Introduction

Splanchnic vein thrombosis (SVT) presents as a common complication of cirrhosis due to modification in hemodynamics and hemostatic balance, and it also frequently associated with solid cancers, myeloproliferative neoplasms and less often with pregnancy, abdominal infections, pancreatitis, or surgery.

Aims & Methods

The SVT registry is an ongoing registry of consecutive patients diagnosed with, treated, and/or followed up for SVT at our Center since January 2005. Baseline and follow-up data, including demographics, clinical features, risk factors, diagnostic procedures, classification of SVT, and treatment were collected during hospitalization, and at scheduled outpatient visits. The aim of this study was to describe patients with SVT and management in a single center, with focus on the differences between cirrhotic and non-cirrhotic patients.

Results

From January 2005 to December 2022, 320 patients were eligible SVT-registry, including 228 patients (71.2 %) with liver disease. Among the latter, 126 (55.3%) had isolated portal thrombosis, 18 (7.9%) isolated mesenteric thrombosis and the remaining multiple site venous thrombosis. Among isolated portal thrombosis, 61 (48.4 %) of patients experienced a complete thrombosis, 47 (37.3 %) a partial thrombosis. Therefore, there is a difference in the site of thrombosis and the extent of portal thrombosis between the two groups (p = 0.046 and p = 0.001, respectively). Ninety-three patients (40.7 %) experienced solid cancer and 45 (19.7 %) had HCC. Patients with liver disease developed a higher rate of portal hypertension-related complications, such as ascites and esophageal varices, than the other population (p < 0.0001). Most patients (77.6%) received an anticoagulation therapy and those with cirrhosis were preferably treated with low molecular weight heparin/heparin related agents (64.5%; p < 0.0001). Only patients treated with anticoagulants experienced a major complication such as bleeding (n=23, 10.1%), which in no case led to the patient’s death. Seventy-seven patients (33.8 %) experienced resolution of SVT with a median time of 8.4 months and no differences were found between the two groups, with 20.8% spontaneous resolution-rate. A lower rate of recanalization is shown in patients presenting with portal hypertension complications (p = 0.0431) such as esophageal varices (p = 0.0299) at the time of SVT diagnosis, regardless of therapeutic approach. Following recanalization, 7 patients with liver disease (9.1%) had a recurrence of venous thromboembolism earlier than the other group. Presence of HCC diagnosis and not long-term use of VKA have been found to be associated with an increased risk of SVT recurrence (p= 0.0099 and p= 0.037, respectively).

Conclusion

SVT-registry is a relatively large ongoing population-based registry of SVT patients, with high-quality data representing a valuable source of real-world data on the management and outcomes of SVT.
Our data show that there are differences in the presentation and course of SVTs between patients with and without liver disease, which may therefore require specific management.

Introduction

Inflammatory bowel disease (IBD), consisting of Crohn's disease (CD) and ulcerative colitis (UC), are characterized by chronic inflammation of the intestines. This is accompanied by oxidative stress, which plays an important role in the pathophysiology of IBD. Oxidative stress-related biomarkers can serve as potential biomarkers for disease activity monitoring. Systemic free thiols (FT) are found to accurately reflect oxidative stress brought on by inflammation and have shown promise as a biomarker for inflammatory disease activity in IBD. However, the clinical significance of this marker warrants validation. This prospective diagnostic study aimed to compare FT to other validated biomarkers and investigate the link between FT and endoscopic disease activity in patients with IBD.

Aims & Methods

An interim analysis was conducted in 52 patients. FT were measured using a colorimetric detection method. Clinical disease activity was quantified by the Harvey-Bradshaw Index (HBI) for CD and Simple Clinical Colitis Activity Index (SCCAI) for UC. Biochemical disease activity was determined by measuring blood C-reactive protein [CRP] and fecal calprotectin [fCal] levels. Endoscopic disease activity was quantified with the Mayo endoscopic sub score for UC and the Simple Endoscopic Score (SES-CD) for CD. Serum FT levels were assessed for correlations with disease activity parameters using linear and logistic regression analyses. Discriminative capacity of FT as biomarker was assessed by calculating receiver operating characteristics (ROC) statistics.

Results

Serum FT levels demonstrated a significant inverse correlation with clinical parameters, such as the HBI (r=-0.53, p<0.05). Additionally, other inflammatory biomarkers, including CRP, exhibited a negative correlation with serum FT levels (r=-0.43, p<0.05), which were decreased in patients with active IBD . Discrimination between clinically quiescent (HBI<5) and active disease based on serum FT levels was accurate (AUC=0.80, p=0.02) with a value numerically higher than that of fCal (AUC=0.55, p=0.83). Serum FT levels did not significantly differ between biochemically quiescent and active disease based on CRP (AUC=0.69, p=0.20). Both endoscopic scores demonstrated a tendency toward negative associations with serum FT levels. Patients with moderate and severe disease activity had lower FT levels compared to those with mild disease activity (estimated marginal means [EMM] 497.2 vs 529.5 µM, p=0.43) and 447.1 vs 529.5µM , p=0.06, respectively).

Conclusion

The interim analysis of this study indicates that plasma FT levels inversely correlate with IBD activity and may surpass traditional markers like fCal in detecting disease states. Plasma FT demonstrates potential as a sensitive biomarker for both clinical and endoscopic disease activity in IBD. Further patient inclusion and longitudinal data are essential to validate FT's utility fully. Continued research could establish FT as a key tool for personalized treatment strategies, improving patient outcomes in IBD management.

