Introduction

Complete removal of pancreatic duct stones is the goal of endoscopic treatment for chronic pancreatitis (CP), which is mainly performed by endoscopic retrograde cholangiopancreatography (ERCP), and is completed with either a basket or a balloon catheter. However, choosing which catheter primarily depends on the operators' preference, and the evidence is still scarce. Thus, this study compared the efficacy and safety of these two devices for pancreatic duct stone extraction.

Aims & Methods

This single center retrospective cohort study reviewed the records of 452 consecutive CP patients who underwent ERCP for the first time, from February 2012 to December 2021. A propensity score-matched analysis (1:1) was performed using age, sex, diabetes mellitus, steatorrhea, pancreatic duct stricture, pancreas divisum, ESWL prior to stone extraction, number of stones, size and location of stones as variables. Finally, 101 patients with basket and 101 with balloon catheter were analyzed. The primary outcome was the clearance rate of pancreatic stones; the secondary outcomes were ERCP peri-procedural outcomes and complications.

Results

The rate of complete clearance was comparable between two groups (86.1% [87/101] vs 84.2% [85/101], P = 0.692). In patients with stones ≥ 2cm before extracorporeal shock wave lithotripsy (ESWL), the rate of complete clearance was significantly higher in balloon than in basket group (100% [19/19] vs 70.0% [14/20], P = 0.031). No significant difference was found in partial (odds ratio [OR] 0.8; 95% confidence interval [CI], 0.3-2.1; P = 0.603) and unsuccessful clearance(OR 1.9; 95% CI, 0.6-5.8; P = 0.274). In multivariate analysis, ESWL prior to stone extraction was the only independent predictor of complete clearance (OR, 2.3; 95% CI, 1.2-4.3; P = 0.013). In ERCP peri-procedural outcomes analysis, no significant difference were found in rates of difficult cannulation (1.0% vs 3.0%, P = 0.614), endoscopic sphincterotomy (53.5% vs 49.5%, P = 0.573), dilation of stenosis (26.7% vs 32.7%, P = 0.357), and extraction through the minor papilla (13.9% vs 10.9%, P = 0.522) between basket and balloon catheter groups. For patients with pancreatic duct stenosis, the rates of clearance were comparable between two groups. The rates of complications were also similar in pancreatitis (6 [5.9%]/9 [8.9%], P = 0.421), infection (0 [0.0%]/1 [1.0%], P = 1.000), and perforation (0 [0.0%]/2 [2.0%], P = 0.477) between the two groups; no bleeding or basket impaction was detected.

Table 2. The Impact Factors for Rate of Complete Clearance Between Basket and Balloon Catheter Groups

Conclusion

Basket and balloon catheters showed similar efficacy and safety for pancreatic stone extraction, while the balloon catheter was superior to the basket if the stone size was ≥ 2cm before ESWL. ESWL prior to stone extraction was an independent predictor for pancreatic stone extraction.

References

1. Beyer G, Habtezion A, Werner J, et al. Chronic pancreatitis. Lancet 2020;396:499-512.
2. Ross AS, Kozarek RA. Therapeutic pancreatic endoscopy. Digestive and Liver Disease 2010;42:749-756.
3. Dumonceau JM, Delhaye M, Tringali A, et al. Endoscopic treatment of chronic pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Updated August 2018. Endoscopy 2019;51:179-193.
4. Ishiwatari H, Kawakami H, Hisai H, et al. Balloon catheter versus basket catheter for endoscopic bile duct stone extraction: a multicenter randomized trial. Endoscopy 2016;48:350-7.
5. Ozawa N, Yasuda I, Doi S, et al. Prospective randomized study of endoscopic biliary stone extraction using either a basket or a balloon catheter: the BasketBall study. J Gastroenterol 2017;52:623-630.
6. Sharma R, Sharma V, Singhal U, et al. Outcomes of balloon vs basket catheter for clearance of choledocholithiasis: a systematic review and meta-analysis. Endosc Int Open 2022;10:E1447-e1453.
7. Zhao ZH, Hu LH, Ren HB, et al. Incidence and risk factors for post-ERCP pancreatitis in chronic pancreatitis. Gastrointest Endosc 2017;86:519-524.e1.
8. Wang D, Ji JT, Zou DW, et al. Extracorporeal shock wave lithotripsy as rescue for a balloon dilator trapped in the pancreatic duct. Endoscopy 2015;47 Suppl 1:E604-6.

