Introduction

Paediatric-onset inflammatory bowel disease (PIBD) is a distinct phenotype with more aggressive and extensive gut inflammation at diagnosis in comparison to adult-onset IBD.¹ Disease activity in paediatric IBD is typically monitored using a combination of clinical, endoscopic, and laboratory parameters. Circulating cell-free DNA (cfDNA) and mitochondrial DNA (mtDNA) are damage-associated molecular patterns (DAMPS) released into the bloodstream during tissue damage and cell death and can be detected in peripheral blood samples. There is a growing interest in the use of cfDNA and mtDNA as potential non-invasive biomarkers for disease activity. Recent studies have suggested that levels of cfDNA and mtDNA may correlate with disease activity in adult IBD² but their utility in paediatric populations, where mitochondrial dysfunction is strongly implicated,³ remains largely unexplored. This study aims to present initial data on the potential use of cfDNA and mtDNA as biomarkers for disease activity in paediatric-onset IBD.

Aims & Methods

GI-DAMPs/MUSIC is an ongoing cross-sectional and longitudinal multi-centre translational research study in Scotland (2020 – 2025) with a primary aim of investigating the inflammatory mechanisms of IBD with a focus on multi-omics, immune- and microbiome-profiling aligned to careful clinical prospective follow-up. We measured circulating cfDNA and mtDNA, using mtDNA-specific ND2 gene dPCR, in the peripheral blood of patients diagnosed under 17 years (A1 phenotype)⁴ and correlated this with detailed phenotypic data, clinical disease activity scores and standard biomarkers.

Results

24 patients, out of a total GI-DAMPS cohort of 338, were A1 phenotype and included in the analysis (14/24 (58%) male, 23 Crohn’s disease (CD), 1 Ulcerative colitis (UC)) with a median (IQR) age at diagnosis of 13 (11.5-15 years). Patients with highly active disease had higher levels of cfDNA levels compared to those in remission (median 0.435 (0.246-0.700 ng/µl) vs 0.123 (0.066-0.160 ng/µl), p=0.005). mtDNA levels were also significantly higher in those with highly active disease compared to those in remission (median 363.6 (135.2-639.6 copies/µl) vs 96.4 (78.2-129.8 copies/µl), p=0.024). cfDNA was moderately correlated with total white cell count (Pearson correlation, r=0.41, p=0.48) and negatively correlated with haemoglobin (r=-0.42, p=0.41), though these correlations were not seen with mtDNA (all p=>0.05).

Conclusion

In conclusion, our initial data demonstrate that the levels of circulating cell-free DNA (cfDNA) and mitochondrial DNA (mtDNA) in the blood are potentially valuable biomarkers for differentiating disease activity in paediatric IBD. These findings suggest that measuring cfDNA and mtDNA levels could provide a non-invasive method for monitoring disease activity in young patients with IBD, enabling early detection of disease flare-ups and facilitating prompt intervention. Further investigation is needed to validate these results and determine the clinical utility of these biomarkers in the management of paediatric IBD.

References

1. van Rheenen, P. F. et al. The Medical Management of Paediatric Crohn’s Disease: an ECCO-ESPGHAN Guideline Update. J. Crohn’s Colitis 15, 171–194 (2021).
2. Boyapati, R. K. et al. Mitochondrial DNA Is a Pro-Inflammatory Damage-Associated Molecular Pattern Released During Active IBD. Inflamm. Bowel Dis. 24, 2113–2122 (2018).
3. Haberman, Y. et al. Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response. Nat Commun 10, 38 (2019).
4. Levine, A. et al. ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. J. Pediatr. Gastroenterol. Nutr. 58, 795–806 (2014).

Introduction

Acute severe colitis (ASC) is an important cause of morbidity and mortality in Ulcerative Colitis (UC), requiring hospitalisation and, frequently, colectomy. Intravenous corticosteroids (CS) remain the first-line medical treatment. Approximately 40% of episodes of ASC do not respond to this treatment and require rescue therapy with ciclosporin (CIC) or infliximab (IFX)¹. In the past decades, these treatments and protocol-driven management algorithms led to reduced mortality and colectomy rates. A simple clinical scoring system (the Admission Model for the Intensification of Therapy in Acute Severe Colitis (ADMIT-ASC))³, based on CRP, albumin, and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score, was recently developed to predict the steroid response on admission.

