bluuebunny/crossref_metadata_2025 huggingface dataset:
A188 ENHANCED MICROBIAL TRYPTOPHAN METABOLISM ACTIVATES THE ARYL HYDROCARBON RECEPTOR AND AMELIORATES INTESTINAL INFLAMMATION
Authors: Rondeau L , Barbosa B , Dang R , Caminero A
Published: February 2024

Background

Intestinal microbiota, diet, and the immune system have been proposed to contribute to the development of inflammatory bowel diseases (IBD). The aryl hydrocarbon receptor (AhR) is a critical regulator of intestinal immunity and mucosal barrier homeostasis that is activated by agonists such as host and microbial tryptophan metabolites. IBD patients have altered microbiota and reduced AhR agonists in intestinal content resulting in downregulation of AhR. Our recent findings indicate that mice harbouring microbiota with impaired tryptophan metabolism and AhR agonist production develop more severe inflammation during colitis.

Aims

To study the influence of diet-microbe interventions on AhR activation and intestinal inflammation in mice with impaired microbial tryptophan metabolism.

Methods

Germ-free C57BL/6 mice from McMaster’s Axenic Gnotobiotic Unit were colonized with cecal content of mice harbouring reduced microbiota with impaired tryptophan metabolism with and without tryptophan metabolizing Clostridium sporogenes. Following three weeks of microbial stabilization, mice were provided a high tryptophan (HT) diet or a low tryptophan (LT) diet as a control. Experimental colitis was induced using dextran sulfate sodium in drinking water (DSS; 2.5% w/v). Briefly, DSS was provided ad libitum for five days, followed by two days of recovery before tissue collection. Activation of AhR was measured in stool and C. sporogenes cultures using an in vitro AhR luciferase reporter assay. AhR agonists were quantified by capillary-electrophoresis-mass spectrometry. Colonic expression of AhR pathway genes was evaluated by RT-qPCR. Susceptibility to colitis was assessed by histologic analysis of distal colon sections, fecal lipocalin-2, weight loss, and clinical scores. Inflammatory gene transcripts were quantified in colon tissue by Nanostring.

Results

C. sporogenes efficiently produces AhR agonists in vitro and in vivo. In mice with impaired tryptophan metabolism, the HT diet increased AhR agonists in intestinal content and colonic AhR pathway gene expression, which was further enhanced in mice colonized with C. sporogenes. Compared to mice fed LT and HT diets, mice colonized with C. sporogenes and fed HT were most protected from weight loss, tissue damage, and immune cell infiltration.

Conclusions

These findings highlight the potential of tryptophan-rich diets and targeted microbe interventions as a novel approach to enhance AhR activation and mitigate inflammation during colitis. Consequently, exploring methods to improve tryptophan metabolism through diet and manipulation of the microbiota could be a promising therapeutic avenue for IBD patients with impaired AhR activation.

Funding Agencies

CCC, CIHR
A191 THE NEURAL SIGNAL, CALCITONIN GENE-RELATED PEPTIDE (CGRG) ENHANCES A REGULATORY PHENOTYPE IN THE HUMAN IL-4-TREATED MACROPHAGE
Authors: Callejas Pina B E , Sousa J A , Flannigan K , Wang A , Li S , Rajeev S , Panaccione R , McKay D
Published: February 2024

Background

Interlukin-4 activated human macrophages (M(IL4) promote epithelial wound healing and exert an anti-colitic effect in a murine model. Blood monocyte-derived M(IL4)s from healthy donors and individuals with Crohn’s disease had increased mRNA expression of the calcitonin gene-related peptide (CGRP) receptor chain, RAMP1, raising the issue of neural modulation of the M(IL4)s reparative function.

Aims

To determine if CGRP-RAMP1 signalling in human IL-4 treated macrophages enhances the anti-colitic phenotype.

Methods

Peripheral blood mononuclear cells from healthy volunteers (HD) and individuals with Crohn’s disease were cultured on plastic (2h, 37°C) and non-adherent cells removed. The adherent cells were cultured with recombinant hM-CSF (10 ng/ml) for 7 days. The resultant macrophages (2.5×105) were differentiated with IL-4 (48h 10 ng/mL). In other cells, CGRP (10 nM) was added 24h after IL-4 and phenotype assessed by qPCR. Rag1-/- mice were treated with M(IL4)±CGRP (1x106 i.p.): 48h later, colitis was induced by oxazolone. FITC dextran was used to evaluate epithelial barrier integrity. A wound healing assay was conducted using CaCo2 epithelial cells and conditioned medium (CM,1:2 dilution) from the different treatments. Prostaglandin D2 production was evaluated by ELISA and cyclooxygenase (COX)-1 and -2 activity inhibited using SC560 and indomethacin.

Results

Compared to non-treated macrophages (M(0)), M(IL4)s from HD had increased RAMP1 and CLR mRNA. M(IL4)s treated with CGRP showed enhanced expression of CD206, CCL26, RAMP1 and CCL18. When delivered systemically to oxazolone-treated rag1-/- mice, M(IL4,CGRP) had an anti-colitic effect superior to M(IL4)s from the same healthy blood donor. Use of the the human colon CaCo2 cell in vitro wounding model revealed that CM from M(IL4,CGRP) had increased amounts of TGFb and increased wound-healing capacity compared to matched M(IL4)-CM. Moreover, M(IL4,CGRP)s displayed increased COX-1 and PGD2. CM from M(IL4,CGRP)s treated with indomethacin or SC-560 to inhibit COX1 activity failed to promote repair of wounded CaCo2 cell monolayers.

Conclusions

Neuronal input is revealed as an important local modifier capable of boosting the anti-colitic effect of autologous M(IL4) transfer to treat enteric inflammation.

