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Introduction

While histo-endoscopic improvement is achieved with Upadacitinib (Upa) treatment of ulcerative colitis (UC), its effect on the inflammatory microenvironment (IME) has yet to be fully resolved. Unlocking quantitative insights of histologic features of the IME has the potential to reveal biomarkers for treatment selection. Here, we assessed machine learning (ML)-derived histologic IME features associated with endoscopic response (ER) using UC biopsies at baseline and induction in two Upa clinical trials.

Aims & Methods

IBD Explore¹ (PathAI, Boston, version 1.3), a suite of ML models previously trained to quantify tissue regions (e.g., epithelium) and cells (e.g., goblet cells), was deployed on hematoxylin and eosin (H&E)-stained whole-slide images (WSI) of baseline and induction biopsies from patients with UC (N=732) enrolled in two clinical trials (NCT02819635, NCT03653026). Human interpretable features (HIFs) were extracted from each WSI and associated with Upa treatment and ER measured at induction (week 8; Mayo Endoscopic score≤1). Analysis of Covariance (ANCOVA) was used to associate change from baseline (CBL) of HIFs with Upa treatment, and logistic regression was used to associate baseline HIFs with ER, using baseline clinical data and total Geboes scores as covariates. Multivariable classification models, using baseline HIFs, were also trained to predict ER in Upa treated patients. Models were trained using 5-fold cross-validation and evaluated on the held-out test set using average predictions across these folds.

Results

ML-derived HIFs (N=402) displayed a significant CBL after Upa treatment, and 193 HIFs were prognostic of ER. These HIFs included fraction of goblet cell mucin area, fraction of normal epithelium, density of goblet cells in epithelium, fraction of infiltrated epithelium relative to all epithelium, fraction of crypts with abscess (CA) + complete granulation tissue (CGT) area relative to mucosa, and density of neutrophils (Table 1). HIFs quantifying the fraction of eosinophils and neutrophils within 20 μm of goblet cells were both independently prognostic and Upa- dependent predictive of ER. Baseline HIFs were also prognostic, as a group, of ER in the treatment group (mean validation AUROC = 0.78, test-set AUROC = 0.84).

Feature	Adjusted Odds Ratio [95% confidence interval]
Elevated fraction of goblet cell mucin area	1.49 [1.18,1.88]
Elevated fraction of normal epithelium area	1.65 [1.32,2.07])
Elevated density of goblet cells in epithelium	1.77 [1.39, 2.25]
Elevated fraction of infiltrated epithelium area relative to all epithelium	0.69 [0.53, 0.89]
Elevated fraction of crypts with abscess(CA) and complete granulation tissue(CGT) area relative to mucosa	0.52 [0.38, 0.72]
Elevated density of neutrophils in all tissue regions	0.48 [0.32, 0.71]

Table 1. IME features associated with response to Upa

Conclusion

Here, using an ML-based approach to assess the UC IME, we identified a significant association between features relating to goblet cells, goblet cell mucin, and immune cells near goblet cells and Upa ER. These findings underscore the importance of granular IME characterization to better understand treatment mechanisms. These results also highlight the potential of histological biomarkers for predicting therapeutic outcomes. Further validation of these potential biomarkers in larger cohorts is necessary.

References

¹IBD Explore is for research use only. Not for use in diagnostic procedures.

Disclosure

PathAI authors are employees at PathAI and holders of company stock.
AbbVie authors are employees at AbbVie and holders of company stock

QUANTITATIVE HISTOLOGIC FEATURES OF THE INFLAMMATORY MICROENVIRONMENT IN PATIENTS WITH ULCERATIVE COLITIS ASSOCIATE WITH ENDOSCOPIC RESPONSE TO UPADACITINIB AT INDUCTION

John Shamshoian 1, Neel Patel 2, Sandrine Degryse 1, Jacqueline Brosnan-Cashman 1, Lara Murray 1, Christina Jayson 1, Kevin Kolahi 3, Jan-Renier Moonen 3, Aditee Shrotre 3, Xiao Zhou 3, Patrick Caplazi 3, Steven Chirieleison 3, Stephen Laroux 4

1 PathAI, Boston, United States

2 PathAI at time of submission, Boston, United States

3 AbbVie, South San Francisco, United States

4 AbbVie, Worcester, United States

Conference

UEG Week Berlin 2025

Topics

IBD

Submission format

Abstract

Session

The value of histology and ancillary tests (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

UEG Presentation

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BEYOND ENDOSCOPY: EVALUATING NON-INVASIVE TOOLS FOR MONITORING POSTOPERATIVE CROHN'S DISEASE RECURRENCE

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Introduction

Post-operative recurrence (POR) affects a substantial proportion of Crohn's disease (CD) patients following intestinal resection. While ileocolonoscopy remains the gold standard for detecting recurrence, its invasive nature and patient burden have spurred interest in non-invasive monitoring approaches. This study evaluates the performance of faecal calprotectin (FC) and cross-sectional imaging at different timepoints in predicting endoscopic recurrence in postoperative CD patients.

