Introduction

Colorectal cancer associated to chronic colitis (CAC) has a different pathogenesis compared to sporadic or familial colorectalcancer (CRC) and represents the major complication of inflammatory bowel disease (IBD). It is now well-established that IL-33 and its receptor, ST2, are important factors in the pathogenesis of IBD. Emerging evidence also suggests its critical role in epithelial proliferation and the potential contribution to inflammation-driven tumorigenesis that can lead to CRC.

Aims & Methods

The aim of our study was to characterize the precise contribution of IL-33/ST2 axis in the azoxymethane (AOM)/dextran sodium sulfate (DSS) model of colitis-associated CRC.
C57/BL6 wild-type (WT), Il33-/-, T1/St2-/- and Nt5e-/- mice were given a single dose of AOM (10 mg/kg) followed by two cycles of 3% DSS for 7d in drinking water. Vehicle-treated WT mice served as controls and were sacrificed at the same time points. Another group of WT followed the same protocol and received CD73 inhibitor i.p. treatment or vehicle. Disease Activity Index (DAI), as well asendoscopic, stereomicroscopic and histological evaluations of colons were performed. IHC, immunofluorescence (IF), qPCR, and ELISA were done on full-thickness colons of WT for IL-33 and ST2localization and identification, as well as mRNA and protein expression, respectively. RNA-Seq was performed on whole tissues from AOM/DSS treated WT, Il33-/- and T1/St2-/-. qPCR analysis was done on isolated polyps from WT, Il33-/- and T1/St2-/- for Nt5e (CD73) and adenosine pathway targets.

Results

Il33, Ilrl1(ST2L), and Ilrl1(sST2) mRNA transcripts, as well asIL-33 and total ST2 proteins were dramatically elevated in AOM/DSS-treated WT mice vs. controls. IHC and IF of treated WT mice revealed localization of IL-33 to the colonic epithelium and to cells within the polyp LP morphologically consistent with stromal and mast cells. Little to no staining for IL-33 was present in controls. Using IF, IL-33 co-localized with sub-epithelial myofibroblast markers Actin and Vimentin, or with mast cell markers Tryptase and MCPT1. AOM/DSS treatment in Il33-/- and T1/St2-/- mice resulted in a significant decreased polyp number and size vs. WT, with colonoscopy revealing the development of protruding lesions with abnormal vascular patterns, suggesting tumorous lesions in WT mice, while all deficient mice showed their absence with a more impressive mucosal inflammation, likely due to reduced epithelial proliferation and repair caused by the deficiency of IL-33 signaling. RNA-Seq identified a significant reduction of Nt5e and adenosine pathway targets in Il33-/- and T1/St2-/- vs. WT. qPCR on isolated polyps confirmed this observation. AOM/DSS-treated Nt5e-/-showed a significant decreased polyp number and size vs. controls. Therapeutic inhibition of CD73 produced similar results.

Conclusion

Our results suggest that the IL-33/ST2 axis promotestumorigenesis in colitis-associated CRC through the activation of CD73.Further studies are underway to determine mechanisms of action that support these findings.

Introduction

Duodenal stump fistula (DSF) represents a significant complication that can arise following gastrectomy, with a prevalence ranging from 1.0% to 2.5%. This condition is characterised by a high mortality risk (12.5% to 28%) and a high morbidity rate (75%). In instances where conservative management has proven ineffective, percutaneous transhepatic biliary drainage (PTBD) emerges as a valuable intervention. This procedure involves the aspiration of bile, thereby reducing duodenal pressure and diminishing fistula output. However, it is important to note that PTBD does necessitate a prolonged healing period and frequently requires subsequent treatments, such as percutaneous or endoscopic injection of glue. The prolonged hospitalization is also to be considered in these patients, in which the resolution of the fistula generally requires a period of between 60 and 240 days.
The objective of this study was to ascertain the viability and effectiveness of a pioneering technique involving percutaneous DFS embolization with ethylene vinyl alcohol copolymer (EVOH) in combination with an occlusion balloon, utilised in the management of DSF following gastrectomy for malignant or benign indications.

Aims & Methods

The present study encompassed patients with a diagnosis of DSF, as determined by the presence of duodenal juice in the surgical drainage or its leakage through the abdominal wall. This diagnosis was confirmed through surgical approach and/or a computerised tomography (CT) scan. A retrospective analysis was conducted on 15 consecutive patients who underwent PTB-A embolization with Ethylene-Vinyl Alcohol Copolymer (EVOH) as a treatment for DSF, following the failure of medical, surgical, or endoscopic interventions.
An analysis was conducted of clinical and technical success, morbidity and mortality.

