Introduction

Patients with inflammatory bowel diseases (IBD) exhibit distinct shifts in circulating metabolite levels that have been associated with clinical disease activity and disease phenotype. However, there are limited data on the impact of metabolomic changes on disease progression in IBD. In this study, we aimed to understand the association of circulating metabolite levels and related pathways with the risk of disease progression in patients with IBD. Furthermore, we aimed to predict disease progression in these patients using both clinical and metabolomic features.

Aims & Methods

We conducted an observational cohort study using the Mount Sinai Crohn’s and Colitis Registry (MSCCR). Patients were prospectively enrolled with baseline questionnaires and biospecimens that were then linked to longitudinal electronic health record data. A total of 1,456 serum metabolites were measured in 277 patients with UC and 375 patients with CD using untargeted metabolomics. Disease progression was defined as any new steroid or biological prescriptions, IBD-related hospitalizations, or surgery. Multivariable Cox proportional hazards regression (CoxPH) models, adjusted for age, sex, smoking, biologic use, and surgery were used to explore metabolite associations with risk of disease progression. Metabolite set enrichment analysis (MSEA) was performed to identify underlying metabolic pathways associated with disease progression. Prediction analyses were performed using L1-regularized CoxPH models with Random Survival Forests (RSF), and applied using different preceding feature selection approaches. Clinical parameters and metabolites were used as input features individually and in combination. Models were evaluated using Harrell’s C-index, the Brier Score, and the area under the curve (AUC) at 3-years follow-up time.

Results

During a median of 2-year follow-up (IQR 0.3-5.1 years), 375 patients (57.5%) had a disease progression event. Among CD, 151 metabolites significantly correlated with the composite outcome (FDR<0.1). Of these, 81 (53.6%) were linked to higher risk, mainly enriched in amino acids, purine, and pyrimidine metabolism, fibrinogen cleavage peptides, and bile acid pathways. Additionally, 70 (46.4%) metabolites associated with lower risk with enrichment in fatty acid metabolism, steroid biosynthesis, histidine, tryptophan, and antioxidant pathways. In CD, aspartate metabolism was most significantly associated with increased risk and linoleic metabolism with decreased risk. In UC, 84 metabolites were significantly associated with disease progression (FDR<0.1), with 29 (34.5%) associated with increased and 55 (65.5%) with decreased risk. Metabolic pathways linked to higher risk were sphingolipid, benzoate, hydrogen sulfide, polyamine, and tyrosine metabolism, while protective metabolites were enriched in branched-chain amino acid (BCAA), steroid biosynthesis, histidine, and phenylalanine pathways. In UC, sphingolipid metabolism was prominently associated with increased risk and BCAA metabolism with decreased risk. The combination of metabolomic and clinical features best predicted disease progression in both CD and UC, with 20 and 25 features robustly selected, respectively.

Conclusion

Specific metabolites and metabolic pathways are associated with risk of disease progression in patients with IBD, highlighting potential prognostic metabolite biomarkers and pathways that may be important in modulating risk of disease progression. ​Metabolomic features improve overall model performance ​when predicting disease progression in IBD, with distinct metabolites showing high predictive value.

Introduction

Among patients with celiac disease (CeD), following a gluten-free diet after diagnosis is expected to reduce symptom burden. Using a large US claims database, we compared symptoms in individuals with CeD pre- and post-diagnosis with those in matched individuals without CeD to evaluate the burden of CeD.

Aims & Methods

This case-control study was conducted among individuals of all ages enrolled in MarketScan from 2002 to 2023. CeD diagnosis (index date) was defined as ≥1 inpatient or ≥2 outpatient International Classification of Diseases (ICD)-9/-10 diagnostic codes; controls were matched (1:5 ratio) for age, sex, region, and diagnosis year. All individuals had continuous medical and pharmacy enrolment for 2 years pre- and post-index. Core CeD symptoms (abdominal pain, diarrhoea, joint pain, bloating, fatigue, and nausea) were defined as ≥1 inpatient or ≥2 outpatient ICD-9/-10 codes during each 2-year period. Unadjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated by logistic regression comparing CeD cases versus controls.

Results

During the 21 years of data coverage, we identified 39 814 patients with CeD and 198 961 matched individuals without CeD with similar age and sex distribution (mean age 41.6 years [standard deviation 20.1]; 70.5% female). The burden of CeD symptoms pre-diagnosis was significantly higher among patients with CeD versus controls, particularly for diarrhoea, bloating, and abdominal pain. The pre-diagnosis OR (95% CI) for abdominal pain was 5.37 (5.22, 5.52), joint pain 1.87 (1.81, 1.93), diarrhoea 11.64 (11.10, 12.20), bloating 8.64 (7.86, 9.51), fatigue 3.63 (3.48, 3.79), and nausea 5.78 (5.36, 6.24). As expected, symptom burden decreased post-diagnosis, however all symptoms (except joint pain) had an approximately twofold greater burden compared with controls, 2 years post-diagnosis: OR (95% CI) abdominal pain 2.43 (2.57, 2.30), joint pain 1.61 (1.51, 1.71), diarrhoea 2.47 (2.21, 2.76), bloating 2.47 (1.86, 3.27), fatigue 2.17 (1.98, 2.38), and nausea 2.24 (1.83, 2.74). When we evaluated symptoms only among individuals with CeD, on average symptom persistence 2 years after diagnosis occurred in 29.7% of patients while an average of 6.3% had new-onset symptoms (most commonly abdominal pain; 17.0%).

