Introduction

Granulocyte–monocyte apheresis (GMA) is a non-pharmacological therapy approved for the treatment of ulcerative colitis (UC), mainly in steroid-dependent cases. Its mechanism of action is based on the removal of activated leukocytes, but its exact immunological changes have not been fully described yet.

Aims & Methods

Our aim was to characterize the response in the transcriptome at the single-cell resolution level and cell population effects of GMA device. We analysed scRNASeq data from peripheral blood mononuclear cells (PBMC) of two UC patients undergoing their first GMA session. Their gene expression profile was compared before (PRE) and one month after (POST) the GMA treatment, from the inflow and outflow lines, respectively. The analytical pipeline included quality control and filtering, cell-type annotation, differential gene expression and pathway enrichment analysis.

Results

Two patients with UC (mean age 59 years; both E2) were included. Overall, the cell populations that appear to have been affected by the GMA treatment were natural killer cells and monocytes with both populations being reduced after the treatment. The distribution of the annotated cell-types was 2,369 B cells (PRE:50%, POST:49%), 11,462 CD4+ (PRE:49%, POST:50%) and 8,845 CD8+ T-cells (PRE:51%, POST:48%), 47 dendritic cells (PRE:40%, POST:59%), 3,773 natural killer cells (PRE:54%, POST:45%) and 2,352 monocytes (PRE:59%, POST:40%). Annotation at higher resolution identified 27 cell-types with monocytes being subannotated as 1,972 CD14 (PRE:62%, POST:37%) and 380 CD16 (PRE:48%, POST:51%) monocytes. Differential gene expression analysis identified in total 86 significant genes across six cell-types (CD4+ naive and central memory T-cells, natural killer cells, B intermediate cells, double-negative T-cells and CD14 monocytes) with 63% of these genes being downregulated after the GMA treatment. Pathway enrichment analysis identified higher contribution of the double-negative T-cells to the enriching genes. More specifically, after the treatment the double-negative T-cells exhibited upregulation of the NEFL that is associated with the MAPK cascade and downregulation of genes related to immune response and signalling pathways. Regarding the CD14 monocytes, after the GMA treatment we observed significant downregulation of the genes LINC02315, IGHEP1 and IGHE, with the latter being linked to innate immune response pathways.

Conclusion

GMA induces a range of modifications in the gene expression profile across different cell types that change the immunological environment of UC patients.

Disclosure

Financial support from an unrestricted grant from Adacyte, who had no role in the study design, interpretation of data or drafting the abstract.

Introduction

Screening for Barrett’s esophagus (BE) could lead to earlier detection (EAC) and improve survival of esophageal adenocarcinoma (EAC). The Cytosponge, a non-endoscopic cell collection device that is coupled with the biomarker Trefoil Factor 3 (TFF3), has been shown in the Barrett’s Esophagus Screening Trial 3 (BEST3) trial, to lead to a 10-fold increase in BE diagnosis in a reflux population. The aims of this study were to: 1) Estimate the proportion of missed BE or stage-1 EAC under the current primary care reflux referral pathway, 2) Define a target screening population and, 3) To estimate the trade-off between the target population to screen and the proportion of BE or stage-1 EAC diagnosed.

Aims & Methods

This was a retrospective analysis and modelling from the multicentre, pragmatic, randomised controlled BEST3 trial that took place across 109 general practices in England. The findings from the main study were previously reported.¹ For aim 1, we used the BEST3 intervention (n=6834) and control arm (n=6388) data to estimate the number of missed BE or stage-1 EAC under the current reflux referral pathway. For aim 2, we determined which clinical risk factors predict a diagnosis of BE or stage-1 EAC in individuals who swallowed the Cytosponge (n=1654) and then modelled the probability of a diagnosis of BE and stage-1 EAC. For aim 3, we used different probabilities of a diagnosis of BE and stage-1 EAC to estimate the starting age to screen, to estimate the trade-off of the number-needed-to-screen and the proportion of BE or stage-1 EAC that would be diagnosed.

