Introduction

Intestinal ultrasound is emerging as a non-invasive method of monitoring patients with ulcerative colitis (UC). Our goal was to prospectively evaluate the association between ultrasound and endoscopic response and remission.

Aims & Methods

This is a prospective cohort of patients with left-sided UC (E2) or extensive UC (E3) with active disease (defined by SCCAI≥5), proposed to initiate/optimize therapy. Clinical activity (PRO2/SCCAI), biochemical activity (fecal calprotectin (FCal)/CRP), ultrasound (wall thickening (BWT)/Milan-Ultrasound Criteria (MUC) score) was assessed at week 0 (W0), 2 (W2), 6 (W6), 14 (W14), and 30 (W30), and endoscopic (Mayo endoscopic sub-score (sMayo)) at W0, W14, and W30. Ultrasound response was defined as: 1-reduction in BWT >25%, 2-reduction in BWT >2mm, or 3-decrease in BWT >1mm + decrease in Modified Limberg score ≥1. Endoscopic response was defined as a decrease in sMayo ≥1. Ultrasound remission was defined as MUC <6.2, and endoscopic remission as sMayo = 0.

Results

Twenty patients with UC were included (65% male, median age 54 (28-67) years, 50% E3, 60% on biologic therapy). Clinical, biochemical, ultrasound, and endoscopic activity characterization is found in Table 1. Clinical, biochemical, ultrasound, and endoscopic remission was achieved at W30 in 56%, 57%, 40%, and 33%, respectively. Patients with ultrasound response at W2 or ultrasound remission at W6 showed more endoscopic remission at W14 (p=0.032 and p=0.014, respectively). The presence of ultrasound remission at W14 was associated with endoscopic response at W30 (p=0.011).

Table 1 - Clinical, biochemical, ultrasound, and endoscopic activity characterization

Conclusion

The presence of ultrasound response at W2 and ultrasound remission at W6 was associated with endoscopic remission at W14. Additionally, ultrasound remission at W14 was associated with endoscopic response at W30. Ultrasound response in active ulcerative colitis appears to be early, allowing its use as a non-invasive tool for tight control, enabling early optimization of therapy.

Introduction

The biomarker fecal calprotectin (FC) is an efficacious tool for evaluating the level of disease activity in Crohn's and Ulcerative colitis, as well as for discriminating between inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Fecal Alpha-1 Antitrypsin (A1AT) is an excellent marker for intestinal protein loss and for an increased mucosal permeability.

Aims & Methods

The aim of this investigation was to determine the relationship between these two inflammatory fecal markers.
The study was performed retrospectively. We've collected test results for both markers between 2018 and 2022 from 459 patients who performed both tests (67.4% females; mean age 35.1±22.7). Linear correlation evaluation between FC and A1At was performed using the Pearson Correlation Coefficient (PCC).

Results

Out of the 459 patients, 274 were diagnosed with IBD, 61 with IBS and the rest with other, non-GI disorders. Out of these, 37.7% were positive for both markers, 45.3% were negative for both markers, 7.6% were positive for A1AT and not FC and 9.4% were positive for FC and not A1AT. Linear correlation between the two markers using six categories for data scoring, was found to be significant by PCC test (R=0.83, P values < 0.001) and sensitivity and sensitivity, specificity and accuracy were 80.1%, 85.6% and 83.0% respectively. Out of the 274 patients in the IBD group, 39.2% were positive for both markers, 45.8% were negative for both markers, 5.4% were positive for A1AT and not FC and 7.6% were positive for FC and not A1AT. Linear correlation between the two markers was found to be significant by PCC test (R=0.87, P values < 0.0001) and sensitivity, specificity and accuracy were 83.7%, 89.8% and 86.9% respectively.

Conclusion

Our study demonstrates that FC had a significant relationship with A1AT in patients with IBD and IBS. Furthermore, A1AT might be used as a surrogate marker for FC in the diagnosis of IBD, IBS-IBD discrimination and disease severity and treatment follow up. In addition to that, both markers used together may be used as a new clinical score for the assessment of IBD and IBS severity.