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)

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

Mirikizumab (miri), a p19-directed IL-23 antibody, showed efficacy in ulcerative colitis (UC)¹. Miri modulates transcripts associated with disease activity and anti-TNF resistance in UC and increases expression of transcripts associated with healthy mucosa². Here, we evaluate the transcription profile of patients with UC who respond to placebo (PBO, 20.6%) or miri 200mg treatment (59.7%) versus non-responders and build a model that can predict response in patients with UC.

Aims & Methods

In the phase 2 AMAC trial (NCT02589665), patients were randomized 1:1:1:1 to receive intravenous PBO (N=63), 50mg miri (N=63), or 200mg miri (n=62) with possible exposure-based dose increases or fixed 600mg miri (n=61) at Week (W)0, 4 and 8. Colonic biopsies were collected at baseline, W12, and W52. An Affymetrix HTA2.0 microarray measured gene expression. Limma comparing values at baseline and W12 determined differentially expressed genes (DEGs). DEGs maintaining their W12 expression level through W52 among responders in either the PBO and miri 200mg arms were designated as similarly expressed genes (DEGSEGs).
XGBoost models³ were trained to predict clinical response (decrease in 9-point Mayo subscore [rectal bleeding, stool frequency, endoscopy] of ≥2 points and ≥35% from baseline [BL] with either a decrease of RB subscore of ≥1 or an RB subscore of 0 or 1) using baseline levels of DEGSEGs and TNF biomarkers. Leave-one-out cross validation of the models using AMAC data and validation experiments by training on the PROTECT data⁴ then predicting in AMAC were used to evaluate our models.

Results

Miri 200mg responders were associated with 84 DEGSEGs, PBO responders were associated with 26 DEGSEGs, and 21 DEGSEGs were common to both. When using the PROTECT data as the training data and AMAC data as the validation cohort, we were able to achieve high ROC-AUC and PR-AUCs using the top 36 (FC > 1.5) miri DEGSEGs (PR-AUC=0.78), or combined (PR-AUC=0.93) gene sets as the features and found that the response prediction was significantly higher in AMAC responders vs. non-responders.

Conclusion

Baseline transcript features were predictive of clinical response in patients with UC treated with miri 200mg and our model distinguished responders from non-responders. Future studies are underway to validate this model.

References

1. Sandborn WJ, et al. Gastroenterology. 2020;158(3):537-549.e10.
2. Steere B, et al. J Crohns Colitis. 2020;S103-S104.
3. Chen T, et al. Proceedings of the 22^nd ACM SIGKDD International Conference. 2016;7285-794.
4. Hyams JS, et al. Lancet Gastroenterol Hepatol. 2017;2(12):855-868.