Aims & Methods

In this multicenter retrospective cohort of 895 CD patients who underwent ileocecal resection, we analyzed the diagnostic accuracy of FC measurements at 3, 6-12, and 18-24 months postoperatively for predicting endoscopic recurrence (Rutgeerts score ≥i2 or SES-CD ≥3). Additionally, we assessed the concordance between intestinal ultrasound (IUS) and magnetic resonance imagings (MRI) and endoscopic findings at both 6-12- and 18-24-months using kappa statistics.

Results

FC demonstrated modest discriminatory ability at 3 months (AUC 0.642, 95% CI: 0.530-0.753) and 6-12 months (AUC 0.653, 95% CI: 0.593-0.713), with improved performance at 18-24 months (AUC 0.676, 95% CI: 0.608-0.744). The optimal cutoff values for FC (47.5 μg/g at 3 and 6-12 months; 80.0 μg/g at 18-24 months) were substantially lower than standard thresholds (150-250 μg/g) used in non-operated patients.
At 6-12 months, radiological and endoscopic assessments showed moderate agreement (κ=0.426, p<0.001) with 63.2% concordance. At 18-24 months, IUS demonstrated superior agreement with endoscopic findings (κ=0.531, p<0.001; sensitivity 83.8%, specificity 72.7%) compared to MRI (κ=0.324, p<0.001). Notably, radiological remission at 18-24 months was identified as a significant protective factor against surgical recurrence (OR 0.356, 95% CI: 0.179-0.705, p=0.003).

Table I: Concordance between endoscopic and radiologic findings (IUS and MRI) for inflammation and remission at 18–24 months post-ileocecal resection. Abbreviations: IUS: Intestinal ultrasound, MRI: Magnetic resonance imaging.

Comparison	n	κ	Strength of Agreement	p-value	Condition	Endoscopic Activity	Endoscopic Remission
Endoscopic Remission 18–24m vs. IUS 18–24m	123	0.531	Moderate	<0.001	Active Inflammation	60	7
					Remission	21	35
					Total	81	42
Endoscopic Remission 18–24m vs. MRI 18–24m	140	0.324	Fair	<0.001	Active Inflammation	64	17
					Remission	28	31
					Total	92	48

Conclusion

Non-invasive monitoring with FC shows promise in postoperative CD surveillance, though diagnostic thresholds differ substantially from those established for non-operated patients. IUS demonstrates superior concordance with endoscopic findings compared to MRI, particularly at later timepoints. The protective role of radiological remission against surgical recurrence highlights the importance of transmural healing. Combining FC with radiological assessment, especially IUS, may provide a comprehensive, patient-friendly approach to monitoring postoperative CD, potentially reducing the need for invasive procedures in selected patients but further studies are needed in this direction.

BEYOND ENDOSCOPY: EVALUATING NON-INVASIVE TOOLS FOR MONITORING POSTOPERATIVE CROHN'S DISEASE RECURRENCE

Luisa Bertin 1, Benedetta Masoni 2, Silvia Ferretti 2, Alessandro Armuzzi 2, Cristina Bezzio 2, Miriana Zanconato 1, Gianluca Semprucci 1, Davide Giuseppe Ribaldone 3, Adele Capello 3, Giorgia Bodini 4, Francesco Calabrese 4, ANDREA PASTA 4, Linda Ceccarelli 5, Francesco Costa 5, Lorenzo Bertani 6, Marco Marino 7, Luca Navarria 7, Gianluca Benevento 8, Renato Sablich 8, Marta Ascolani 9, Michele Campigotto 9, Andrea Buda 10, Gaia Riguccio 10, Nicoletta Merlini 11, Elisabetta Dal Pont 12, Daniele Canova 13, Fabiana Zingone 1, Edoardo Vincenzo Savarino 1

1 University of Padova, Padova, Italy

2 IBD Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

3 University of Turin, Turin, Italy

4 Policlinico San Martino, Genova, Italy

5 AOU Pisa, Pisa, Italy

6 University of Pisa, Pisa, Italy

7 Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy

8 Ospedale S.Maria degli Angeli, Pordenone, Italy

9 Ospedale Ca'Foncello, Treviso, Italy

10 Ospedale di Santa Maria del Prato di Feltre, Feltre, Italy

11 Ospedale Vittorio Emanuele III, Montecchio, Italy

12 Ospedale San Martino di Belluno, Belluno, Italy

13 San Bortolo Hospital, Vicenza, Italy

Event

UEG Week Berlin 2025

Topics

IBD

Submission format

Abstract

Session

Predicting clinical outcomes in IBD

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

UEG Presentation

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THE EFFICACY AND SAFETY OF ETRASIMOD IN MILDLY TO MODERATELY ACTIVE ULCERATIVE COLITIS: RESULTS FROM THE GLADIATOR TRIAL

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Introduction

Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)_1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC), with demonstrated efficacy in patients (pts) with baseline modified Mayo Score (MMS) 4–9.¹ No prior clinical trials of advanced therapies in UC have studied efficacy only in pts with baseline MMS ≤6.