Introduction

Endoscopic retrograde cholangiopancreatography (ERCP) is recognized as a foundational procedure within the realm of interventional gastroenterology. Nevertheless, a significant amount of hands-on experience is required to achieve proficiency in this procedure, particularly with regard to the performance of sophisticated therapeutic maneuvers. Access to authentic training cases remains limited, while the use of cadaveric or live animal models presents distinct ethical, logistical and financial challenges (1). The advent of 3D printing technology paved the way for the development of advanced medical simulators. This study utilized computer-aided design and fused deposition modeling techniques to engineer an ERCP simulator that is both anatomically accurate and enables the training of trainee physicians in the intricate procedures of their chosen discipline (2). The simulator's modular design allows it to replicate a spectrum of papillary conditions, enabling targeted training in anatomies that are resistant to cannulation, as well as high-risk procedures like precut sphincterotomy and fistulotomy.

Aims & Methods

The design process for the ERCP simulator employed accessible parametric modeling software. Fabrication of the primary structural components, including the pancreas, the duodenum, and the bile ducts, were undertaken using polylactic acid (PLA) filament, a material that is both widely accessible and economical, thereby ensuring adequate rigidity and durability. The interchangeable papillary components were produced using flexible thermoplastic polyurethane (TPU) 95A filament, selected for its elasticity and capacity to be readily incised during procedures such as endoscopic sphincterotomy (EST). This allowed for easy exchangeability and facilitated the acquisition of skills by novice endoscopists. This process were selected on the basis of accessibility, user-friendly interface and cost-effectiveness, enabling replication in diverse settings. The biliary and pancreatic ductal lumens were meticulously calibrated to represent a range of procedural difficulty, with internal diameters that closely mirrored real anatomical variations.

Results

The simulator exhibited a high degree of anatomical and biomechanical fidelity, featuring a structurally stable duodenal framework and a flexible papillary interface. The simulator accurately reproduced tactile feedback experienced by gastroenterologists during ERCP, thereby validating its efficacy as a training tool. Furthermore, the simulator was enabled meticulous rehearsal of EST through sphincterotomy incisions and facilitated fistulotomy simulation using an elastomeric papilla structure. The simulator's design is both cost-effective and easily replicable, making it a valuable asset for continuing education and training in this field (3,4).

Conclusion

The ERCP simulator, fabricated using 3D printing technology, can be regarded as both technologically advanced and economically efficient for a number of complex procedures. These encompass endoscopic sphincterotomy, precut techniques, fistulotomy and stent placement. The simulator's design, featuring a modular papillary system, was crafted to provide a structured and progressive learning environment for novice users as well as experienced endoscopists. The simulator's cost-effectiveness, ease of scaling up and potential for wide dissemination signify a paradigm shift in ERCP education, facilitating proficiency acquisition in complex interventional endoscopy with greater efficiency and safety. Further investigations are needed for the simulator in ERCP training.

References

1. Lee S, Ahn JY, Han M, Lee GH, Na HK, Jung KW, et al. Efficacy of a three-dimensional-printed training simulator for endoscopic biopsy in the stomach. Gut and liver. 2017;12(2):149.
2. Zhang Y, Chen L, Hu B. Advances of 3D printing in gastroenterology and where it might be going. International Journal of Bioprinting. 2023;9(6):0149.
3. Lee DS, Ahn JY, Lee GH. A newly designed 3-dimensional printer-based gastric hemostasis simulator with two modules for endoscopic trainees (with video). Gut and Liver. 2019;13(4):415.
4. Bundy JJ, Weadock WJ, Chick JFB, Srinivasa RN, Patel N, Johnson E, et al. Three-dimensional printing facilitates creation of a biliary endoscopy phantom for interventional radiology-operated endoscopy training. Current Problems in Diagnostic Radiology. 2019;48(5):456-61.

Introduction

Alkaline phosphatase (ALP) is an important marker in primary biliary cholangitis (PBC) associated with risk for disease progression. In the pivotal, Phase 3, placebo-controlled RESPONSE trial (NCT04620733), seladelpar, a first-in-class delpar (selective PPAR-delta agonist), led to a significantly higher percentage of PBC patients achieving the composite biochemical endpoint (ALP <1.67 x upper limit of normal [ULN], ALP decrease ≥15%, and total bilirubin [TB] ≤ULN) compared with placebo (61.7% vs 20%) and decreased mean ALP levels after one year (-42.4% vs -4.3%, respectively). Here, we report additional data on ALP changes in the RESPONSE trial.

