difficult to treat medical condition, where nearly 40% of patients are refractory to standard medical intervention, which typically begins with a proton pump inhibitor (PPI). These PPI nonresponders represent a population of patients, where treatment planning must be individualized; multidisciplinary and psychiatric comorbidities should be considered. This review highlights treatment options that include neuromodulators, lifestyle, and psychological interventions for the PPI nonresponder. RECENT FINDINGS: Mental health specialists in the field of psychogastroenterology can aid in the management of esophageal hypersensitivity, which can drive the symptom experience of a PPI nonresponder. Considerations for comorbid anxiety and depression in this population require careful assessment and treatment. Physicians are encouraged to create realistic expectations for symptom management and offer multidisciplinary options for treatment early in care. Patients will frequently benefit from working with a GI psychologist and find value in behavioral interventions.

Eosinophilic esophagitis: update on management and controversies.

Eosinophilic esophagitis is a chronic allergen driven immune mediated disease that is increasingly recognized as a leading cause of dysphagia and foregut symptoms in children and adults. Much knowledge has been gained in recent years on the genetic and environmental risk factors for this disease, the associated inflammatory milieu, and the long term complications from esophageal remodeling. In this review we will highlight recent progress made in research into this disease, focusing on adults. We will discuss ongoing efforts to develop a minimally invasive technique that may obviate the need for repeated endoscopic assessment of disease activity. Moreover, we will review studies using novel tools such as mucosal impedance and functional lumen imaging as potential surrogate markers for mucosal integrity and esophageal remodeling. With regard to the treatment of eosinophilic inflammation, we will discuss the controversies surrounding responsiveness to proton pump inhibitors in some patients. Therapeutic trials continue to support the use of topical glucocorticoids and empiric food elimination diets as first line treatments. We will discuss ongoing efforts to optimize the elimination diet protocol to decrease the level and duration of food restrictions. Looking ahead, our growing knowledge on the pathogenesis of eosinophilic esophagitis has enabled further advancement of promising targeted biologic therapies.

Esophagogastric junction distensibility assessed using the functional lumen imaging probe.

AIM: To assess reference values in the literature for esophageal distensibility and cross-sectional area in healthy and diseased subjects measured by the functional lumen imaging probe (FLIP). METHODS: Systematic search and review of articles in Medline and Embase pertaining to the use of FLIP in the esophagus was conducted in accordance with the PRISMA guidelines. Cross-sectional area and distensibility at the esophagogastric junction (EGJ) were abstracted for normal subjects, achalasia, and gastroesophageal reflux disease (GERD) patients, stratified by balloon length and volume of inflation. RESULTS: Six achalasia studies (n = 154), 3 GERD (n = 52), and 5 studies including healthy controls (n = 98) were included in the systematic review. Normative data varied widely amongst studies of healthy volunteers. In contrast, studies in achalasia patients uniformly demonstrated low point estimates in distensibility ≤ 1.6 mm2/mmHg prior to treatment that increased to ≥ 3.4 mm2/mmHg following treatment at 40mL bag volume. In GERD patients, distensibility fell to the range of untreated achalasia (≤ 2.85 mm2/mmHg) following fundoplication. CONCLUSION: FLIP may be a useful tool in assessment of treatment efficacy in achalasia. The drastic drop in EGJ distensibility after fundoplication suggests that FLIP measurements need to be interpreted in the context of esophageal body motility and highlights the importance of pre-operative screening for dysmotility. Future studies using standardized FLIP protocol and balloon size are needed.