Aims & Methods

GLADIATOR (NCT04607837) was a proof-of-concept, global, randomised, double-blind, placebo-controlled trial to evaluate the efficacy and safety of etrasimod in adults with mildly to moderately active UC (MMS 4–6; endoscopic subscore ≥2; rectal bleeding subscore ≥1) and inadequate response, loss of response or intolerance to ≥1 UC therapy. Pts were randomised 2:1 to etrasimod 2 mg or placebo once daily, stratified by previous biologic/Janus kinase inhibitor exposure and baseline corticosteroid use. GLADIATOR used a treat-through design (12-week [wk] induction period followed by a 40‑wk maintenance period). From Wk 12, pts whose disease had worsened or not improved vs baseline may have been eligible to enrol in an open-label extension trial (NCT03950232). The primary efficacy endpoint was the proportion of pts achieving clinical remission at Wk 52; additional endpoints are shown in the Table. Safety was monitored throughout the study.

Results

In the primary analysis set for efficacy, 127 and 60 pts received etrasimod and placebo, respectively. At Wk 52, 26.0% and 18.3% of pts receiving etrasimod and placebo, respectively, were in clinical remission (p=0.2524; Table). At Wk 12, a greater proportion of pts receiving etrasimod achieved clinical remission, endoscopic improvement (EI) and endoscopic improvement-histologic remission (EIHR) vs placebo (p<0.05; Table). Pts receiving etrasimod were more likely to achieve sustained clinical remission vs placebo (p=0.0104; Table). Etrasimod was generally well tolerated and findings were consistent with the known safety profile.

Table. Proportions of pts (n [%]) achieving endpoints at Wk 12 and Wk 52 in GLADIATOR (nonresponder imputation)^a	Endpoint	Placebo (N=60)	Etrasimod 2 mg (N=127)	% difference from placebo^b (95% CI)	Difference from placebo p value^c
Wk 12 Wk 12 completers: Placebo: 56 (93.3)^d Etrasimod: 122 (96.1)^e	Clinical remission^f	7 (11.7)	36 (28.3)	15.6 (4.3, 26.9)	0.0068
	EI^g	12 (20.0)	56 (44.1)	23.3 (9.8, 36.9)	0.0007
	EIHR^h	8 (13.3)	37 (29.1)	15.0 (3.2, 26.8)	0.0128
Wk 52 Wk 52 completers: Placebo: 28 (46.7)ⁱ Etrasimod: 76 (59.8)^j	Clinical remission^f	11 (18.3)	33 (26.0)	7.4 (-5.2, 19.9)	0.2524
	EI^g	14 (23.3)	41 (32.3)	8.2 (-5.2, 21.7)	0.2302
	EIHR^h	9 (15.0)	32 (25.2)	9.6 (-2.1, 21.3)	0.1089
	CS-free clinical remission^k	10 (16.7)	32 (25.2)	8.5 (-3.7, 20.7)	0.1726
Wk 12 and Wk 52	Sustained clinical remission^l	3 (5.0)	21 (16.5)	11.2 (2.6, 19.8)	0.0104
^aAll randomised pts who received ≥1 dose of study treatment with baseline MMS 4–6, baseline ES ≥2 and baseline RBS ≥1 were included in the primary analysis set for efficacy analysis. All pts with missing data were treated as nonresponders in the primary analysis. ^bEstimated common risk difference using the Mantel–Haenszel weighted method, stratified by naïve to biologic/JAKi therapy at trial entry (yes/no) and baseline CS use (yes/no). ^cFrom Mantel–Haenszel test and not adjusted for multiplicity. ^dIn the placebo group, prior to Wk 12, the following reasons for discontinuation were reported: AE (n=2 [3.3%]); withdrawal by pt (n=2 [3.3%]). ^eIn the etrasimod group, prior to Wk 12, the following reasons for discontinuation were reported: AE (n=3 [2.4%]); withdrawal by pt (n=1 [0.8%]); disease worsening (n=1 [0.8%]). ^fClinical remission was defined as SFS=0 or 1 (and no greater than baseline), RBS=0 and ES ≤1 (excluding friability). ^gEI was defined as ES ≤1. ^hEIHR was defined as ES ≤1 with histologic remission measured by Geboes Index score <2.0. ⁱIn the placebo group, after Wk 12, the following reasons for discontinuation were reported: disease worsening (n=26 [43.3%]); withdrawal by pt (n=2 [3.3%]). ^jIn the etrasimod group, after Wk 12, the following reasons for discontinuation were reported: disease worsening (n=33 [26.0%]); withdrawal by pt (n=5 [3.9%]); AE (n=4 [3.1%]); physician decision (n=2 [1.6%]); lack of efficacy (n=1 [0.8%]); study termination by sponsor (n=1 [0.8%]). ^kCS-free clinical remission was defined as clinical remission at Wk 52 and CS free for ≥12 wks immediately prior to Wk 52. ^lSustained clinical remission was defined as clinical remission at both Wk 12 and Wk 52. AE, adverse event; CI, confidence interval; CS, corticosteroid; EI, endoscopic improvement; EIHR, endoscopic improvement-histologic remission; ES, endoscopic subscore; JAKi, Janus kinase inhibitor; MMS, modified Mayo score; N, number of pts in cohort; pt, patient; RBS, rectal bleeding subscore; SFS, stool frequency subscore; wk, week.

