Introduction

Delayed bleeding after gastric endoscopic submucosal dissection (ESD) is one of the most frequent complications (up to 7%). The BEST-J score is a risk predictive model for delayed bleeding following gastric ESD. We aim to assess potential risk factors associated with bleeding and validate the BEST-J score in a population of patients undergoing ESD.

Aims & Methods

Prospective cohort study, single centre, of patients who underwent gastric ESD between 2017 and 2023. The characteristics of the lesion were evaluated, and logistic regression of risk factors associated with bleeding after ESD was performed. The BEST-J score was calculated for each patient and the discriminative ability was evaluated through the area under the receiver operating characteristic curve (AUC-ROC).

Results

Included 101 gastric ESDs (63.4% female), with a mean age of 69.7 ± 8 years. 17.8% of patients were on antiplatelet therapy and 13.9% were on anticoagulant therapy. Among the analyzed lesions: 43.6% measured between 0-20mm, 56.4% were ≥ 20mm; 13.9% were sessile, 60.4% flat, 14.9% depressed and 10.9% subepithelial; 22.8% were located in the cardia, fundus, or body, 17.8% in the incisura angularis and 59.4% in the antrum. The most frequent histological results were: 38.6% low-grade dysplasia, 26.7% high-grade dysplasia and 19.8% intramucosal adenocarcinoma. The mean procedure duration was 87±43 minutes. Delayed bleeding after ESD occurred in 5.9% (n=6) of cases. In the univariate analysis of risk factors, the lesion size ≥ 20mm showed statistical significance (10.5% vs. 0%; p=0.034), but not the location in the antrum (6.7% vs. 4.9%; p=0.5), lesion nature (7.1% vs. 8.2% vs. 0% vs. 0%; p=0.5) or procedure duration ≥60 minutes (5% vs. 9.5%; p=0.3). The BEST-J score predicted the risk of delayed bleeding after gastric ESD with an AUC of 0.70 (95% CI: 0.53-0.87; p=0.1).

Conclusion

The use of bleeding predictive scores may be useful in identifying high-risk patients; in our series, the BEST-J score was not very effective, with only lesion size ≥ 20mm being a relevant factor for bleeding after ESD.

Introduction

Endoscopic resection of lesions involving the appendiceal orifice is an alternative to surgery. Long term outcomes have not been determined.

Aims & Methods

To determine the long-term efficacy and safety of endoscopic resection of appendiceal lesions.
Retrospective analysis of the endoscopic resection of lesions with appendiceal involvement was performed in seven centers in Spain between January 2016 and July 2022. The technical success rate (complete macroscopic resection at index procedure), recurrence rate and short- and long-term complications were evaluated, including delayed appendicitis with a clinical follow-up of at least 12 months. The intra-appendicular extension of the lesion was described as superficial (visible appendiceal margin) or deep (if it was not possible to determine the appendiceal margin of the lesion before resection) and the circumferential extension was described according to the affected percentage.

Results

98 lesions with appendiceal involvement were treated, 73 had a clinical follow-up >12 months with a median follow-up of 26 months ([IQR]16-37 months). There were 35 lesions with deep intra-appendicular involvement and 63 with superficial appendiceal involvement, 64 with a circumferential involvement ≥50%. The median size of the lesions was 20mm([IQR]10-30mm) and 19(19%) had previous manipulation. Underwater endoscopic mucosal resection (UEMR) was performed in 53% of the lesions (24% by underwater cap-suction pseudopolyp formation, CAP-UEMR) with a technical success of 93% (49% en bloc and 51% piecemeal).
Among these cases, there were 7 incomplete resection, with 3 patients undergoing surgery and the remaining 4 undergoing endoscopic treatment during a subsequent session. Within the entire cohort, there were 3 cases of malignant histology: one low-risk pT1 which underwent surgery resulting in no residual cancer and negative lymph nodes, another low-risk pT1a (which chose follow-up and experienced no recurrence), and a third with suspected incomplete resection and pT2 cancer, necessitating surgery.
There were 6 intraprocedural bleeding and 2 delayed bleeding, all managed endoscopically. 45 patients completed at least 12 months of endoscopic follow-up (median 18, [IQR] 8-29months), showing recurrence in 12 cases (6 lesions with deep intra-appendicular extension), 8 (67%) treated endoscopically. There was 1 case of intraprocedural perforation, managed endoscopically.
Surgery was needed during follow-up in 7 additional cases [recurrence=3; pT2 cancer =1; pT1a =1; appendicitis=2 (at 11 months and 56 months post-endoscopic resection)], in total 10 surgeries were needed in the entire cohort.

Table 1- Baseline characteristics of patients and resected lesions

Conclusion

The endoscopic management of lesions involving the appendix may indeed prove effective and safe after following a minimum follow-up of 12 months, offering a viable alternative to surgery. It is important to note that delayed-onset acute appendicitis, though rare can be observed beyond 11 months post-procedure, although a casual mechanism cannot be proven.

