Abstract Focal high-copy number oncogene and resistance gene amplification via extrachromosomal DNA (ecDNA) is associated with high-risk disease and therapeutic failure across many cancer types. New therapies that target ecDNA function are needed to address this significant unmet need. We identified a novel kinesin motor protein, Kinesin, as a key regulator of proper mitotic ecDNA segregation and ecDNA maintenance in cancer cells. Genetic inactivation of Kinesin resulted in ecDNA mis-segregation during anaphase, reduced ecDNA levels, and a corresponding loss of tumor cell proliferation and survival. Pharmacological degradation of Kinesin using the highly selective heterobifunctional degrader KNSNd-1 recapitulated these cellular phenotypes. Furthermore, the antiproliferative effects of KNSNd-1 coincided with induction of pHH3 and γH2AX, indicating mitotic arrest and genotoxic stress as a putative mechanism of action underlying sensitivity. KNSNd-1 demonstrated potent degradation in vitro (∼1 nM DC₅₀ in HEK293T Kinesin-HiBiT cells), with exquisite selectivity. Global proteomics studies in CAL51 breast cancer cells treated with KNSNd-1 revealed Kinesin as the only protein significantly degraded (log₂ fold change ≥ 1; −log₁₀ p-value ≥ 4). In vitro sensitivity to KNSNd-1 correlated with ecDNA status, as determined by metaphase analysis (p = 0.01, Mann-Whitney test), across a panel of breast cancer cell lines. Oral administration of KNSNd-1 monotherapy resulted in significant tumor growth inhibition (TGI), including tumor regressions, and this activity correlated with ecDNA status across multiple models and indications. Moreover, combination treatment with KNSNd-1 and targeted therapies in ecDNA-positive breast and gastric cancer models resulted in significantly greater TGI compared with targeted therapy alone. Together, these findings support the clinical development of Kinesin degraders for the treatment of ecDNA-associated high-risk cancers, including breast cancer. Citation Format: Deepti Wilkinson, Frederick A. Derheimer, Ardalan Adreshi, Joan Chen, Yuan Chien, Cory DuPai, Rachel Elsdon, Ryan J. Hansen, Kimberly Johnson, Shailaja Kasibhatla, Laura Layman, Zhengke Li, Ronghua Li, Debbie Liao, Taylor Loe, Jacques Mauger, Jafar Moininazeri, Ben Norman, Anne Marie Pferdekamper, Joshua Plum, Casey Sarkissian, Dave Solis, Auzon Steffy, Huikai Sun, Yen Truong, Julie Wiese, Anthony B. Pinkerton, Christian A. Hassig. Selective degradation of a novel kinesin as a potential therapeutic strategy addressing high-risk extrachromosomal DNA (ecDNA) positive cancers, including breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB361.