Aims & Methods

PBC patients who received ursodeoxycholic acid (UDCA) for ≥12 months or were UDCA intolerant and had ALP ≥1.67 x ULN and TB ≤2 x ULN were randomised 2:1 to daily seladelpar 10 mg or placebo. We assessed ALP changes across demographic subgroups, baseline ALP quartiles, and in patients who did not meet the composite biochemical endpoint. Worsening of ALP (increase >0 U/L from baseline) and safety by baseline ALP subgroup were also evaluated.

Results

128 patients were randomised to seladelpar and 65 to placebo with mean baseline ALP 314.6 U/L and 313.8 U/L, respectively; 53 (27.5%) patients had baseline ALP ≥350 U/L. Seladelpar reduced ALP at month 12 similarly across all subgroups, including in patients with cirrhosis, aged <50 years at PBC diagnosis, and of Hispanic/Latino ethnicity, vs placebo. For patients with baseline ALP ≥350 U/L, seladelpar led to a greater decrease (-44.8%; -216.1 U/L) in ALP vs placebo (-11.6%; -56.4 U/L); similar percent decreases were seen in patients with baseline ALP <350 U/L. Seladelpar reduced ALP similarly across baseline ALP quartiles. Among patients who did not meet the composite biochemical endpoint at month 12, ALP was decreased by -129.9 U/L for seladelpar vs -6.4 U/L for placebo. Seladelpar prevented worsening of ALP, with 7 (5.5%) seladelpar patients vs 19 (29.2%) placebo with increases in ALP from baseline at month 12. Adverse events were reported in 86.4% of patients with baseline ALP <350 U/L and 84.9% of patients with ALP ≥350 U/L, with similar proportions in seladelpar vs placebo patients.

Conclusion

Seladelpar led to robust and consistent ALP decreases across all subgroups studied. Substantial ALP decreases were also observed in patients who did not meet the composite endpoint criteria at month 12. Seladelpar was overall safe and well tolerated, regardless of baseline ALP level.

Disclosure

KVK reports receiving grants or contracts from 89Bio; Boston Scientific; Corcept Therapeutics; CymaBay Therapeutics; Genfit; Gilead Sciences, Inc.; GSK; Hanmi Pharmaceuticals; Intercept Pharmaceuticals; Ipsen; Janssen; Madrigal Pharmaceuticals; Mirum Pharma; NGM Bio; Novo Nordisk; Pfizer; Pliant Therapeutics; Terns Pharmaceuticals; Viking Therapeutics; and Zydus Pharmaceuticals; royalties or licences from UpToDate; consulting fees from 89Bio; CymaBay Therapeutics; Genfit; Gilead Sciences, Inc.; GSK; HighTide Biopharma; Inipharm; Intercept Pharmaceuticals; Ipsen; Madrigal Pharmaceuticals; Mirum Pharma; NGM Bio; and Zydus Pharmaceuticals; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie; Gilead Sciences, Inc.; and Intercept Pharmaceuticals; participation on a data safety monitoring board or advisory board with CTI and Medpace; and stock or stock options with Inipharm. KKY reports receiving honoraria from Gilead Sciences, Inc. SK reports receiving grants or contracts from Gilead Sciences, Inc.; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead Sciences, Inc. EM reports receiving payment or honoraria for speakers bureaus from AbbVie; Eli Lilly; Gilead Sciences, Inc.; and Ipsen; and support for attending advisory boards from AbbVie; Eli Lilly; Gilead Sciences, Inc.; and Ipsen. AB reports receiving grants or contracts and consulting fees from Chemomab; CymaBay Therapeutics; Gilead Sciences, Inc.; GSK; Intercept Pharmaceuticals; Ipsen; and Mirum Pharma; royalties or licences from UpToDate; payment for expert testimony from UMass; and participation on a data safety monitoring board or advisory board with Pfizer. KGR reports receiving grants or contracts from COUR Pharmaceuticals; CymaBay Therapeutics; Gilead Sciences, Inc.; and Pliant Therapeutics; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Mallinckrodt Pharmaceuticals and Gilead Sciences, Inc. CC reports consulting for CymaBay Therapeutics and Ipsen. JMS reports consultant honoraria from 89Bio; Alentis; Alexion; Altimmune; AstraZeneca; Bionorica; Boehringer Ingelheim; Gilead Sciences, Inc.; GSK; Inventiva Pharma; Ipsen; Lilly; Madrigal Pharmaceuticals; MSD; NorthSea Therapeutics; Novartis; Novo Nordisk; Pfizer; Roche; Sanofi; and Siemens Healthineers; speaker honoraria from AbbVie; Boehringer Ingelheim; Echosens; Gilead Sciences, Inc.; Madrigal Pharmaceuticals; Medscape; and Novo Nordisk; and stockholder options with AGED Diagnostics and Hepta Bio. SC, KY, and DBC are employees of Gilead Sciences, Inc., and may own stock in Gilead Sciences, Inc. CAM reports former employment with CymaBay Therapeutics, a Gilead Sciences, Inc., company, from 2007 to 2024; receiving consulting fees from Gilead Sciences, Inc.; being listed as an inventor on seladelpar patents; and a leadership or fiduciary role (paid or unpaid) with 89Bio (independent director).

