Introduction

Acute Severe Colitis (ASC) is a medical and surgical emergency that requires prompt and well-coordinated treatment. The initial treatment typically involves intravenous corticosteroids. However, a significant number of patients (around 30-40%) do not respond to corticosteroids and need alternative treatment. Predicting resistance to the first-line treatment early on is a challenge that has not been fully addressed. A new index called ADMIT-ASC (Admission Model for Intensification of Therapy in ASC), which considers biological and endoscopic data, has been developed to predict the failure of steroid treatment.
Our goal is to validate this index's effectiveness in predicting corticosteroid resistance in ASC associated with ulcerative colitis (ASUC).

Aims & Methods

We conducted a retrospective chart review of 210 patients admitted to the gastroenterology department at Sahloul Sousse for ASUC between March 2010 and February 2020. Failure of corticosteroid therapy was defined as the need for second-line medical treatment or colectomy.
The ADMIT-ASC score is an index ranging from 0 to 4, calculated by adding points based on specific parameters at admission: CRP ≥ 100 mg/L (1 point), albumin ≤ 25 g/L (1 point), and endoscopic UCEIS score ≥ 4 (1 point) or ≥ 7 (2 points). The area under the ROC curve (AUROC) was calculated to evaluate the accuracy of this score in predicting the failure of corticosteroid therapy.

Results

Two hundred and seventy patients were included in the study, with an average age of 33.5 years and a male-to-female ratio of 0.68. Of these patients, 62.8% had a history of UC, while ASC was the initial episode in 37.2% of cases. Fifty-two point thirty-eight percent (52.38%) of patients did not respond to intravenous corticosteroid treatment. Among them, 34.3% responded to ciclosporin, 2.4% to infliximab, and 5.2% underwent salvage colectomy. The average ADMIT-ASC score was 2.14 ± 0.99. Patients with scores of 0, 1, 2, 3, and 4 had response rates of 100%, 62.7%, 56%, 43.4%, and 25%, respectively (p=0.01). The failure rate of first-line medical treatment was 52.7% for a score ≥ 2 and 62% for a score ≥ 3 (95% CI). The AUROC of ADMIT-ASC in predicting corticosteroid resistance was 0.628 (p=0.01, 95% CI [0.552; 0.703]).

Conclusion

The ADMIT-ASC index seems to be a reliable predictor of response to corticosteroid therapy in ASC patients, starting from admission. This could help identify patients early on who would benefit from switching to second-line treatment promptly. However, larger prospective studies are needed to confirm these results.

Disclosure

I confirm that I do not have any conflicts of interest regarding this subject

Introduction

Patients suffering from inflammatory bowel diseases (IBD) manifest an increased risk of developing colitis-associated colon cancer (CAC). Interleukin 22 (IL22) is a cytokine involved in the proliferation and survival of epithelial cells. However, it also correlates with the development of tumoral lesions. IL22 is secreted by different immune cell types, including iNKT cells, tissue resident cells possessing cytotoxic properties in colorectal cancer (CRC). In IBD patients, though, iNKT cells perform both pro-inflammatory or tolerogenic functions in a microbiota-dependent fashion, opening questions on their functional role in CAC development.

Aims & Methods

Immune cell composition and iNKT cell phenotype of inflamed, non-tumor and cancerous tissue lesions of CAC (n=49), IBD (n=20) and sporadic CRC (n=38) patients were analysed in samples obtained from Policlinico Hospital, Milan, and IOV-IRCCS, Padua. High-dimensional single-cell flow cytometry, metagenomics, RNAseq, spatial immunophenotyping and trascriptomic (Cosmx, Nanostring), ex vivo and in vitro experiments were performed to evaluate the phenotype and function of human iNKT cells. Metabolomics was performed to identify microbial-derived molecules involved in iNKT cells activation.Mechanisms were dissected in CAC murine models, either iNKT proficient or deficient.

