Introduction

Primary biliary cholangitis (PBC) is a rare, chronic autoimmune liver disease characterized by progressive destruction of small intrahepatic bile ducts, leading to cholestasis and end-stage liver disease. Liver transplantation (LT) remains the definitive treatment, with excellent long-term outcomes. However, a subset of patients experiences disease recurrence (rPBC), which may impact prognosis. Due to the rarity of the condition, risk factors for rPBC remain poorly defined.

Aims & Methods

This study aims to determine the prevalence of rPBC after LT and identify potential risk factors associated with recurrence. A systematic search was conducted in MEDLINE, Embase, and Cochrane CENTRAL using a predefined strategy. We included full-text studies reporting the number of PBC patients who developed rPBC post-LT. Abstracts and studies lacking clear data on prevalence or risk factors were excluded. Prevalence estimates were pooled using a two-step approach with logit transformation and generalized linear mixed models. Hazard ratios (HRs) and 95% confidence intervals (CIs) were synthesized using a random-effects model with restricted maximum likelihood estimation. All analyses were performed using R Studio.

Results

Fifty-five studies met inclusion criteria, most conducted in Europe, followed by North America, Asia, and Australia; two studies were multi-continental. A total of 5,715 patients with PBC who underwent LT were included, with 9.98% being male. Reported prevalence of rPBC ranged from 0% to 50%, with a pooled prevalence of 15% (95% CI: 12%-19%). Significant risk factors for rPBC included younger age at LT (HR = 0.97, 95% CI: 0.96-0.98) and use of tacrolimus in maintenance immunosuppression (HR = 1.79, 95% CI: 1.09-2.95). Protective factors included cyclosporine-based maintenance immunosuppression (HR = 0.50, 95% CI: 0.28-0.87) and post-LT prophylactic use of ursodeoxycholic acid (HR = 0.42, 95% CI: 0.30-0.58). Donor age, donor-recipient sex mismatch, cold ischemia time, and use of tacrolimus, cyclosporine, or azathioprine in initial immunosuppression, as well as maintenance azathioprine or occurrence of acute cellular rejection, were not significantly associated with rPBC.

Conclusion

This is the largest meta-analysis to date evaluating rPBC, including 5,715 liver transplant recipients with PBC. The overall recurrence rate was 15%. Younger age at transplantation and tacrolimus-based immunosuppression were associated with higher recurrence risk, while cyclosporine and post-LT ursodeoxycholic acid appeared protective. These findings may inform risk stratification and guide post-transplant management in PBC. Prospective studies are needed to validate these associations and refine strategies to prevent rPBC.

Disclosure

RVM has received funding from PSC Support. GGLC has received a research grant from IPSEN.

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

Acetaminophen (APAP) overdose is a primary cause of drug-induced liver injury (DILI). Although the inflammatory microenvironment plays a critical role in APAP-induced liver injury (AILI), its cellular interaction network and molecular regulatory mechanisms remain incompletely elucidated. Krüppel-like factor 4 (KLF4), a zinc finger transcription factor, is known to regulate monocyte differentiation, but its functional role in the AILI inflammatory microenvironment remains unclear. This study aims to investigate the regulatory effects of myeloid KLF4 deletion on the AILI microenvironment.

Aims & Methods

By integrating multidimensional omics analysis and a myeloid-specific Klf4 knockout mouse model, we dynamically dissected microenvironmental remodeling during AILI progression. Liver samples were collected for RNA sequencing, combined with single-cell transcriptomics, flow cytometry, and molecular interaction validation to clarify the KLF4-dependent cellular subpopulation interaction network. In vivo liver imaging, histology, biochemical assays, and molecular experiments were performed to validate KLF4-dependent intercellular interactions. Primary hepatocytes and hepatocyte cell lines were used for in vitro verification.

Results

Myeloid-specific KLF4 deletion led to an increase in CXCL2⁺CXCL3⁺CD24⁺ monocytes, which activated the NF-κB signaling pathway to secrete CXCL2/CXCL3 chemokines. These chemokines bound to the CXCR2 receptor on neutrophils, driving neutrophil infiltration and neutrophil extracellular traps (NETs) formation, while amplifying the TNF-α signaling pathway. Concurrently, myeloid KLF4 knockout induced enrichment of CXCL1⁺IL17RA⁺ endothelial cells. Neutrophil-derived NETs promoted endothelial phenotypic switching toward pro-inflammatory polarization, while endothelial-derived CXCL1 further recruited neutrophils, establishing a "monocyte-neutrophil-endothelial" cellular subpopulation interaction that perpetuated microenvironmental inflammation.