Funding Agencies

CCCHelmsley Charity
A193 DECIPHERING THE INFLUENCE OF CROHN’S DISEASE-ASSOCIATED GENETIC RISK FACTOR, NOD2 IN INTESTINAL FIBRO-STENOSIS
Authors: Mukherjee T , Patel S , Yadav J , Ayyaz A , Tsang D , Narimatsu M , Bayer G , Trcka D , Bader G , Wrana J L , Girardin S E , Philpott D
Published: February 2024

Background

Intestinal fibrosis (IF) is a common debilitating complication associated with Crohn’s disease (CD), an idiopathic inflammatory bowel disease (IBD). IF results in severe strictures that affect the entire gastrointestinal tract, often requiring surgery due to limited or no effective treatment. In general, IF is a consequence of chronic inflammation, excessive extracellular matrix (ECM) deposition, aberrant cellular functions and tissue remodeling involving the innate and adaptive immune system. At the cellular level, fibrosis has been proposed to involve the crosstalk between epithelial cells, mesenchymal stromal cells and immune cells. However, the cascade of events that establish IF is poorly understood as it comprises a dynamic interplay between host genetics, immunity, gut microbiome and aberrant environment insults. Notably, polymorphisms in nucleotide-binding oligomerization domain-containing protein 2 (NOD2; a bonafide cytosolic innate immune receptor), strong genetic risk factors for CD, also increase the incidence of IF. In this context, how NOD2 polymorphisms govern intestinal fibrostenosis in CD remains to be investigated.

Aims

To investigate how CD-associated risk gene, NOD2 contributes to intestinal fibrostenotic disease

Methods

We employed a single-cell RNA sequencing (scRNA-seq) approach to explore the cellular landscape in our CD-mouse model, where we challenged Nod2-deficient mice with a chronic inflammatory insult regime, using dextran sulfate sodium (cDSS) for 3 cycles. Subsequently, changes in inflammatory, metabolic and fibrotic markers in the gut were analyzed by quantitative real-time PCR (qRT-PCR), immunohistochemistry (IHC) or western blot analyses. Further, RNA-In-situ hybridization (RNA-ISH) and flow cytometric analyses were performed to validate cell populations contributing to, and the molecular signatures linked with intestinal fibrostenosis.

Results

We found that Nod2-deficient mice show increased expression of pro-inflammatory cytokines (TNF, IL6) and excessive ECM deposition (fibrosis) in the gut compared to wild-type littermate mice post-cDSS. Curiously, scRNA-seq analysis uncovered altered stromal-immune-cell crosstalk along with the identification of a novel subset of the Dpt+ interstitial stromal population with distinct gene signatures regulated by chronic inflammation. Further, we observed increased senescence (Cdkn2a) mediated trans-differentiation of stroma into fibroblast contributing to IF in Nod2-deficient mice.

Conclusions

The study outlined will deepen our understanding of cellular and molecular mediators as well as inter and intra-cellular networks that drive IF. This will be transformative in devising therapeutic strategies to prevent IF in progressive CD patients.

Funding Agencies

CCC, CIHRThe American Association of Immunologist (AAI)
A194 EARLY LIFE WESTERN-TYPE DIET ACCELERATES THE ONSET OF MURINE IL-10 KO COLITIS
Authors: Ren M , Luchak A , Dang C , Philpott D , Croitoru K
Published: February 2024

Background

Early life is a critical time for gut microbiome and immune development, including the establishment of proper host-microbe interactions. While exposures to western world environmental factors are associated with inflammatory bowel disease (IBD) susceptibility, the link between environment in early life and later disease onset is unclear. One of the most important western world environmental factors is diet, which can distinctly alter the gut microbiome. We believe an early life western-type diet (WD) can affect disease progression in a murine IL-10 KO colitis model through dysregulated T-cell responses against the microbiome.

Aims

We aimed to characterize how an early life WD given to IL-10 KO mice would affect colitis development and the gut microbiome.

Methods

IL-10 KO mice were housed in specific pathogen free conditions and fed normal chow (NC) or WD ad libitum, either between days 10 to 35 (early WD, eWD) or days 35 to 60 (adolescent WD, aWD). Stool was collected from mice at days 35, 56, and 84 for lipocalin-2 (LCN-2) and 16S rDNA sequencing. Mice were sacrificed at day 84, assessing mesenteric lymph node weight, gene expression, colon damage by histopathology, and colon lamina propria leukocyte (LPL) phenotype and cytokine expression by flow cytometry.

Results

Compared to NC and aWD, the eWD fed IL-10 KO mice displayed increased fecal LCN-2 at days 56 and 84, indicating greater inflammation. At sacrifice, eWD fed mice had larger mesenteric lymph nodes and more significant colon damage by histopathological scoring. Colon LPL preparations showed that eWD fed IL-10 KO mice had higher proportions and absolute numbers of effector and regulatory T-cells. Additionally, higher proportions and absolute numbers of those T-cells were IFNγ+, IL-17A+, and IL-22+. qPCR of distal colon tissue revealed increased gene expression of innate and type 3 proinflammatory cytokines such as Il1b, Tnfα, and Il23, while showing no change in Il6 and Il4. Taxa positively associated with WD were able to establish a persistent niche in eWD fed mice but not in aWD fed mice. An increase in only one specific taxon was associated with eWD at all timepoints while also most strongly correlating with inflammatory markers.

Conclusions

This data suggests that eWD feeding during gut microbiome and immune development is uniquely capable of increasing long-term susceptibility to intestinal inflammation in IL-10 KO mice. This appears to be associated with persistent colonization of potentially more inflammatory taxa. This work provides insight into the potential role of early life environmental risk factors, i.e. WD, in the later development of IBD.

