Background Liver transplantation (LT) is a life-saving treatment for pediatric patients suffering end-stage liver disease, with the potential to yield positive long-term outcomes. Recently, remarkable progress has been achieved in mainland China. The purpose of this research is to describe the status in our center. Method 116 recipients from July 2019 to July 2023 were included in our study. The characteristics of recipients and donors, preoperative assessments, intraoperative details and posttransplant complications were described. The Kaplan-Meier method was applied to analyze the overall survival curves and was examined with the log-rank test. Result A total of 116 pediatric LTs were performed, including 57 (49.1%) living donor liver transplantation (LDLT), 57 (49.1%) split liver transplantation (SLT) and 2 (1.8%) whole liver transplantation (WLT). The 1- and 3-year overall survival rates were 93.1% and 92.2%. The survival of DDLT was comparable to that of LDLT in our center (89.4% vs. 96.3% for 3-year survival rate). After LT, 7 (6.03%) vascular complications and 3 (2.59%) biliary complications were observed. The primary causes of mortality were drug-resistant bacteria infection and post-transplant lymphoproliferative disorder (PTLD). Conclusion Pediatric LT has achieved tremendous progress in mainland China. The survival rate of our center was comparable to the published results worldwide. The survival rate of SLT from DBD donors was comparable to LDLT. Further research on the postoperative management and attempts of ISW will be required to improve survival.

Glycemic disorders, especially diabetes characterized by elevated blood glucose, significantly increase the risk of various cancers, including increasing the risk of hepatocellular carcinoma (HCC) by 239%. Diabetes mellitus has now been confirmed as an independent risk factor for the development of HCC, with T2DM increasing the risk by 4.59 times. However, little is known about mechanisms regulate glucose signal transduction in HCC. We investigated the relationship between high glucose levels and methylation-related gene expression in HCC. The effects of METTL3-IGF2BP3 on transcriptome profiles were used to identify downstream molecules. Proliferation, glucose uptake, lactate production, ATP levels, extracellular acidification rate, and oxygen consumption rate were examined in HCC cells. The mechanism by which METTL3-IGF2BP3 activates the PI3K-AKT pathway was explored. The results showed that m6A modification levels were significantly elevated in HCC cells under a hyperglycemic microenvironment, primarily due to transcriptional activation of c-MYC-initiated METTL3. Additionally, glucose could directly bind to IGF2BP3 and promote its function in recognizing m6A sites. SLC39A10 as a downstream molecule of METTL3-IGF2BP3, promoting the uptake of Zn2+ in HCC. METTL3, IGF2BP3, or SLC39A10 silencing inhibited proliferation, colony formation, glycolysis in HCC cells. Mechanistically, silencing METTL3-IGF2BP3 significantly reduced the methylation level and function of SLC39A10, decreased intracellular Zn²⁺ levels, inhibited ADAM17 activity, and thus attenuated EGFR phosphorylation-induced PI3K-AKT pathway activation. Concurrently, alterations in intracellular Zn²⁺ levels are associated with altered immune cell infiltration in the HCC tumor microenvironment. In conclusion, the METTL3-IGF2BP3 axis promotes HCC tumorigenesis by enhancing glycolytic reprogramming and remodeling the immunosuppressive tumor microenvironment.

Hepatocellular carcinoma (HCC) remains the leading cause of cancer-related death worldwide. Its high aggressiveness and resistance to therapy arise, in large part, from an immunosuppressive tumor microenvironment (TME). Neutrophil extracellular traps (NETs) are web-like assemblies of chromatin and granular proteins released during NETosis, and they have emerged as major inflammatory drivers within the HCC TME. NETs actively promote tumor progression by physically trapping circulating tumor cells, remodeling the extracellular matrix, stimulating angiogenesis, and facilitating immune evasion. In this review, we systematically dissect the molecular networks that link NETs to HCC. We summarize the signaling pathways that regulate NETs formation, detail the multifaceted roles of NETs in hepatocarcinogenesis, metastasis, and therapy resistance, and assess the translational potential of NETs as diagnostic biomarkers and therapeutic targets. Together, these analyses offer theoretical guidance for developing the next generation of precision-medicine strategies for HCC.

