Introduction

Acute cholangitis (AC) is an important clinical problem which is associated with mortality upto 10%. The association between timing of ERCP and clinical outcomes of AC are not well studied. The current study is aimed to evaluate whether ERCP within 48 hours is associated with improved clinical outcomes.

Aims & Methods

This is single center retrospective analysis of prospectively maintained database. All patients who admitted with AC at AIG Hospitals, Hyderabad between January 2022 to December 2022 were included in study if they underwent ERCP. Patients satisfying diagnostic criteria of AC according to Tokyo Guidelines and stratified according to severity of AC. We evaluated association between ERCP within 48 hours and length of hospital stay, need for reintervention and re-admissions, mortality in-hospital and at 3 months follow.

Results

A total of consecutive 301 patients underwent ERCP during study period; of which 217 patients (31.3% females; mean age 54.02 ± 14.9 years) underwent ERCP within 48 hours of admission. Remaining 84 (32.1% females; mean age 56.56 ± 13.9 years) underwent ERCP after 48 hours. 58 (26.7%) and 22 (26.2%) patients with severe cholangitis (grade 3 as per Tokyo Guidelines) underwent ERCP within 48hours and beyond 48 hours respectively. The proportion of patients with malignant biliary obstruction was 34.1% (74/217) and 46.6% (39/84) in ERCP within 48 hours and beyond respectively. There was no statistically significant difference for overall mortality (6.45%vs7.14%, p 0.83); need for reinterventions (46.1% versus 54.8%, p 0.53) and readmissions (62.2% versus 58.33%; p 0.18). The length of hospital stay during 1^st admission was significantly higher in ERCP beyond 48hours group (9.48 ± 6.50 versus 12.86 ± 7.25 days; p 0.0001).

Conclusion

The current study indicates that ERCP within 48 hours for AC is associated with decreased length of hospital stay while overall mortality, need for reinterventions, readmissions are comparable. There is unmet need to confirm these findings by randomized controlled study.

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

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

Endoscopic retrograde cholangiopancreatography (ERCP) is an essential technique for pancreato-biliary diseases. Pancreatico-biliary infection occurs after 0.4–0.8% of endoscopic biliary procedures, with cholangitis and sepsis occurring in up to 3% of cases. These episodes must always be taken seriously because fatality has been reported in 8–20% of such cases.
During the pandemic from coronavirus disease 19, recommendations by the European Society of Gastrointestinal Endoscopy (ESGE) suggested postponing elective procedures, use of triage, use of personal protective equipment and creation of differentiated in-hospital pathways, in order to protect both patients and endoscopy unit personnel.
Currently, it is not know whether, as a result of the change in these procedures, the overall mortality and the infection's rate related to ERCP has been modified in the post-COVID era.

Aims & Methods

In this study, we retrospectively compared ERCP activity, post-ERCP infection rate and 30 days-mortality in our tertiary center before and after the adoption of new criteria for patient's selection and protective equipment implementation, specifically from October 2016 to December 2019 (before COVID) and from January 2020 to March 2023 (after COVID).

Results

During the 39 months before COVID, we performed 417 ERCP for 285 patients, while in the same amount of time after COVID, we executed 257 consecutive ERCP for 191 patients. The indications for performing ERCP were made for obstructive cholangitis caused by stones, by pancreatic or bile ducts neoplasms, by malignant lymph nodes or for post-surgical complications.
Positive blood cultures done within 1 week from ERCP were 13 among 417 exams before COVID and 9 among 257 ERCP after COVID, with septicemia related to ERCP only in 2 procedures (0.5%) before COVID and another 2 (0.8%) after COVID. Cultures resulted positive for Klebsiella pneumoniae and Candida albicans in the first group, while in the group after COVID, patient’s blood cultures were positive for Enterococcus faecium and Klebsiella oxytoca.
Overall mortality at 30-days after ERCP accounted for 16 patients (5.6%) during 39 months considered before COVID and 9 patients (4.7%) after COVID. In the first group, the fatal complications were related to ERCP in 2 cases (0.7% of patients), due to the perforation of the digestive tract, while in the second group, 1 patient (0.5%) had a septic shock from Klebsiella oxytoca after ERCP.

