BACKGROUND:Accurately predicting long-term survival after liver transplantation (LT) remains a major clinical challenge. Tacrolimus intrapatient variability (Tac-IPV) has emerged as a potential prognostic marker, yet its integration into clinical decision-making remains limited. METHODS:This study analyzed 381 adult LT recipients from two centers: 288 from the First Affiliated Hospital of Xi'an Jiaotong University (2015-2019) and 93 from the First Hospital of Shanxi Medical University (2020-2023). We developed a novel composite index, the Liver Transplantation Prognosis Predictor (LTPP), which integrates Tac-IPV (coefficient of variation), total bilirubin, and donor age using a Euclidean norm-based fusion method. The prognostic value of LTPP was evaluated through survival analysis and compared with conventional scores (model for end-stage liver disease and Child-Pugh scores). In addition, a random forest model was developed and externally validated to predict post-transplant survival. RESULTS:In three-fold cross-validation, the random forest model demonstrated robust predictive performance for 1-, 2-, and 3-year survival (area under the receiver operating characteristic curve: 0.76, 0.73, and 0.68 in internal validation; 0.71, 0.74, and 0.70 in external validation). Survival analysis showed that LTPP significantly outperformed model for end-stage liver disease and Child-Pugh scores in risk stratification (log-rank P < 0.0001), establishing it as a reliable prognostic indicator. CONCLUSIONS:This study introduces LTPP, a clinically accessible composite index incorporating Tac-IPV. Compared to existing scoring systems, LTPP provides superior prognostic accuracy for long-term survival following LT, offering a promising tool for individualized post-transplant management.

Tumor dormancy is a fundamental phenomenon in cancer biology, characterized by malignant cells that remain viable but non-proliferative, thereby frequently evading detection and treatment. This review examines the intricate role of the tumor microenvironment (TME) in regulating tumor cell dormancy. The TME encompasses a diverse array of components, including immune cells, extracellular matrix proteins, and soluble factors, all of which contribute to a dynamic interplay that influences tumor cell behavior. Key mechanisms involved in the maintenance of dormancy include immune surveillance, where immune cells can either suppress or promote tumor growth, and extracellular matrix interactions that provide structural support and biochemical signals essential for quiescence. Additionally, microenvironmental conditions such as hypoxia and acidosis impose selective pressures that can favor dormant states over active proliferation. Emerging therapeutic strategies are being explored to target dormant tumor cells, including the use of mesenchymal stem cell therapies, which may modulate the TME to either awaken dormant cells for targeted treatment or maintain their quiescent state to prevent recurrence. Understanding the TME’s influence on tumor dormancy not only enhances our comprehension of cancer progression but also opens avenues for innovative treatments aimed at improving patient outcomes by mitigating the risks of recurrence and metastasis. This article aims to provide a comprehensive overview of the current knowledge on TME-mediated tumor dormancy and highlight promising therapeutic strategies for future research.

Liver transplantation is an effective treatment for end-stage liver disease. Liver transplantation is technically complex and associated with significant trauma. In recent years, minimally invasive surgical techniques, such as laparoscopy and robotic surgery, have rapidly developed and been widely applied in various surgical fields. Minimally invasive surgery offers advantages including reduced trauma, less bleeding, and faster postoperative recovery, and has become a mainstream trend in surgical development. In the field of liver transplantation, laparoscopic and robotic donor hepatectomy techniques for living donor liver transplantation have made significant progress. However, due to difficulties in exposing the anastomotic sites of the donor liver and challenges in vascular anastomosis, the application of minimally invasive techniques in donor liver implantation has progressed relatively slowly. With advancements in laparoscopic and robotic surgical techniques and related instruments, laparoscopic donor liver implantation has gradually become feasible. Currently, multiple liver transplant centers worldwide have begun to progressively perform laparoscopic or robot-assisted liver transplantation in recipients, demonstrating potential advantages in reducing surgical trauma and accelerating postoperative recovery. However, there is currently a lack of guidelines or consensus on the application of minimally invasive surgery in liver transplant recipients. Therefore, Branch of Organ Transplantation of Chinese Medical Association, Surgery Group of Chinese Society of Surgery of Chinese Medical Association, and Branch of Organ Transplant Physicians of Chinese Medical Doctor Association invited experts in the field to discuss clinical issues. Combining published guidelines, consensus statements, and research advancements, they formulated the "Technical guidelines for laparoscopic-assisted Liver transplantation in recipients," aiming to provide reasonable guidance and references for clinical practitioners in the field of liver transplantation.