Results

The population under scrutiny comprised 10 female and 5 male subjects. Furthermore, it is noteworthy that 74% of patients underwent surgery for a malignant lesion. In the present study, a total of 13 patients underwent subtotal gastrectomy. In all cases, technical success was achieved. A positive outcome was achieved in 11 out of 15 patients following a single treatment. In 4 cases, patients required further treatment to achieve complete fistula healing. In the course of treatment, it was observed that a single patient required four treatment sessions to achieve complete healing. No procedure-related complications or mortalities were recorded. No recurrence of the fistula was observed in the population under study. Radiological follow-up was conducted at one or three months following the procedure for a total of 11 patients. 2 patients expired prior to the scheduled follow-up due to unrelated causes, while 2 patients failed to attend the control appointment.

Conclusion

PTB-A embolization with EVOH of duodenal stump fistula seems to be an effective treatment for DSF, with prompt recovery, no mortality and short hospitalization after the procedure.

References

1. Orsenigo E,et al. Duodenal stump fistula after gastric surgery for malignancies: a retrospective analysis of risk factors in a single centre experience. Gastric Cancer. 2014 Oct;17(4):733-44. doi: 10.1007/s10120-013-0327-x.

2. Paik HJ, et al. Duodenal stump fistula after gastrectomy for gastric cancer: risk factors, prevention, and management. Ann Surg Treat Res. 2016 Mar;90(3):157-63. doi: 10.4174/astr.2016.90.3.157.

3. Gu L, et al. Risk Factors for Duodenal Stump Leakage after Laparoscopic Gastrectomy for Gastric Cancer. J Gastric Cancer. 2020 Mar;20(1):81-94. doi: 10.5230/jgc.2020.20.e4.

4. Naito R, et al. Retrograde drainage for duodenal stump leakage using ileal decompression tube guided by double-balloon endoscopy: a novel case report. Surg Case Rep. 2024 Feb 18;10(1):44. doi: 10.1186/s40792-024-01842-9.

5. Aurello P, et al. Management of duodenal stump fistula after gastrectomy for gastric cancer: Systematic review. World J Gastroenterol. 2015 Jun 28;21(24):7571-6. doi: 10.3748/wjg.v21.i24.7571.

6. Zizzo M, et al. Management of duodenal stump fistula after gastrectomy for malignant disease: a systematic review of the literature. BMC Surg. 2019 May 28;19(1):55. doi: 10.1186/s12893-019-0520-x.

7. Cozzaglio L, et al. Percutaneous transhepatic biliary drainage and occlusion balloon in the management of duodenal stump fistula. J Gastrointest Surg. 2011 Nov;15(11):1977-81. doi: 10.1007/s11605-011-1668-6.

Introduction

Low grade dysplasia (LGD) is a key risk factor for development of high grade dysplasia (HGD) and colorectal cancer (CRC), in individuals with inflammatory bowel disease (IBD). Current clinical guidelines recommend that the detection of LGD should guide decision making, often leading to intensified surveillance or, in some cases, colectomy. As such, the detection of LGD in IBD imposes a considerable burden on both affected individuals and healthcare systems. The incidence, prevalence and treatment of IBD are continuously evolving. This may have influenced the incidence of IBD-related LGD and potentially its progression to HGD and CRC. Despite these developments, limited literature describes temporal trends in the incidence of IBD-related LGD, HGD and CRC, especially over the past decade, a period marked by the widespread use of biological therapies. Therefore, we aimed to utilize nationwide Danish health registers to describe trends over time in the incidence of IBD-related LGD, HGD and CRC.

Aims & Methods

We conducted a nationwide cohort study using data from Danish national health registers from 1990 to 2022. All Danish residents with a first-time diagnosis of either IBD, IBD-related LGD, HGD or CRC during this period were included. IBD-relation was established when a diagnosis of dysplasia or CRC was recorded within 180 days prior to, or at any time after, a first IBD diagnosis. HGD and/or CRC was defined as a composite endpoint, with the date assigned to the first occurring diagnosis if both were present. Incidence rates for IBD, IBD-related LGD, and HGD/CRC were calculated per 100,000 person years. Annual incidence rates and incidence rate ratios (IRRs) with 95 percent confidence intervals (CIs) were calculated using a Poisson approximation.