Results

Among usual care (control), 0.2% (13/6388) of individuals had BE or stage-1 EAC whereas, the expected prevalence of BE or stage-1 EAC within the intervention (Cytosponge) arm was 10.6% (680/6388), leading to the estimation that the proportion of missed pre-symptomatic BE and stage-1 EAC cases under current care is ~98%. Using logistic regression, we showed that male gender (Odds Ratio, OR 2.46, 95% Confidence Interval, CI 1.67-3.64, p<0.001), age (OR 1.05, 95% CI 1.03-1.07, p<0.001) and family history (OR 1.81, 95% CI 1.04-3.15, p=0.036) were significant predictors of BE or stage-1 EAC diagnosis. Next we modelled and simulate the trade-off for the numbers-needed-to screen on a population level according to different probability thresholds for a diagnosis of BE or stage-1 EAC (≥3%, ≥5%, and ≥10% among individuals with reflux). For these models we set an upper age limit of 74 years for practical considerations (Table 1). These data suggest that a 5% threshold is likely the optimal strategy. This reduces the screening population by 45.2% (males age 55-74 and females 65-74) while still diagnosing 71.0% of cases with a number-needed-to-screen to detect one case of 10.7.

Conclusion

A targeted screening strategy has the potential to substantially improve detection rates for BE and stage-1 EAC compared with current care. The trial data can be used to inform the optimal age for screening in males versus females in order to maximise the yield of screening according to the resources available.

References

Fitzgerald RC, di Pietro M, O'Donovan M, et al. Cytosponge-trefoil factor 3 versus usual care to identify Barrett's oesophagus in a primary care setting: a multicentre, pragmatic, randomised controlled trial. The Lancet 2020;396(10247):333-44.

Disclosure

R.C.F. and M.O. are named inventors on patents pertaining to the Cytosponge and associated technology. R.C.F. and M.O are shareholders of Cyted Ltd., a company working on early detection technology. The other authors declare no conflict of interest.

Introduction

Capsule endoscopy (CE) is a minimally invasive exam suitable of panendoscopic evaluation of the gastrointestinal tract. Nevertheless, CE is time-consuming, with suboptimal diagnostic yield in the upper GI tract. Convolutional neural networks (CNN) are human brain architecture-based models suitable for image analysis. However, there is no study about their role in capsule panendoscopy.

Aims & Methods

Our aim was to develop an artificial intelligence (AI) model for panendoscopic automatic detection of pleomorphic lesions (namely vascular lesions, protuberant lesions, hematic residues, ulcers, and erosions). 355110 images (6977 esophageal, 12918 gastric, 258443 small bowel, 76772 colonic) from eight different CE and colon CE (CCE) devices were divided into a training and validation dataset in a patient split design. The model classification was compared to three CE experts’ classifications. The model’s performance was evaluated by its sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and area under the precision-recall curve.

Results

The binary esophagus CNN had a diagnostic accuracy for pleomorphic lesions of 83.6%. The binary gastric CNN identified pleomorphic lesions with a 96.6% accuracy. The undenary small bowel CNN distinguished pleomorphic lesions with different hemorrhagic potential with 97.6% accuracy. The trinary colonic CNN (detection and differentiation of normal mucosa, pleomorphic lesions, and hematic residues) had 94.9% global accuracy.

Conclusion

Our group developed the first AI model for panendoscopic automatic detection of pleomorphic lesions in both CE and colon CE from multiple brands, solving a critical interoperability technological challenge. Deep learning-based tools may change the landscape of minimally invasive capsule panendoscopy.