Conclusion

In pts with mildly to moderately active UC, etrasimod demonstrated higher rates of clinical remission, EI and EIHR at Wk 12, as well as sustained clinical remission at Wk 52, vs placebo. However, the primary endpoint of clinical remission at Wk 52 was not met. Etrasimod demonstrated efficacy in pts with UC with an MMS 4–9, including those with an MMS 4–6, in the ELEVATE UC clinical programme.¹ The proof-of-concept GLADIATOR trial further supports etrasimod’s efficacy in active UC and provides important insights on studying pts with mildly to moderately active UC.

References

1. Sandborn WJ et al. Lancet 2023; 401: 1159–1171.

Disclosure

SD: Lecture fees: AbbVie, Amgen, Ferring Pharmaceuticals Inc, Gilead, Janssen, Mylan, Pfizer Inc, Takeda; Consultancy fees: AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead Sciences, Hospira, Janssen, Johnson&Johnson, MSD, Mundipharma, Pfizer Inc, Roche, Sandoz, Takeda, TiGenix, UCB, Vifor; Directorship: Gastroenterology and Endoscopy.
MG, KL: Employees of Pfizer AG; shareholders of Pfizer Inc.
LPB: Consultancy fees: AbbVie, Abivax, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GlaxoSmithKline, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer Inc, Prometheus, Protagonist, Roche, Roivant, Samsung, Sandoz, Sanofi, Takeda, Theravance, Thermo Fisher, Tigenix, Tillotts, Viatris, Vifor, Vectivbio, Ventyx, Ysopia; Grants: Takeda, Fresenius Kabi, Celltrion; Lectures: AbbVie, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genetech, Gilead, Janssen, Lilly, Medac, MSD, Pfizer Inc, Sandoz, Takeda, Tillotts, Viatris, Vifor.
AJY: Consultancy fees: AbbVie, Arena, BMS, Celltrion, Pfizer Inc, Takeda; Lectures: AbbVie, BMS.
MCD: Consultancy fees: AbbVie, Abivax, Arena Pharmaceuticals, AstraZeneca, BMS, Eli Lilly, Galapagos, Genentech, Gilead Sciences, Janssen Pharmaceuticals, Johnson&Johnson, Merck, Pfizer Inc, Prometheus Laboratories, Prometheus Biosciences, Sanofi, Sphyre, Takeda, UCB; Shareholder: Trellus Health; Directorship: Trellus Health.
DTR: Consultancy fees: AbbVie, Abivax SA, Altrubio, Avalo Therapeutics, Bausch Health, Bristol Myers Squibb, Buhlmann Diagnostics Corp, Celltrion, ClostraBio, Connect BioPharma, Douglas Pharmaceuticals, Eli Lilly & Co., Foresee, Genentech, Image Analysis Group, InDex Pharmaceuticals, Iterative Health, Janssen Pharmaceuticals, Odyssey Therapeutics, Pfizer Inc, Sanofi, Takeda Pharmaceuticals, Throne, Vedanta; Grants: Takeda.
BGF: Senior Scientific Director of Alimentiv Inc, which provides central reading services. He is not a company employee and has no equity stake in the organisation, which is owned by a medical trust; Speaker fees: AbbVie, Janssen, Takeda; Consultancy fees: AbbVie, AbolerIS, AgomAB Therapeutics, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport Inc, Arena Pharma, Avoro Capital Advisors, Atomwise, BioJamp, Biora Therapeutics, Boehringer Ingelheim, Boxer, Celsius Therapeutics,Celgene/BMS, Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech, Gilead, Gossamer Pharma, GSK, Hinge Bio, Hot Spot Therapeutics, Index Pharma, Imhotex, Immunic Therapeutics, JAKAcademy, Janssen, Japan Tobacco Inc, Kaleido Biosciences, Landos Biopharma, Leadiant, L.E.K. Consulting, Lenczner Slaght, LifeSci Capital, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic Therapeutics, Mylan, OM Pharma, Origo BioPharma, Orphagen, Pandion Therapeutics, Pendopharm, Pfizer Inc, Prometheus Therapeutics and Diagnostics, Play to Know AG, Progenity, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Surrozen Inc, Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx Biosciences, VHSquared Ltd, Viatris, Ysios, Ysopia, Zealand Pharma; Shareholder: Gossamer Pharma.
GRDH: Advisory fees: AbbVie, AstraZeneca, Alimentiv, BMS, Boehringer Ingelheim, Celltrion, Cosmo, Eli Lilly, Galapagos, GSK, Johnson&Johnson, Takeda, Pfizer Inc, Polpharma, Prometheus Biosciences, Tillotts, Ventyx; Speaker fees: AbbVie, Boehringer Ingelheim, Celltrion, Eli Lilly, Johnson&Johnson, Takeda, Pfizer Inc, Tillotts.
FB: Research/grants: AbbVie, Amgen, Eurogenerics, Janssen, Takeda; Lectures: AbbVie, Arena Pharmaceuticals, Celltrion, Ferring, Galapagos, Janssen, Merck Sharp & Dohme, Pfizer Inc, Takeda; Consultancy fees: AbbVie, Abivax, Amgen, Arena Pharmaceuticals, Celgene, Celltrion, Ferring, Fresenius Kabi, Janssen, Merck Sharp & Dohme, Pfizer Inc, Sandoz.
GG, JY, NL, CZ, WW, SM, EHL, IM, SS, WN: Employees/shareholders of Pfizer Inc.
SV: Lectures: AbbVie, Dr. Falk Pharma, Ferring, Galapagos, Hospira, Janssen, MSD, Takeda, Tillotts; Consultancy fees: AbbVie, AbolerIS Pharma, Alimentiv, Arena, AstraZeneca, Avaxia, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Eli Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, Johnson&Johnson, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer Inc, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance Biopharma, Tillotts Pharma AG, Zealand Pharma; Grants: AbbVie, MSD, Pfizer Inc, Galapagos, Janssen, Takeda.