Results

During the study period, a total of 92,717 new cases of IBD, 8,406 cases of LGD, and 2,480 cases of HGD/CRC were identified.
The incidence of IBD per 100,000 person years increased markedly over time, rising from 30.36 in 1990 (95% CI: 28.89 to 31.91) to 59.71 in 2020 (95% CI: 57.76 to 61.73). A similar trend was observed for IBD-related LGD, with the incidence increasing from 0.33 (95% CI: 0.21 to 0.53) in 1990 to 10.41 (95% CI: 9.61 to 11.27) in 2020. For IBD-related HGD/CRC, the incidence rose from 0.12 (95% CI: 0.05 to 0.26) to 0.81 (95% CI: 0.61 to 1.07) in the same period. In the yearly incidence curves, the increase for both IBD and HGD/CRC appeared steady over time until a plateau was reached around 2008, whereas a distinct spike in LGD incidence was observed in 2014. This spike coincided with the introduction of a national CRC screening program in Denmark. Notably, the overall increase in IBD-related LGD far exceeded that of advanced dysplasia, with an IRR between 1990 and 2020 of 31.44 (95% CI: 28.01 to 35.28) for LGD, compared to 3.59 (95% CI: 3.35 to 3.85) for HGD/CRC.

Conclusion

The incidence of IBD, IBD related LGD, and IBD-related HGD/CRC has increased substantially in Denmark over the past 30 years. We observed a plateau in the incidence of IBD and IBD-related HGD/CRC within the last decade. Notably the overall increase in incidence was far more pronounced for IBD-related LGD, where we also observed a very notable spike in 2014, temporally aligned with the introduction of CRC screening in Denmark, this was not mirrored in the incidence of IBD-related HGD/CRC.

Introduction

Several factors are known to affect the clinical presentation of Helicobacter pylori (H. pylori) infection including bacterial virulence factors, intensity of the immune response of the host, host’s genetic factors, as well as different environmental factors. Complex interactions between H. pylori and the host’s immunological response result in the production of various cytokines (interferon-γ, tumor-necrosis factor α, interleukin-1β, and interleukin-8) and reactive oxygen species (ROS) which lead to prolonged inflammation and subsequent damage to the gastric mucosa. Various inflammation mechanisms have been studied in H. pylori infection, including those related to the NF-κB signaling pathway, ROS, and more recently NLRP3 inflammasome. When it comes to the multifunctional family of glutathione transferase enzymes, glutathione S-transferase omega (GSTO) and pi (GSTP) are known for their antioxidant, as well as signaling activity. Specifically, the regulatory effects of GSTO and GSTP1, on NLRP3 inflammasome and NF-κB signaling pathway, respectively, have been extensively studied.

Aims & Methods

Based on the known catalytic and signaling functions of GSTO and GSTP and their effect on both redox homeostasis and inflammation, we proposed a possible modifying role of GSTO and GSTP1 polymorphisms in the individual susceptibility towards the development of H. pylori infection. The distribution of polymorphisms in GSTO1 (rs4925), GSTO2 (rs156697), and GSTP1 (rs1695 and rs1138272) were assessed in 101 H.pylori-positive and 107 H.pylori-negative patients, emphasizing their individual and haplotype effects on disease development. Polymorphisms were determined by the appropriate qPCR method.

Results

The obtained results showed no influence of GSTO1 (rs4925) and GSTO2 (rs156697) polymorphisms on H.pylori infection development in both individual and haplotype analyses (p>0.05). However, individuals carrying variant GSTP1 (rs1695 and rs1138272) genotypes exhibit up to three times higher odds of H.pylori infection development, compared to those carrying referent alleles (Table 1). These findings are confirmed by further haplotype analysis. Carriers of H3 haplotype, comprising GSTP1*G and GSTP1*T variant alleles were at more than a 3-fold increased risk of H. pylori infection development (p=0.012).
Table1. Distribution of GSTP1 genotypes in H. pylori-positive and H. pylori-negative patients.

GSTP1 rs1695 genotype	HP negative, n (%)	HP positive, n (%)	OR (95% CI)	p
*A/A	47 (44)	35 (35)	1a
*A/G	53 (50)	50 (49)	1.27 (0.71-2.27)	0.427
*G/G	7 (6)	16 (16)	3.07 (1.14-8.26)	0.026
*A/G + *G/G	60 (56)	66 (65)	1.47 (0.84-2.58)	0.172
GSTP1 rs1138272 genotype
*C/C	92 (87)	74 (73)	1a
*C/T	14 (13)	22 (22)	1.95 (0.93-4.08)	0.075
*T/T	0 (0)	5 (5)	/	/
*C/T + *T/T	14 (13)	27 (27)	2.39 (1.17-4.89)	0.016

HP – Helicobacter pylori; OR – odds ratio; CI – confidence interval;

Conclusion

GSTP1 polymorphisms modify susceptibility to developing H. pylori infection. Further studies are needed to clarify the specific roles of glutathione transferases in innate and acquired immune response in the context of H. pylori infection development and maintenance.