Aims & Methods

We aimed to retrospectively assess the steroid non-response during admission with ASC and the usefulness of the new prognostic clinical index ADMIT-ASC at admission to predict steroid response in a Belgian tertiary center. All patients admitted with ASC between 1^st January 2015 and 1^st April 2023 were identified from our inflammatory bowel disease database at Erasme University Hospital. Inclusion criteria were ASC patients admitted at the hospital, standard treatment with at least 3 days of intravenous CS and endoscopy evaluation upon admission. ASC was defined according to modified Truelove and Witts’ criteria as ≥6 bloody stools/day with one or more markers of systemic disturbance (tachycardia >90 beats/min, temperature >37.8°C, haemoglobin <105 g/L or CRP >30 mg/L). Steroid non-response was defined as the need for medical rescue therapy (CIC of IFX) or colectomy during the admission. ADMIT-ASC index consists of four points: CRP ≥100 mg/L (1 point), albumin ≤25 g/L (1 point) and UCEIS score ≥4 (1 point) or ≥7 (2 points).

Results

Table I Admission Demographics data (n= 84)	Steroid response (n=49)	Steroid non-response (n=35)	P value
Median disease duration (years) (IQR)	3.6 (0.3-0.9)	2.1 (0.8-5.5)	0.5
Montreal Classification	E1 : 5/49 (10%) E2 : 20/49 (41%) E3 : 24/49 (49%)	E1 : 0/35 E2 : 12/35 (34%) E3 : 23/35 (66%)	0.084
5-ASA, n (%)	22 (45%)	10 (29%)	0.13
Methotrexate or thiopurine, n (%)	6 (12%)	9 (26%)	0.11
Infliximab, n (%)	4 (8.2%)	8 (23%)	0.058
Vedolizumab, n (%)	7 (14%)	5 (14%)	>0.9
Tofacitinib, n (%)	2 (4.1%)	2 (5.7%)	>0.9
Readmission, n (%)	12 (24%)	10 (29%)	0.7
5-ASA, 5-aminosalicylate P values from Wilcoxon rank-sum test or Fisher’s exact test.

Out of 127 patients admitted with UC and treated with intravenous CS during three days, 84 (45% male, median age of 31 years old) were included in the study. Admission demographics and clinical characteristics are described in Table 1.
For 17 patients (20%), the admission was their index presentation of UC. Response to CS was seen in 49 patients (58%). Thirty-three patients (39%) received medical rescue therapy (17/33 IFX and 16/33 CIC). Colectomy rate during admission was 13% after a median duration of 18 days (IQR: 16-54). Admission C reactive protein (CRP) (p=0.036), albumin (p=0.026) and UCEIS scores (p=0.022) were significantly associated with steroid non-response. Patients scoring 0, 1, 2, 3 and 4 had steroid response rates of 90%,75%, 55%, 19% and 0%, respectively. Scoring of ≥3 was 75% (95% CI, 0.43 to 0.95) predictive of steroid failure (OR 5.08, 95%, CI 1.38 to 24.5).

Conclusion

In this tertiary referral cohort study, we confirmed that the ADMIT-ASC index is a simple clinical tool that can be used on the day of admission to predict steroid non-response in ASC with a threshold of ≥3 to identify patients who are unlikely to respond to intravenous CS and enabling timely treatment escalation or surgery.

References

1. Travis S, Satsangi J, Lémann M. Predicting the need for colectomy in severe ulcerativecolitis: a critical appraisal of clinical parameters and currently available biomarkers. Gut 2011;60:3–9.
2. Travis SP, Farrant JM, Ricketts C, et al. Predicting outcome in severe ulcerative colitis.Gut 1996;38:905–10.
3. Adams A, Gupta V, Mohsen W, et al. Gut 2023;72:433–442.