Disclosure

TJ and KH report no conflicts of interest. WR reports grant support and personal fees from Abbott Laboratories, AbbVie, Aesca, Centocor, Falk Pharma GmbH, Immundiagnostik, and Merck Sharp & Dohme, and personal fees from Aptalis, Celltrion, Danone Austria, Elan, Ferring, Mitsubishi Tanabe Pharma Corporation, Otsuka, PDL BioPharma, Pharmacosmos, Schering-Plough, Shire, Takeda, Therakos, Vifor, Yakult, Amgen, AM Pharma, Astellas, AstraZeneca, Avaxia, Bioclinica, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Covance, Galapagos, Genentech, Gilead Sciences, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millennium, Nestle, Novartis, Ocera, Pfizer, Procter & Gamble, Prometheus, Robarts Clinical Trial, Second Genome, SetPoint Medical, TiGenix, UCB, Zyngenia, and 4SC. BS, CH, NM, and VK are employees and shareholders of Eli Lilly and Company. CM is a former employee of Eli Lilly and Company. GD has served as an advisor for: AbbVie, Ablynx, Active Biotech, AgomAb Therapeutics, Allergan, AlphaBiomics, Amakem, Amgen, AM-Pharma, Applied Molecular Therapeutics, Arena Pharmaceuticals, AstraZeneca, Avaxia Biologics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Celltrion, Cosmo Pharmaceuticals, Dr. Falk Pharma, DSM Pharmaceuticals, Echo Pharmaceuticals, Eli Lilly and Company, enGene, Exeliom Biosciences, Ferring Pharmaceuticals, Galapagos NV, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Immunic Therapeutics, Johnson & Johnson, Kintai Therapeutics, Lycera, Medimetrics, Medtronic, Merck Sharp & Dohme, Mitsubishi Pharma, Mundipharma, Nextbiotics, Novo Nordisk, Otsuka, Pfizer, PhotoPills, ProciseDx, ProDigest, Progenity, Prometheus Laboratories/Nestlé, Protagonist Therapeutics, RedHill Biopharma, Robarts Clinical Trials, Salix Pharmaceuticals, Samsung Bioepis, Sandoz, Seres Therapeutics/Nestec/Nestlé, Setpoint, Shire, Takeda, Teva, TiGenix, Tillotts Pharma AG, Topivert, Versant, and Vifor Pharma; and received speaker fees from: AbbVie, Biogen, Ferring Pharmaceuticals, Galapagos NV/Gilead Sciences, Johnson & Johnson, Merck Sharp & Dohme, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millenium/Takeda, Tillotts Pharma AG, and Vifor Pharma.

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

Inflammatory bowel diseases are chronic disabling conditions with a complex and multifactorial aetiology, which is still not completely understood. OCTN1, an organic cation transporter could have a role in modulating the inflammatory response, whose genetic polymorphisms were associated to increased risk of inflammatory bowel diseases. Up to now, limited information exists on its role in predicting/modulating response to therapies.

Aims & Methods

The aim of this study was to evaluate the role of OCTN1 in modifying gut microbiota and immune composition to Infliximab therapy in murine colitis. Dextran sodium sulphate model of colitis on C57BL/6 mice and ocnt1 gene knockout mice was used to assess clinical efficacy of infliximab administered intravenously. Stool, colon and mesenteric lymph node samples were collected to assess differences in gut microbiota composition, histology for Rachmilewitz score and T cell populations respectively.

Results

Octn1^-/-influences microbiota profile and is associated with a worse dysbiosis in colitis mice. Infliximab treatment attenuates colitis-associated dysbiosis with increase of bacterial richness and evenness in both strains. In comparison with wild type, octn1^-/- mice have a higher baseline percentage of Treg, Tmemory, Th2 and Th17.

Conclusion

Our data support murine model to study OCTN1 genetic asset in inflammatory bowel diseases. This could be the first step to consider this membrane transporter as a biomarker in inflammatory conditions and as a predictor of response to therapies.

Introduction

Inflammatory bowel disease (IBD) is characterized by chronic inflammation due to an uncontrolled immune response orchestrated through, i.e. neutrophils. The basement membrane acts as a front-line defense promoting tissue integrity, where the α-3 chain of type IV collagen is solely expressed on the outermost layer of the mucosa. Detection of subclinical ulceration is crucial since early-stage IBD presents a unique window of opportunity for intervention, as the disease might become a self-sustaining process once deep inflammation becomes established. We therefore, wanted to develop a biomarker reflecting early tissue injury, aiding in the implementation of prompt treatment.

Aims & Methods

A competitive enzyme-linked immunosorbent assay quantifying a human neutrophil elastase (HNE) degraded fragment of type IV collagen α-3 chain was developed (C4A3-HNE). Dilution- and spiking recovery, inter- and intra-variability, and interference were evaluated. Acceptance criteria for technical validation were a recovery of 100% ±25 and an inter-intra variability of <15%. Commercial serum samples were purchased from ProteoGenex. Biological relevance was validated in an observational study from Odense University Hospital (OUH) and healthy controls. Groups were compared using Kruskal Wallis (Dunn‘s corrected).