Conclusion

This study reveals the molecular mechanism by which KLF4 drives inflammatory cascades in the AILI microenvironment through regulation of the myeloid-endothelial interaction network. We propose therapeutic strategies targeting NETs formation or the CXCL2/CXCL3-CXCR2 axis, providing novel targets for precise intervention in AILI.

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

• Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

• Winawer SJ, Zauber AG, Ho MN, O'Brien MJ, Gottlieb LS, Sternberg SS, et al. Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med. 1993;329(27):1977–81.

• Facciorusso A, Del Prete V, Antonino M, Buccino VR, Muscatiello N. Efficacy of endoscopic polypectomy techniques for colorectal polyps: a systematic review and network meta-analysis. Gastrointest Endosc. 2020;91(4):733–745.e9.

• Pohl H, Srivastava A, Bensen SP, Anderson P, Rothstein RI, Gordon SR, et al. Incomplete polyp resection during colonoscopy—results of the complete adenoma resection (CARE) study. Gastroenterology. 2013;144(1):74–80.e1.

• Tutticci N, Hewett DG. Cold snare polypectomy: A safe, effective technique for sessile polyps. Gastrointest Endosc Clin N Am. 2015;25(2):291–301.

• 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.

Introduction

Gastric outlet obstruction (GOO) is a severe complication of unresectable gastric and pancreatic cancers. Conventional gastrojejunostomy (CGJ) is a standard surgical intervention, but it is associated with a high incidence of delayed gastric emptying (DGE). Stomach-partitioning gastrojejunostomy (SPGJ) has emerged as an alternative to improve gastric emptying and enhance clinical outcomes.

Aims & Methods

We conducted a meta-analysis comparing SPGJ and CGJ in patients with GOO due to unresectable gastric or pancreatic cancers. Electronic databases were searched up to February 8, 2025. Outcomes included DGE, major postoperative complications, need for reintervention, short-term mortality, operation time, gastric outlet obstruction scoring system (GOOS), length of hospital stay (LOS), adherence to postoperative chemotherapy, and overall survival. For continuous outcomes, mean differences (MD) with 95% confidence intervals (CI) were calculated. For dichotomous outcomes, relative risks (RR) with 95% CI were reported. Reconstructed individual patient data (IPD) from Kaplan-Meier curves was utilized for survival analysis.

Results

A total of 11 studies comprising 456 patients were included. SPGJ was associated with significantly reduced DGE (RR = 0.24, 95% CI: 0.12–0.47) and postoperative major complications (RR = 0.26, 95% CI: 0.12–0.54) compared to CGJ. No significant differences were found in the need for reintervention (RR = 0.59, 95% CI: 0.21–1.64), short-term mortality (RR = 0.99, 95% CI: 0.42–2.33), or LOS (MD = -1.47 days, 95% CI: -3.10 to 0.16). GOOS scores were comparable between groups. Overall survival was also similar between SPGJ and CGJ (HR = 1.06, 95% CI: 0.66–1.70).

Conclusion

Our meta-analysis supports SPGJ as a superior option to CGJ for managing malignant GOO, offering significant reductions in DGE and postoperative complications, similar GOOS scores, and comparable safety regarding reintervention, short-term and long-term mortality, and LOS. High-quality RCTs are needed to confirm these findings and guide clinical practice.

References

1. T. Oida, K. Mimatsu, A. Kawasaki, H. Kano, Y. Kuboi, and S. Amano, “Modified Devine Exclusion with Vertical Stomach Reconstruction for Gastric Outlet Obstruction: A Novel Technique,” Journal of Gastrointestinal Surgery, vol. 13, no. 7, pp. 1226–1232, Jul. 2009, doi: 10.1007/s11605-009-0874-y IF: 2.2 Q2 2. W. Zhang et al., “The Validation of Deep Learning-Based Grading Model for Diabetic Retinopathy,” Front. Med., vol. 9, p. 839088, May 2022, doi: 10.3389/fmed.2022.839088 IF: 3.1 Q1 .
3. R. Yildirim, “Efficacy of stomach-partitioning on gastric emptying in patients undergoing palliative gastrojejunostomy for malign gastric outlet obstruction,” Ulus Travma Acil Cerrahi Derg, 2020, doi: 10.14744/tjtes.2020.14668 IF: 0.8 Q4 .