Funding Agencies

CAG, CIHRUniversity of Toronto, Taconic Biosciences
A196 CSF2 AUTOANTIBODIES AS A SEROLOGICAL MARKER FOR CROHN'S DISEASE
Authors: Tai S , Del Valle D , Urango R , Croitoru K , Gnjatic S , Korzenik J , Colombel J , Mortha A
Published: February 2024

Background

Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that severely affects quality of life. Despite technological advances, CD diagnoses remain difficult and invasive, with delayed diagnoses correlated with worse prognosis and complications. CD is multifactorial, involving complex interactions between genetic and environmental risk factors, which leads to difficulty in identifying a cause and cure. However, research alludes to an underlying dysregulation of immune activity that leads to chronic intestinal inflammation. Mononuclear phagocytes (MNP) are essential immune cells that promote intestinal homeostasis through supporting immune tolerance, antimicrobial activity, and barrier integrity. A crucial cytokine that promotes the survival and function of intestinal MNP is Colony Stimulating Factor 2 (CSF2). Intriguingly, previous work in our lab demonstrated that CSF2 autoantibodies (CSF2-Ab) can be detected in the serum of every third CD patient and antedate the onset of CD by up to 6 years. In contrast, these titers are not seen in healthy donors or ulcerative colitis. Moreover, CSF2-Ab were predictive of disease location and severity, and are able to neutralize CSF2 by binding to glycosylations, impacting downstream signaling in MNP. These data suggest a role for CSF2-Ab in promoting intestinal immune dysregulation in CD.

Aims

Our work aims to characterize CSF2-Ab and their role in CD.

Methods

We developed a bead-based flow cytometric assay to screen CD patient serum for CSF2-Ab in several cohorts that contain samples at time points prior to, at, and after diagnosis.

Results

Our preliminary data demonstrate that our assay is rapid and specific for detecting CSF2-Ab of various isotypes in human serum and can be validated using ELISA. Furthermore, we show that this assay can be used to determine the epitope specificity of CSF2-Ab in CD patients in just one single sample.

Conclusions

We have developed a rapid and accessible assay to predict CD development years before diagnosis using minimal serum samples. Moreover, this screen will enable subclassification of patients based on their autoantibody reactivity to glycovariants of CSF2. Glycovariants that escape recognition by CD-specific CSF2-Ab could potentially be used as a therapeutic to ameliorate disease. Beyond treatment, understanding how CSF2-Ab epitope specificity and isotypes may change over the course of disease development will serve as a roadmap for elucidating the role of CSF2-Ab in CD.

Funding Agencies

CAG, CIHR
A197 A ROLE FOR NOD2 IN INTESTINAL T CELL MEMORY DEVELOPMENT AND FUNCTION
Authors: Tsankov B K , Luchak A , Nathan N , Philpott D
Published: February 2024

Background

Aberrant resident memory T cell (TRM) responses have been associated with increased intestinal inflammation and Crohn’s disease (CD) pathology in humans. Intestinal TRM cells are not only important for maintaining the integrity of the intestinal epithelial barrier, but also for the rapid clearance of pathogens in the intestine during infection. Understanding the signals received by the intestinal immune system to generate TRM responses is paramount to elucidating treatments for CD. Genetic mutations in NOD2 are associated with the highest risk of CD development. As a host intracellular sensor of bacterial peptidoglycan, NOD2 is critical for initiating both innate and adaptive immune responses. Furthermore, work from our lab as well as those of our collaborators suggest that NOD2 deficiency reduces systemic memory B and T cell responses. However, the role of NOD2 in establishing memory T cell responses in the intestine remains unclear. This work will therefore establish the role of NOD2 signaling in initiating and maintaining optimal TRM responses to achieve intestinal homeostasis and resilience to intestinal inflammation.

Aims

It is the main objective of this project to determine whether NOD2-mediated signalling affects:

1. Antigen-specific intestinal T cell priming in vivo

2. Bona fide intestinal TRM generation

3. Bona fide intestinal TRM function

Methods

Intraperitoneal LCMV-Armstrong infection results in long-lived CD4+ and CD8+ resident-memory T cell generation in the intestinal lamina propria of mice. Wildtype and NOD2 deficient littermate mice were infected with LCMV-Armstrong, and the effects on intestinal T cell priming, effector function, and memory T cell function were examined by flow-cytometry, ex vivo and in vivo antigen-recall experiments, qPCR, and viral plaque assays.

Results

Augmented NOD2 signalling during priming increased LCMV-specific CD4+ T cell numbers in the mesenteric lymph nodes - but not in the spleen, independent of proliferation or cell death. Furthermore, NOD2-deficiency resulted in decreased effector and memory T cell numbers in the small intestinal lamina propria. This effect was associated with decresead memory CD4+ and CD8+ T cell functions in NOD2-deficient mice during ex vivo and in vivo peptide recall experiments.

Conclusions

NOD2 affects T cell priming in the mesenteric lymph nodes, which later affects effector and memory T cell functions in the intestinal lamina propria.

Funding Agencies

CAG, CIHREmerging and Pandemic Infections Consortium
A203 PERORAL ENDOSCOPIC MYOTOMY (POEM) FOR COMPLEX ACHALASIA AND THE POEM DIFFICULTY SCORE: AN UPDATE
Authors: Ching Hui Yee C , Youssef M , Woo M , Bechara R
Published: February 2024

Background

POEM for achalasia can be challenging in patients with complex achalasia (CA) (i.e., type III achalasia, multiple prior treatments, prior myotomy, and sigmoid type). The POEM difficulty score (PDS) identifies factors that contribute to challenging POEM procedures. (Figure 1) Here, we present an update on the PDS in a series of patients with non-CA and CAs.

Aims

Our aim was to determine whether, with the introduction of the TT-J knife with waterjet functionality, the PDS still maintains a strong correlation with procedural efficiency and technical difficulty.

Methods

We retrospectively reviewed patients who underwent POEM for achalasia between May 2018 to July 2023 at the Kingston Health Sciences Center. 139 consecutive POEMs were performed, with 74 CAs. Primary outcomes include correlation of procedural efficiency with the PDS. Secondary outcomes include clinical success at the last followup and adverse events. Demographics and procedural variables were compared with descriptive statistics (mean ± SD; median, min-max range) and the Mann-Whitney U-test. Pre and post-POEM Echkhardt scores were compared using the Wilcoxon signed-rank test.