Introduction

Distal malignant biliary obstruction (DMBO) is a serious diagnosis that often results in significant morbidity and mortality due to development of obstructive jaundice and related complications. Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) has been described as a salvage therapy for patients with DMBO following unsuccessful ERCP and/or EUS-guided biliary drainage [1,2]. EUS-GBD leverages the proximity of the gallbladder to the gastrointestinal lumen to establish a new passage for biliary drainage, which offers a viable and potentially safer alternative to current EUS-BD techniques, particularly when the gallbladder is distended [3]. There is a paucity of data reporting on the outcomes of EUS-GBD for this indication, limited by small cohorts an​d single-centre design. We report a multi-centre study of outcomes for EUS-GBD performed for DMBO in non-surgical candidates.

Aims & Methods

A review of a prospectively collected database of 28 EUS-GBD cases was performed between 2017 and 2024 at two referral centres in New Zealand. At both centres, patients were consented for biliary drainage via ERCP, EUS-BD, and/or EUS-GBD prior to sedation so that drainage could be achieved in a single anaesthetic session. Ethics approval was provided at participating centres before commencement. Included participants were adults diagnosed with DMBO who had unsuccessful ERCP and/or EUS-BD, and a patent hepatocystic junction. A transduodenal approach was universal, using electrocautery-enhanced lumen apposing metal stents (LAMS), and propofol-assisted anaesthesia. Technical success (TS), clinical success (CS), length of hospital stay (LOS), adverse events (AEs), reinterventions, and survival were recorded. CS was defined by improvement in biochemistry and symptoms within 72 hours. AEs were categorised into serious and non-serious events. Re-interventions were categorised into early (<7 days) or delayed (≥7 days) procedures. Follow up duration was from time of intervention until patient death.

Results

Mean age was 74 years with 32.1% females. Pancreatic cancer was the most common diagnosis. Mean Charlson comorbidity index was 9.8 ± 1.4 and mean ASA physical status classification was 3.9 ± 0.5. The 10mm LAMS was most commonly used (78.6%), with co-axial plastic stent placement performed in 25%. TS and CS was achieved in all cases. Pre-procedure bilirubin improved from mean 126 ± 115 umol/L to 63 ± 49 umol/L at 72 hours. There were no intra-procedural complications and no early reinterventions recorded. Mean LOS was 3 ± 3 days. There were 9 non-serious AEs, all infective in aetiology and treated with antibiotics. 5 serious AEs were recorded (cholangitis (n=1), recurrent obstruction (n=3) and LAMS obstruction (n=1)) and only these cases required reintervention. These were treated with ERCP (n=1), percutanous drainage (n=3), and stent removal (n=1) respectively. No repeat procedure was required in 23/28 (82.1%) patients. Median cohort survival was 135 days.