THE EFFICACY AND SAFETY OF ETRASIMOD IN MILDLY TO MODERATELY ACTIVE ULCERATIVE COLITIS: RESULTS FROM THE GLADIATOR TRIAL

Silvio Danese 1, Martina Goestch 2, Laurent Peyrin-Biroulet 3, Andres Yarur 4, Marla C. Dubinsky 5, David T. Rubin 6, Brian G. Feagan 7, Geert R. D'Haens 8, Filip Baert 9, Krisztina Lazin 2, Guibao Gu 10, Jin Yu 10, Nervin Lawendy 11, Chuanbo Zang 11, Wenjin Wang 11, Sujatha S. Menon 12, Ernest Law 13, Irene Modesto 13, Sarah Sidhu 13, Wojciech Niezychowski 11, Severine Vermeire 14

1 Division of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital and Vita Salute San Raffaele University, Milan, Italy

2 Pfizer AG, Zürich, Switzerland

3 Department of Gastroenterology, CHRU Nancy, INSERM NGERE, Université de Lorraine, Vandœuvre-lès-Nancy, France

4 Inflammatory Bowel Disease Center and Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, United States

5 Susan and Leonard Feinstein IBD Center, Icahn School of Medicine, Mount Sinai, New York, NY, United States

6 University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, United States

7 Division of Gastroenterology, Department of Medicine, Western University, London, ON, Canada|||Alimentiv Inc, London, ON, Canada

8 Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Amsterdam, Netherlands

9 Department of Gastroenterology, AZ Delta, Roeselare, Belgium

10 Pfizer Inc, La Jolla, CA, United States

11 Pfizer Inc, Collegeville, PA, United States

12 Pfizer Inc, Groton, CT, United States

13 Pfizer Inc, New York, NY, United States

14 Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium

Event

UEG Week Berlin 2025

Topics

IBD Mechanisms & Personalised Medicine

Submission format

Abstract

Session

Advanced therapies in ulcerative colitis

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

UEG Poster

Standard Poster

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Introduction

Lateral lymph node dissection (LLND) is considered for patients with advanced lower rectal cancer because of possibility of metastasis. The standard surgical procedure for ulcerative colitis (UC)-associated cancer is total colectomy; however, the significance of LLND in UC-associated rectal cancer remains unclear.

Aims & Methods

The aim of this study is to clarify the outcomes of LLND for UC-associated rectal cancer. Of 1,249 patients treated for UC-associated colorectal neoplasms between 1983 and 2020 at 43 Japanese institutions, we retrospectively analyzed 415 patients with rectal cancer.