Pancreatic neuroendocrine tumours (PanNETs) are characterized by metabolic reprogramming, but the underlying mechanisms driving their progression remain poorly understood. Therefore, we investigated whether serine/threonine kinase 33 (STK33) promotes PanNET growth and aerobic glycolysis via mTORC1/S6K1/HIF-1α signalling. PanNET specimens and adjacent nontumorous pancreatic tissues from 102 patients who underwent curative surgery for PanNETs were subjected to immunochemical staining for STK33 and HIF-1α. The relationships among STK33 expression levels, HIF-1α expression levels, clinicopathological parameters and clinical prognoses were statistically analysed. The effects of STK33 on PanNET growth and glycolysis were examined via shRNA-mediated knockdown and overexpression in vitro and in vivo. Increased STK33 expression in PanNETs correlated significantly with shorter disease-free survival (P < 0.001). STK33 knockdown suppressed cell proliferation, glucose uptake, lactate/ATP production, and S6K1 phosphorylation, whereas STK33 overexpression enhanced these effects. Inhibition of S6K1 (PF-4708671) reversed STK33-driven glycolysis and tumorigenesis. In vivo, STK33 increased tumour growth concurrent with enhanced S6K1 phosphorylation. Mechanistically, HIF-1α transcriptionally upregulated STK33, whereas STK33 promoted increased HIF-1α protein levels via mTORC1/S6K1 signalling, enhancing the expression of the glycolytic enzyme LDHA. Clinically, STK33 and HIF-1α were strongly coexpressed in PanNET tissues (ρ = 0.771; P < 0.001), and both predicted poor prognoses. Our results support a model in which STK33 functions as a key regulator of the mTORC1/S6K1/HIF-1α signaling-metabolic axis in PanNETs, highlighting its potential as a therapeutic target.

To investigate the mechanisms underlying the interaction and influence between microvascular invasion (MVI), which contributes to metastasis and poor prognosis of pancreatic ductal adenocarcinoma (PDAC), and tumor microenvironment. This study employed an integrative multi-omics approach, combining spatial proteomics (multiplex immunofluorescence), transcriptome sequencing, and single-cell RNA sequencing (scRNA-seq) to profile MVI⁺ and MVI⁻ PDAC samples. The functional role of key genes was validated through in vitro and in vivo assays (migration, invasion, xenograft models). Molecular mechanisms were dissected using Co-IP, ubiquitination assays, and ChIP-qPCR. The epithelial-mesenchymal transition (EMT) process was significantly activated in MVI⁺ tumors, with EMT-positive cells located spatially closer to microvessels. scRNA-seq identified a distinct epithelial subpopulation characterized by CXCL5 that exhibited a strong EMT phenotype and was enriched in MVI⁺ samples. Mechanistically, the transcription factor ZBTB7B was found to directly promote TRIM29 transcription. TRIM29 directly binds to IκBα via its BB2 domain and catalyzes its K48-linked ubiquitination and proteasomal degradation. This event relieves the inhibition of the NF-κB signaling pathway, leading to its activation and the subsequent induction of EMT, ultimately enhancing the invasive and metastatic capabilities of pancreatic cancer cells. Clinical correlation analysis revealed a significant negative correlation between TRIM29 and IκBα protein levels, and high TRIM29, low IκBα, and high CXCL5⁺EMT levels were all associated with poor prognosis. This study reveals the critical role of the ZBTB7B-TRIM29-IκBα-NF-κB signaling axis in promoting EMT in CXCL5-marked pancreatic cancer cells surrounding MVI, establishing TRIM29 as a potential therapeutic target for inhibiting early metastasis of PDAC. This study provides deep insights into the biology of MVI, a crucial prognostic indicator in pancreatic cancer. TRIM29 expression could serve as a potential biomarker for predicting tumor aggressiveness and patient outcome. More importantly, targeting TRIM29’s E3 ligase activity or its interaction with IκBα represents a promising novel therapeutic strategy to inhibit early metastasis and improve the resectability of pancreatic cancer. Integrated Multi-omics Profiling: First study to combine spatial proteomics, transcriptomics, and scRNA-seq to systematically characterize the microenvironment and cellular ecosystem of MVI in PDAC. Identification of a Key Cellular Subset: Discovered a CXCL5-expressing epithelial subpopulation (CXCL5⁺EPCs) via scRNA-seq as the key cellular state driving MVI-associated EMT. Elucidation of a Novel Mechanism: Uncovered a novel mechanism where TRIM29 activates the NF-κB pathway by ubiquitinating and degrading IκBα at Lys21/22. Strong Clinical Relevance: Demonstrated that the TRIM29-IκBα-EMT axis is strongly correlated with MVI status and patient prognosis, highlighting its significant translational value.