KRAS targeted inhibitors have shown promising clinical data in multiple recalcitrant cancers with activating KRAS mutations. The mutant-specific, pan, and multi-RAS targeting landscape is rapidly evolving; however, both intrinsic and acquired resistance to these therapies remain a significant clinical challenge. Mechanisms of acquired resistance to KRAS targeted inhibitors include high copy number amplification of KRAS and/or MAPK-pathway genes, activation of alternative oncogenic pathways, and secondary mutations in RAS-family members. In KRAS driven cancers, estimated to represent more than 15% of all solid tumors, DNA synthesis is uniquely dependent on the de novo synthesis of deoxyribonucleotide triphosphates (dNTPs), which depends on the enzyme ribonucleotide reductase (RNR). We developed an oral, potent, and selective small molecule inhibitor of RNR, BBI-825, that we have previously shown to preclinically prevent amplification mediated resistance to KRASG12C inhibitor adagrasib, and which is currently in clinical development as part of the STARMAP (Study Treating Acquired Resistance; MAPK Amplifications) Phase 1/2 trial, including KRASG12C inhibitor resistant tumors (NCT06299761). In this preclinical study, we sought to understand whether BBI-825 broadly antagonizes acquired resistance to mutant-specific, pan, and multi-RAS inhibitors in a range of tumor models. We tested the ability of BBI-825 to prevent or delay development of acquired resistance to RAS targeting in a panel of KRASG12D/C/V driven tumor cell lines when used in combination with mutant specific KRASG12D (MRTX-1133, RMC-9805), KRASG12C (adagrasib, sotorasib), pan-KRAS (BI-2493), and multi-RAS (RMC-6236) inhibitors. Across the models tested, BBI-825 demonstrated a consistent ability to prevent or delay acquired resistance to mutant-specific and multi-RAS targeting. We found that combinational activity of BBI-825 and RAS targeting was independent of the mode of acquired resistance being driven by genetic or non-genetic mechanisms. BBI-825 was found to abrogate increases of KRAS, RAF1, and MYC copy number in models where acquired resistance to RAS targeting was mediated via amplification of these genes. BBI-825 also showed combinational activity in RAS-targeting resistant cell lines where resistance was driven by non-genetic signaling alterations. Overall, we found that BBI-825 successfully antagonizes the development of acquired resistance to mutant-specific, pan, and multi-RAS inhibitors in a range of preclinical models. These findings support clinical investigation of BBI-825 in combination with mutant-specific, pan, and multi-RAS inhibitors to prevent or delay resistance and prolong duration of response. Joshua Lange, Salvador Garcia, Evan Holmes, AnneMarie Pferdekamper, Ben Norman, Auzon Steffy, Joshua Plum, Nicholas Catalano, Cory DuPai, HuiYong Zhao, Elisa de Stanchina, Claire Kuelbs, Austin Christofferson, Ardalan Ardeshiri, Edison Tse, Frederick Derheimer, Joan Chen, Debbie Liao, Ryan Hansen, Rona Yaeger, Sudhir Chowdhry, Christian Hassig. Oral and selective ribonucleotide reductase (RNR) inhibitor, BBI-825, suppresses acquired resistance to mutant-specific, pan, and multi-RAS targeting inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6387.

BACKGROUND & AIMS:Functional lumen imaging probe (FLIP) panometry provides assessment of the esophagogastric junction opening and esophageal body contractile activity during an endoscopic procedure and is increasingly being incorporated into comprehensive esophageal motility assessments. The aim of this study was to provide a standardized approach and vocabulary to the procedure and interpretation and update the motility classification scheme. METHODS:A working group of 19 FLIP panometry experts convened in a modified Delphi consensus process to produce and assess statements on the FLIP panometry procedure and interpretation. Three rounds of voting were conducted on an agreement scale of 1-9 for appropriateness, followed by face-to-face discussions and an opportunity for revisions of statements. The "percent agreement" was the proportion of votes with score ≥7 indicating level of agreement on appropriateness. RESULTS:A total of 40 statements were selected for final inclusion in the Dallas Consensus, including FLIP panometry protocol, interpretation of esophagogastric junction opening and contractile response, and motility classification scheme. Key statements included: "FLIP panometry should be interpreted in the context of the clinical presentation, the accompanying EGD [esophagogastroduodenoscopy] findings and other relevant complementary testing" (median response 9.0; 100% agreement). "A major motor disorder is unlikely in the setting of a 'normal' FLIP panometry classification" (median response 9.0; 94% agreement). "Diminished or absent contractile response with reduced esophageal opening (ie, nonspastic obstruction) supports the diagnosis of a disorder of EGJ [esophagogastric junction] outflow" (median response 8.5; 94% agreement). CONCLUSIONS:The standardized approach for performance and interpretation of the Dallas Consensus can facilitate use of FLIP panometry in broad clinical settings.

Esophagogastric junction outflow obstruction (EGJOO) is a rapidly evolving diagnosis that can represent early or variant achalasia. Since the publication of the Chicago Classification version 4.0, the criteria for this diagnosis have been more stringent. Currently, the criteria include an elevated median integrated relaxation pressure (IRP) in both the supine and upright positions, elevated intrabolus pressure in at least 20% of supine swallows, dysphagia and/or chest pain, as well as an abnormal timed barium esophagram and/or impedance planimetry testing. Additionally, other secondary causes may result in an elevated IRP and must be excluded. The management of conclusive EGJOO is targeted therapy to the lower esophageal sphincter (LES), although treatment is not straightforward. Overall, adjuvant testing and data should be scrutinized for appropriateness of LES disruption. The spectrum of treatment options includes simple monitoring as well as more invasive therapies such as endoscopic dilation and myotomy. This article explores the newest criteria and management options for clinically relevant EGJOO.