Conclusion

EUS-GBD offers excellent TS and CS as a salvage therapy for DMBO in the second or third-line setting. Furthermore, it is safe with a favourable AE profile, short LOS and low rate of reintervention. This is particularly important in this cohort of patients with advanced malignancy. EUS-GBD offers a durable therapy and can be used as destination platform for other DMBO therapeutics. We have also demonstrated feasibility of sequential deployment within the same interventional session as ERCP and EUS-BD procedures creating a streamlined process for limiting cumulative anaesthetic exposures.

References

1. Imai, H., et al., EUS-guided gallbladder drainage for rescue treatment of malignant distal biliary obstruction after unsuccessful ERCP. Gastrointestinal endoscopy, 2016. 84(1): p. 147-151.
2. Debourdeau, A., et al., Effectiveness of endoscopic ultrasound (EUS)‐guided choledochoduodenostomy vs. EUS‐guided gallbladder drainage for jaundice in patients with malignant distal biliary obstruction after failed endoscopic retrograde cholangiopancreatography: Retrospective, multicenter study (GALLBLADEUS Study). Digestive Endoscopy, 2024.
3. Kamal, F., et al., Efficacy and safety of EUS-guided gallbladder drainage for rescue treatment of malignant biliary obstruction: A systematic review and meta-analysis. Endoscopic ultrasound, 2023. 12(1): p. 8-15.

Introduction

Eosinophilic esophagitis (EoE) is an inflammatory disease that is the leading cause of food impaction in children and young adults. EoE is thought to be a food antigen-driven allergic disease, best characterized by eosinophil-predominant inflammation, esophageal dysfunction, and expression of Th2 cytokines. Thymic stromal lymphopoietin (TSLP) is a cytokine primarily secreted by epithelial cells in barrier tissues in response to danger signals, infectious agents, Th2 cytokines and environmental antigens. TSLP is a master regulator of Th2 inflammation. Genetic studies have linked single nucleotide polymorphisms in TSLP to Th2 driven diseases, including eosinophilic esophagitis. Recent single-cell sequencing studies demonstrated memory CD4 T cells expressing TSLP receptor correlated with esophageal eosinophil counts. While some data suggest a key role of TSLP in the pathogenesis of EoE, its relative contribution has not been established in in vivo models.

Aims & Methods

Experimental EoE was induced in male wild type mice by an initial skin-sensitization using oxazolone (OXA, 17 days) followed by intraesophageal challenge with oxazolone or vehicle control (19 days, total duration 36 days). TSLP expression in the esophagus was measured during the sensitization and challenge periods. To determine the role of TSLP in EoE, treatment with a TSLP neutralizing antibody or isotype control began prior to esophageal challenge. Eosinophil counts, epithelial and lamina propria thickening, epithelial cell proliferation and esophageal vascularization were assessed in esophageal tissue on day 36.

Results

Intraesophageal challenge with OXA induced a transient upregulation of TSLP in the esophagus at day 29, with TSLP being expressed primarily in esophageal epithelial cells. Inhibition of TSLP activity with a blocking antibody in OXA sensitized mice resulted in 60% fewer eosinophils compared to isotype treated controls (p<0.001). Additionally, anti-TSLP treatment also induced statistically significant reductions in epithelial and lamina propria thickness and basal cell zone proliferation (Table 1). When assessed by region, TSLP neutralization statistically significantly reduced esophageal vascularization in regions with the highest degree of eosinophil infiltration.

Conclusion

This is the first time neutralization of TSLP in an experimental mouse model of EoE is reported, demonstrating a key role of TSLP in EoE disease pathogenesis. Inhibition of TSLP markedly decreased esophageal eosinophilia, a key diagnostic criterion for EoE. Other histologic features of EoE were also reduced upon TSLP neutralization. Together with genetic and mechanistic studies associating TSLP with EoE pathogenesis, this data suggests TSLP may serve as a treatment target for patients with EoE.

Disclosure

KK, LW, and HO are employees of Uniquity Bio