Results

74 (56.7% male) complex and 65 (55.4% male) non-complex POEM procedures were carried out. The mean age is 56.7 ± 16.5 years and 47.3 ± 20.2 years in CA and non-CA respectively. PDS correlates moderately with procedural efficiency with a correlation coefficient of 0.595 (Spearman’s Pampersand:003C0.001). A subanalysis is available in Table 1.

The mean efficiency for non-CA was 3.3min/cm±1.2. The median PDS for non-CA was 1 (0-5). In comparison, the mean efficiency for CA were 3.3min/cm ± 1.3 (type III), 5.3min/cm ± 2.3 (prior myotomy), 4.0min/cm ± 1.7 (≥4 prior procedures), and 5.2min/cm ± 2.4 (sigmoid type). The median PDS for CA was 3 (0-6) (type III), 4 (0-8) (prior myotomy), 3 (0-8) (≥4 prior procedures), and 3 (0-6) (sigmoid type).

CA and non-CA POEM procedures were completed with 97% and 98% clinical success, respectively.

Conclusions

PDS continues to moderately correlate with procedural efficiency using the TT-J knife. However, the presence of spastic contractions correlated poorly with procedural efficiency. Thus, it may be omitted with the use of the TT-J knife. The order of increasing difficulty of POEM in CA appears to be type III, prior myotomy, sigmoid type, and ≥4 prior procedures. Multi-center prospective studies are needed to validate PDS in different clinical settings.

Table 1: Sub-analysis of individual PDS factors and procedural velocity

Figure 1: Peroral Endoscopic Myotomy (POEM) difficulty score (PDS): "FOODS"

Funding Agencies

None
A204 DUPILUMAB IMPROVES HISTOLOGIC, ENDOSCOPIC, AND SYMPTOMATIC ASPECTS OF EOSINOPHILIC ESOPHAGITIS IN PATIENTS AGES 1–ampersand:003C12 YEARS
Authors: Chehade M , Dellon E , Spergel J M , Rothenberg M E , Pesek R D , Collins M H , Hirano I , Liu R , Laws E , Mortensen E , Abdulai R , Maloney J , McCann E , Kosloski M P , Hamilton J D , Samuely C , Glotfelty L , Shabbir A , Chow M
Published: February 2024

Background

Dupilumab is approved in Canada for eosinophilic esophagitis (EoE) in patients (pts) aged ≥12 years who weigh ≥40 kg; no treatments are approved for pts aged ampersand:003C12 years.

Aims

The Phase 3 EoE KIDS trial evaluated dupilumab efficacy and safety vs placebo (PBO) in pts aged 1–ampersand:003C12 years with EoE.

Methods

Part A was a 16-week (W) PBO-controlled study; pts were randomized 2:2:1:1 to weight-tiered dupilumab on a higher-exposure (HE) or lower-exposure (LE) regimen, or PBO (2 groups) to W16. In Part B, pts continued dupilumab, or switched from PBO to dupilumab (HE/LE), to W52.

Results

At W16 (Part A), the HE dupilumab group had an improved proportion of pts achieving peak esophageal intraepithelial eosinophil count (PEC) ≤6 eosinophils/high-power field (hpf) vs PBO (67.6% vs 2.9%, Pampersand:003C0.0001; primary endpoint). At W52 (Part B), 62.9% of HE dupilumab/dupilumab pts, and 52.9% of PBO/HE dupilumab pts, achieved PEC ≤6. At W16, the following improved with HE dupilumab vs PBO: EoE-Histologic Scoring System grade and stage scores (–0.88 vs +0.02 and –0.84 vs +0.05, respectively, both Pampersand:003C0.0001); EoE-Endoscopic Reference Score (–3.5 vs +0.3, Pampersand:003C0.0001); overall caregiver assessed EoE status (global impression of change mean [SD], 2.1 [1.2] vs 3.3 [1.4]; lower scores represent more improvement). Improvements were maintained with continuous dupilumab and improved in PBO/dupilumab pts at W52. LE dupilumab maintained similar improvements achieved through W52; however, effects were generally either comparable or numerically lower with LE dupilumab vs HE dupilumab. At W16, COVID-19, rash, headache, and injection-site erythema occurred more frequently in patients receiving dupilumab, with higher incidence than PBO; AEs were similar through W52.

Conclusions

HE dupilumab met the primary endpoint of PEC ≤6 eos/hpf vs PBO, demonstrated significant changes in histologic and endoscopic aspects of EoE, and improved symptoms with benefits maintained/increased to W52.

Funding Agencies

Research sponsored by Sanofi and Regeneron Pharmaceuticals Inc.
A206 DUPILUMAB TREATMENT REDUCES THE FREQUENCY OF DYSPHAGIA DAYS AND ACTIONS TO RELIEVE DYSPHAGIA IN PATIENTS WITH EOSINOPHILIC ESOPHAGITIS (EOE): RESULTS FROM THE PHASE 3 LIBERTY EOE TREET STUDY
Authors: Dellon E , Hirano I , Chehade M , Fugere N , Sun X , Pela T , Durrani S , Jacob-Nara J A , Radwan A , Tilton S T , McCann E
Published: February 2024

Background

Dysphagia is the predominant symptom of EoE in adolescents and adults.

Aims

To assess change in number of days with dysphagia, number of days with action taken to relieve dysphagia, and change in pain associated with dysphagia in patients receiving dupilumab 300 mg once weekly (qw) vs placebo in LIBERTY EoE TREET.