Abstract Focal amplification on extrachromosomal DNA (ecDNA) drives high gene copy number and intercellular genomic heterogeneity, which can fuel tumor adaptation and drug resistance. Targeted therapies have largely failed in patients with oncogene amplification, and patients whose tumors harbor ecDNA-based gene amplification have particularly worse survival compared to patients whose cancers harbor other genetic drivers. Due to the lack of approved therapies for patients with oncogene amplified cancers, many patients receive chemotherapy; however, resistance often develops through mechanisms such as ATP-binding cassette (ABC) transporter overexpression, rendering cross-resistance to other forms of chemotherapy. We examined whether ecDNA amplification in tumor cell lines drives ABC transporter overexpression to mediate resistance to paclitaxel, a commonly prescribed taxane chemotherapy for cancer patients. We selected non-amplified (DLD1 and SW48) and amplified cell lines, including COLO320DM and COLO320HSR (MYC amplified on ecDNA or chromosomal loci, respectively); SNU16 and H716, (FGFR2 and MYC amplified ecDNA); and H2170 (ERBB2 and MYC amplified on ecDNA). All cell lines developed paclitaxel resistance, with the majority (5/7) gaining focal amplification of ABCB1, which encodes P-glycoprotein (P-gp), a common multi-drug resistance transporter. Four models–COLO320DM, COLO320HSR, SNU16, and H2170—developed ABCB1 amplification on ecDNA; one non-amplified cell line (DLD1) acquired focal ABCB1 amplification via a breakage-fusion-bridge (BFB) mechanism, a distinct form of amplification from ecDNA. ecDNA-based ABCB1 amplifications exhibited hallmarks of ecDNA, including intercellular copy number heterogeneity and paclitaxel dose-dependent rapid evolution of ABCB1 copy number. We next assessed whether drug resistance was reversible in ABCB1 amplified cell lines following removal of paclitaxel. Reversal of resistance was observed in COLO320DM and COLO320HSR via loss of ABCB1 ecDNA within 4-6 weeks. However, in SNU16 and H2170 resistant cells, ABCB1 amplification was retained up to 12 weeks of drug removal, with apparent integration into MYC ecDNA, demonstrating that ecDNA-enabled plasticity can result in both short- and long-term paclitaxel resistance. Although targeted therapies have revolutionized treatment approaches for patients with actionable oncodriver alterations, most cancer patients do not have actionable drivers and most patients still receive chemotherapy at some point in their course of treatment. We demonstrated that ecDNA-based resistance to paclitaxel is common in cancer cell lines and may also drive resistance to chemotherapy in patients. Thus, ecDNA-directed therapies (ecDTx) may be an important treatment option for chemo-resistant patients, who currently do not have many effective therapeutic options. Citation Format: Kristen Holmes, Dean Perusse, Cory DuPai, Homa Hemmati, Julie Weiss, Claire Kuelbs, John Bibay, Joan Chen, Debbie Liao, Christian Hassig, Shailaja Kasibhatla. Taxane-based chemotherapy leads to acquired resistance through ecDNA-based amplification of multi-drug resistance genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5870.

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.

INTRODUCTION:Dupilumab, the first US Food and Drug Administration-approved treatment for eosinophilic esophagitis (EoE), lacks real-world data on use and effectiveness. METHODS:We conducted a retrospective cohort study of 70 patients with EoE prescribed dupilumab, comparing prescriber type, indication, follow-up, and response. RESULTS:Indications varied with gastroenterologists commonly prescribing for treatment-refractory cases and allergists as first-line therapy. Endoscopic assessment was lacking in 25.9%, but those with follow-up showed high histologic remission (92.3% first-line and 85% previous treatment failure). DISCUSSION:Dupilumab demonstrates effectiveness across EoE severity, including milder disease without previous treatment failure. Improving follow-up and assessing cost-effectiveness will help clarify its role in the treatment algorithm.

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.

