Introduction

Biliary leaks are a well-recognized complication following liver transplantation (LT). Despite advancements in ERCP techniques, there remains variability in treatment success, Considering the peculiarities of this patient group, characterized by specific post-surgical anatomy, variations in endoductal pressure, and immunosuppressive therapy. This study was conducted to identify predictive factors influencing the healing of biliary leaks and the development of post-leak strictures, with the goal of refining management strategies and enhancing patient outcomes.

Aims & Methods

A retrospective analysis was performed on 34 LT patients who developed biliary leaks and were managed with ERCP within 24 hours from diagnosis. Variables included: the type of biliary stricture (anastomotic vs. non-anastomotic), presence of clinical symptoms (pain, fever, jaundice), time interval between multiple ERCPs to reach leak healing, characteristics of the stents (number, diameter in French, and length in cm), and leak parameters (high-grade vs. low-grade, early vs. late leak onset). Statistical analyses included Chi-square and Fisher's exact tests for categorical variables, Student's t-test and Mann-Whitney U test were used for continuous variables. The significance threshold was p<0.05.

Results

Among 34 patients with post-liver transplant biliary leaks, the overall healing rate was 94.1% (32/34). Early leaks (≤4 weeks) had longer healing times than late leaks (>4 weeks) (21.1 vs. 13.0 days). Strictures developed in 54.5% of patients (18/33). All strictures occurred in high-grade leaks: 66.7% in early high-grade and 60.0% in late high-grade groups. No strictures were observed in any low-grade leak, regardless of timing.
Based on cholangiographic appearance, high-grade leaks (visible before full biliary opacification) accounted for all strictures and often required multiple ERCPs. Low-grade leaks (visible only after full opacification) never led to strictures and typically healed after a single procedure. Notably, no strictures occurred in low-grade leaks, regardless of timing, while all strictures developed in patients with high-grade leaks, both early and late.
Shorter healing times were associated with the presence of symptoms, use of 10 Fr vs. 7 Fr stents, and intervals <1 month between ERCPs. In contrast, use of multiple stents, pre-existing NAS, and early high-grade leaks were linked to prolonged healing courses or non-resolution with standard ERCP strategy. The Kehr tube showed no significant impact.

Conclusion

Leak grade and timing are key predictors of post-transplant biliary leak healing. High-grade leaks, especially when early, were associated with delayed recovery and the need for multiple ERCPs, while low-grade leaks followed a consistently favorable course. Faster healing was also observed in symptomatic patients, with the use of 10 Fr stents and short ERCP intervals (<1 month). Strictures occurred exclusively in high-grade leaks, further supporting the prognostic relevance of cholangiographic grading. Incorporating leak grade and timing into early ERCP decision-making can accelerate healing, reduce complications, and significantly improve post-transplant outcomes.

References

1. Girotra, M., Soota, K., Klair, J. S., Dang, S. M., Aduli Mohit Girotra, F., Aduli, F., & Endoscopic, A. F. (2015). Endoscopic management of post-liver transplant biliary complications. World Journal of Gastrointestinal Endoscopy, 7(5), 446
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3. Lee, H. W., Shah, N. H., & Lee, S. K. (2017). An Update on Endoscopic Management of Post-Liver Transplant Biliary Complications. Clinical Endoscopy, 50(5), 451– 463
4. Sendino, O., Fernández-Simon, A., Law, R., Abu Dayyeh, B., Leise, M., Chavez- Rivera, K., Cordova, H., Colmenero, J., Crespo, G., Rodriguez de Miguel, C., Fondevila, C., Llach, J., Navasa, M., Baron, T., & Cárdenas, A. (2018). Endoscopic management of bile leaks after liver transplantation: An analysis of two high-volume transplant centers. United European Gastroenterology Journal, 6(1), 89–96
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Introduction

Acetaminophen-induced liver failure (AILF) has a high fatality rate and limited therapeutic approaches at present. Type 1 conventional dendritic cells (cDC1) are one of the major subgroups of cDCs in the liver, which is not only an important type in initiating adaptive immune response, but also can promote the generation, stability and function of Regulatory T (T_reg) cells through various mechanisms. cDC1 maintains liver immune homeostasis by regulating the balance between immune activation and tolerance. Nevertheless, the precise involvement and mechanistic contributions of hepatic cDCs in AILF remain to be elucidated.

Aims & Methods

Multiplex Immunohistochemistry (mIHC), flow cytometry, spatial transcriptomics (ST), single-cell RNA sequencing (scRNA-seq) and intravital 3D imaging were used to characterize the distribution and frequency of the cDC1. Bulk RNA-seq, metabolomic analyses, Cleavage Under Targets and Tagmentation (CUT&Tag) and Chromatin immunoprecipitation (ChIP)-qPCR assay were employed to explore the molecular mechanisms. CD11c^creXCR1^f/f, CD11c^creIDO1^f/f, CD11c^creP300^f/f and Foxp3^DTR mice, various mouse primary cells, human liver and serum samples were applied to verify the discoveries of bioinformatics analysis. Intravenous delivery of tolerogenic dendritic cells (tolDCs) was used to elucidate their regulatory effects on T_reg cells and roles in the AILF process.