Disclosure

VB has not disclosure.
CDT has not disclosure.
CM has not disclosure.
AC has received lecture fees from Galapagos, Abbvie, Janssen, celltrion, Pfizer, Takeda.
DF has received lecture fees from Abbvie, Astrazeneca, Dr.Falk Pharma, Ferring, Janssen, Mundipharma, MSD, Pfizer, Takeda, Amgen, and advisory board fees from Abbvie, Janssen,Takeda, Celltrion, Amgen.
CL has received consultancy fees from Janssen, Abbvie, Takeda and Galapago and speaker fees from Sandoz, Janssen, Abbvie

Introduction

Fibrosis constitute an important complication of CD. MicroRNAs (miRNAs), which are small RNA molecules that regulate gene expression, have been shown to participate in the molecular interactions of both inflammation and fibrosis. Lower levels of miR-378a-3p have been reported associated to murine liver fibrosis [1] and we analyze here the relevance of miR-378a-3p on intestinal fibrosis.

Aims & Methods

B57BL/6 mice were intravenously injected with 2,5mg/kg of negative control (NC) or mm-miR-378a-3p mimic, twice a week and received vehicle or Dextran Sulfate Sodium (DSS) for 2 cycles (7 days drinking DSS 2% in water solution followed by 10 days drinking water). Body weight and DAI score was obtained every day and the colon was collected after sacrifice. Sirius and hematoxylin-eosin dyes were employed to determine the fibrosis and structural state in 5µm slides of intestinal tissue. Gene expression and miRNA profiles were analyzed by RT-qPCR. Human small intestinal fibroblasts (HSIF; P10760, Innoprot, Spain) were transfected with 20nM of NC or hsa-miR-378a-3p mimic during 24h.

Results

No significant changes in body weight, DAI score, and colon length were detected between mice receiving NC and those receiving mimic, all along the two DSS cycles. Colon of mice treated with DSS, exhibited a significant diminution in the mRNA expression of mm-miR-378a-3p compared with naïve samples. In DSS-treated mice, the iv administration of the mimic compared with the NC: a) significantly increased levels of miR-378a-3p in the colon; b) increased the number of neutrophils, and heightened changes in the glandular epithelia and architectural distortion C) decreased the number of lymphoid follicles; d) slightly increased collagen deposition, as analyzed by sirius red and e) significantly increased the mRNA expression of Tgfb1, Il1b, and Mmp2. Treatment of human intestinal fibroblasts with hsa-miR-378a-3p mimic did not significant modify the mRNA expression of markers of fibrosis but it significantly increased the mRNA expression of two antiapoptotic molecules BCL2 and MCL1.

Conclusion

Levels of mm-miR-378a-3p are diminished in a murine model of intestinal fibrosis; The exogenous administration of miR-378a-3p, increased the acute inflammatory response and the expression of fibrosis markers in murine fibrotic colon and the expression of antiapoptotic molecules in human intestinal fibroblasts.

References

1. Hyun, J.; Wang, S.; Kim, J.; Rao, K.M.; Park, S.Y.; Chung, I.; Ha, C.S.; Kim, S.W.; Yun, Y.H.; Jung, Y. MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression. Nat Commun 2016, 7, 10993, doi:10.1038/ncomms10993.

Introduction

Epstein-Barr virus (EBV) associated gastric cancer (GC) has been reported to be about 5-16% of all gastric cancers with good prognosis compared to EBV-negative GC. The aim of this study was to evaluate the clinicopathological characteristics of EBV-positive GC including survival analysis in the prospective observational cohort study in a tertiary hospital in South Korea.

Aims & Methods

Total 4,586 patients who underwent EBV in situ hybridization (EBV-ISH) testing among 14,613 patients diagnosed with GC were prospectively enrolled at Seoul National University Bundang Hospital from 2003 to 2023. Data including age, sex, smoking, cancer type and stage, tumor size and location, histologic type, molecular features (p53 expression and MSI), and survival information including causes of death were collected and analyzed.