Nearly all patients with systemic sclerosis (SSc) are negatively affected by dysfunction in the gastrointestinal tract, and the severity of gastrointestinal disease in SSc correlates with high mortality. The clinical complications of this dysfunction are heterogeneous and include gastro-oesophageal reflux disease, gastroparesis, small intestinal bacterial overgrowth, intestinal pseudo-obstruction, malabsorption and the requirement for total parenteral nutrition. The abnormal gastrointestinal physiology that promotes the clinical manifestations of SSc gastrointestinal disease throughout the gastrointestinal tract are diverse and present a range of therapeutic targets. Furthermore, the armamentarium of medications and non-pharmacological interventions that can benefit affected patients has substantially expanded in the past 10 years, and research is increasingly focused in this area. Here, we review the details of the gastrointestinal complications in SSc, tie physiological abnormalities to clinical manifestations, detail the roles of standard and novel therapies and lay a foundation for future investigative work.

Tables S1-S3, Figures S1-S5

Abstract Background: Focal high copy number oncogene amplification frequently occurs on extrachromosomal DNA (ecDNA), acentric circular DNA derived from chromosomes during neoplastic transformation and tumor progression. The unique properties of ecDNA facilitate a high degree of genomic plasticity and tumor heterogeneity, which enables rapid acquired resistance to targeted therapies and results in poor patient outcomes. Reintegrated ecDNA, also referred to as homogeneously staining regions (HSR), can exist in dynamic equilibrium with their circular form, although their potential adaptive and resistance properties have not been well characterized. Elucidating the genomic plasticity and mechanisms afforded to cancer cells harboring HSR may provide insights into new therapeutic approaches necessary to address this ecDNA-derived focal amplification. Methods: A novel model was developed that recapitulates the genomic plasticity of focal oncogene amplifications involving FGFR2 and EGFR in response to the FGFR inhibitor, infigratinib. Results: KATOIII gastric cancer cells harbor focal amplification of the FGFR2 oncogene (absolute copy number (CN) = 136 based on next-generation sequencing (NGS) that resides on an HSR as determined by FISH. Short- and long-read NGS revealed prior DNA breakpoints consistent with circular structures containing FGFR2, suggestive of reintegrated ecDNA as HSR. Despite initial sensitivity to FGFR2 inhibition (EC50 = 20 nM), cells acquired resistance following infigratinib dose escalation within 12 weeks. Infigratinib-resistant KATOIII cells retained the FGFR2 HSR while further amplifying FGFR2 on ecDNA, which correlated with increased FGFR2 CN, mRNA, and protein expression. Structural breakpoint analysis of the FGFR2 amplicon revealed conservation between baseline and ecDNA-amplified infigratinib resistant cells, suggesting that the HSR gave rise to ecDNA. Removal of infigratinib resulted in near-complete disappearance of FGFR2 ecDNA and return to near-baseline FGFR2 CN, protein expression, and signaling within 3 weeks. Strikingly, at high infigratinib concentrations that effectively inhibit FGFR2 signaling, cells rapidly switched to EGFR amplified on ecDNA, with concomitant reduction of FGFR2 ecDNA (CN = 553 to 238) and signaling and increased EGFR (CN = 3 to 30), mRNA, and EGFR signaling. Following ecDNA switching from FGFR2 to EGFR, KATOIII cells remained insensitive to infigratinib while acquiring sensitivity to the EGFR inhibitor erlotinib. Mutational analysis revealed no new oncogenic mutations including FGFR2 and EGFR, indicating the EGFR overexpression afforded by ecDNA was sufficient to drive acquired resistance to high infigratinib concentrations. Conclusions: These findings indicate that tumor cells with ecDNA-derived chromosomally reintegrated HSR retain the capacity to amplify ecDNA, thus enabling rapid adaptation to therapeutic pressure. Consequently, new treatment strategies that disable adaptive genomic plasticity are needed to address oncogene amplified cancers that leverage ecDNA biology. Citation Format: Kristen Turner, Homa Hemmati, Cory DuPai, John Bibay, Claire Klebs, Joan Chen, Debbie Liao, Christian Hassig, Shailaja Kasibhatla. Intrinsic genomic plasticity of extrachromosomal DNA (ecDNA) enables oncogene amplified tumor cells to develop rapid acquired resistance to targeted therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B092.

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.