Methods

Dysphagia Symptom Questionnaire (DSQ) score (range 0–84) was calculated from daily responses over 14 days for Q2 (frequency) and Q3 (severity); Q4 (pain) was separately assessed (range 0–56). Higher scores indicate a worse outcome. Inclusion criteria required patients to have a baseline DSQ score ≥10. Number of days with dysphagia (Q2), action taken to relieve dysphagia (Q3), and pain (Q4) were analyzed at baseline and Week (W) 24 for the placebo-controlled study parts (A and B). P-values are nominal.

Results

81 patients enrolled in Part A (dupilumab/placebo: n=42/39) and 159 in Part B (n=80/79). Mean number of days with dysphagia was similar with dupilumab vs placebo at baseline, but lower in the dupilumab group at W24 (Figure). Mean [SD] change from baseline (dupilumab vs placebo) was –6.5 [3.78] vs –3.9 [4.61], Pampersand:003C0.05 in Part A, and –7.8 [4.24] vs –4.7 [4.02], Pampersand:003C0.0001 in Part B. Mean [SD] number of days with any action taken to relieve dysphagia was similar in the dupilumab vs placebo group at baseline (Part A: 7.3 [3.76] vs 8.2 [3.82]; Part B: 9.5 [3.53] vs 8.7 [3.85]) but lower (numerically) in the dupilumab group at W24 (Part A: 3.6 [3.73] vs 5.7 [4.78]; Part B: 3.0 [3.84] vs 5.3 [4.69]). At W24, numerically fewer days with more severe dysphagia (need to cough/gag, vomit, or seek medical attention to relieve dysphagia) occurred with dupilumab vs placebo. Baseline DSQ pain score was similar in dupilumab vs placebo groups. Least squares mean [95% CI] change from baseline at W24 in DSQ pain score was −10.1 [–12.2, –7.9] vs −4.4 [–6.8, –2.0] for dupilumab vs placebo in Part A (difference vs placebo: −5.7 [95% CI −8.67, –2.72]; P=0.0002), and −10.0 [–11.7, –8.1] vs −6.5 [–8.3, –4.6] in Part B (difference vs placebo: −3.5 [95% CI −5.90, −1.03]; P=0.0053).

Conclusions

At W24, patients in the dupilumab 300 mg qw group experienced fewer days with dysphagia, fewer days with any action taken for dysphagia relief, and less pain associated with dysphagia vs placebo.

Funding Agencies

Research sponsored by Sanofi and Regeneron Pharmaceuticals Inc.
A207 SLING-FIBER PRESERVATION DURING POEM IS AN INDEPENDENT FACTOR IN REDUCING POST-POEM GERD SYMPTOMS: A CANADIAN SINGLE-CENTER RETROSPECTIVE STUDY
Authors: Fujiyoshi Y , Fujiyoshi M , Khalaf K , May G , Teshima C
Published: February 2024

Background

Gastroesophageal reflux disease (GERD) after peroral endoscopic myotomy (POEM) has been a limiting factor with POEM procedure. Preservation of the sling-fiber during POEM was reported to reduce post-POEM GERD in Japan, but there are no reports of this technique in a western population.

Aims

The aim is to investigate the association of sling-fiber preservation during POEM and post-POEM GERD symptoms at our institution, which is a large therapeutic endoscopy referral center in Canada.

Methods

This is a retrospective, single-center study of patients who underwent POEM from October 2017 to January 2023 at our center. The initial cohort of patients were treated by conventional POEM until June 2021, after which a second cohort underwent POEM with sling-fiber preservation, as the techniques advanced. The primary outcome was the rate of positive GERD symptoms after POEM. The secondary outcomes were clinical success rate, adverse events rate, use of PPI at follow-up. Multivariate regression was performed to identify factors that reduce post-POEM GERD symptoms.

Results

148 POEM cases (52.5±15.6y/o, female:61(43%)) were included in this study. There was no significant difference in patient characteristics between the groups. The mean procedure time (108.6±34.5 vs 109.1±45.7 min, P=0.93) and rate of adverse events (20% vs 18%, P=0.85) were similar between the traditional and modified groups. In the sling fiber preservation group, gastric myotomy length was significantly longer (2.2±0.7 vs 1.6±0.8 cm, Pampersand:003C0.05) yet the GERD symptom rate at follow-up was significantly lower (22% vs 42%, Pampersand:003C0.05), although PPI use was similar (52% vs 48%, P=0.73). The clinical success rate was similar between groups (88% vs 84%, P=0.6). Regression analysis indicated that, after adjusting for other risk factors of post-POEM GERD, sling-fiber preservation during POEM had an odds ratio of 0.24 (95%CI:0.07-0.85, Pampersand:003C0.05) for post-POEM GERD symptoms.

Conclusions

Sling-fiber preservation during POEM effectively reduces post-POEM GERD symptoms, despite a longer gastric myotomy length. It stands as a independent factor in reducing post-POEM GERD symptoms. Hence, sling-fiber preservation may be a beneficial solution for reducing post-POEM GERD symptoms in Western populations.

Outcomes of conventional POEM and sling-fiber preservation POEM

POEM; Peroral endoscopic myotomy, SD; standard deviation, GERD; gastroesophageal reflux disease, PPI; proton pump inhibitor

Funding Agencies

None
A210 ESOPHAGEAL SQUAMOUS PAPILLOMATOSIS AFTER ENDOSCOPIC SUBMUCOSAL DISSECTION
Authors: Gilhotra R , Zarrin A , Jiang S X , Xiong W , Shahidi N
Published: February 2024

Background

Squamous papillomatosis is a rare benign epithelial finding, generally found incidentally in the distal esophagus. The pathophysiology is not well understood but felt to be secondary to reflux and chemical irritation leading to leukoplakia and verrucous hyperplasia of the epithelium and papilloma formation.

Aims

To present a case of esophageal squamous papillomatosis after endoscopic submucosal dissection (ESD) and radiofrequency ablation (RFA) of Barrett’s esophagus (BE) and early esophageal cancer.