References

1. Ferlitsch M, Moss A, Hassan C, et al. Colorectal polypectomy and endoscopic mucosal resection (EMR): European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. Endoscopy. 2017 Mar;49(3):270-297. doi: 10.1055/s-0043-102569. Epub 2017 Feb 17. PMID: 28212588.
2. Albéniz E, Pellisé M, Gimeno García AZ, et al; en nombre del Grupo Español de Resección Endoscópica de la Sociedad Española de Endoscopia Digestiva. Clinical guidelines for endoscopic mucosal resection of non-pedunculated colorectal lesions. Gastroenterol Hepatol. 2018 Mar;41(3):175-190. English, Spanish. doi: 10.1016/j.gastrohep.2017.08.013. Epub 2018 Feb 12. PMID: 29449039.
3. Mi Song E, Yang H, Jung Lee H, et al. Endoscopic Resection of Cecal Polyps Involving the Appendiceal Orifice: A KASID multicenter Study. Dig Dis Sci. 2017, 62, 3138–3148, DOI: 10.1007/s10620-017-4760-2.
4. Jacob H, Toyonaga T, Ohara Y, et al. Endoscopic submucosa dissection of cecal lesions in proximity to the appendiceal orifice. Endoscopy, 2016. 48(09): v23-v23. DOI:10.1055/S-0042-110396.
5. Schmidt A. Lesions at the appendiceal orifice- the Achilles’heel of endoscopic resection? Endoscopy, 2022. 54(01): 25-26
   DOI: 10.1055/a-1686-8800
6. Patel AP, Khalaf MA, Riojas-barrett M, et al. Expanding endoscopic boundaries: Endoscopic resection of large appendiceal orifice polyps with endoscopic mucosal resection and endoscopic submucosal dissection. World J Gastrointest Endoscp 2023, 15(5):386-396. DOI: 10.4253/wjge.v15.i5.386.

Disclosure

Dr Hugo Uchima collaborates as proctor with Erbe Spain and Olympus Iberia. Has received congress registration from Casen Recordati.

Introduction

Antibiotic resistance is a growing challenge in the eradication of Helicobacter pylori (Hp). However, the benefits of sensitivity-guided approach compared to empirical regimens is to be established. In this study, we evaluated the effectiveness of the recommended therapeutic protocols, as well as the factors linked to therapeutic failure.

Aims & Methods

A single centre, prospective cohort study, including all consecutive patients undergoing Hp eradication therapy between 2013 and 2022. The evaluated therapeutic protocols were the triple therapy (TRI), concomitant quadruple therapy (QUADC), sequential quadruple therapy (QUADS), and bismuth-based quadruple therapy (QUADB). We analysed the demographic and clinical characteristics of the population, and compared the regimens’ effectiveness, adherence and adverse events.

Results

Included 523 patients, 57% female, with a median age of 56 years (IQR 46-65). The main indication for eradication was dyspepsia (59.8%). The prescribed therapeutic protocols were QUADC in 34.4% of patients, QUADB in 28.7%, TRI in 25.6%, and QUADS in 11.3%. The compliance rate was 97.1%, with no significant differences between the regimens (p=0.49). According to intention-to-treat analysis, the eradication rates in naive patients were TRI 76.1%, QUADS 82%, QUADB 91.1% and QUADC 92.5%. There were statistically significant differences between QUADB/QUADC vs. QUADS/TRI eradication rates (91.9% vs. 78.3%, p<0.001) and adverse event rates (16.2% vs. 4.4%, p<0.001). Multivariate analysis demonstrated an association between therapeutic failure and the following: previous eradication therapy (OR-2.6; 95%CI: 1.5-4.6), noncompliance (OR-80.1; 95%CI: 9.8-664.6) and lack of statin use (OR-2.7; 95%CI: 1.2-6.1).

Conclusion

Bismuth-based quadruple therapy and concomitant quadruple therapy are the most effective therapeutic regimens. To achieve the best eradication rates, attention should be direct to significantly modifiable factors such as non-compliance or absence of concomitant statin use.

Introduction

Inflammatory bowel disease (IBD), a chronic inflammatory disease of the gastrointestinal tract, is caused by various factors, including genetic factors and environmental factors, as well as dysregulated immune responses. LMT503, a novel organic small-molecule compound, has the potential to suppress pro-inflammatory cells and induce anti-inflammatory cells by modulating their cell metabolisms. We evaluated the anti-inflammatory effects of LMT503 in a murine adoptive T cell transfer-induced colitis model.