Results

LLND was performed in 45 (10.8%) patients with UC-associated rectal cancer: 33 of 139 (23.7%) patients with pT3–4 cancer and 12 of 276 (4.3%) patients with pTis–T2. Of the 45 patients with LLND, 11 (24.4%) had lateral lymph node metastasis (LLNM). LLNM-positive group (n = 11) had a significantly higher proportion of patients with pT3-4 cancer (100% vs. 64.7%, P < 0.0046) and poorly differentiated adenocarcinoma/ signet-ring cell carcinoma/ mucinous adenocarcinoma (por/sig/muc) (70% vs. 17.7%, P = 0.002) than LLNM-negative group (n = 34). There was no significant difference in R0 resection rate between the LLND and non-LLND groups (81.8% vs. 91.2%, P = 0.41). The LLNM-positive group showed significantly worse 5-year overall (30.8% vs. 82.8%, P = 0.0005) and 5-year disease-free (0% vs. 72.4%, P < 0.001) survival rates than the LLNM-negative group. There was no significant difference in the administration of adjuvant chemotherapy between the two groups (54.6% vs. 40.6%, P = 0.42).

Conclusion

The LLND rate for UC-related rectal cancer was 23% in patients with T3-4 cancer in Japan. The LLNM-positive group had more advanced disease, more por/sig/muc histology, and showed poor prognostic outcomes even after LLND.

OUTCOMES OF LATERAL LYMPH NODE DISSECTION FOR ULCERATIVE COLITIS-ASSOCIATED RECTAL CANCER

Satoshi Okada 1, Takahide Shinagawa 1, Koichi Komatsu 1, Kaoruko Funakoshi 1, Ayano Saito 1, Motoi Uchino 2, Hiroki Ikeuchi 2, Kohei Shigeta 3, Shiro Oka 4, Kitaro Futami 5, Michio Itabashi 6, KAZUHIRO WATANABE 7, Tatsuki Noguchi 1, Yoichi Ajioka 8, Kenichi Sugihara　 9, Soichiro Ishihara 1

1 The University of Tokyo, Tokyo, Japan

2 Hyogo College of Medicine, Hyogo, Japan

3 Keio University School of Medicine, Tokyo, Japan

4 Hiroshima University Hospital, Hiroshima, Japan

5 Fukuoka University Chikushi Hospital, Fukuoka, Japan

6 Tokyo Women’s Medical University, Tokyo, Japan

7 Tohoku University Graduate School of Medicine, Miyagi, Japan

8 Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan

9 Institute of Science Tokyo, Tokyo, Japan

Conference

UEG Week Berlin 2025

Topics

IBD

Submission format

Abstract

Session

IBD (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

UEG Presentation

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EXACERBATED COLITIS AND ALTERED METABOLOME IN MICE COLONIZED WITH PRE-DIAGNOSIS MICROBIOME OF HUMANS WITH CROHN’S DISEASE

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Introduction

Crohn’s disease (CD), as a type of inflammatory bowel disease (IBD), is characterized by chronic inflammation in the intestinal tract and its incidence is rising globally. The factors involved in causing or triggering Crohn’s disease (CD) have yet to be confirmed. We recently demonstrated that the intestinal microbiome composition is associated with the risk of CD development; however, its potential causal effect remains unknown. Our study investigated whether stool microbiome might contribute to or trigger dysregulated immune response by transplanting stool into germ-free mice (GFM).

Aims & Methods

Fecal samples were collected from 12 discordant pairs of siblings (one who did not develop CD referred to as Healthy Matched Control (HMC) and another who subsequently developed CD, referred to as pre-CD). These subjects were recruited as part of the Crohn's and Colitis Canada Genetic, Environmental, Microbial Project (CCC-GEM) project, a cohort of prospectively followed healthy first-degree relatives. The stool was transplanted into RAG1-/- GFM before T-cell transfer-induced colitis (3 transplanted mice per donor). Body weight was monitored for 6 weeks after T-cell transfer. Fecal Lipocalin-2 (LCN-2) was measured by ELISA to assess gut inflammation. Intestinal tissue damage was assessed by a validated histology scoring. Pro-inflammatory cytokine gene profiles of intestinal tissue were measured by qPCR. The feces of colitic mice were collected after 6 weeks of T-cell transfer and used to investigate metabolic profile measured by UHPLC-MS/MS.