BACKGROUND:Tacrolimus is a widely used immunosuppressant in organ transplantation, but it is characterized by a narrow therapeutic index and high interindividual variations of its pharmacokinetics. Tacrolimus is a substrate for CYP3A. It has been conjectured that CYP3A5 polymorphism is associated with tacrolimus pharmacokinetic variations. The objective of this study was to evaluate the contribution of polymorphisms of the donor and recipient CYP3A5 gene on tacrolimus disposition in liver transplantation. METHODS:Fifty-three liver transplant recipients treated with tacrolimus were enrolled in this study. Tacrolimus dosage and blood trough concentration were investigated at 1 week, 2 weeks, and 1 month after transplantation. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was applied to determine the genotype of CYP3A5 gene. RESULTS:The concentration/dose (C/D) ratios in patients with *1/*1(*1/*3) genotype donor were significantly lower than in patients with *3/*3 genotype donor at 2 weeks (P = 0.036) and 1 month (P = 0.021), but not at 1 week posttransplantation. Combination analysis showed that such significance still existed between CYP3A5 expressor group and nonexpressor group for both donor and recipient genotype. Also differences of C/D ratio between CYP3A5 expressor and nonexpressor donors in nonexpressor recipients were larger than those between recipients in nonexpressor donors. CONCLUSION:The large interindividual variation of tacrolimus dose requirement is influenced by the metabolic activity of CYP3A5. Polymorphisms of the donor CYP3A5 gene seem to contribute more to such variation than the recipient. A larger population and further studies are needed to explore the exact mechanisms for tacrolimus pharmacokinetics.

Pupil examination has been used as a basic measure in critically ill patients and has great importance for the prognosis and management of disease. An automated pupillometer is a computer-based infrared digital video system by which the accuracy and precision of the pupil examination are markedly improved. We conducted an observational study of pupil assessment with automated pupillometry in clinical liver transplantation settings, including pretransplant evaluations and posttransplant surveillance. Our results showed that unconscious patients (grade 4 hepatic encephalopathy) had a prolonged latency phase (left side: 283 +/- 80 milliseconds; right side: 295 +/- 96 milliseconds) and a reduced pupillary constrictive ratio (left direct response: 0.23 +/- 0.10; left indirect response: 0.21 +/- 0.07; right direct response: 0.20 +/- 0.08; right indirect response: 0.21 +/- 0.08) in comparison with normal and conscious patients. After liver transplantation, the recovery of pupillography in these patients was slower than that in conscious patients. However, the surviving recipients without major complications all had a gradual recovery of pupillary responses, which occurred on the first or second posttransplant day. We also reported 4 cases of futile LT in the absence of pretransplant pupillary responses and other pupillary abnormalities revealed by automated pupillometry in our study. In conclusion, patients with grade 4 hepatic encephalopathy had a sluggish pupil response and a delayed recovery pattern after LT. An automated pupillometer is potentially a supplementary device for pretransplant screening and posttransplant monitoring in patients undergoing LT, but further prospective studies are required.