Aims & Methods

This study was conducted to evaluate the anti-inflammatory effect of LMT503 in the murine chronic colitis model. Naïve CD4⁺CD25^-CD45RB^high CD62L^high T cells that were isolated from wild-type mice by flow cytometry based-method and transferred to Rag1 knock-out mice by intraperitoneal injection to induce murine adoptive T cell transfer-induced colitis. LMT503 was orally administrated (50mg/kg, 100mg/kg) for 2 weeks starting at 5 weeks after naïve T cell transfer. The disease activity index (DAI) was checked daily, and histopathological score, macroscopic injury score, and colon length were evaluated upon sacrifice. Macrophages and T cells from the spleen were analyzed by flow cytometry. Gene expression in colon tissue was measured by qRT-PCR and cytokine profiles in plasma was measured by cytometric bead array. Myeloperoxidase (MPO) activity was measured using the MPO activity kit.

Results

Oral administration of LMT503 ameliorated adoptive T cell transfer-induced colitis in mice. The DAI, histopathological score, and macroscopic injury score were significantly decreased after the administration of LMT503 in a dose-dependent manner. The LMT503-treated group showed significantly increased mucin production in the colon. Th1, Th17 cells, and M1 macrophages in the spleen were suppressed, and M2 macrophages were induced by the administration of LMT503. MPO activity and gene expressions of pro-inflammatory cytokines, such as IL-6, IL-1β, and TNF-α, in colon tissue were suppressed by the administration of LMT503. And the level of inflammatory cytokines, such as IL-2, TNF-α, and IFN-γ, in plasma were significantly suppressed by the administration of LMT503. Especially, LMT503 treatment significantly increased the gene expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a), a master regulator of mitochondrial biogenesis, suggesting that LMT503 modulates cellular metabolism towards an anti-inflammatory metabolism.

Conclusion

Our data suggest that the anti-inflammatory effect of LMT503 ameliorates murine adoptive T cell transfer-induced colitis by modulating cellular metabolism and immune cell modulation. Therefore, LMT503 may be a novel therapeutic drug that opens new avenues for the treatment of IBD.

References

1. Erben U, Loddenkemper C, Doerfel K, et al. A guide to histomorphological evaluation of intestinal inflammation in mouse models. Int J Clin Exp Pathol. 2014;7(8):4557-4576.
2. Ostanin DV, Bao J, Koboziev I, et al. T cell transfer model of chronic colitis: concepts, considerations, and tricks of the trade. Am J Physiol Gastrointest Liver Physiol. 2009;296(2):G135-G146.
3. Ghoreschi K, Jesson MI, Li X, et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J Immunol. 2011;186(7):4234-4243.
4. Burke JR, Cheng L, Gillooly KM, et al. Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain. Sci Transl Med. 2019;11(502):eaaw1736.
5. Kiesler P, Fuss IJ, Strober W. Experimental Models of Inflammatory Bowel Diseases. Cell Mol Gastroenterol Hepatol. 2015;1(2):154-170.

Introduction

No single pharmacological approach is currently available for the treatment of inflammatory bowel disease (IBD) in active and maintenance stages. As evidence is growing on the immuno-modulatory activities of the G-protein coupled receptor GPR120 and on its role in modulating the pathophysiology of IBD, its potential as a therapeutic target for this disease is worthy of exploration.

Aims & Methods

Herein, we have developed DFL23806, a new GPR120 selective small molecule agonist, and propose it as a potential therapeutic approach for IBD. We employed our in-house proprietary Exscalate platform for molecular docking simulations to define the site and mode of binding of the compound with the receptor and used in vitro studies and in vivo models (murine dextran sodium sulfate (DSS)-induced acute and chronic colitis and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced chronic colitis models) to characterize the mechanism of action of our molecule and evaluate its therapeutic effects.

Results

DFL23806 is a selective agonist of human and mouse GPR120 that can activate both the G-protein dependent and independent signaling (β-arrestin pathway) of the receptor. DFL23806 has been designed to have high metabolic stability and reach the ileum and colon at optimal concentrations that allow for the activation of GPR120 while, notably, delaying its internalization. This can lead to prolonged periods of signal transduction compared to other commercially available GPR120 agonists and amplification of signaling effects. In vivo, intrarectal treatment with DFL23806 exerted consistent immunomodulatory action in DSS-induced acute colitis in mice. Moreover, oral treatment with DFL23806 significantly inhibited both DSS- and TNBS-induced chronic colonic inflammation and fibrosis by improving the disease activity index, endoscopic score, and reducing body weight loss and colonic tissue damage. Interestingly, DFL23806 treatment also modulated the composition of microbiota, inhibiting the concentration of pathogenic bacteria, and rescued intestinal dysbiosis induced by TNBS.

Conclusion

These results suggest that the stimulation of GPR120 could be an effective strategy for managing colitis, and that DFL23806 has great potential as a therapeutic for the treatment of IBD.

Disclosure

The authors are employees of Dompé farmaceutici s.p.a., Italy. The company has interests in the development of GPR120 selective agonist for the treatment of IBD and metabolic diseases.