BACKGROUND:Male sex is a risk factor of the development and prognosis of primary liver cancers. However, sex difference of tumor recurrence following curative resection and the underlying mechanism need to be clarified. METHODS:Sex and outcomes among patients undergoing resection for hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) were investigated in two international multi-institutional databases. Murine model of postoperative HCC recurrence was used following hepatic ischemia-reperfusion (I/R) injury to mimic surgical injury in hepatocyte-specific sex-determining region Y gene (SRY) knock-in (KI) and knockout (KO) mice, as well as wildtypes (WTs). RESULTS:Men had a significantly worse recurrence-free survival (RFS) following curative resection of HCC or ICC versus women (5-year RFS: HCC, men 30.0% vs. women 43.9%, P  = 0.041; ICC, men 18.7% vs. women 26.8%, P  = 0.006, respectively) in the matched cohort. Male mice consistently developed larger recurrent tumor versus females after hepatic I/R injury, accompanied by increased polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs) and decreased CD8 + T cells. Of note, SRY KI in both male and female mice increased, whereas SRY KO decreased tumor recurrence upon I/R injury. Moreover, SRY was associated with increased immunosuppressive PMN-MDSCs and decreased CD8 + T cells in both patient and murine livers after I/R injury. Mechanistically, hepatocyte SRY recruited PMN-MDSCs to the liver microenvironment following I/R injury through NF-κB-dependent CXCL1 secretion. CONCLUSIONS:Men are more likely to recur than women after liver resection of liver cancers. SRY promotes immunosuppressive microenvironment in the liver and accounts for male susceptibility of liver cancer recurrence. Targeting SRY-NFκB-CXCL1 axis may have potential value in male-specific surveillance and immunomodulatory therapy of primary liver cancer.

To define the impact of perineural invasion (PNI) on long-term survival of patients following curative-intent resection of pancreatic neuroendocrine tumors (pNETs). Patients with pNETs who underwent curative-intent resection (R0/R1) between 2000 and 2020 were identified from a multi-institutional database. The impacts of PNI on overall survival (OS) and disease-free survival (DFS) were analyzed. Among 700 patients, 171 (n = 24.4

BackgroundBy performing AI-driven workflow analysis, intelligent surgical systems can provide real-time intraoperative quality control and alerts. We have upgraded an Intelligent Surgical Assistant (ISA) through integrating a redesigned hierarchical recognition algorithm, an expanded surgical dataset, and an optimized real-time intraoperative feedback framework.ObjectiveWe aimed to assess the accuracy of the ISA in real-time instrument tracking, organ segmentation, and phase classification during laparoscopic hemi-hepatectomy.MethodsIn this retrospective multi-center analysis, a total of 142861 annotated frames were collected from 403 laparoscopic hemi-hepatectomy videos across 4 centers to build a comprehensive database of surgical video annotations. Each frame was labeled for surgical phase, organs, and instruments. The algorithm in the ISA was retrained using a hybrid deep learning framework integrating instrument tracking, organ segmentation, and phase classification. We then established a scoring system for surgical image recognition and evaluated the algorithm’s recognition accuracy and inter-operator consistency across different surgical teams.ResultsThe upgraded ISA achieved an accuracy of 89% in real-time recognition of instruments and organs. The programmatic phase classification for laparoscopic hemi-hepatectomy reached an average accuracy of 91% (p<0.001), enabling a correct recognition of surgical events. The inter-operator variability in recognition was reduced to 14.3%, highlighting the potential of AI-assisted quality control to standardize intraoperative alerts. Overall, the ISA demonstrated high precision and consistency in phase recognition and operative field evaluation across all phases (accuracy >87%, specificity ~90% in each phase). Notably, critical phases (Phase 1 and Phase 5) were identified with an exceptional accuracy area under the curve (AUC 0.96 in Phase 1; AUC 0.87 in Phase 5), indicating that key surgical procedures could be phased with very low false-alarm rates.ConclusionsThe optimized ISA provides a highly accurate real-time interpretation of surgical phases and a strong potential to standardize surgical procedures, thus guaranteeing the outcomes and safety of laparoscopic hemi-hepatectomy.