Disclosure

S. Geertsema, A.R. Bourgonje., H. van Goor, G. Dijkstra, and K.N. Faber are supported by a research grant from Janssen Research & Development LLC. A.R. Bourgonje received speaker fees from AbbVie. G. Dijkstra received research grants from Royal DSM, Takeda, and Janssen Pharmaceuticals and speaker fees from AbbVie, Pfizer, Takeda, and Janssen Pharmaceuticals.

Introduction

Chronic pancreatitis is a progressive inflammatory disease characterized by irreversible damage to the pancreas. The etiology of the disease is heterogenous and includes alcohol abuse, smoking, genetic risk factors and autoimmune diseases. Several clinical classification and severity scoring systems have been proposed, but none have been globally accepted or reached broad clinical use. Identifying patients at a higher risk of death is crucial for improving patient care and management.

Aims & Methods

This study aimed to develop a prediction model based on promoter hypermethylation of specific genes and clinical factors to differentiate patients with chronic pancreatitis who are at a higher risk of mortality. Clinical variables such as age, sex, smoking status, alcohol consumption, exocrine insufficiency, and endocrine insufficiency, as well as the methylation status of 16 genes, were analyzed using a backward stepwise Cox regression model. The methylation status was determined by a specialized bisulfite based PCR technique. The final model's performance was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC), and used to determine a risk score for each patients. The “cutpt” package in Stata was used to determine an optimal cut-off, in order to stratify patients into low and high-risk groups. Kaplan-Meier survival curves, and cox regression, and AUC were used to determine the accuracy of the risk groups.

Results

Ninety-seven patients with chronic pancreatitis were included in the study. The final prediction model included age, sex, exocrine insufficiency, endocrine insufficiency, and the methylation status of 5 genes: SFRP2, HIC1, MLH1, RASSF1A, and CDKN2B. The AUC of the model was 0.84, indicating high reliability. The model was superior to a model including only clinical variables (AUC = 0.76), indicating added value of the methylation markers. The optimal cut-off value for the risk score was 7.76. According to this, 67 patients were in the low-risk group, and 30 in the high-risk group. The 5-year survival in the high-risk group was 53% compared to 94% in the low-risk group. Being in the high-risk group was significantly associated with an increased HR of death of 10.2 (95% CI; 4.9-21.1), demonstrating the model's strong prognostic value.

Conclusion

The developed prediction model, which combines clinical factors and gene promoter hypermethylation status, could be a valuable tool for identifying patients with chronic pancreatitis who are at a higher risk of death. This study serves as proof-of-concept of the unexplored potential of methylation analysis in cell-free DNA in chronic pancreatitis. This model can potentially enhance patient care by enabling targeted interventions and monitoring for high-risk individuals, ultimately improving their prognosis and quality of life.

Disclosure

S.D.H., P.H.M., O.T.-U., and H.B.K. declare that they have a patent on a diagnostic panel including the promoter hypermethylation status of 8 genes. Application No. 16161073.8 – 1403 Pancreatic Cancer methylation Markers (18.03.2016)

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

Insulinomas are rare, functioning neuroendocrine neoplasms that cause non-ketotic hypoglycemia due to hyperinsulinism. Surgery is considered the gold-standard treatment, although endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) has been recently described as a less invasive, efficient therapeutic option for these tumors. In this study, we aim to compare post-procedural outcomes of surgical resection versus EUS-RFA for pancreatic insulinomas.

Aims & Methods

All patients who underwent surgical resection or EUS-RFA for pancreatic insulinoma in our Institution were included in the study, and data from all procedures were retrospectively recorded and statistically analyzed. EUS-RFA was indicated for all subjects either unfit for surgery or unwilling to undergo surgical treatment. Patients’ baseline characteristics, location, size of insulinomas, procedural time, and intra- and postoperative outcomes were compared.

Results

From April 2012 to July 2022, 11 and 10 patients with pancreatic insulinoma underwent surgical resection and EUS-RFA, respectively. The median age was 65.5 (51-84) and 37 years (28-72, p<0.001) for the EUS-RFA and surgery cohorts, respectively. As a whole, 15 (71.4%) out of 21 were female. The median tumor size was 15mm (8-30) for the surgical group and 11mm (8-19) for the EUS-RFA group (p=0.17). The majority of the insulinomas were located in the pancreatic body (28.6%) and tail (28.6%), with no statistical difference between the two groups (p=0.16). Operative time was significantly longer in the surgical population (280min, 120-372) as compared to the endoscopic one (28min,18-40, p<0.001). Clinical success, defined as the normalization of glucose blood levels, was reached in all cases. The complication rate was significantly higher in the surgical group compared to the endoscopic group (7-63.6% vs 1-10%, p=0.01). Specifically, 7 patients in the surgical cohort developed a pancreatic fistula while one patient in the EUS-RFA population had self-limiting bleeding after the procedure. One patient of the surgical cohort underwent reoperation for an infected abdominal fluid collection.

Table 1. Characteristics of patients classified by treatments.

Conclusion

As compared to surgical resection, EUS-RFA for pancreatic insulinomas may be considered a safe and efficient treatment option with a shorter operative time and a lower rate of related complications. Prospective comparative studies are needed to ascertain the role of EUS-RFA as a treatment of choice for selected patients with pancreatic insulinoma.

References

Fahmawi Y, Mehta A, Abdalhadi H et al. Efficacy and safety of endoscopic ultrasound-guided radiofrequency ablation for management of pancreatic lesions: a systematic review and meta-analysis. Transl Gastroenterol Hepatol. 2022 Jul 25;7:30.
Zhao YP, Zhan HX, Zhang TP et al. Surgical management of patients with insulinomas: Result of 292 cases in a single institution. J Surg Oncol. 2011 Feb;103(2):169-74.

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.