This study aimed to develop an optimal alternative site for islet transplantation, addressing the limitations of the current clinical standard, the intrahepatic site. In this study, prevascularized muscle sinus tracts (MSTs) in mice were created by implanting and then removing polyamide rods, leveraging a controlled foreign body reaction to generate a highly vascularized, porous collagen matrix. Transplantation of 350 syngeneic islets into these MSTs consistently reversed diabetes in mice, achieving long-term normoglycemia for over 180 days, with efficacy comparable with kidney capsule transplantation. The approach also supported the survival of human islets in immunodeficient mice and demonstrated feasibility in a porcine autotransplantation model. This work establishes the MST as a simple, effective, and clinically promising strategy that enhances islet engraftment through localized prevascularization, potentially improving the therapeutic outcomes of islet transplantation.

Background: A significant portion of primary liver cancer patients in China are diagnosed at intermediate-to-advanced stages, often making them ineligible for curative surgery. Furthermore, high postoperative recurrence rates, reaching up to 70%, pose a major challenge for long-term survival. The emergence of novel systemic treatments, such as immune checkpoint inhibitor combinations, and advancements in locoregional therapies have created new opportunities for conversion and perioperative strategies. This updated consensus aims to standardize the clinical application of these therapies based on the latest evidence, with the objective of improving patient prognosis. Methods: A multidisciplinary committee of 97 experts was convened to revise previous guidelines. The process involved a comprehensive search of medical databases and conference proceedings, with evidence graded according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Consensus statements were finalized through a formal electronic voting process, requiring at least 80% agreement for approval, resulting in 18 updated statements. Results: The consensus provides refined definitions for conversion and perioperative therapy. It recommends various strategies for oncological conversion, including systemic therapy with anti-angiogenic drugs plus immunotherapy, and locoregional approaches like precision transarterial chemoembolization (TACE) and hepatic artery infusion chemotherapy (HAIC). The document strongly affirms surgical resection as a crucial step for achieving long-term survival after successful conversion and offers guidance on surgical timing and adjuvant therapy. For resectable patients with high-risk features, neoadjuvant and adjuvant treatments are outlined to mitigate recurrence. The consensus also advocates for using dynamic enhanced magnetic resonance imaging ( MRI) and the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria for efficacy assessment and underscores the essential role of a multidisciplinary team in management. Conclusions: This updated consensus offers standardized, evidence-based guidance for clinicians on implementing conversion and perioperative strategies to optimize patient-centered care and highlights the need for continued research to further refine these promising approaches.

Liver transplantation is the most effective treatment for end-stage liver disease. However, the shortage of donor livers has become a significant obstacle to the advancement of liver transplantation. Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been extensively investigated in liver diseases. However, the underlying mechanisms of how they can protect organ donation after cardiac death (DCD) livers remain unclear. In this study, an arterialized mouse non-heart-beating (NHB) liver transplantation model was used to investigate the effect of MSCs-Exo on NHB liver transplantation. The survival rates, histology, pro-inflammatory cytokine and chemokine expression, and underlying mechanisms were investigated. The infusion of MSCs-Exo reduced the injury to DCD liver graft tissue. In vitro and in vivo experiments demonstrated that MSCs-Exo could inhibit hydrogen peroxide-induced pyroptosis of Kupffer cells. We found that miR-17-5p was significantly abundant in MSCs-Exo, targeting and regulating the TXNIP expression. This action inhibited NLRP3-mediated pyroptosis of Kupffer cells through the classical Caspase1-dependent pathway, alleviating DCD liver graft injury. Our study elucidated a protective role for MSCs-Exo in a NHB liver transplantation model. This mechanism provides a theoretical basis and new strategies for the clinical application of MSCs-Exo to improve liver graft quality and alleviate the organ shortage in liver transplantation.