Methods

Case report and review of the literature

Results

A 78-year-old male with C3M3 BE and previous band mucosectomy for nodular dysplasia was referred for ESD of an early esophageal cancer. ESD was successfully performed, with histopathology identifying a low-risk well-differentiated intramucosal adenocarcinoma without lymphovascular invasion and negative margins. Radiofrequency ablation was performed 3-months post-resection for residual BE. Subsequent surveillance gastroscopy 6 months post-resection identified extensive fleshy pink granulation tissue at the ESD scar, histopathology revealing SP. This was confirmed on subsequent repeat gastroscopy and biopsy. Compliance with double dose proton pump inhibitor therapy was confirmed.

Conclusions

To our knowledge, this is the first reported case of SP developing post-ESD and RFA; further expanding our knowledge of potential Barrett’s endotherapy-related adverse events.

Funding Agencies

None
A212 SYMPTOMS IN PATIENTS WITH NORMAL ESOPHAGEAL MOTILITY MAY DIFFER BASED ON AGE AND SEX
Authors: Kim D R , Woo M
Published: February 2024

Background

High resolution esophageal manometry (HREM) is used to diagnose esophageal motility disorders. While esophageal symptoms including dysphagia are common and seen in up to 20% of adults, a minority of symptomatic patients have esophageal dysmotility, when defined by the Chicago Classification v4 (CCv4). The generation of esophageal symptoms in a patient with normal esophageal motor function is complex, but may relate to visceral hypersensitivity, inappropriate pain perception or unidentified contraction abnormalities. The Esophageal Symptom Questionnaire (ESQ-30) is a validated tool in the assessment of esophageal symptoms and measures the frequency and severity of dysphagia, reflux and globus through three separate sub-scales (ESQ-D, ESQ-R, ESQ-G respectively).

Aims

To determine age and sex in esophageal symptoms (as measured by ESQ-30 sub-scales) in a population of symptomatic patients with normal esophageal motility.

Methods

Retrospective analysis of consecutive reports from HRM studies performed between October 2021 – March 2023 who provided consent for inclusion in the motility databank and completed ESQ-30 questionnaires. All values expressed as median (IQR: 25-75-centile). Spearman’s bivariate correlations were performed between ESQ-D, ESQ-R, ESQ-G and manometric variables (IRP, DCI, % failed, and % weak) as well as demographic variables (age). Group means were compared with the non-parametric Mann-Whitney U test.

Results

Within the study period, 681 patients underwent HREM and had complete ESQ-30 questionnaires. Of these patients, 151 female and 73 male participants (mean age 51.8 +/- 15.2 years) had normal esophageal motility by CCv4. ESQ-D and ESQ-R scores were significantly higher in women in comparison to men. ESQ-D was 10 in women and 5 in men (p=.021), and ESQ-R was 28 in women and 19 in men (p=.029). There was a weak negative correlation between age and reflux symptoms (R2 -.139, p = 0.038). There was no significant difference in manometric parameters between males and females (p ampersand:003E .05 for all comparisons). Dysphagia and globus weakly negatively correlated with median IRP (R2 -.156, p = .019 and R2 -.139, p = .038 for dysphagia and globus respectively).

Conclusions

In a population of symptomatic patients with normal esophageal motility, symptom profile differed based on age and sex. Women had higher dysphagia and reflux symptoms compared to men, while older patients had lower reflux symptoms. These findings suggest that esophageal sensitivity may vary with age and sex in patients with normal esophageal motility.

The finding of higher dysphagia and globus symptoms in patients with lower median IRP (integrated relaxation pressure) is an unexpected finding and may reflect reflux effect. Further studies to assess for the impact of GERD (using 24h pH-metry/MII) on patients with normal esophageal motor function are warranted.

Funding Agencies

None
A213 DUPILUMAB EFFICACY IN EOSINOPHILIC ESOPHAGITIS PERSISTS FOR HISTOLOGIC, SYMPTOMATIC, AND ENDOSCOPIC OUTCOMES REGARDLESS OF CONCOMITANT HIGH-DOSE PROTON PUMP INHIBITOR USE
Authors: Rothenberg M , Dellon E , Bredenoord A J , Martire E , Sun X , Laws E , Mortensen E , Maloney J , Glotfelty L , Shabbir A
Published: February 2024

Background

Proton-pump inhibitor (PPI) therapy is the most commonly used first-line therapy for eosinophilic esophagitis (EoE) but data informing long-term outcomes are limited.

Aims

This pre-specified analysis of data from the phase 3 LIBERTY EoE TREET (NCT03633617) study assessed the efficacy of weekly dupilumab vs placebo in patients (pts) with and without concomitant PPI use.

Methods

Pts with peak intraepithelial eosinophil (eos) count ≥15 eos/high-power field (hpf) after ≥8 weeks’ high-dose PPI were randomized to dupilumab or placebo. Pts on high-dose PPIs at screening remained on a high-dose regimen during the treatment period; switching of PPI types was permitted but new initiation of PPIs was prohibited. Endpoints at Week 24 were: proportion of pts achieving ≤6 eos/hpf, absolute change from baseline in Dysphagia Symptom Questionnaire (DSQ) score, % change in peak eos count, absolute change in Endoscopic Reference Score (EREFS) and Histologic Scoring System (HSS) grade/stage scores.