Introduction

Apelin, an adipokine secreted from visceral fat, has been associated with endothelial cells dysfunction‐related chronic inflammatory diseases. Decreased serum apelin levels have been found in patients with cardiovascular disease (CVD). Higher apelin levels have been measured in mesenteric adipose tissue and inflamed colonic epithelium of patients with Inflammatory Bowel Disease (IBD), but data on the role of serum apelin levels in IBD patients are lacking.

Aims & Methods

We aimed to a) compare serum apelin levels between 104 consecutive IBD patients and 104 age and sex matched healthy controls (blood donors), b) to evaluate the correlation between serum apelin levels with demographics, disease characteristics, treatment and disease course.
Serum apelin-13 levels were measured using ELISA (Wuhan Fine Biological Technology Co., Ltd). Statistical analysis was performed with SPSS 24 (SPSSInc. Chicago, IL, USA).

Results

Mean apelin levels were significantly higher in IBD patients compared to their matched healthy controls (1996.29 ± 1592.96pg/ml vs 1552.99 ± 809.64, p=0.012). Among the examined parameters only smoking was found independently associated with serum apelin levels in IBD patients (p<0.001).
IBD patients with CVD (25) had lower but not significant different serum apelin levels compared to patients without CVD (79) (1743.01 ± 1116.26pg/dl vs 2465.09 ± 2006.51pg/ml, p=0.122). In a subgroup analysis of patients without CVD (79 IBD patients) significantly elevated serum apelin levels were found in patients with extended UC, history of immunomodulator use and absence of musculoskeletal EIMs (2539,69 ± 1969.29pg/ml vs 1164.45 ± 818.89pg/ml, p=0.044, 2317.69 ± 1867.99pg/ml vs 1451.40 ± 1024.20pg/ml, p=0.043 and 2340.58 ± 1850.16pg/ml vs 1392.09 ± 1054.99pg/ml, p=0.027, respectively).
Finally, a moderate positive correlation was found among UC extent and serum apelin levels in patients without CVD (r=0.525, p=0.004). Νegative correlations were found among age at study entry and serum apelin levels in both IBD patients without CVD and all IBD patients (r=-0.263, p=0.001 and r=-0.214, p=0.002, respectively) and between immunomodulator use, history of musculoskeletal EIMs and serum apelin levels in patients without CVD (r=-0.26, p=0.021 and r=-0.336, p=0.005, respectively).

Conclusion

The circulating serum apelin levels are significantly increased in IBD patients compared to matched healthy controls. Increased apelin levels are independently associated with smoking status and disease extend (in UC). IBD patients with musculoskeletal manifestations have decreased serum apelin levels compared to IBD patients without musculoskeletal manifestations. Further investigation with larger studies on the role of serum apelin in IBD is needed.

Disclosure

None

Introduction

As many as 40% of IBD patients do not respond to targeted therapies¹. Enhancing the efficacy of these therapies is a key priority, and defective host-microbe interplay is often thought to underpin a proportion of mechanistic therapeutic failure. Interactions of macrophages with the microbial-derived SCFAs (Butyrate, Propionate and Acetate) in particular; may be critical for disease remission. Therefore, we examined the manner that macrophages interacted with, and changed their behaviour according to exposure to SCFAs in order to identify new therapeutic targets.

Aims & Methods

This study aimed to explore phenotypic changes of macrophages upon sensing of SCFAs in the context of IBD. We hypothesised that SCFAs would alter the inflammatory signature of macrophages, and that de-orphanized transmembrane G-protein receptor Free-fatty acid receptor 3 (FFA3) expressed by immune cells in GI tract would be critical for this process, and furthermore that effective sensing of SCFAs would be necessary for shaping macrophage phenotype. THP-1 and monocyte-derived macrophage models were developed for exploring inflammatory signatures in the presence of 1mM or 4mM of each SCFA (Butyrate/Propionate/Acetate). By using a pharmacological activator of FFA3 (AR420626) we aimed to identify whether this receptor play an important role in directing macrophage phenotype. Secretion of (type-I Interferon) IFN-I and pro-inflammatory cytokines were measured using ELISA. Expression of Interferon-stimulated genes (ISGs) was quantified using RT-PCR. Subsequent experiments aimed to validate our findings with a knock-down model of FFA3.