Background: Liver failure remains a critical clinical challenge with limited treatment options. Cross-circulation, the establishment of vascular connections between individuals, has historically been explored as a potential supportive therapy but with limited success. This study investigated the feasibility of combining cross-circulation with a rapidly deployable venovenous bypass (VVB) graft for multiorgan support in a rat model of total hepatectomy, representing the most severe form of liver failure. Materials and methods: A Y-shaped VVB graft was fabricated using coaxial electrospinning of PLCL/heparin nanofibers and magnetic rings for rapid anastomosis. After total hepatectomy in rats, the VVB graft was implanted to divert blood flow. Cross-circulation was then established between anhepatic and normal host rats. Hemodynamics, biochemical parameters, blood gases, and survival were analyzed across three groups: hepatectomy with blocked vessels (block group), hepatectomy with VVB only (VVB group), and hepatectomy with VVB and cross-circulation (VVB/cross-circulation group). Results: The VVB graft exhibited suitable mechanical properties and hemocompatibility. VVB rapidly restored hemodynamic stability and mitigated abdominal congestion posthepatectomy. Cross-circulation further ameliorated liver dysfunction, metabolic derangements, and coagulation disorders in anhepatic rats, significantly prolonging survival compared to the VVB group (mean 6.56±0.58 vs. 4.05±0.51 h, P<0.05) and the block group (mean 1.01±0.05 h, P<0.05). Conclusion: Combining cross-circulation with a rapidly deployed VVB graft provided effective multiorgan biosystemic support in a rat model of total hepatectomy, substantially improving the biochemical status and survival time. This approach holds promise for novel liver failure therapies and could facilitate liver transplantation procedures.

Background: radiation-induced skin injury (RISI) is a common complication of radiotherapy, affecting 85-95% of patients. Current treatments lack sufficient evidence of efficacy. Acellular dermal matrix (ADM) hydrogels have shown promise in treating chronic wounds, burns, and ulcers, but their potential in RISI remains unexplored. Methods: ADM hydrogels were prepared from porcine dermis and characterized using histological staining, scanning electron microscopy (SEM), and rheological assessments. A rat model of RISI was established, and the therapeutic effects of the ADM hydrogel were evaluated by gross observation, histological analysis, and immunofluorescence staining. Oxidative stress, angiogenesis, apoptosis, macrophage infiltration, and inflammatory responses were also assessed. Results: ADM hydrogel treatment significantly reduced wound area, radiation injury scores, and apoptosis while increasing epithelial thickness and hair follicle regeneration compared to the control group. The hydrogel promoted angiogenesis, vascular maturation, and M2 macrophage polarization. It also decreased the expression of pro-inflammatory cytokines (IL-1 beta and IL-6) and increased the expression of the anti-inflammatory cytokine IL-10. No significant differences in antioxidant effects were observed between the groups. Conclusion: The ADM hydrogel effectively promotes the healing of RISI in a rat model by modulating the inflammatory microenvironment and enhancing angiogenesis. These findings suggest that the ADM hydrogel could serve as a promising novel biomaterial for the management of RISI. Using a novel rat model of RISI, the research demonstrates that ADM hydrogel effectively reduces wound area and severity, increases epithelial thickness, and accelerates healing compared to controls.