Results

In Parts A and B, respectively, 61.9% and 71.3% of pts in the dupilumab group and 64.1% and 72.2% in the placebo group were using PPIs at randomization. For pts treated with dupilumab vs placebo in Parts A and B, respectively, ≤6 eos/hpf was achieved by 69.2% (95% confidence interval [CI] 48.2–85.7) vs 8.0% (95% CI 1.0–26.0) and 59.6% (95% CI 45.8–72.4) vs 7.0% (95% CI 2.0–17.0) of pts using PPIs, and by 43.8% (95% CI 19.8–70.1) vs 0% (95% CI 0–23.2) and 56.5% (95% CI 34.5–76.8) vs 4.5% (95% CI 0.1–22.8) of pts not using PPIs. Least squares mean change from baseline in DSQ score for dupilumab vs placebo was –18.5 vs –12.9 and –21.8 vs –14.0 for pts using PPIs in Parts A and B, respectively, and –27.8 vs –3.8 and –28.4 vs –13.3 for those not using PPIs (Figure 1). Dupilumab improved outcomes vs placebo for secondary endpoints, with comparable results in pts with and without concomitant PPI use. Absolute change from baseline in EREFS score is shown in Figure 1. Dupilumab was generally well tolerated.

Conclusions

Dupilumab improved histologic, symptomatic, and endoscopic aspects of EoE in adults and adolescents, up to 24 weeks, regardless of concomitant high-dose PPI use.

Figure 1. Effect of dupilumab 300 mg qw versus placebo on primary endpoints (A) proportion of patients with peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf (B) absolute change from baseline in DSQ total score at Week 24 (C) absolute change from baseline in EREFS total score at Week 24, by concomitant PPI use

CI, confidence interval; DSQ, Dysphagia Symptom Questionnaire; EREFS, endoscopic reference score; eos, eosinophils; hpf, high-power field; LS, least squares; PPI, proton pump inhibitor; pt, patient; qw, once weekly; SE, standard error.

Funding Agencies

Research sponsored by Sanofi and Regeneron Pharmaceuticals Inc.
A215 DEFINING THE MODERN GLOBAL INCIDENCE AND PREVALENCE OF EOSINOPHILIC ESOPHAGITIS IN POPULATION-BASED STUDIES
Authors: Ray C M , Buhler K , Ma C
Published: February 2024

Background

Eosinophilic esophagitis (EoE) is an immune-mediated condition that results in esophageal dysfunction. Previous research demonstrated a marked increase in both incidence and prevalence of EoE globally, associated with a concomitant increase in type 2 inflammatory diseases. A previous meta-analysis suggested that the pooled prevalence of EoE was 34.4 cases/100,000 population and the incidence was 6.6 cases/100,000 person-years, but this analysis included only studies conducted to 2018.

Aims

To assess the current global incidence and prevalence of EoE, through systematic review and meta-analysis of population-based studies.

Methods

Electronic databases (Medline and Embase) were searched to February 22, 2023. Abstracts were screened, and full texts were reviewed for inclusion in meta-analysis. Original population-based studies published after 2018 that reported the incidence or prevalence of EoE in adults or children were included. Meta-analysis of incidence and prevalence rates, reported per 100,000 person-years or per 100,000 population, respectively, were pooled using a random-effects model. Heterogeneity was quantified using the I2 statistic.

Results

A total of 1916 unique reports were identified, and abstracts were reviewed. 129 full texts were read, and 21 reports met inclusion criteria for population based, incidence and prevalence studies. The pooled global incidence of EoE was 8.43 cases per 100,000 person-years [95% CI: 6.52, 10.34] (I2=99%) (Figure 1). The incidence was similar in adult and pediatric subgroups. The pooled global prevalence of EoE was 68.0 cases per 100,000 population [95% CI: 37.5, 123.4] (I2=99%).

Conclusions

The incidence and prevalence of EoE in recent studies is higher than that previously published. The prevalence of EoE is anticipated to compound, given that this is a disease typically diagnosed in young patients without an associated increased risk of mortality.

Funding Agencies

None
A216 MODERATE TO SEVERE ACUTE UPPER GASTROINTESTINAL BLEEDING IN RURAL NORTHERN ONTARIO: AN EPIDEMIOLOGICAL ANALYSIS OF AETIOLOGIES, GEOGRAPHIC LIMITATIONS, AND OUTCOMES
Authors: Saunders M , Savage D , Zezos P
Published: February 2024

Background

Hospitalizations for upper gastrointestinal bleeds (UGIBs) are resource-demanding as they often require blood transfusion, endoscopy, and intensive care unit admission. Referral centers that provide higher levels of care to remote regions treat illnesses, including UGIB, in much later stages of disease and of higher severity. The Thunder Bay Regional Health Sciences Center (TBRHSC) is a referral center servicing over 250,000 people over a geographically expansive region of Northern Ontario. Despite known barriers to accessing care, little data is currently available to guide our understanding of UGIB aetiologies, severity, and outcomes among patients living remotely in Canada.

Aims

This retrospective study aimed to evaluate epidemiological data among patients with UGIB at TBRHSC.

Methods

Of 441 patients with a discharge diagnosis of gastrointestinal hemorrhage from 2016–2022, inclusion criteria were met for 333. Patients under 18 y or with lower GIB were excluded. Patients were classified as regional if their primary address was outside the District of Thunder Bay.

Results

Patients were highly comorbid (median CCI = 5) and presented with a median (IQR) GBS of 9 (6) and Clinical Rockall Score of 3 (1). Of those who received inpatient endoscopy (n=248), findings included erosive gastritis (21%), gastric ulcer (14%), esophagitis (12%), duodenal ulcer (8%), AVM (7%), and variceal (6%). No definite lesion was observed in 62 patients (22%). The median (IQR) Complete Rockall Score was 4 (2) with major stigmata of recent hemorrhage found in 20%. There was a high prevalence (19%) of cirrhosis, of which 83% had a history of liver decompensation. In 49% of cirrhotic patients, culprit lesions did not include portal hypertensive gastropathy or variceal bleeding. Regional patients accounted for 14% of the population and travelled an average of 424 km to seek care at TBRHSC. Regional patients were younger and required more ICU admissions (p=0.01). ICU admission primarily due to UGIB was 5.4% and all-cause thirty-day mortality was 3.3%. Oral anti-coagulation use prevalence was 43.2% and was associated with a longer length of stay (pampersand:003C0.0001), higher proportion of all-cause 30-day mortality (pampersand:003C0.005). Forty-eight patients did not receive endoscopy due to bleeding stability, palliation, and preference.