Results

EBV-positive cancer group showed significant differences compared to EBV-negative cancer group. That is, they showed higher proportion of males (p<0.001), predominant presence in the proximal stomach (p<0.001), higher proportion of undifferentiated cancer (p<0.001), and lower cancer stage (p=0.004) (Table). In Cox multivariate analyses, age (HR 1.022, p<0.001), tumor size (HR 1.118, p<0.001) along with cancer stage (stage 2 HR 5.843, p<0.001; stage3 HR 15.570, p<0.001; stage4 HR 50.075, p<0.001, respectively) were significant risk factors for GC-specific mortality, while EBV positivity was inversely correlated (HR 0.537, p=0.023). In the survival analyses, EBV-positive cancer group showed statistically significant survival advantages over EBV-negative cancer group in both overall (p=0.016) and gastric cancer-specific survival (p=0.005)

Variables		Total patients (n=4,586) (%)	EBV positive (n=456) (%)	EBV negative (n=4,130) (%)	P value
Sex	Male	3028 (66)	404 (88.6)	2624 (63.5)	<0.001
	Female	1558 (34)	52 (11.4)	1503 (36.5)
Location (n=4,579)	Cardia, Body	2076 (45.3)	367 (80.5)	1709 (41.5)	<0.001
	Antrum	2503 (54.7)	89 (19.5)	2414 (58.5)
Histology type (n=3,799)	Differentiated	1891 (49.8)	123 (35.5)	1768 (51.2)	<0.001
	Undifferentiated	1908 (50.2)	223 (64.5)	1685 (48.8)
TNM staging	1	2818 (61.4)	316 (69.3)	2502 (60.6)	0.001
	2	683 (14.9)	52 (11.4)	631 (15.3)
	3 or above	1085 (23.7)	88 (19.3)	997 (24.1)

Overall survival
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GC-specific survival
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Conclusion

EBV-positive GC group was associated with male sex, proximal location, poorly differentiated histology and lower cancer stage, and showed significantly better prognosis than EBV-negative gastric cancer. EBV might play a role in the gastric carcinogenesis to make less metastasis resulting in better survival.

Introduction

Fecal microbiota transplantation (FMT) is a highly effective treatment for recurrent Clostridioides difficile infection (CDI), but its safety is jeopardized by the potential risk of transmitting microbial pathogens. Stool biobanks have established to provide both a widespread and equitable access to FMT and high safety, quality, and traceable workflows. To guarantee the safety of each donor stool batch, international guidelines recommend either a quarantine or a direct stool testing with a rapid molecular assay for gut pathogens. While reports of the quarantine-based approach are emerging, data on the direct testing-based approach are still limited

Aims & Methods

Our aim is to report outcomes of a donor screening program for FMT including a direct stool testing-based approach based on a rapid molecular assay for gut pathogens.We prospectively evaluated all candidates enrolled in our FMT donor program since the introduction of a direct stool testing with a rapid molecular assay for gut pathogens, in 2019. Following international guidelines, donor screening consisted of a five-step framework, including: 1) collection of clinical history; 2) blood and stool testing; 3) a further questionnaire the day of each donation; 4) nasopharyngeal swab and stool RT-PCR assay for SARS-CoV-2 the day of each donation (after March 2020); 5) a direct stool testing with a rapid molecular assay for gut pathogens and cultures for MDRO evaluation. Specifically, the RT-PCR Allplex™ Gastrointestinal Panel Assay (Seegene, Korea) was used for a comprehensive identification of common gastrointestinal pathogens. The QIAamp Fast DNA Stool Mini Kit (QIAGEN, Hilden, Germany) was used for nucleic acid extraction. We evaluated rates of donations per year, rates and reasons of candidates’ exclusion at each step of the donor screening, as well as the rate of unsuitable fecal donations and the intestinal pathogens that caused their rejection. Finally, we recorded the number of total fecal aliquots provided by eligible donors, and related safety outcomes at 12 weeks after their use within FMT.