Conclusion

In conclusion, our retrospective analysis of a real life cohort of consecutive patients undergoing ERCP in a single tertiary center, demonstrated that the shortages of medical resources caused a significant drop in the ERCP activity, notably about 38%, Ultimately, the delay due to the COVID pandemic, the rational use of antibiotics and the intensification of personal protective equipment did not change significantly the rate of adverse events, like post-ERCP septicemia (0.5-0.8% before and after COVID respectively), or the 30-days mortality rate after ERCP (0.7%-0.5% before and after COVID respectively).

References

- Khashab MA, Tariq A, Tariq U, et al. Delayed and unsuccessful endoscopic retrograde cholangiopancreatography are associated with worse outcomes in patients with acute cholangitis. Clin Gastroenterol Hepatol 2012;10:1157-61
- Gralnek I M, Hassan C, Beilenhoff U et al. ESGE and ESGENA Position Statement on gastrointestinal endoscopy and the COVID-19 pandemic. Endoscopy. 2020;52:483–490.
- Dumonceau JM, Kapral C, Aabakken L, Papanikolaou IS, Tringali A, Vanbiervliet G, Beyna T, Dinis-Ribeiro M, Hritz I, Mariani A, Paspatis G, Radaelli F, Lakhtakia S, Veitch AM, van Hooft JE. ERCP-related adverse events: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2020 Feb;52(2):127-149.
- Casini B, Pan A, Guarini A, Rivara C, Zullo A, Monica F, Cimbro M, Casarano S, Inglese A, Vaghi A, Schiffino L, Capezzuto E, Da Massa Carrara P, Pasquale L; Working Team on Infections in Endoscopy. Multisocieties position paper: Microbiological surveillance on flexible endoscopes. Dig Liver Dis. 2021; 53(9):1105-1111.

Introduction

Rare early onset cases of diabetes stem from single gene mutations, whereas frequent gene variants can also contribute to multifactorial diabetes, indicating shared disease mechanisms. Our recent study has identified ONECUT1 as a gene implicated in both monogenic and multifactorial diabetes, establishing it as crucial target for investigating fundamental signaling pathways in diabetes pathology [1,2]. However, numerous diabetic characteristics remain unexplained by typical genetic alterations, highlighting the underestimated significance of the non-coding genome. We have identified a neonatal diabetes patient carrying a heterozygous ONECUT1 truncating variant. Remarkably, the patient exhibited a phenotype akin to individuals with homozygous ONECUT1 truncating mutations. Upon further examination, we detected an additional heterozygous deletion in the non-coding genome, leading us to hypothesize that it could impact the regulation of the remaining ONECUT1 allele. Consequently, the dysregulation of the ONECUT1-dependent transcriptional machinery crucial for proper beta-cell development occurs, ultimately leading to the severe diabetic phenotype observed in the patient.

Aims & Methods

Following deletion of specific genomic regions in human embryonic stem cells, we initiated their differentiation into the pancreatic endocrine lineage and meticulously characterized the developmental stages.

Results

Importantly, we successfully replicated the patient’s diabetic phenotype, elucidating deficiencies in both pancreatic development and beta-cell functionality. The differentiation of pancreatic progenitors was notably hindered by the loss of the regulatory region associated with nearly complete ablation of ONECUT1. Moreover, the stem cell-derived islets exhibited a reduced number of beta-cells as well as impaired insulin secretion, even in heterozygous knockouts.

Conclusion

Altogether, our ongoing comprehensive mechanistic characterization provides insights into the precise role of the identified regulatory element in pancreatic beta-cell development and diabetes pathophysiology, emphasizing the significance of the non-coding genome. By unveiling unknown molecular pathomechanisms linked to alterations in regulatory sequences, we contribute to a deeper understanding of the pancreatic transcriptional network and establish the foundation for personalized diabetes treatment.

References

[1] Philippi, A., Heller, S., Costa, I.G. et al. Mutations and variants of ONECUT1 in diabetes. Nat Med 27, 1928–1940 (2021). https://doi.org/10.1038/s41591-021-01502-7
[2] Heller, S., Li, Z., Lin, Q. et al. Transcriptional changes and the role of ONECUT1 in hPSC pancreatic differentiation. Commun Biol 4, 1298 (2021). https://doi.org/10.1038/s42003-021-02818-3