Objective The right upper transversal hepatectomy (RUTH) is considered a complex technique of parenchymal-sparing hepatectomies. The intraoperative management of the right hepatic vein (RHV) is still controversial because it may cause obstruction of outflow in the remnant hepatic segment. The aim of this study is to present our experience of laparoscopic RUTH and the strategy of RHV resection and reconstruction in different settings. Methods Five patients who underwent laparoscopic RUTH for liver tumor were enrolled retrospectively. Clinical and pathological features of the patients, peri-operative treatment, as well as short- and long-term outcomes were collected for analysis. Results Laparoscopic RUTH was successfully performed in all five patients. Two individuals underwent RUTH while preserving RHV. Among the remaining patients who underwent RUTH with RHV resection, one patient underwent RHV reconstruction but the others did not. Immediate or long-term venous related complications did not occurred in a median follow-up period of nine months. Conclusions Laparoscopic RUTH surgery for tumors in the right upper region of the liver is safe and feasible. The strategic workflow we proposed for the resection and reconstruction of the RHV offers a reliable method for preserving liver parenchyma and reducing the risk of postoperative liver failure.

OBJECTIVES:The objective of the current study was to characterize prognostic factors related to long-term recurrence-free survival after curative-intent resection of intrahepatic cholangiocarcinoma (ICC). METHODS:Data on patients who underwent curative-intent resection for ICC between 2000 and 2020 were collected from an international multi-institutional database. Prognostic factors were investigated among patients who recurred within 5 years versus long-term survivors who survived more than 5 years with no recurrence. RESULTS:Among 635 patients who underwent curative-intent resection for ICC, 104 (16.4%) patients were long-term survivors with no recurrence beyond 5 years after surgery. Patients who survived for more than 5 years with no recurrence were more likely to have less aggressive tumor features, as well as have undergone an R0 resection versus patients who recurred within 5 years after resection. On multivariable analysis, tumor size (>5 cm) (HR: 1.535, 95% CI: 1.254-1.879), satellite lesions (HR: 1.253, 95% CI: 1.003-1.564), and lymph node metastasis (HR: 1.733, 95% CI: 1.349-2.227) were independently associated with recurrence within 5 years. Patients who recurred beyond 5 years (n = 23), 2-5 years (n = 60), and within 2 years (n = 471) had an incrementally worse post-recurrence survival (PRS, 28.0 vs. 20.0 vs. 12.0 months, p = 0.032). Among patients with N0 status, tumor size (>5 cm) (HR: 1.612, 95% CI: 1.087-2.390) and perineural invasion (PNI) (HR: 1.562,95% CI: 1.081-2.255) were risk factors associated with recurrence. Among patients with N1 disease, only a minority (5/128, 3.9%) of patients survived with no recurrence to 5 years. CONCLUSION:Roughly 1 in 6 patients survived for more than 5 years with no recurrence following curative-intent resection of ICC. Among N0 patients, tumor recurrence was associated with tumor size and PNI. Only a small subset of N1 patients experienced long-term survival.

Background: Small-diameter (<6 mm) artificial vascular grafts (AVGs) are urgently required in vessel reconstructive surgery but constrained by suboptimal hemocompatibility and the complexity of anastomotic procedures. This study introduces coaxial electrospinning and magnetic anastomosis techniques to improve graft performance.Methods: Bilayer poly(lactide-co-caprolactone) (PLCL) grafts were fabricated by coaxial electrospinning to encapsulate heparin in the inner layer for anticoagulation. Magnetic rings were embedded at both ends of the nanofiber conduit to construct a magnetic anastomosis small-diameter AVG. Material properties were characterized by micromorphology, fourier transform infrared (FTIR) spectra, mechanical tests, in vitro heparin release and hemocompatibility. In vivo performance was evaluated in a rabbit model of inferior vena cava replacement.Results: Coaxial electrospinning produced PLCL/heparin grafts with sustained heparin release, lower platelet adhesion, prolonged clotting times, higher Young’s modulus and tensile strength versus PLCL grafts. Magnetic anastomosis was significantly faster than suturing (3.65 ± 0.83 vs. 20.32 ± 3.45 min, p < 0.001) and with higher success rate (100% vs. 80%). Furthermore, magnetic AVG had higher short-term patency (2 days: 100% vs. 60%; 7 days: 40% vs. 0%) but similar long-term occlusion as sutured grafts.Conclusion: Coaxial electrospinning improved hemocompatibility and magnetic anastomosis enhanced implantability of small-diameter AVG. Short-term patency was excellent, but further optimization of anticoagulation is needed for long-term patency. This combinatorial approach holds promise for vascular graft engineering.