Results

At week 2 after T-cell transfer, mouse recipients of pre-CD stool experienced greater weight loss than mice receiving stool from HMC (p=0.004). LCN-2 of pre-CD mice was significantly higher after T-cell transfer at week 3. Intriguingly, pre-CD stool recipient mice had a higher histological damage score in the ileum (p=0.031). Mice receiving pre-CD stool had increased expression of selected pro-inflammatory cytokine genes in the ileum including Tnfα, Il-1β, Ifnγ, Il-10 and Tgfβ compared to mice that received HMC stool. Colonic tissue showed significant increases in TNFα and Tgfβ in the mice recipient of the pre-CD stool. Moreover, pre-CD stool led to significant changes in 40 fecal metabolites compared to HMC microbiome (0.01<p≤0.05). Spearman correlation between certain metabolites and colitis markers in mouse was observed. Fecal metabolomics in humans revealed two shared metabolic pathways associated with future onset of CD and murine inflammatory markers. Notably, there was a positive correlation between sphingolipids in humans and mice that was associated with increased colitis in mice. Sphingolipid metabolites also demonstrated positive correlation with mouse colitis marker and human CD subclinical markers.

Conclusion

These results showed that transplanted pre-CD stool worsened T cell transfer colitis in mice compared to HMC stool. This suggests that stool microbiome of individuals with CD is functionally altered years before diagnosis, exhibiting greater inflammatory potential when transferred to susceptible mice. Modulating pre-CD microbiome composition and/or function could lead to novel methods of CD prevention.

EXACERBATED COLITIS AND ALTERED METABOLOME IN MICE COLONIZED WITH PRE-DIAGNOSIS MICROBIOME OF HUMANS WITH CROHN’S DISEASE

Cong Phi Dang 1, Alice Chen-Liaw 2, Mingyue Xue 3, Alexander Luchak 1, Kaiwen Mu 1, Qilong Li 3, Ren Mu Yan 1, Sun-Ho Lee 3, Paul Moayyedi 4, Anne Griffiths 5, Colette Deslandres 6, Sanjay Murthy 7, Allan Hillary Steinhart 8, Anthony Otley 9, Levinus Dieleman 10, Kevan Jacobson 11, David T. Rubin 12, Remo Panaccione 13, Brian G. Feagan 14, Catherine Streutker 15, Ilaria Mogno 2, Graham J. Britton 2, Jeremiah J. Faith 2, Kenneth Croitoiru 3, Williams Turpin 3

1 University of Toronto, Toronto, Canada

2 Icahn School of Medicine at Mount Sinai, New York, United States

3 Mount Sinai Hospital, Toronto, Canada

4 McMaster University Dept. of Medicine Dept. of Gastroenterology - McMaster University Dept. of Medic, Hamilton, Canada

5 Hospital for Sick Children, Toronto, Canada

6 University of Montreal, Montreal, Canada

7 Ottawa Hospital Research Institute, Ottawa, Canada

8 Mount Sinai Hospital Dept. of Medicine, Toronto, Canada

9 Dalhousie University, Halifax, Canada

10 University of Alberta Division of Gastroenterology Dept. of Medicine, Edmonton, Canada

11 British Columbia Children's Hospital, Vancouver, Canada

12 University of Chicago Medicine, Chicago, United States

13 University of Calgary, Calgary, Canada

14 Alimentiv Inc., London, Canada

15 St Michael’s Hospital, Toronto, Canada

Event

UEG Week Berlin 2025

Topics

Colorectal Gut Microbiota Mechanisms & Personalised Medicine IBD

Submission format

Abstract

Session

Dissecting the microbiome in gut inflammation

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Clinical Case Summary

Background: Hepatic artery aneurysm (HAA) is a rare and often asymptomatic pathology with a high risk of rupture [1]. HAA is mostly asymptomatic, and 60-80% of the patients are diagnosed when the aneurysm has complications [2]. HAA is a rare cause of jaundice, the most common causes are cholelithiasis, cholangitis, pancreatic head cancer and cholangiocarcinoma [3]. True aneurysms involve all layers of the wall, while pseudoaneurysms result from a tear in the vessel wall with subsequent periarterial hematoma formation.
Case Report: A 45-year-old male presented to the hospital with painless jaundice and fever. Patient is known to have chronic hepatitis B virus, with no treatment. Magnetic resonance cholangiopancreatography (MRCP) was done revealing dilated biliary radicles down to long common bile duct (CBD) stricture by mostly external compression.
Endoscopic retrograde cholangiopancreatography (ERCP) was done, opacification of biliary tree showed dilated biliary radicles on both sides down to tight long CBD stricture about 5 cm in length. Placement of plastic biliary stent was done with adequate biliary drainage.
Computed tomography (CT) done showed evidence of contrast extravasation of common hepatic artery (CHA), forming a large pseudoaneurysm 7x4 cm, compressing the CBD.
After discussion with the patient about treatment options, interventional radiology consultation was done, angiography with occlusion of aneurysm using mixture of lipiodol and histoacryl successfully. Follow-up CT showed reduction size of the aneurysm with no flow inside.
Discussion: Management of HAA is highly variable and depends on clinical presentation and anatomic location. Biliary stenting provides temporary relief for patients with obstructive jaundice. Definitive options include open aneurysmal repair versus endovascular therapy. Hepatic artery aneurysms represent a significant risk for hemorrhage and therefore must be addressed promptly once discovered [4].