Conclusion

Claims databases were able to capture CeD symptom burden and demonstrated that patients with CeD continue to experience symptoms (including new-onset) post-diagnosis. Although a gluten-free diet might control some symptoms, there is still considerable remaining burden and some unresolved symptoms (e.g. joint pain and fatigue) or new-onset symptoms.

Disclosure

MA, SM, VG, SG, RS, DAL, IP, and NC are employees and shareholders of Takeda. BL has nothing to disclose. FZ served as a speaker for Werfen and a consultant for Takeda.

Introduction

Potential therapeutic effects of natural compounds, such as grape polyphenols, have been suggested in the prevention and treatment of mucositis induced by radiotherapy or bacterial infections. Lipopolysaccharide (LPS) significantly increases the paracellular permeability of gut epithelium downregulating the expression of tight junctions. In this study, the protective effect of proanthocyanidin-rich grape seed extract (GSE) was investigated on epithelial barrier damage and ROS production induced by LPS and ionizing radiations in an in vitro model.

Aims & Methods

GSE chemical analysis was performed by high-performance liquid chromatography (HPLC-DAD) and nuclear magnetic resonance (NMR).
Human intestinal epithelial cell line Caco-2, previously treated with LPS [10 µg/m] (pathogenic strain of Escherichia Coli 0111:B4) [1], GSE [6,25 mg/ml] and LPS + GSE, were irradiated with 10 Gy subdivided in 5 daily fractions using TrueBeam™ radiotherapy system by Varian Medical System. Epithelial barrier integrity was investigated measuring the paracellular flux of fluorescein isothiocyanate-dextran (FD-4) [1] and ROS production was assessed by adding 2′,7′-dichlorodihydrofluorescein diacetate (H2-DCF-DA) [3] using a multiplate reader (Tecan). Each experiment was performed twice in triplicates with independent controls among the three conditions.

Results

HPLC-DAD and NMR revealed a 70% content of total procyanidins in both the extract obtained from the virgin hydroalcoholic mixture and quantify 24 metabolites classified as amino acids, organic acids, classified as amino acids, organic acids, carbohydrates and miscellaneous molecules. Among them, it is interesting the presence of ascorbate, procyanidin B1 and polymeric procyanidins.
Our in vitro experiments showed a significant increased permeability was observed in LPS-treated cells over time compared to control (5.215 vs 0.3418; p<0.05), which is prevented by co-treatment with GSE (5.215 vs 0.3407; p<0.05). Irradiation significantly increased intestinal permeability over time and in a dose dependent manner compared to control both in Caco2 cells without LPS treatment (at day 5 with maximal dose of 10 Gy: 3.64 vs 0.441; p<0.05) and in LPS-treated cells (25.5 vs 2.42; p<0.05). GSE treatment significantly reduced this damage in both conditions (25.5 vs 2.04; p<0.05 and 38.87 vs 2.675; p<0.05 respectively). Moreover, LPS significantly increased ROS production in Caco2 cells (12,9 vs 104; p<0.0001) and GSE treatment significantly prevented this damage (104 vs 11.3; p<0.0001). Irradiation increased ROS production in LPS-treated cells (3056 vs 362; p<0.0001) and also in this case GSE treatment was able to reduce ROS production due to irradiation (502 vs 357; p<0.0001). this beneficial effect was observed also in LPS treated cells and then exposed to irradiation (3056 vs 681; p<0.0001).

Conclusion

In an in vitro model, GSE is able to prevent the intestinal epithelium permeability damage and ROS production induced by LPS and by ionizing radiations suggesting a potential therapeutic effect. Further studies are needed to better understand the mechanism underlying radiation-induced mucositis and the antioxidant effect of GSE in its prevention and management.

References

[1] Gori M, Altomare A, Cocca S, Solida E, Ribolsi M, Carotti S, Rainer A, Francesconi M, Morini S, Cicala M, Guarino MPL. Palmitic Acid Affects Intestinal Epithelial Barrier Integrity and Permeability In Vitro. Antioxidants (Basel). 2020 May 13;9(5):417
[2] Calabriso N, Massaro M, Scoditti E, Verri T, Barca A, Gerardi C, Giovinazzo G, Carluccio MA. Grape Pomace Extract Attenuates Inflammatory Response in Intestinal Epithelial and Endothelial Cells: Potential Health-Promoting Properties in Bowel Inflammation. Nutrients. 2022 Mar 11;14(6):1175

Introduction

Upper gastrointestinal bleeding (UGIB) is associated with an unfavorable prognosis in cancer patients. In biliary tract cancers (BTCs), little is known about the occurrence of UGIB and its prognostic relevance for the course of the disease.