Results

Our analyses revealed that the amount of cDC1 was significantly reduced across both clinical AILF cohorts and mouse AILF models, with the magnitude of depletion exhibiting dose- and duration-dependent associations with APAP exposure. mIHC, ST, scRNA-seq and intravital 3D imaging delineated that cDC1 depletion impaired T_reg cells priming capacity, ultimately disrupting hepatic immune homeostasis and exacerbating AILF. Intravenous tolDCs injection demonstrated therapeutic efficacy by orchestrating hepatic T_reg cells infiltration, attenuating inflammatory responses, potentiating liver regeneration, and ultimately reversing AILF-associated pathological manifestations. The therapeutic effect of intravenous tolDCs administration was abolished after diphtheria toxin-mediated T_reg cells depletion in Foxp3^DTR mice. CD11c^creXCR1^f/f mice andwild-type mice clearing cDC1 with XCL1-antibody had exacerbated liver pathology. Mechanistically, EP300-mediated histone 3 lysine 27 acetylation (H3K27ac) in IDO1 promoter region enforced stable tolerogenic states of cDC1, these epigenetically programmed cDC1 subsequently initiated tryptophan catabolism, generating kynurenine metabolites that triggered both differentiation and functional maturation of T_reg cells. Both the DC-specific knockout and inhibition of EP300 could reduce the H3k27ac levels of IDO1. And the CD11c^creIDO1^f/f mice with APAP exposure had less T_reg cells recruitment and worse phenotype.

Conclusion

This study elucidated that EP300 orchestrated tolDCs differentiation via H3K27ac/IDO1 signaling axis, this epigenetic-metabolic cascade licensed tolDCs to recruit and activate T_reg cells, thereby preserving hepatic immune homeostasis while promoting hepatocyte proliferation and tissue repair. These findings highlight novel therapeutic targets for reversing AILF pathogenesis.

Introduction

Colorectal cancer is the third most common cancer worldwide and the second leading cause of cancer-related death. Most colorectal cancers arise from benign polyps, especially dysplastic adenomas. Colonoscopy with polypectomy is the gold standard for preventing cancer by interrupting the adenoma-carcinoma sequence. This has led to the development of various techniques and devices for improved prevention and treatment. Hot snare endoscopic mucosal resection (HS-EMR), which combines submucosal injections with electrocautery, is commonly used for excising various colorectal polyps. However, it carries risks of diathermy-related complications, such as perforation, and bleeding. To address these issues, cold snare endoscopic mucosal resection (CS-EMR) has been proposed as an alternative. Concerns about residual adenoma/recurrence have been raised with CS-EMR. Therefore, we conducted this meta-analysis to compare the two techniques.

Aims & Methods

We searched electronic databases, including MEDLINE via PubMed, Scopus, Web of Science, and Cochrane, without restrictions on publication date or language. We included RCTs comparing CS-EMR and HS-EMR for colorectal polyp resection. Primary outcomes included the incidence of delayed bleeding and residual/recurrent adenoma (RRA).

Results

On Nov 5, 2024, our literature search across electronic databases retrieved a total of 1,888 records. Following a meticulous screening process, six studies met the eligibility criteria encompassing 1,449 patients and 1,947 polyps. Regarding safety, the overall effect estimates regarding delayed bleeding showed statistically significant results favoring CS-EMR group [OR 0.31, 95 % CI (0.12–0.76), P = 0.01] with no heterogeneity (P = 0.40; I² = 0 %). However, statistical superiority for CS-EMR could not be detected regarding early bleeding [OR 0.78, 95 % CI (0.31–1.97), P = 0.60]. Only two studies reported data on delayed perforation, showing a numerical difference favoring CS-EMR; however, statistical significance could not be obtained [OR 0.26, 95 % CI (0.03–2.41), P = 0.24]. Regarding efficacy, the overall effect estimates regarding complete resection and RRA did not favor either of the groups [OR 0.62, 95 % CI (0.25–1.53), P = 0.30], [OR 2.81, 95 % CI (0.43–18.47), P = 0.28] respectively.

Conclusion

Evidence obtained from this meta-analysis suggests that CS-EMR offers superior safety compared to HS-EMR for colorectal polyp resection. Current evidence remains limited due to the small number of studies included. Therefore, further high-quality randomized controlled trials with larger sample sizes are needed.

References

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• Kawamura T, Takeuchi Y, Asawa S, Yokota I, Matsuno T, Omori T, et al. A comparison of cold and hot snare polypectomy for small colorectal polyps: a randomized controlled trial. Am J Gastroenterol. 2018;113(3):403–411.