Summary Background Optimal ambulatory reflux monitoring methodology in symptomatic reflux patients continues to be debated. Aims To utilise published literature and expert opinion to develop recommendation statements addressing use of ambulatory reflux monitoring in clinical practice Methods The RAND Appropriateness Method (RAM) was utilised among 17 experts with discussion, revision and two rounds of ranking of recommendation statements. Ambulatory reflux monitoring protocol, methodology and thresholds ranked as appropriate by ≥80% of panellists met the criteria for appropriateness. Results Prolonged (96‐h recommended) wireless pH monitoring off proton pump inhibitor (PPI) was identified as the appropriate diagnostic tool to assess the need for acid suppression in patients with unproven gastro‐oesophageal reflux disease (GERD) and persisting typical reflux symptoms despite once‐daily PPI. Acid exposure time (AET) <4.0% on all days of monitoring with negative reflux‐symptom association excludes GERD and does not support ongoing PPI treatment. Conversely, AET >6.0% across ≥2 days is conclusive evidence for GERD and supports treatment for GERD, while AET >10% across ≥2 days identifies severe acid burden that supports escalation of anti‐reflux treatment. In previously proven GERD, impedance‐pH monitoring on PPI is helpful in defining refractory GERD and mechanisms of continued symptoms; the presence of <40 reflux events, AET <2.0% and a negative reflux‐symptom association does not support escalation of anti‐reflux treatment. In contrast, AET > 4.0% and positive reflux‐symptom association support escalation of anti‐reflux treatment, including use of invasive therapeutics. Conclusions Statements meeting appropriateness for average clinical care have been identified when utilising reflux monitoring in patients with typical reflux symptoms and PPI non‐response.

Ineffective esophageal motility (IEM) is a hypomotility disorder with decreased contraction vigor and normally relaxing lower esophageal sphincter. Although IEM has been associated with poor esophageal clearance and gastroesophageal reflux, it is also seen in asymptomatic subjects and is often of unclear clinical significance. The Chicago classification version 4.0 updated the diagnostic threshold to require >70% weak or fragmented swallows or ≥50% failed swallows for a conclusive diagnosis of IEM. Provocation testing are recommended in borderline cases to assess clinical relevance. Prospective trials are needed to further refine the diagnostic criteria, understand the pathophysiology, and develop an effective treatment for IEM.

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.

Upper endoscopy (EGD) is frequently performed in patients with esophageal complaints following anti-reflux surgery. However, the evaluation of fundoplication wrap integrity in this setting may be challenging and associated with disagreement among providers. We therefore performed a multi-center study to evaluate the accuracy and confidence of assessing Nissen fundoplication integrity and hiatus herniation among endoscopists.

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.

INTRODUCTION: Functional luminal imaging probe (FLIP) panometry can evaluate esophageal motility in response to sustained esophageal distension at the time of sedated endoscopy. This study aimed to describe a classification of esophageal motility using FLIP panometry and evaluate it against high-resolution manometry (HRM) and Chicago Classification v4.0 (CCv4.0). METHODS: Five hundred thirty-nine adult patients who completed FLIP and HRM with a conclusive CCv4.0 diagnosis were included in the primary analysis. Thirty-five asymptomatic volunteers (“controls”) and 148 patients with an inconclusive CCv4.0 diagnosis or systemic sclerosis were also described. Esophagogastric junction (EGJ) opening and the contractile response (CR) to distension (i.e., secondary peristalsis) were evaluated with a 16-cm FLIP during sedated endoscopy and analyzed using a customized software program. HRM was classified according to CCv4.0. RESULTS: In the primary analysis, 156 patients (29%) had normal motility on FLIP panometry, defined by normal EGJ opening and a normal or borderline CR; 95% of these patients had normal motility or ineffective esophageal motility on HRM. Two hundred two patients (37%) had obstruction with weak CR, defined as reduced EGJ opening and absent CR or impaired/disordered CR, on FLIP panometry; 92% of these patients had a disorder of EGJ outflow per CCv4.0. DISCUSSION: Classifying esophageal motility in response to sustained distension with FLIP panometry parallels the swallow-associated motility evaluation provided with HRM and CCv4.0. Thus, FLIP panometry serves as a well-tolerated method that can complement, or in some cases be an alternative to HRM, for evaluating esophageal motility disorders.