References

1. Pennazio M, Rondonotti E, Despott EJ, Dray X, Keuchel M, Moreels T, et al. Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2022. Endoscopy. 2023 Jan;55(1):58-95. PubMed PMID: 36423618. Epub 20221124.
2. Le Berre C, Trang-Poisson C, Bourreille A. Small bowel capsule endoscopy and treat-to-target in Crohn's disease: A systematic review. World J Gastroenterol. 2019 Aug 21;25(31):4534-54. PubMed PMID: 31496630. PMCID: PMC6710184.
3. Iddan G, Meron G, Glukhovsky A, Swain P. Wireless capsule endoscopy. Nature. 2000 May 25;405(6785):417. PubMed PMID: 10839527.
4. Rondonotti E, Pennazio M. Colon capsule for panendoscopy: a narrow window of opportunity. Endosc Int Open. 2021 Dec;9(12):E1860-E2. PubMed PMID: 34917450. PMCID: PMC8670997. Epub 20211214.
5. Vuik FER, Moen S, Spaander MCW. Colon capsule endoscopy as panendoscopy: Using current knowledge to enhance possibilities. Endosc Int Open. 2022 May;10(5):E584. PubMed PMID: 35571484. PMCID: PMC9106432. Epub 20220513.

Introduction

Apelin (APL), originally isolated from alimentary tract, has been defined as the endogenous ligand for APJ, which is a known G protein-coupled receptor. It has been reported that APL is upregulated in the colonic tissues of an animal model of acute colitis induced by dextran sodium sulfate (DSS), and it is suggested to be associated with the pathogenesis of inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, in humans. However, the mechanism and function of APL in the context of IBD remain unclear.

Aims & Methods

The aim of this study was to define the function of APL in the pathogenesis of IBD. To this end, each cell type in the colonic tissue, including epithelial cells and lamina propria lymphocytes, were first isolated from wild-type C57BL6 mice (WT) to assess APL expression. Next, naïve T cells isolated from WT were adoptively transferred into Rag deficient mice (Rag^-/-) to induce chronic colitis, followed by isolation of splenic and colonic CD4⁺ T cells from these T cell-reconstituted Rag^-/- to compare with those of WT. In addition, WT naïve T cells were differentiated into either Th1, Th2 or Th17 in vitro to analyze APL expression. Finally, the Rag^-/- receiving naïve T cells were administered synthetic APL peptide, APL-13, to assess the severity of colitis.

Results

Semi-quantitative PCR (qPCR) revealed that CD4⁺ T cells express relatively higher level of APL when compared to other cell types including the epithelial cells in colonic tissue from WT. However, APL expression in the colonic tissues from the Rag^-/- induced chronic colitis was unexpectedly downregulated compared to those without colitis, which is not consistent with the previous report using acute DSS colitis model. Subsequently, qPCR revealed significantly decreased APL expression in the splenic and colonic T cells from Rag^-/- induced colitis compared to that of WT. APL expressions in all of the differentiated T cells in vitro, such as Th1, Th2 and Th17, were also significantly downregulated compared to that of non-differentiated control T cells. Given these results, APL-13 was injected into the Rag^-/- that underwent T cell reconstitution to antagonize the APL downregulation. This resulted in reduced severity of colitis compared to that of vehicle control-injected mice.

Conclusion

Our results indicate that T cells can be one of the major sources of APL in colonic tissues, and the downregulated APL expression in effecter T cells may lead to the development of chronic colitis. In addition, our current study also suggests that APL may be a novel therapeutic target for IBD.

Introduction

Pancreatic steatosis (PS) has been increasingly recognized and associated with some relevant metabolic implications. However, data on its correlation with exocrine pancreatic function remain limited. We conducted a systematic review and meta-analysis to evaluate whether PS is associated with exocrine pancreatic insufficiency (EPI).

Aims & Methods

This study aimed to investigate whether imaging-detected PS is related to exocrine pancreatic dysfunction, assessed by fecal elastase-1 (FE-1) levels. We searched PubMed, EMBASE, and Cochrane Central for studies including adults with and without PS identified on imaging, and reporting FE-1 concentrations. Data were pooled using random-effects models.

Results

Three studies evaluating a total of 1,864 patients were included. Fecal elastase levels were significantly lower in patients with PS compared to controls, indicating worse exocrine pancreatic function in this group (MD -199.78; 95% CI -303.66 to -95.91; p < 0.05; I² = 97%). Moreover, PS was associated with a significantly increased risk of exocrine pancreatic insufficiency (RR 3.13; 95% CI 1.17–8.40; p = 0.023; I² = 81%), reinforcing the link between fat accumulation in the pancreas and impaired exocrine function.