Aims & Methods

The aim of this study was to analyze the prevalence of UGIB in BTC patients, compare therapeutic approaches for efficacy, and identify parameters associated with survival and recurrence rates. This retrospective observational study included all patients with BTCs and UGIB, that were treated in our tertiary care hospital between 2010 and 2023.

Results

A total of 1033 patients with BTC were analyzed. 41 (4.0%) of these patients had a total of 60 bleeding events. At the time of the bleeding event, 30.8% of patients displayed symptoms of shock, and 67.5% received red blood cell transfusions. The most common causes of bleeding were tumor infiltration (24.4%), variceal bleeding (19.5%), or ulcer bleeding (14.6%). At the time of presentation, 56.4% of patients had stage IV cancer. Most patients had perihilar (39.0%) or intrahepatic (34.1%) cholangiocarcinoma. At index bleeding, endoscopic treatment was performed in 41,5% of cases, while conservative measures (53,7%) or interventional radiological procedures (4.9%) were used in the remaining cases. In cases of bleeding caused by tumor infiltration, endoscopic hemostasis was usually performed using hemostatic powder (18.8%) or clip application (12.5%). Admission to an intermediate or intensive care unit (odds ratio 6.7; 95% CI 1.5 – 33.9) as well as symptoms of shock at the time of the bleeding event (odds ratio 2.6; 95% CI 0.5 – 15.6) were risk factors of rebleeding within 14 days. In patients with UGIB due to tumor infiltration, bleeding recurred after endoscopic therapy in 33.3% of cases. With conservative therapy, the recurrence rate was 28.6%. Survival of Patients with UGIB due to tumor infiltration was significantly shorter compared with patients having non-tumor-associated UGIB (median survival 0.93 vs. 6.5 months, log-rank test p = 0.018).

Conclusion

UGIB is a rare but serious complication in patients with BTC. Patients with major bleeding episodes should be closely monitored for short-term rebleeding. The occurrence of UGIB due to tumor infiltration is associated with adverse outcomes and significantly shortened survival time.

Introduction

Recent advances in endoscopic imaging have improved the diagnostic accuracy for superficial non- ampullary duodenal epithelial tumors (SNADETs). Endoscopic resection is the treatment of choice for these lesions and endoscopic mucosal resection (EMR) is the commonly used technique. Endoscopic resection with the use of a specific distal attachment (cap-assisted EMR (CEMR)) has been reported as a safe and effective method for SNADETs.¹ However, there is limited data on the technical aspects of the same. Duodenal resections have a high risk of delayed bleeding and perforation probably due to direct exposure of ulcer to biliary and pancreatic juices. Hence, appropriate closure is absolutely essential. We have previously reported safety of closure of duodenal endoscopic resections using over-the-scope and conventional clips.² We now report on the safety and efficacy of using only hemoclips for defect closure of CEMR of SNADETs.

Aims & Methods

This prospective study aimed to evaluate the safety and efficacy of using only hemoclips for closure of SNADETs resected by CEMR. 21 patients from December, 2022 to March, 2023 who underwent the procedure at our center for lesions <10mm in size were included in the study. The pimary outcome was post procedural adverse events that included the rate of delayed bleeding and perforation, and ulcer dehiscence. The secondary outcomes were en bloc and R0 resection rates, complete closure rate, number of clips used, total procedure time, and duration of hospital stay. Descriptive statistics were used to summarize the outcomes.

Results

16 males and 5 females with median age of 59(38-75) years underwent CEMR for SNADETs and closure with hemoclips only. Paris classification morphology of 67.7% lesions was 0-IIa and 33.3% lesions was 0-IIc. All lesions of median size 4(2-6) mm were successfully resected en bloc. The median specimen size was 14(12-25) mm and the median number of hemoclips used for complete closure were 7(5-11). The mean resection and closure times were 5.7+1.8 and 9.3+3.9 minutes respectively. The mean total procedure time was 14.9+4.9 minutes. Complete closure rate was 100% with no dehiscence seen on check endoscopy (done one day post index procedure). Pathology revealed 42.9% of the lesions having low grade dysplasia and 57.1% having high grade dysplasia with R0 resection rate being 100%. There was no delayed bleeding or perforation. The mean duration of post procedure hospitalization was 2.2+0.9 days.

Outcomes of closure of CEMR for SNADETs with hemoclips only

Conclusion

Our single center study is the first to demonstrate an excellent safety profile for the use of only hemoclips in closing post CEMR defects of SNADETs. It is easy to perform, requires no additional accessories, and reduces procedure time and cost compared to other available methods of closure. Furthermore, in lesions under 10mm, CEMR was effective at en-bloc resection with favorable procedure time and duration of post procedural hospital stay. Larger scale studies may be warranted to confirm this method of resection for SNADETs and safety of closure technique.

References

1. Jamil LH, Kashani A, Peter N, et al. Safety and efficacy of cap-assisted EMR for sporadic nonampullary duodenal adenomas. Gastrointest Endosc 2017; 86:666-72.
2. Ohata K, Sakai E, Suzuki Y et al. Risk factors of delayed bleeding after endoscopic resection of superficial non-ampullary duodenal epithelial tumors and prevention by over-the-scope and conventional clipping. Dig Endosc 2021; 33: 390–8.