Results

An increased expression of IL22 and a higher NKT22 infiltration was observed in CAC tissues, as well as an enrichment of Odoribacter, a gram-negative bacteria implicated in tryptophan metabolism. Stimulation of iNKT cells with Odoribacter-derived metabolites induced Ahr-dependent IL22 production by iNKT cells. Metabolomic analyses revealed an increased presence of tryptophan metabolites in the Odoribacter supernatant, promoting NKT22 differentiation both in vitro and in vivo models. Moreover, the administration of Odoribacter Supernatant or of the single purified metabolites were sufficient to increase tumorigenesis in CAC mouse models, but not in iNKT-deficient mice.
Spatial proteomics and trascriptomic analyses of human CAC tissues confirms the microbiota-dependent functional skewing of iNKT cells residing closely to cancer cells.

Conclusion

iNKT cells in CAC patients are the major IL22 producing cells and are induced by the recognition of microbiota-derived metabolites implicated in tryptophan metabolism and Aryl hydrocarbon receptor (AhR) stimulation. NKT22-microbiota interaction in CAC patients plays a potential crucial role in tumor development.

Introduction

Oesophageal squamous cell carcinoma (OSCC) represents approximately 90% of the nearly half-million annual cases of oesophageal cancer globally. The invasiveness and high costs associated with traditional upper endoscopy limit its use in the routine surveillance of at-risk populations, including individuals with a history of head and neck cancer (HNC). Previous data suggest that copy number abnormalities (CNAs) are a feature of OSCC development.

Aims & Methods

This study explored the efficacy of shallow whole-genome sequencing (sWGS) to detect genome-wide CNAs in cells collected using a non-endoscopic sponge pan-oesophageal sampling device. Our objective was to develop and validate a predictive model for the early detection of oesophageal squamous dysplasia and neoplasia, aiming to improve disease prognosis through timely intervention.
We prospectively collected oesophageal specimens from 178 participants using the Cytosponge device as part of the EDEN and OSCAR projects: OSCC (n = 24), high-risk individuals (n = 61), and healthy controls with dyspeptic symptoms (n = 93). The samples underwent 1.5-2x sWGS as well as H&E staining for atypia assessment and p53 immunohistochemistry (IHC) which were performed by two gastrointestinal (GI) pathologists who were blinded to the reference endoscopic diagnoses. Through penalised regression analysis, we identified significant CNAs indicative of dysplasia or early neoplasia. These critical genomic insights were then used to develop and refine a logistic regression model aimed at predicting dysplasia or early neoplasia in cytosponge-derived specimens. The predictive accuracy of the model was subsequently confirmed through validation against sWGS in microdissected ESD samples which represented known pathological states.

Results

Key genomic indicators for oesophageal squamous dysplasia and early neoplasia were identified, including significant CNAs in chromosome arms chr2q, chr3q, chr9p, and chr11q along with the Genome-Wide Instability Score (GWIS), a percentage-based metric quantifying genomic instability across the genome. Our logistic regression model, which integrated these genomic biomarkers, achieved an Area Under the Receiver Operating Characteristic Curve (AUROC) of 0.947, with sensitivity and specificity rates of 89% and 88.2%, respectively. This model outperformed another that utilised only pathological data (definite squamous atypia and p53 IHC), which achieved an AUROC of 0.880, with a sensitivity and specificity of 83.6% and 84.6%, respectively. However, when pathological data were combined with the genomic indicators, the diagnostic performance of our model improved significantly, resulting in an AUROC of 0.969 with enhanced sensitivity and specificity of 95.9% and 90.5%, respectively. Further validation of the genomic model against microdissected ESD samples with known pathological states reinforced its robustness, achieving an AUROC of 0.879, which improved to 0.905 when low grade dysplasia (LGD) samples were excluded, highlighting the diagnostic challenges and variability in LGD classification.

Conclusion

The integration of shallow whole-genome sequencing with non-endoscopic sponge sampling has the potential for the early detection of OSCC. This approach is particularly valuable in high-risk populations and settings where traditional endoscopy is impractical.