Conclusions

Patients with UGIB at TBRHSC are a highly multimorbid population with a significantly burden of anticoagulant use, cirrhosis, and variceal bleeding. Comparative analysis with metropolitan centers will expand our understanding for providing UGIB care in Northern Ontario.

Funding Agencies

NOAMA
A217 EVALUATING PREDICTIVE SCORING AND OUTCOMES OF PATIENTS DISCHARGED HOME FROM THE EMERGENCY DEPARTMENT WITH UPPER GASTROINTESTINGAL BLEEDING
Authors: Saunders M , Jones M , Lawlor C , Savage D , Zezos P
Published: February 2024

Background

Upper gastrointestinal bleed (UGIB) is a common emergency department (ED) presentation. The Glasgow-Blatchford Bleeding Score (GBS) is a validated tool for predicting UGIBs requiring admission for endoscopic evaluation. Utilization of GBS in Northern Ontario EDs may help risk stratify UGIB to decrease return to care.

Aims

This study aimed to evaluate factors and outcomes of patients discharged from the ED with suspected UGIB.

Methods

A total of 1,139 charts were identified with an ICD-10 ED diagnosis of gastrointestinal hemorrhage from 2016-2022. Of these, 92 charts met inclusion criteria. Patients admitted to hospital from the index ED visit, who were below the age of 18 years at the time of presentation, or with clinically suspected lower gastrointestinal hemorrhage were excluded. Patient were further grouped by place of residence if their primary address was within Thunder Bay city limits or not.

Results

There were 48 males (52%) with a median age of 58.7 (IQR 32.2) at presentation with UGIB to ED. The median (IQR) Charlson Comorbidity Index (CCI) and GBS were 3 (5) and 3 (6), respectively. The odds ratio for returning to the ED and being admitted for UGIB within sixty days was 4.07 times greater for patients from the region compared to Thunder Bay residents (95% CI 1.28–12.97). GBS was found to be significantly greater (p=0.048, Mann-Whitney U-Test) among seven patients who underwent emergent endoscopy from the ED and were discharged home. In univariate K-M survival analysis, the mean survival time to hospital admission at sixty days was 45 days among those with a presenting GBS score of ampersand:003E3, compared to 57 days when GBS was 3 or less (pampersand:003C0.005, log rank Mantel-Cox). After adjustment for age, sex, place of residence, and CCI, there was a 17% increase in the expected hazard for hospital admission at sixty days for each point increase in GBS (95% CI 1.03–1.34). Similarly, the expected hazard for follow-up hospital admission was 2.95 times higher (95% CI 1.11–7.85) in patients living outside Thunder Bay travelling to seek care. There were no statistically significant hazards identified between age, sex, or CCI and hospital admission (Cox proportional hazards model, p=0.001). Of patients admitted to hospital within sixty days of ED discharge (n=17), the median length of stay was five days with 56% requiring blood transfusion and 83% receiving endoscopy.

Conclusions

Higher GBS scores and residence outside of Thunder Bay increase the likelihood of revisit and admission to hospital for UGIB following ED discharge. Future research will aim to compare outcomes among larger urban centers.

Funding Agencies

NOAMA
A220 MORTALITY IN PATIENTS WITH ULCERATIVE COLITIS UNDERGOING COLECTOMY (2016-2020)
Authors: Ahmed N S , Krawchuk S , buhler k , Stukalin I , Besney J , Shaheen A , Seow C , Novak K , Ingram R , Lu C , Kaplan G G , Panaccione R , Ma C
Published: February 2024

Background

Despite an expanding armamentarium of medical treatment options, the 10-year cumulative risk of colectomy for patients with ulcerative colitis (UC) remains 5-10%. Surgery for UC is associated with a substantial burden of mortality. A previous meta-analysis of population-based studies found that postoperative mortality was 0.7% of patients undergoing elective surgery and 5.3% of patients undergoing emergent colectomy.

Aims

Given improvements in managing acutely ill patients with UC, we aimed to evaluate contemporary rates of postoperative mortality following colectomy.

Methods

We analyzed data in the National Inpatient Sample (NIS) for 2016-2020. The NIS is an all-payer administrative health database, capturing information from ampersand:003E7 million inpatient admissions at ampersand:003E1000 hospitals across the United States annually. All analyses were weighted to account for the complex stratified survey design. Adult patients (≥18 yrs) with a primary diagnosis of UC undergoing colectomy were identified with ICD-10 coding. Rates of in-hospital postoperative mortality were calculated, and predictors of mortality were evaluated in survey-adjusted logistic regression.

Results

A total of 8570 hospitalizations for patients with UC undergoing colectomy were included. Mean age at colectomy was 44.5 years and 47% of patients were female. Emergency colectomy was performed in 38.2% [95% CI: 35.9%, 40.7%] of patients, and was attempted laparoscopically in 55.9% [53.1%, 58.7%]. Overall mortality from 2016-2020 was 1.2% [0.8%, 1.9%], but was 0.2% [0.1%, 0.8%] for elective surgery and 2.9% [1.9%, 4.5%] for emergent surgery. Stratified rates of mortality are summarized in Table 1. In multivariable analysis, age was not an independent predictor of mortality but laparoscopic surgery (adjusted odds ratio 0.24 [0.06-0.98], p=0.047) and elective resection (aOR 0.16 [0.04-0.68], p=0.01) were associated with a lower risk of postoperative death.

Conclusions

Approximately 1 in 100 patients undergoing colectomy for UC will die postoperatively. This risk is highest in comorbid patients undergoing open laparotomy or emergency colectomy. The risk of mortality in both emergent and elective settings is lower than previously reported.

Table 1. Stratified risks of mortality after colectomy for ulcerative colitis

Funding Agencies

None