References

1- Jana M, Gamanagatti S, Mukund A, Paul S, Gupta P, Garg P, Chattopadhyay TK, Sahni P. Endovascular management in abdominal visceral arterial aneurysms: A pictorial essay. World J Radiol 2011;3:182-7.
2- Sheldon DM, Crawford M, Mihrshahi S, Gallagher J, Storey D. Therapeutic considerations in obstructive jaundice due to hepatic artery aneurysm. HPB (Oxford) 2006;8:74.
3- Hama Y, Chakiri A, Azzaoui F, Dahmane H, Lafrouji S, et al. (2019) Hepatic Artery Aneurysm: A Rare Presentation as Painless Obstructive Jaundice. Med Rep Case Stud 4: 173.
4- Schick C, Ritter RG, Balzer JO, et al. Hepatic artery aneurysms: treatment options. Eur Radiol. 2004;14:157–159.

HEPATIC ARTERY ANEURYSM AS A RARE CAUSE OF OBSTRUCTIVE JAUNDICE

Fady Karam 1, Ahmed Altonbary 1, Amr Elrabat 1

1 Mansoura University, Mansoura, Egypt

Conference

UEG Week Berlin 2025

Topics

Hepatobiliary

Submission format

Clinical Case

Session

CLINICAL CASES (Posters)

Published

2025

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Introduction

Colorectal cancer (CRC) screening has been widely implemented, and recent advances in fecal immunochemical testing (FIT) have led to a shift in screening modalities from guaiac fecal occult blood testing (gFOBT) to FIT. In Japan, FIT was introduced into the national screening program in 1992, and a two-sample method has been offered to individuals aged 40 years and older. However, there is no standardized use of testing devices or cutoff values. Although hemoglobin concentrations of 100-150 ng/g are commonly used, few studies have evaluated cut-off values in population-based screening. An optimal cut-off value should be defined for adequate quality assurance by considering the benefits and harms of CRC screening.

Aims & Methods

To evaluate the optimal cutoff value for population-based screening, we compared the test performance of FIT according to different cutoff values. A total of 383,793 individuals participated in population-based screening in Ibaraki Prefecture from April 2021 to March 2023. The OC-sensor was used as the testing modality, with a default cut-off value of 100 ng/g. Test performance indicators, including positive rate, detection rate, positive predictive value (PPV), cancer miss rate, and number needed to scope (NNS), were assessed across cut-off values ranging from 100 to 250 ng/g. Detection rate, PPV, and NNS were explicitly calculated for CRC/ Advanced neoplasia (AN). Since the colonoscopy completion rate is typically around 70％, PPV and NNS were calculated on a per-protocol basis.

Results

Subjects who submitted two samples were 370419. Among them, 863 cases of CRC and 1944 cases of advanced adenomas were diagnosed. At a cutoff value of 100 ng/g at the baseline, the positive rate was 6.7% (95%CI: 6.7-6.8) and the colonoscopy completion rate was 76.0% (95%CI: 75.4-76.5) (Table). For AN, the detection rate was 0.76％ (95%CI: 0.73-0.79), 14.8% for PPV (95%CI: 14.3-15.3), and 6.8% (95%CI: 6.5-7.0) for NNS. For CRC detection, the detection rate was 0.23％ (95%CI: 0.22-0.25), 4.5% for PPV (95%CI: 4.3-4.8), and 22.0% (95%CI: 22.0-23.5) for NNS. The NNS decreased as the cutoff value increased, but the CRC miss rate also increased. The cutoff value reached 180 ng/g, the CRC miss rate became 19.5% (95%CI:16.8-22.1), whereas the positive rate was 4.2% (95%CI: 4.2-4.3), 0.19％ (95%CI: 0.17-0.20) for CRC detection rate, 5.9% (95%CI: 5.5-6.3) for PPV, and 16.9 (95%CI: 15.8-18.2) for NNS.

Conclusion

The current cutoff value led to high detection rates for both CRC and AN, but it also required a greater number of colonoscopies. The availability of colonoscopy services varies across local municipalities and is often insufficient in rural areas. Adjusting the cutoff value is frequently used to address disparity in access to colonoscopy. However, the trade-off among benefits, harms, and resources is influenced by the social context, including individual preference and value. Therefore, an acceptable level of cancer miss rates should be carefully evaluated. Since the optimal cutoff value cannot be determined unequivocally, a comprehensive decision should be made by balancing benefits, harms, and resources, while also considering the preference of local residents.

References

Young GP, et al. Detection of advanced colorectal neoplasia and relative colonoscopy workloads using quantitative faecal immunochemical tests: an observational study exploring the effects of simultaneous adjustment of both sample number and test positivity threshold. BMJ Open Gastroenterol. 2020 ;7: e000517