Results

From January 2019 to December 2022, 227 candidates were assessed for eligibility. Of them, 122 were excluded at different steps of the screening process. Finally, we enrolled 69 eligible donors (37 females, 53,6%; mean age 37, 30% of the total pool). Thirty-seven fecal aliquots were collected in 2019 (13 donors), 39 in 2020 (20 donors); 51 in 2021 (24 donors), and 104 in 2022 (43 donors). Overall, we collected 231 fecal donations, of which 136 (58.8%) were considered eligible and stored at -80°C for FMT. Eight donations were discarded for insufficient amount of feces (<50 g - 3%), and 87 (37.6%) for positivity to intestinal pathogens, including Enteropathogenic E. coli (EPEC) (n=31 samples – 13.4%), ESBL (extended-spectrum beta-lactamase) E. coli (n=15 samples, 6.5%), Blastocystis hominis (n=17 samples, 7.3%).Notably, we found a seasonal variation among pathogen positivity, as most pathogens were observed in Autumn (from September to December: n=48/87, 55.8%).All donations have been used, and no serious adverse events or infections have been observed at 12 weeks after FMT.

Conclusion

Our screening of donor feces based on direct stool testing guarantees high safety of FMT, although with high rates of donor exclusion, with the need of a well-established framework to guarantee a continuous availability of eligible donors to avoid shortages of fecal aliquots.

Disclosure

G.I. has received personal fees for acting as speaker for Biocodex, Danone, Sofar, Malesci, Metagenics and Tillotts Pharma, and for acting as consultant and/or advisor for Ferring Therapeutics, Giuliani, Malesci and Tillotts Pharma. A.G. reports personal fees for consultancy from Eisai Srl, 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, SinergieSrl, Board MRGE and Sanofi SpA personal fees for acting as a speaker for Takeda SpA, AbbVie and Sandoz SpA and personal fees for acting on advisory boards for VSL3 and Eisai. G.C. has received personal fees for acting as advisor for Ferring Therapeutics. All other authors have no conflicts of interest to disclose.

Introduction

Thiopurines are one of the major drugs for inflammatory bowel disease. In Asian individuals, the SNP p.Arg139Cys in exon 3 of NUDT15 is associated with leucopenia and hair loss.

Aims & Methods

The aims of this study are to evaluate the long-term effects of NUDT15 on clinical outcomes.
The patients (ulcerative colitis130, Crohn’s disease 55 cases) were divided into the mutant and the wild group of NUDT15, and the daily dosage of thiopurines and the effect of the mutation on hospitalization and surgery were investigated.

Results

Compared to the mutant group (n = 48), the daily thiopurine dosage increased in the wild group (n = 137)(p = 0.024). The time to dose reduction and discontinuation of thiopurine was significantly shorter in the mutant group, respectively (p < 0.001, p = 0.039). The mutant group tended to have more hospitalizations (p = 0.067), and surgeries were significantly more frequent (p = 0.028). In ulcerative colitis, thiopurine discontinuation was associated with hospitalization and surgery, respectively (p = 0.003, HR 2.87, 95% CI 1.44 - 5.71, p = 0.036, HR 5.45, 95% CI 1.12 - 26.5). In Crohn's disease, the presence of SNPs was associated with hospitalization (p = 0.019, HR 3.68, 95% CI 1.24-10.97) and surgery (p = 0.036, HR 6.81, 95% CI 1.14 - 40.86).

Conclusion

In ulcerative colitis, it is important to continue thiopurine with fine-tuning of the dosage to avoid hospitalization and surgery. In Crohn's disease, a direct association between the NUDT15 SNP and hospitalization and surgery was demonstrated.