BackgroundTumors of the spleen are uncommon, and most represent metastases from primary organs. Primary mucinous cystadenocarcinoma of the spleen is an extremely rare tumor. Only 11 cases have been reported in the literature.Case presentationHerein, we present a case of primary mucinous cystadenocarcinoma in the spleen in a 50-year-old woman. Abdominal CT and MRI revealed a 9.5 × 6.5 cm mixed solid-cystic lesion with heterogeneous enhancement of the mural nodules and septations, with secondary extension abutting the gastric fundus and pancreatic tail. Notably, tumor biomarker profiling demonstrated remarkable increases in CA19-9 (>12,000 U/ml) and CEA (41.5 ng/ml) levels. Following splenectomy, histopathology revealed the mass to be a mucinous cystadenocarcinoma. Given that metastatic cystadenocarcinoma is relatively common, investigations were performed to evaluate the primary site of malignancy. A whole-body PET-CT scan did not reveal any metabolically active lesions in any part of the body. Neither upper gastrointestinal endoscopy nor colonoscopy revealed any primary malignant lesions. Hence, it was reported as a primary mucinous cystadenocarcinoma of the spleen.ConclusionThe need for presenting this case is due to its rarity and because mucinous cystadenocarcinoma can be a rare differential diagnosis in cases of malignant splenic cysts.

BACKGROUND:The increasing morbidity of liver cancer has led to a growing demand for transplantation. Split liver transplantation (SLT) is a promising way to ameliorate organ shortages. However, the safety and efficacy of SLT are still controversial. The aim of this study was to assess the clinical outcome of SLT in liver cancer patients at our center. METHODS:A total of 74 patients who received liver transplantation at a tertiary hospital from March 2019 to July 2023 were retrospectively studied, of whom 37 recipients underwent SLT and 37 recipients underwent whole-graft liver transplantation (WGLT). Clinical data were analyzed and compared between patients who underwent SLT and WGLT. RESULTS:SLT and WGLT were successfully performed, with no intraoperative transplant-related mortality. Postoperatively, no significant differences in total bilirubin (TB, P=0.266), alanine transaminase (ALT, P=0.403) and aspartate transaminase (AST, P=0.160) levels within 30 d were detected between the two groups. The transplant-related mortality rates were 8.1% in the SLT group and 5.4% in the WGLT group within 30 d of surgery (P=1.000), and 10.8% and 8.1%, respectively, at 90 d after surgery (P=1.000). There were no significant differences in overall survival (OS) and progress-free survival (PFS) between the SLT and WGLT groups (P=0.910, P=0.190). CONCLUSION:Our results show that SLT does not imply additional risks in treating liver cancer compared with WGLT.

BACKGROUND:Enucleation has the advantages of preserving function and avoiding pancreaticoduodenectomy for benign and low-grade malignant neoplasms in the pancreatic head. However, laparoscopic enucleation (LEn) of pancreatic head tumors remains challenging in terms of bleeding control and duct integrity preservation because of the complicated blood supply to the pancreatic head and the adjacent relationships of lesions with the main pancreatic duct (MPD), especially for deep-seated or broad-based lesions. Here, we developed a novel dual-arterial occlusion technique to facilitate LEn of pancreatic head tumors and evaluated its feasibility and safety. METHODS:Between May 2023 and August 2024, we prospectively included patients with deep-seated or broad-based pancreatic head tumors who received LEn via the dual-arterial occlusion technique. The technique was applied by temporary clamping of both the celiac trunk (CT) and superior mesenteric artery (SMA) to achieve inflow control of the pancreaticoduodenal arcade, minimizing intraoperative hemorrhage and optimizing the surgical field during enucleation. The demographic, intraoperative and postoperative data were analyzed. RESULTS:In this study, 14 patients underwent laparoscopic pancreatic enucleation via the dual-arterial occlusion technique. The median occlusion time and operative time were 25.0 (interquartile range, IQR 22.8-27.3) min and 200.0 (IQR 172.5-222.5) min, respectively. The median blood loss was 50.0 (IQR 27.5-50.0) mL. No major bleeding, MPD injury or conversion to open surgery occurred. Three patients developed Grade B postoperative pancreatic fistula (POPF) (3/14, 21.4%), and one experienced Grade III complications (1/14, 7.1%). No Grade C POPF or Grade IV/V complications were observed. The 90-day mortality and reoperation rates were zero. No patient experienced endocrine or exocrine insufficiency. CONCLUSION:This dual-arterial occlusion appears to be a safe and feasible inflow control technique for LEn of deep-seated or broad-based pancreatic head tumors, with minimal intraoperative blood loss and acceptable overall complication rates.