Conclusion

This meta-analysis demonstrates a significant association between PS and impaired pancreatic exocrine function, compared to individuals without known pancreas disease. These findings underscore the importance of a comprehensive metabolic assessment in patients with PS, given its potential role in pancreatic dysfunction.

Introduction

The impact of underweight and obesity on clinical outcomes for intestinal Behçet’s disease (BD) is unknown. We aimed to identify the association between body mass index (BMI) and clinical outcomes in patients with intestinal BD.

Aims & Methods

We categorized 760 patients with intestinal BD according to the BMI at diagnosis into four groups (underweight, normal, overweight, obese) at Severance Hospital, Seoul, Korea between 1997 and 2021.We performed a Cox proportional hazard analysis to investigate the predictive capability of BMI for clinical outcomes such as biologics use, surgery, hospitalization and emergency room visit.

Results

Of the 760 patients, 130 patients were classified into underweight group (BMI<18.5), 384 patients into normal group (BMI 18.5~22.9), 152 patients into overweight group (BMI 23~24.9), and 94 patients into obese group (BMI≥25). Patients with a higher BMI group showed significantly lower cumulative rates of biologics use (p trend = 0.001), surgery (p trend = 0.008), hospitalization (p trend = 0.002), and emergency room visits (p trend = 0.003) than those with a lower BMI group. In a multivariate analysis, normal BMI group (HR: 0.667, 95% CI 0.483-0.992, p =0.014), overweight group (HR: 0.589, 95% CI 0.394-0.879, p=0.010), and obese group (HR: 0.515, 95% CI 0.321-0.828, p=0.006) were negatively associated with future hospitalization compared to underweight group. Overweight group (HR: 0.490, 95% CI 0.241-0.996, p =0.049) and obese group (HR: 0.312, 95% CI 0.116-0.840, p =0.021) were negatively associated with future biologics use compared to the underweight group. Normal BMI group (HR: 0.706, 95% CI 0.484-1.029, p=0.070) and obese group (HR : 0.556, 95% CI 0.303-1.020, p=0.058) were negatively associated with future surgery compared to the underweight group. Normal BMI group (HR: 0.711, 95% CI 0.513-0.985, p=0.041) and obese group (HR: 0.602, 95% CI 0.376-0.963, p=0.034) were negatively associated with future emergency room visit compared to the underweight group.

Variables		BMI
		<18.5 (n=130) Underweight	18.5~22.9 (n=384) Normal	23~24.9 (n=152) Overweight	≥25 (n=94) Obese	p value for trend
Biologics use	Event	34 (26.2%)	50 (13.1%)	21 (13.8%)	9 (9.6%)	0.001
	Multivariable-adjusteda	Reference	0.619 (0.366-1.047)*	0.490 (0.241-0.966)**	0.312 (0.116-0.840)**
Surgery	Event	45 (34.6%)	87 (22.7%)	35 (23%)	15 (16%)	0.008
	Multivariable-adjusteda	Reference	0.706 (0.484-1.029)*	0.669 (0.411-1.088)	0.556 (0.303-1.020)*
Hospitalization	Event	87 (66.9%)	194 (50.8%)	69 (45.4%)	46 (48.9%)	0.002
	Multivariable-adjusteda	Reference	0.667 (0.483-0.922)**	0.589 (0.394-0.879)**	0.515 (0.321-0.828)**
Emergency room visit	Event	71 (55%)	144 (37.6%)	61 (40.1%)	32 (34%)	0.003
	Multivariable-adjusteda	Reference	0.711 (0.513-0.985)**	0.775 (0.523-1.149)	0.602 (0.376-0.963)**

*p <0.10
**p <0.05
^aMultivariate Cox proportional hazard analysis, including the confounders such as, age, gender, medical aid, smoking, appendectomy history, family history of BD, marriage status, DAIBD score, extraintestinal manifestation, systemic BD, number of ulcers, shape of ulcers, depth of ulcers, type of ulcers, laboratory findings.

Conclusion

Underweight could affect poor outcomes in intestinal Behçet’s disease. Physicians should pay attention to the patients with underweight and make an effort to improve nutritional status.