Results

We demonstrated that polarisation of macrophages with LPS & IFN-γ rapidly led to the induction of type-I interferon responses and release of pro-inflammatory cytokines. This heightened secretion of IFN-I was almost entirely muted in the presence of butyrate and propionate (1mM and 4mM). As IFN-I drives the expression of ISGs though activation of IFNAR1-JAK/STAT axis, we quantified expression of the ISGs MX1 and IFIT1 as an indirect measure of bioactive IFN. Induction of MX1 and IFIT1, were strongly repressed by butyrate and propionate. Based on these observations, we determined that these responses to both SCFAs were being mediated by FFA3. Intriguingly, our results were closely mimicked by pharmacological intervention with AR420626 in a dose-dependent manner (10 – 50 μM), suggesting that IFN-I secretion could be attenuated through activation of FFA3. Introducing a knock-down to our model, we validated our findings, and macrophages displayed impaired sensing of SCFA in the absence of FFA3.

Conclusion

We identified that macrophages reduce IFN-I release in the presence of butyrate and propionate, which is partly mediated through FFA3, and FFA3 ligands may be helpful for dampening inflammation in the gut mucosa in IBD.

References

(1). Ben-Horin, S., Kopylov, U. & Chowers, Y. Optimizing anti-TNF treatments in inflammatory bowel disease. Autoimmun. Rev. 13, 24–30 (2014).

Introduction

Oesophageal food bolus impaction [OFBI] is a common presentation to emergency room [ER] and often requires endoscopic intervention. We aimed to describe the incidence of OFBI in Canterbury, New Zealand and examine factors predicting the need for endoscopic intervention and complications in the population-based cohort.

Aims & Methods

All ER presentations of OFBI in Canterbury between October 2018 and August 2023 were included. Population data for the Canterbury population was obtained from Statistics NZ. Ethnicity was defined according to hospital records based on patients’ self-identification. Endoscopic intervention was defined as the presence of bolus during the endoscopy requiring any endoscopic manoeuvre for clearance. Complications were defined as unsuccessful attempts requiring a repeat procedure or procedure-related injuries.

	Total (n = 187)
Age (years)	Mean 55 Median 54.9
Gender - Male (%) : Female (%)	113 (60.4) : 74 (39.6)
Ethnicity - European (%) : Non-European (%)	163 (87.2) : 24 (12.8)
Cause of oesophageal impaction (%)	EoE 42 (22.5) Stricture 43 (23)£ Other 15 (8)* Idiopathic/unknown 87 (46.5)¥
Food type (%)	Meat 141 (86.5) Non-meat 46 (24.5)
Spontaneous clearance of food bolus clinically, without endoscopy performed (inpatient or outpatient) (%)	42 (22.5)
Spontaneous clearance of food bolus diagnosed on endoscopy as an inpatient (%)	37 (19.8)
Inpatient endoscopic intervention required (%)	92 (49.2)
Total complications (%)	8 (4.3)

£ cause of impaction from Schatzi ring or benign esophageal stricture
* cause of impaction from severe reflux oesophagitis (Los Angeles Grade C or D), esophageal dysmotility, malignant stricture, or esophageal candidiasis
¥ no cause for impaction found; either no endoscopy performed as an inpatient or outpatient or no pathology found on endoscopy

Results

There were 187 ER presentations of OFBI between October 2018 and August 2023. Clinical characteristics of the population-based cohort are presented in Table 1.
The average annual incidence of ER presentations of OFBI in Canterbury region between 2019 – 2022 was 5.82 per 100,000 population (95% CI 3.96-7.68/100,000). The incidence of ER presentations of OFBI in Europeans and non-Europeans over the same period was 8 per 100,000 European population (95% CI 5.27-10.73/100,000) and 1.94 per 100,000 non-European population (95% CI 0.15-3.73/100,000).
A total of 92 cases (49%) required endoscopic intervention. Factors predicting the need for endoscopic intervention were meat bolus [p= 0.01], stricture [p<0.01], and early endoscopy performed <12hrs [p<0.01]. There were only 8 complications. Predictors with a trend associated with complications were after-hours presentation [p=0.06] and early endoscopy performed <6hrs [p=0.06].

Conclusion

Our population-based cohort showed a significantly higher incidence of ER presentations of OFBI in Europeans than in non-European ethnic groups. Factors predicting the need for endoscopic intervention were meat bolus, stricture and early endoscopy. After-hours presentation and early endoscopy <6hrs showed a trend towards a higher risk of complications. The results suggest that a delayed approach may be associated with a higher chance of spontaneous clearance and a lower risk of complications, although further study is needed.

Disclosure

Not applicable