BACKGROUND:This study aimed to assess the global, regional, and national burden of liver cirrhosis and other chronic liver diseases between 1990 and 2019, considering five etiologies (hepatitis B, hepatitis C, alcohol use, NAFLD and other causes), age, gender, and sociodemographic index (SDI).METHODS:Data on liver cirrhosis and other chronic liver diseases mortality, incidence, and disability-adjusted life years (DALYs) were collected from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2019.RESULTS:In 2019, liver cirrhosis and other chronic liver diseases accounted for 1,472,011 (95% UI 1,374,608-1,578,731) deaths worldwide, compared to 1,012,975 (948,941-1,073,877) deaths in 1990. Despite an increase in absolute deaths, the age-standardized death rate declined from 24.43 (22.93-25.73) per 100,000 population in 1990 to 18.00 (19.31-16.80) per 100,000 population in 2019. Eastern sub-Saharan Africa exhibited the highest age-standardized death rate (44.15 [38.47-51.91] per 100,000 population), while Australasia had the lowest rate (5.48 [5.05-5.93] deaths per 100,000 population in 2019). The age-standardized incidence rate of liver cirrhosis and other chronic liver diseases attributed to hepatitis B virus has declined since 1990, but incidence rates for other etiologies have increased. Age-standardized death and DALYs rates progressively decreased with higher SDI across different GBD regions and countries. Mortality due to liver cirrhosis and other chronic liver diseases increased with age in 2019, and the death rate among males was estimated 1.51 times higher than that among females globally.CONCLUSION:Liver cirrhosis and other chronic liver diseases continues to pose a significant global public health challenge. Effective disease control, prevention, and treatment strategies should account for variations in risk factors, age, gender, and regional disparities.

Liver transplantation is the primary treatment for end-stage liver disease. However, the shortage and inadequate quality of donor organs necessitate the development of alternative therapies. Bioartificial livers (BALs) utilizing decellularized liver matrix (DLM) have emerged as promising solutions. However, sourcing suitable DLMs remains challenging. The use of a decellularized spleen matrix (DSM) has been explored as a foundation for BALs, offering a readily available alternative. In this study, rat spleens were harvested and decellularized using a combination of freeze-thaw cycles and perfusion with decellularization reagents. The protocol preserved the microstructures and components of the extracellular matrix (ECM) within the DSM. The complete decellularization process took approximately 11 h, resulting in an intact ECM within the DSM. Histological analysis confirmed the removal of cellular components while retaining the ECM's structure and composition. The presented protocol provides a comprehensive method for obtaining DSM, offering potential applications in liver tissue engineering and cell therapy. These findings contribute to the development of alternative approaches for the treatment of end-stage liver disease.

Background & Aims: Men are more prone to develop and die from liver fibrosis than women. In this study, we aim to investigate how sex -determining region Y gene (SRY) in hepatocytes promotes liver fibrosis. Methods: Hepatocyte-specific Sry knock -in (KI), Sry knockout (KO), and Sry KI with platelet -derived growth factor receptor a ( Pdgfra ) KO mice were generated. Liver fibrosis was induced in mice by bile duct ligation for 2 weeks or carbon tetrachloride treatment for 6 weeks. In addition, primary hepatocytes, hepatic stellate cells (HSCs), and immortalized cell lines were used for in vitro studies and mechanistic investigation. Results: Compared to females, the severity of toxin- or cholestasis-induced liver fibrosis is similarly increased in castrated and uncastrated male mice. Among all Y chromosome -encoded genes, SRY was the most significantly upregulated and consistently increased gene in fibrotic/cirrhotic livers in male patients and in mouse models. Sry KI mice developed exacerbated liver fibrosis, whereas Sry KO mice had alleviated liver fibrosis, compared to age- and sex -matched control mice after bile duct ligation or administration of carbon tetrachloride. Mechanistically, both our in vivo and in vitro studies illustrated that SRY in hepatocytes can transcriptionally regulate Pdgfra expression, and promote HMGB1 (high mobility group box 1) release and subsequent HSC activation. Pdgfra KO or treatment with the SRY inhibitor DAX1 in Sry KI mice abolished SRY-induced HMGB1 secretion and liver fibrosis. Conclusions: SRY is a strong pro -fibrotic factor and accounts for the sex disparity observed in liver fibrosis, suggesting its critical role as a potentially sex -specific therapeutic target for prevention and treatment of the disease. (c) 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

