Introduction

Colorectal cancer associated to chronic colitis (CAC) has a different pathogenesis compared to sporadic or familial colorectal cancer (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 as endoscopic, 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 ST2 localization 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 as IL-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 promotes tumorigenesis in colitis-associated CRC through the activation of CD73. Further studies are underway to determine mechanisms of action that support these findings.

Clinical Case Summary

A 39-year-old woman was admitted on June 20, 2024, with a right middle cerebral artery stroke, nine weeks after starting Upadacitinib for ulcerative colitis. She presented with dysarthria, dysphagia, and severe left-sided weakness. CT imaging revealed a wedge-shaped infarction without intracranial hemorrhage (CT head/ Brain MRI).
She was diagnosed with ulcerative colitis in November 2023, she initially responded to Mezavent and steroids but was hospitalized on March 31, 2024 for moderate UC flare, requiring infliximab rescue therapy. The patient presented with four bloody bowel movements and elevated inflammatory markers (CRP>100), confirmed by a Mayo score of 2 on flexible sigmoidoscopy and cytomegalovirus (CMV) infection was excluded. Clostridium difficile tests were negative twice and a CT scan revealed pancolitis. Despite minimal response to rescue therapy, she opted for medical treatment over colectomy.
On April 23, 2024, she began an eight-week induction of Upadacitinib 45 mg, which she tolerated well. However, on June 20, she developed sudden stroke symptoms while eating dinner, including difficulty swallowing, choking, left-sided weakness, and numbness. She had no vascular risk factors or family history of premature cardiovascular conditions. Lupus, and vasculitis work up were unremarkable and extensive thrombophilia screenings were all negative.
Discussion: Thrombosis in IBD patients can result from various potential causes. First of all, Inflammation and hypercoagulability, driven by elevated cytokines like TNF, interleukins, and CRP, activate the coagulation cascade, increasing thrombosis risk.
Conclusion: IBD is a known risk of thromboembolic disease, this risk increased during flare up will raise future research questions regarding extended anticoagulation prophylaxis during flare and uses of Jak stats inhibitor.

References

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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

Diverticular disease of the colon is one of the most common diseases in Western world. Despite in the natural history in most of cases diverticulosis remains asymptomatic or manifests with mild abdominal pain, complications may occur. Bleeding from diverticula is one of the most common complications and, despite it is usually a self-limiting event, it may lead to anemia or shock. Among the endoscopic interventions for active bleeding, direct or indirect clipping of the diverticulum is the most diffuse one. However, it has been hypothesized that endoscopic band ligation (EBL) may be more effective, since it may improve the chance to close the bleeding vessel, with a better outcome on long term. Therefore we performed a meta-analysis comparing clipping versus EBL for diverticular bleeding.

Aims & Methods

Literature search on main databases (PubMed, Web of science, SCOPUS, EMBASE) was performed in November 2022. Studies comparing clip versus EBL for acute diverticular bleeding were selected. We excluded case series, abstract and articles not written in English. The following outcomes were analysed: short term effectiveness, early rebleeding, tardive rebleeding and need for surgery or radiologic embolization. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculate according to Mantel-Haenszel method. Heterogeneity was estimated by I² statistic with chi square test, and, if present, a random effect model was used, otherwise a fixed one was adopted.

Results

Seven studies were selected, overall enrolling 2322 patients (979 in EBL and 1343 in clip groups). Immediate haemostasis was achieved in the EBL and clipping group respectively in the 96.8% and 96.5% (OR=0.94, 95% CI 0.59-4.19, p=0.79). Early rebleeding was observed more frequently in the clipping (25.0%) than in the EBL group (11.8%), with an OR=0.40 (95% CI 0.32-0.51, p<0.001). Similarly, tardive rebleeding was more common in the clipping arm (37.4%) than in the EBL (24.5%), OR=0.39, 95% CI 0.22-0.68, p=0.0001. Patients receiving clipping needed more frequently salvage surgery or embolization than EBL (1.48% versus 0.53%, OR=0.40, 95% CI 0.17-0.93, p=0.03).

Conclusion

Despite EBL and clip have similar effectiveness in achieving immediate haemostasis, EBL showed better effectiveness in maintaining it on longer interval times, with less probable need for major surgical/radiologic interventions.