Introduction

Crohn’s disease (CD), a variant of inflammatory bowel disease, is a complex, debilitating, chronic and relapsing disorder of the gastrointestinal tract. If poorly controlled, patients are at risk of intestinal obstruction and infection due to the formation of strictures, fistulae and narrowing of the intestinal lumen, often requiring surgical intervention. As the precise aetiology remains unclear, current treatments for CD are limited. An altered composition of native gut microbiota may play a role in CD pathogenesis, with recent faecal microbiota transplantation (FMT) studies revealing variable therapeutic efficacy in CD management. Orally administered Emu Oil, derived from Emu adipose tissue, has demonstrated anti-inflammatory and reparative properties in models of intestinal disease.

Aims & Methods

The current study aimed to determine whether Emu Oil-modulated FMT could reduce disease severity and modulate the gut microbiota in a mouse model of trinitrobenzene sulfonic acid (TNBS)-induced Crohn’s-like colitis. Female ARC(s) mice were assigned to FMT donor (n=5/group) and recipient (n=10/group) groups. Donor mice were orally administered either Water (80μl), Olive Oil (OO) or Emu Oil (160μl) daily (days -7 to 0); fresh faeces were collected (days -1 to 3) and pooled per group. Recipient mice were administered TNBS (3mg; day 0) and donor faecal supernatant (120μl; day 3) intrarectally and euthanised on day 6. Daily bodyweight and disease activity index (DAI), colonoscopically-assessed disease severity, organ weights, intestinal permeability (fluorescein isothiocyanate [FITC]-dextran uptake), histologically-assessed colonic damage (disease severity, crypt depth), intestinal barrier function (mucin-secreting cells), acute inflammation (myeloperoxidase [MPO]) and faecal microbiome (16S rRNA amplicon sequencing) were assessed. p<0.05 was considered statistically significant.

Results

TNBS induced bodyweight loss in all groups, which normalised to day 0 values on the final day of the experimental period. Daily DAI remained elevated throughout the trial in all groups; only Emu Oil FMT normalised DAI on day 6 compared with day 0 (p<0.05). TNBS increased colonoscopically-assessed disease severity scores (p<0.05), with no significant Emu Oil nor OO FMT effect. Emu Oil FMT decreased liver weights and increased small intestinal weights relative to bodyweight, reduced histologically assessed disease severity and increased colonic mucin counts compared with Water and OO FMT (p<0.05). The most abundant genera across all groups were Muribaculaceae, Eisenbergiella and Bacteroides; while alpha and beta diversity, taxonomic profiles, FITC-dextran, crypt depth and MPO activity remained unchanged in all treatment groups (p>0.05).

Conclusion

Emu Oil-modulated FMT improved histologically-assessed indicators of intestinal disease and barrier function, compared with Water FMT and OO FMT. Interestingly, Emu Oil-modulated FMT affected liver and small intestinal organs weights, suggesting a systemic effect in this setting of disease. Importantly, key genera across taxonomic profiles were identified, however, the microbiome and remaining disease indicators were largely unchanged between treatments. Overall, Emu Oil-modulated FMT demonstrates therapeutic potential in CD management. Future studies would benefit from a deeper assessment of the gastrointestinal microbiome through long-read whole genome sequencing to further determine the role of the microbiome in EO FMT efficacy compared with conventional FMT.

Introduction

Faecal microbiota transplantation (FMT) involves the transfer of microbiota from healthy donors to patients with the aim of correcting dysbiosis and restoring intestinal diversity. FMT has been shown to be successful in the treatment of recurrent or refractory Clostridioides difficile infection. The main limiting factor to carry out FMT is access to treatments due to the absence of intestinal microbiota banks (IMB), a process that requires a complex structure.

Aims & Methods

• Define and standardize procedures for the creation of an IMB.
• Fabrication of viable FMT samples.

The project was carried out at the Hospital Clinic of Barcelona. Processes were defined for recruitment donors, collection and processing samples for their later use in clinical practice. A multidisciplinary team was made up with gastroenterologists, microbiologists, infectologists and two clinical nurses.