Local invasion is considered a premonitor of tumor metastasis which cause curative difficulties and undesired prognosis in patients with Pancreatic ductal adenocarcinoma (PDAC). The importance of mRNA N6-methyladenosine (m6A) modification during tumor invasion is controversial as it plays distinct roles which mainly attributed to different m6A reader proteins exert function. In current study, the level of m6A expression in PDAC was analyzed by IHC and ELISA, all m6A-regulated genes in PDAC detected by qPCR. The downstream gene EMP1 was screened by analyzing IGF2BP3 knockdown RNA-seq, IGF2BP3-RIP, MeRIP-seq, and PDAC-survival related genes. And m6A modification sites of EMP1 RNA was verified by MeRIP-qPCR, RIP-qPCR, and dual luciferase assays. EMP1-binding protein VASP was identified by mass spectrometry. Cell migration and invasive activity were detected using cytoskeletal staining, scratch assay, transwell assay, subcutaneous tumor and lung metastasis models. Finally, prognosis and immune microenvironment was analyzed in PDAC by IHC and multiple immunofluorescence staining. This work shows that m6A reader IGF2BP3 is remarkably upregulated in local invasion PDAC and indicates worse prognosis of patients. Mechanistically, IGF2BP3 recognized m6A-modified EMP1 mRNAs to prolong stability of them, which inhibits the hindrance of SMAD7 to SMAD3/4 phosphorylation by promoting the binding of VASP and SMAD7. Finally, a tight correlation of the local invasion/IGF2BP3/EMP1 and infiltration of immune cells in the tumor microenvironment is evidenced in clinical PDAC. In conclusions, IGF2BP3 functions as an invasion driver that induces PDAC development via the EMP1/TGF-β axis. And IGF2BP3/EMP1 axis may be involved in regulating microenvironmental remodeling in pancreatic cancer.

Background: Cholangiocarcinoma (CCA) is an epithelial malignancy with a dismal prognosis. Here, we presented the largest single-center experience in treating CCA using a novel surgical procedure, ex vivo liver resection and auto-transplantation (ELRA). Methods: We retrospectively enrolled 175 patients with CCA after tumor resection in our single center between September 2021 and June 2024, with the last follow-up conducted on November, 2024. The primary outcome was overall survival (OS). A 1:1 propensity score matching (PSM) approach was employed to adjust potential confounders between the ELRA cohort and the conventional liver resection (CLR) cohort. Results: After matching, a total of 27 pairs were included in our study. The median OS was significantly improved in the ELRA cohort compared to the CLR cohort, with a hazard ratio (HR) for death of 0.301 [95% confidence interval (CI): 0.107-0.847; P=0.02]. The survival rate was 95.7% in the ELRA cohort vs. 60.0% in the CLR cohort at 1 year, and 75.2% vs. 42.0% at 2 years. The median recurrence-free survival (RFS) was 17.0 months in the ELRA cohort as compared with 9.7 months in the CLR cohort (HR for disease recurrence or death =0.351; 95% CI: 0.161-0.766; P=0.006). Univariate and multivariate Cox regression analyses revealed that ELRA was an independently factor associated with improved outcomes in both OS (P=0.006) and RFS (P=0.009). Complications related to surgical procedures were observed in 66.7% of patients in the ELRA cohort compared to 59.3% in the CLR cohort (P=0.78). For the grade 3-5 complications, the rates were 14.8% in the ELRA cohort and 11.1% in the CLR cohort (P>0.99). Conclusions: ELRA was a promising method to improve outcomes for patients with CCA.