BACKGROUND:The effect of preoperative anemia on clinical outcomes of patients undergoing resection of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has not been previously investigated. This study aimed to characterize how preoperative anemia affected short- and long-term outcomes of patients undergoing curative-intent resection of GEP-NETs. METHODS:Patients who underwent curative-intent resection for GEP-NETs between January 1990 and December 2020 were identified from 8 major institutions. The last preoperative hemoglobin level was recorded; anemia was defined as <13.5 g/dL in males or <12.0 g/dL in females based on the guides of the American Society of Hematology. The effect of anemia on postoperative outcomes was assessed on uni- and multivariate analyses. RESULTS:Among 1559 patients, the median age was 58 years (IQR, 48-66), and roughly one-half of the cohort was male (796 [51.1%]). Most patients had a pancreatic tumor (1040 [66.7%]), followed by small bowel (259 [16.6%]), duodenum (103 [6.6%]), stomach (66 [4.2%]), appendix (53 [3.4%]), and other locations (38 [2.6%]). The median preoperative hemoglobin level was 13.4 g/dL (IQR, 12.2-14.5). Overall, 101 (6.7%) and 119 (8.5%) patients received an intra- or postoperative packed red blood cell (pRBC) transfusion, respectively. A total of 972 patients (44.5%) experienced a postoperative complication. Although the overall incidence of complications was no different among patients who did (anemic: 48.7%) vs patients who did not (nonanemic: 47.3%) have anemia (P = .597), patients with preoperative anemia were more likely to develop a major (Clavien-Dindo grade ≥IIIa: 48.9% [anemic] vs 38.0% [nonanemic]; P = .006) and multiple (≥3 types of complications: 32.2% [anemic] vs 19.7% [anemic]; P < .001) complications. Of note, 1-, 3-, and 5-year overall survival (OS) rates were 96.7%, 90.5%, and 86.6%, respectively. On multivariable analysis, anemia (hazard ratio, 2.0; 95% CI, 1.2-3.2; P = .006) remained associated with worse OS; postoperative pRBC transfusion was associated with an OS (5-year OS: 75.0% vs 87.7%; P = .017) and recurrence-free survival (RFS; 5-year RFS: 66.9% vs 76.5%; P = .047). CONCLUSION:Preoperative anemia was commonly identified in roughly 1 in 3 patients who underwent curative-intent resection for GEP-NETs. Preoperative anemia was strongly associated with a higher risk of postoperative morbidity and worse long-term outcomes.

Background:Some cases of laparoscopic-assisted liver transplantation (LA-LT) with utilization of reduced-size grafts has been reported. The authors here introduced successful utilization of LA-LT with whole liver grafts and magnetic portal vein anastomosis.Methods:Eight patients with liver cirrhosis were included for LA-LT using donor organs after cardiac death. The surgical procedures included purely laparoscopic explant hepatectomy and whole-liver graft implantation via the midline incision. After explant removal, the whole-liver graft was then placed in situ, and a side-to-side cavo-caval anastomosis with 4-5 cm oval opening was performed. The magnetic rings were everted on the donor and recipient portal vein, respectively, and the instant attachment of the two magnets at the donor and recipient portal vein allowed fast blood reperfusion, followed by continuous suturing on the surface of the magnets.Results:The median operation time was 495 (range 420-630). The median time of explant hepatectomy and inferior vena cava anastomosis was 239 (range 150-300) min and 14.5 (range 10-19) min, respectively. Of note, the median anhepatic time was 25 (range 20-35) min. All the patients were discharged home with no major complications after more than 12 months follow-up.Conclusion:LA-LT with full-size graft is feasible and utilization of magnetic anastomosis would further simplify the procedure.