Results

The technical validation of the C4A3-HNE assay demonstrated acceptable results for recovery, variation, and interference. Biological relevance was assessed in commercial IBD samples and healthy donors. C4A3-HNE was elevated in both CD and UC compared to healthy (p=0.001 and <0.0001)(AUC [95% CI]: 0.820 [0.669-0.971]; 0.875 [0.775-1.000]). The results were validated in an independent cohort of IBD patients (both p<0.0001). For UC, analysis showed that compared to patients in endoscopic remission, C4A3-HNE is elevated in patients with mild endoscopic activity, decreasing dose-dependently for moderate and severe disease (T1). Fecal calprotectin and CRP levels were also lower in IBD patients with high levels of C4A3-HNE (T1). With a cut-off value of 54.1 ng/ml, C4A3-HNE could significantly discriminate between mild and severe endoscopic disease (T1).

Conclusion

Our study demonstrates the biological and possible clinical relevance of the novel C4A3-HNE biomarker. The biomarker is elevated in patients with IBD compared with healthy, and high levels may reflect early mucosal damage in patients with UC. Furthermore, inflammatory markers were lower in IBD patients with high levels of C4A3-HNE, pointing towards high levels being indicative of early disease. C4A3-HNE may provide early detection of mucosal damage or prediction of relapse; however, further studies are required to assess the clinical validity of this biomarker.

Disclosure

MA, MP, MK, and JM are employees of Nordic Bioscience A/S. MK owns stocks in Nordic Bioscience A/S.

Introduction

Small bowel activity detected by endoscopy is known to be associated with unfavourable clinical outcome in Crohn’s disease, regardless of symptoms. The treat-to-target approach whereby endoscopic remission is set as a treatment target is recommended. Imaging modalities for monitoring the small bowel are limited, as well as being invasive.

Aims & Methods

In this study, our objective was to investigate which of the existing biomarkers for Crohn’s disease best indicates endoscopic small bowel activity, and whether combining the biomarkers can improve accuracy. 104 consecutive patients with ileal and ileocolonic type Crohn’s disease who underwent balloon assisted enteroscopy (BAE) at our hospital from October 2021 to August 2022 were enrolled, with clinical and laboratory data prospectively collected and analysed. BAE was evaluated using the modified Simple Endoscopic Score for CD (modified SES-CD). Ulcers were defined as those ≧ 0.5 cm.

Results

Haemoglobin, platelet count, C-reactive protein (CRP), leucine-rich alpha-2 glycoprotein (LRG), faecal calprotectin, and faecal haemoglobin values all demonstrated a significant difference in those with ulcers found on BAE. All biomarkers significantly correlated with modified SES-CD. LRG and faecal calprotectin showed the highest areas under the curve (0.841 and 0.853) by ROC analysis for detecting small bowel ulcers. LRG showed a sensitivity of 78% and specificity of 80% at a cut-off value of 13 μg/mL, whereas faecal calprotectin showed a sensitivity of 91% and specificity of 67% at a cut-off value of 151 μg/g. Dual positivity for LRG and faecal calprotectin, as well as LRG and faecal haemoglobin, both predicted the presence of ulcers with a further improved specificity of 92% and 100%. A positive result for either LRG or faecal calprotectin/haemoglobin showed an improved sensitivity of 96% and 91%. Positivity for LRG and either of the faecal biomarkers was associated with poor clinical outcome in terms of hospitalisation, surgery, and relapse.

Conclusion

This is the first study comparing the major existing biomarkers for Crohn’s disease in terms of monitoring for small bowel activity. LRG, faecal calprotectin, and faecal haemoglobin are accurate biomarkers, especially when used in combination. Patients who are dual-positive for LRG and faecal calprotectin or faecal haemoglobin should be assessed by early endoscopic evaluation of the small bowel and considered for change in treatment, as they are at higher risk for hospitalisation, relapse, and surgery.