References

1. Yang, S. K. et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet 46, 1017-1020, doi:10.1038/ng.3060 (2014).
2. Kojima, Y. et al. Influence of NUDT15 variants on hematological pictures of patients with inflammatory bowel disease treated with thiopurines. World J Gastroenterol 24, 511-518, doi:10.3748/wjg.v24.i4.511 (2018).
3. Coenen, M. J. H. et al. Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease. Gastroenterology 149, 907-917.e907, doi:10.1053/j.gastro.2015.06.002 (2015).
4. Hirotsu, Y. et al. Detection of BRCA1 and BRCA2 germline mutations in Japanese population using next-generation sequencing. Mol Genet Genomic Med 3, 121-129, doi:10.1002/mgg3.120 (2015).
5. Sakamoto, I. et al. BRCA1 and BRCA2 mutations in Japanese patients with ovarian, fallopian tube, and primary peritoneal cancer. Cancer 122, 84-90, doi:10.1002/cncr.29707 (2016).
6. Hirotsu, Y. et al. Intrinsic HER2 V777L mutation mediates resistance to trastuzumab in a breast cancer patient. Med Oncol 34, 3 (2017).
7. Hirotsu, Y. et al. Multigene panel analysis identified germline mutations of DNA repair genes in breast and ovarian cancer. Mol Genet Genomic Med 3, 459-466 (2015).

Disclosure

The authors have no conflict of interest to declare. All co-authors have seen and agree with the contents of the manuscript, and there is no financial interest to declare.

Introduction

The sex differences in the incidence of gastric cancer have been well known. However, uncertainty still exists in terms of prognosis of GC. For example, the US SEER data reports a significantly better prognosis in females than in males, but the prognosis is better in males than in females in Korean Central Cancer Registry data. Roles of molecular markers and gut microbiota as new prognostic factor are emerging recently, but few studies seem to try to reveal sex differences.

Aims & Methods

In this background, we aimed to analyze the differences in GC characteristics according to sex in Korean patients, mainly focused on survival. This was a single-center retrospective study. A total of fifteen thousand patients diagnosed with GC at the Seoul National University Bundang Hospital between 2003 and 2023 were included. Clinicopathological characteristics, histologic types, survival rates with age- and stage-stratification, and associated risk factors were analyzed. Information related to death was cross-verified using medical record review and data from the National Statistical Office.

Results

The ratio of males and females was about 2:1, and there was no differences in stage between sexes. Female patients were significantly younger than males, had more gastric body cancers and tumors with diffuse type or poorly differentiated histology. Females underwent less endoscopic treatment and more surgery, and tumors with microsatellite instability was more common in females, while mutation of p53 was less common. In histological types according to Lauren classification, diffuse type histology was more common in younger patients in both males and females. The proportion of intestinal type GC increased with age, but the proportion increased rapidly in males while increased gradually in females. In Cox multivariate regression analysis for GC-related death, older age, proximal tumor location, diffuse type histology and advanced tumor stage were risk factors. In terms of survival, overall and GC-specific survival did not show significant differences between sexes in the analysis of the total population. However, sex differences in survival reversed with age, that younger females under 50 showed survival disadvantages, but the survival became similar in 50s, and older females over 60 showed survival advantages in both overall and GC-specific survival. Furthermore, in the stratification analysis according to the stage, there were no significant differences in stages I to III. But, stage IV female patients showed significant survival disadvantages. In subgroup analysis of stage IV patients, the differences between males and females in median survival were two months, and female patients were significantly younger and had a higher proportion of diffuse type GC than male patients, which shows aggressive feature and is related to poorer survival.

		Total (N=1,924) (%)	Male (n=1,282) (%)	Female (n=642) (%)	p
Median survival (mo)		10	11	9	0.022
Age (mean±SD)		61.59±14.25	62.41±13.23	59.96±15.97	0.001
Age (in diffuse type patients, mean±SD)		54.55±14.71	56.43±14.29	52.26±14.91	0.001
Lauren classification	Intestinal	554 (48.0)	438 (56.7)	116 (30.4)	<0.001
	Diffuse	574 (49.7)	315 (40.7)	259 (68.0)
	Mixed / Indeterminate	26 (2.3)	20 (2.6)	6 (1.6)

Conclusion

Significant differences in survival between sexes were observed with stratification analysis, although sex itself was not an independent prognostic factor. These age-dependent changes are thought to suggest the effect of sex hormones. These differences should be considered in clinical practice and later research in terms of tailored medicine.