Alcohol use is a major risk factor for the burden of mortality and morbidity. Alcoholic cirrhosis (AC) and alcoholic liver cancer (ALC) are most important and severe liver disease outcomes caused by alcohol use. The objectives of the current study were to investigate the global prevalence and burden of disease in disability-adjusted life years (DALYs) for AC and ALC, based on data from the Global Burden of Disease (GBD). Incidence, prevalence, death, and DALYs for GBDs in different locations, years, sex, and age groups were estimated using DisMod-MR 2.1 and a generic Cause of Death Ensemble Modeling approach. The correlations between the age-standardized incidence rate or age-standardized death rate and gender, sociodemographic index (SDI), and alcohol usage were conducted by Generalized Linear Models. Globally, the changes of age-standardized rates of indicators were not much significant over the 30-year period. However, the changes varied widely across regions. Central Asia and East Europe contributed the highest age-standardized incidence, prevalence, death, and DALYs and increased sharply by past 30 years. Generalized Linear Models (GLMs) showed male gender as a risk factor of AC, with the relative risk of incidence of 1.521 and relative risk of death of 1.503. Globally, there were improvements in overall health with regard to GBDs over the 30 years. However, the prevention of AC and ALC should be promoted in middle and middle-high SDI regions, especially Central Asia and East Europe, whereas more medical resources should be provided to improve treatment levels in low SDI region.

Liver fibrosis is a fibrogenic and inflammatory process that results from hepatocyte injury and is characterized by hepatic architectural distortion and resultant loss of liver function. There is no effective treatment for advanced fibrosis other than liver transplantation, but it is limited by expensive costs, immune rejection, and postoperative complications. With the development of regenerative medicine in recent years, mesenchymal stem cell (MSCs) transplantation has become the most promising treatment for liver fibrosis. The underlying mechanisms of MSC anti-fibrotic effects include hepatocyte differentiation, paracrine, and immunomodulation, with immunomodulation playing a central role. This review discusses the immune cells involved in liver fibrosis, the immunomodulatory properties of MSCs, and the immunomodulation mechanisms of MSC-based strategies to attenuate liver fibrosis. Meanwhile, we discuss the current challenges and future directions as well.

Introduction: To investigate the impact of prognostic nutritional index (PNI) on short- and long-term outcomes of patients who underwent curative-intent resection for gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). Methods: Patients with GET-NETs who underwent curative-intent resection were identified from a multi-center database. The prognostic impact of clinicopathological factors including PNI on post-operative outcomes were evaluated. A novel nomogram was developed and externally validated. Results: A total of 2,099 patients with GEP-NETs were included in the training cohort; 255 patients were in the external validation cohort. Median PNI (n=973) was 47.4 (IQR 43.1-52.4). At the time of presentation, 1,299 (61.9%) patients presented with some type of clinical symptom. Low-PNI (≤ 42.2) was associated with gastrointestinal symptoms, as well as nodal metastasis and distant metastasis (all p<0.05). Patients with a low PNI had a higher incidence of severe (≥ Clavien-Dindo grade IIIa: low PNI 24.9% vs. high PNI 15.4%, p=0.001) and multiple (≥ 3 types of complications: low PNI 14.5% vs. high PNI 9.2%, p=0.024) complications, as well as a worse overall survival (OS)(5-year OS, low PNI 73.7% vs. high PNI 88.5%, p<0.001), and RFS (5-year RFS, low PNI 68.5% vs. high PNI 79.8%, p=0.008) versus patients with high PNI (>42.2). A nomogram based on PNI, tumor grade and metastatic disease demonstrated excellent discrimination and calibration to predict OS in both the training (C-index 0.748) and two external validation (C-index 0.827, 0.745) cohorts. Conclusions: Low PNI was common and associated with worse short- and long-term outcomes among patients with GEP-NETs.