Results

From May to December 2021, through a questionnaire distributed to the donation unit of the Blood and Tissue Bank (BTB) of Hospital Clinic, 207 potential donors were identified. 52.7% (109/207) of them were considered suitable, but after the a first screening including clinical visit and microbiological analytical studies carried out, only 18.3% (20/109) of them were able to start the donation process. During this period, 79 donations were collected which enabled the processing of 155 stool samples for FMT. After 2 months of quarantine and the second screening, only 73% of the samples (114/155) were ready to be released for clinical use. Two donors were responsible for 40.5% of the donations, while 30% (6/20) did not contribute any samples during the donation period. If we consider suitable donors those who did not present exclusion criteria in any phase of the established screening, the final number was only 9.1% (10/109).

Conclusion

1. Correct organization of all processes is essential for the establishment of a IMB.
2. Loyalty of committed donors is essential.
3. This was the first step of a collaborative project currently ongoing at the Clinic Hospital and the Bellvitge Hospital, supported by the Department of Health in Catalonia.

Introduction

This study looks at the profile of Crohn's patients who have been on at least 3 different advanced treatments, such as tumour necrosis factor inhibitors (TNFi), integrin blockers and IL12/23 inhibitors.

Aims & Methods

Objective: The purpose of this study was to evaluate the profile of Crohn’s disease patients who are in the 3^rd or 4^th line of an advanced treatment and to consider whether patients may be likely to switch to a different treatment.
Methodology: In both Q1 and Q3 2023, ~200 gastroenterologists from France, Italy, Germany, Spain, and the UK contributed ~1200 anonymous patient record forms for individuals receiving advanced therapy for Crohn’s Disease. All the forms were collected through the Therapy Watch IBD (UC and Crohn’s) online survey by Research Partnership. The survey has been conducted with similar numbers of gastroenterologists for 3 years at regular intervals. Informed consent from physicians was obtained. Where relevant, statistical comparisons were performed using a pairwise z-test.
In addition, Research Partnership has conducted research with 138 Crohn’s disease patients through their Living With Crohn’s EU5 survey. Quantitative online interviews were conducted with patients who were currently on an advanced treatment for Crohn’s.

Results

Of all the Crohn’s disease patient record forms collected in the Therapy Watch survey in 2023, 104 patients were on their 3^rd or 4^th line of advanced treatment.
The majority of 3^rd or 4^th line patients were on a non TNFi treatment, such as an integrin blocker or an IL12/ IL23 inhibitor. ~20% of patients were on a TNFi.
The patients were a mix of male and female, at 44% and 56% respectively, and with a wide age range (42% under 40, 30% aged 41-50 and 28% aged over 50). 42% had suffered with Crohn’s disease for over 10 years. The majority of patients had an existing co-morbidity, most commonly a CV condition or depression.
At the time of the survey, the current severity of Crohn’s was reported by physicians to be: 32% mild, 50% moderate and 18% severe. Approximately a quarter of them also were reported as having flares that are increasing in frequency.
From our Living With Crohn’s survey, out of 138 Crohn’s patients currently on an advanced therapy*, approximately a quarter stated that their flares had increased in the last 6 months, but they have not requested a different treatment from their physician. The reasons for not requesting a new treatment were mainly: patients feel they can still tolerate the symptoms that they experience and they are scared of potential side effects of a different treatment.
* Living With patients include those in any line of advanced treatment, not only 3^rd or 4^th line.

Conclusion

Our data suggests that the majority of 3^rd and 4^th line Crohn’s patients have moderate or severe disease, and therefore may be candidates for a switch to a new treatment as these become available for Crohn’s. 30% of 3^rd and 4^th line Crohn’s disease patients are classified as mild in severity, and this segment appear to have found a level of efficacy at this stage.
Our patient survey (Living With) has shown that even those patients who suffer increasing frequency of Crohn’s symptoms do not feel confident in switching to a different therapy; there is a level of fear of switching.

Introduction

Cendakimab is a recombinant, humanized, high-affinity, neutralizing monoclonal antibody that binds to interleukin 13 (IL-13) and blocks interaction with both its receptors, IL-13Rα1 and IL-13Rα2. IL-13 is a cytokine implicated in the pathogenesis of atopic dermatitis (AD) and is thought to be a key driver of the complex pathophysiology of eosinophilic esophagitis (EoE). IL-13 signals through both IL-13Rα1 and IL-13Rα2 to regulate cellular and molecular pathways across a variety of cell types. The binding of IL-13 to IL-13Rα1 promotes a Type 2 immune response and eosinophil recruitment, whereas the binding of IL-13 to IL-13Rα2 is believed to play a role in fibrosis and epithelial tissue remodeling. Several biomarkers associated with Type 2 inflammatory diseases are known to be regulated by IL-13. Eotaxin-3, a key biomarker, plays a central role in attracting eosinophils to the site of inflammation. Periostin, an extracellular matrix protein linked to activated fibroblasts, is implicated in tissue remodeling and fibrosis. Another enzyme governed by IL-13 is matrix metalloproteinase-12 (MMP-12)—this enzyme contributes to tissue remodeling and breakdown of extracellular matrix components. Here, we evaluate the pharmacodynamic effects of IL-13 inhibition with cendakimab on the key serum biomarkers eotaxin-3, periostin, and MMP-12 in patients with AD, with a focus on exploring potential implications for EoE.

Aims & Methods

In this phase 2, multicenter, global, randomized, double-blinded, placebo-controlled, parallel-group study (NCT04800315), 220 adults with moderate-to-severe AD received cendakimab 360 mg Q2W, 720 mg QW, 720 mg Q2W, or placebo for 16 weeks. Blood samples were collected, and a panel of biomarkers were assessed. The current analysis focuses on the assessment of serum levels of eotaxin-3, periostin, and MMP-12 using Proximity Extension Assay pre- and post-treatment on day 1 (baseline), at week 1 and week 2, and then biweekly until week 16. The least square mean percent change from baseline at week 16 for each treatment group was evaluated.

Results

For all 3 doses of cendakimab, there was a significant decrease from baseline in the levels of eotaxin-3, periostin, and MMP-12 as early as week 1 post-treatment and continued through week 16 of cendakimab treatment (Table). Compared with placebo, cendakimab resulted in significantly greater reductions in these biomarker levels through week 16.

Conclusion

Cendakimab decreased levels of key inflammatory and remodeling biomarkers over 16 weeks of treatment in patients with AD. These findings suggest that cendakimab modulates pathways of inflammation, fibrosis, and tissue remodeling in AD and add to the existing clinical evidence of its modulation in other Type 2 inflammatory diseases such as EoE.
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Table. Least square mean percent change from baseline in key serum biomarker levels at week 16 in patients with AD

Disclosure

ESD served as a consultant for Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/ Bristol Myers Squibb, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GlaxoSmithKline, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio, received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/ Bristol Myers Squibb, Regeneron, Revolo, Shire/Takeda, and received educational grant from Allakos, Aqilion, Holoclara, and Invea. JL, SH, LG, CDO, and CC are employees and stockholders of Bristol Myers Squibb. JS served as consultant for Abbvie, Alamar, Aldena, Amgen, AObiome, Apollo, Arcutis, Arena, Asana, Aslan, Attovia, BioMX, Biosion, Bodewell, Boehringer-Ingelheim, Bristol Myers Squibb, Cara, Castle Biosciences, Celgene, Connect Biopharma, Corevitas, Dermavant, Eli Lilly, FIDE, Galderma, GlaxoSmithKline, Incyte, Invea, Kiniksa, Leo Pharma, Merck, My-Or Diagnostics, Nektar, Novartis, Optum, Pfizer, RAPT, Recludix, Regeneron, Sandoz, Sanofi-Genzyme, Shaperon, TARGET-RWE, Teva, Union, UpToDate, participated on a data safety monitoring board or advisory board for Biosion and Sanofi, received grants or contracts from Galderma, Incyte, Pfizer, received honoraria from Abbvie, Eli Lilly, Leo Pharma, Pfizer, Regeneron, Sanofi-Genzyme.