Background: Posttransplant lymphoproliferative disorders (PTLDs) are a unique set of complications following solid organ and hematopoietic stem cell transplantation, predominantly originating from CD20 + B-cells. In pediatric recipients, the long-term prognosis warrants particular consideration. Methods: To enhance our understanding of PTLD in a large cohort, we performed a retrospective analysis of 2032 pediatric recipients who underwent liver transplantation (LT) between 2006 and 2019. Results: Among the 2032 individuals, 84 (4.13%) were diagnosed with PTLD. The cumulative incidence rates were 5.9% at 5 years and 7.7% at 10 years posttransplant. The median time to PTLD onset was 15.7 (4.9–24.3) months, with the majority (78.6%) of patients developing PTLD between 3 and 18 months post-LT. Notably, the peak occurrence of pediatric PTLD cases were observed between 3 and 6 months after transplantation. In a multivariable cox regression analysis, Epstein–Barr virus infection (hazard ratio [HR]: 9.4559; 95% confidence interval [CI]: 4.612–22.818; P < 0.001) and immunosuppression with tacrolimus (HR: 6.2101; 95% CI: 1.4715–31.3545; P = 0.0151) were identified as significant risk factors. The long-term graft survival rate for PTLD patients was 85.5%. Conclusions: PTLD is a significant concern for pediatric transplant recipients, potentially affecting their quality of life. Our study highlights the necessity for enhanced prevention strategies and prompts detection, particularly during periods of elevated incidence.

Liver ischemia-reperfusion injury (IRI) drives graft dysfunction and postsurgical morbidity. We show that hepatocellular MST1 is markedly upregulated in IRI and exacerbates damage by blocking PINK1-dependent mitophagy. Defective mitochondrial clearance causes mtDNA leakage, which activates macrophage cGAS-STING signaling and fuels inflammatory injury. Curcumin inhibits this MST1-PINK1 axis, restoring mitophagy and limiting mtDNA release. To translate these insights, we engineered Curcumin@EV@Se-stem-cell-derived extracellular vesicles surface-modified with diselenide-PEG for ROS-responsive, "stealth" delivery. In oxygen-glucose deprivation/reoxygenation models, Curcumin@EV@Se improved hepatocyte viability, preserved mitochondrial potential, reduced ROS and inflammatory cytokines, and promoted reparative/angiogenic programs. In a murine hepatic IRI model, systemic Curcumin@EV@Se decreased necrosis and TUNEL positivity and improved serum transaminases and histology, indicating enhanced liver function and regeneration. These data identify MST1-mediated mitophagy blockade with secondary cGAS-STING activation as a central pathogenic axis in IRI and present Curcumin@EV@Se as a mechanism-guided therapy that restores mitochondrial quality control and dampens innate immune activation, with translational promise for liver transplantation and acute hepatic injury.

Liver transplantation is a highly effective treatment for end-stage liver disease; however, long-term immunosuppression leads to various adverse effects. Thus, operational tolerance has gained attention. Pediatric liver transplant recipients show a greater likelihood of attaining operational tolerance compared to adults in a previous study, serving as an ideal model for exploring immune reconstitution and tolerance. Here, we used single-cell transcriptomics to monitor immune reconstitution in pediatric recipients initially treated with tacrolimus and later withdrawn to identify tolerance. Our data revealed that comprehensive immune reconstitution occurs after pediatric liver transplantation, including the activation of CD4+ T cells, NK cells and B cells, and a marked inflammatory signature in myeloid cells, demonstrating that liver-infiltrating immune cells maintain long-term activation phenotypes. Intriguingly, recipients with failed tacrolimus withdrawal exhibited higher proinflammatory status in myeloid cells and increased cytotoxicity in FGFBP2high CD8 T cells, compared to those with successful withdrawals. More importantly, we revealed that FGFBP2high CD8 T cells enriched in the transplanted liver after tacrolimus withdrawal potentially interacted with HSCs via TGFB1-TGFBR2 pathways. Concurrently, HSCs underwent an activation, indicating a risk of liver fibrotic progression, even among patients who had attained operational tolerance. Hence, our findings illuminate a dynamic immune reconstitution landscape occurring within transplanted livers, offering valuable insights into operational tolerance associated with pediatric liver transplantation.

BACKGROUND:Patients with acute-on-chronic liver failure (ACLF) are susceptible to fungal infections. However, pretransplant invasive pulmonary Aspergillosis (IPA) is generally considered a relative contraindication for liver transplantation (LT). METHODS:We conducted a multi-center retrospective study involving ACLF adult patients with pretransplant IPA who underwent LT at four hospitals between January 2021, and June 2024. For comparative analysis, we included a control group of ACLF patients without preoperative Aspergillus infection during the same period, from the Renji Hospital cohort with matching approach. Posttransplant outcomes were then evaluated and compared between the two groups (ACLF patients with IPA vs. those without IPA). RESULTS:A total of 21 patients who had IPA before LT was identified. The mean age was 46.7 ± 9.2 years. The mean MELD score of these patients was 28.6. Most (71.4%, 15/21) patients received antifungal therapy immediately after the diagnosis of IPA. Twelve patients received voriconazole, one received isavuconazole, one received posaconazole, one received amphotericin B plus caspofungin and isavuconazole, the remaining six patients did not receive any antifungal drugs before LT. The median duration of antifungal therapy was 9 days (range: 0.5-34.5 days) before transplantation, overall median duration of antifungal treatment was 58 days (range: 22-83). The 3-month (38.1%, 8/21) and 12-month mortality (42.9%, 9/21) were significantly higher than patients without pretransplant IPA (p = 0.049 and p = 0.026, respectively). CONCLUSIONS:The survival of LT for ACLF patients with pretransplant IPA was suboptimal, although they had received appropriate antifungal treatment within the peri-transplantation period. Multidisciplinary discussions before transplantation are necessary on case-by-case.

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.

ObjectiveHB is the most common liver malignancy in children. Giving the rarity of the research reporting outcomes of LT for HB in China, updated long-term data are needed. The primary objective was to evaluate the outcomes of liver transplantation in HB. The secondary objective was to assess the clinical parameters that influence the outcomes of liver transplantation in HB.MethodsWe retrospectively analyzed the dataset of a single-center cohort from RJ-SJTUM. Outcomes were OS and PFS. Cox proportional hazard models were used to estimate mortality adjusted HRs with 95% CIs.ResultsRJ-SJTUM has accounted for 68.5% of the total cases in China since 2019. The 5-year PFS and OS rates were 63.6% and 84.6% respectively. AFP ≥13,686.5 ng/ml before LT was an independent risk factor for PFS (P < 0.001), and distal metastasis before LT was an independent risk factor for OS (P = 0.028). All patients received post-LT chemotherapy, and two patients experienced severe liver injury. Patients with localized tumor recurrence after LT had favorable outcomes if radical resection of the recurrence was achieved. Sirolimus played a role in prolonging the survival of patients with recurrent HB after LT (P = 0.0307).ConclusionLT achieved favorable outcomes for patients with locally advanced hepatoblastoma. This study suggests that a judicious patient selection to exclude patients with high-risk predictors, as well as standardized postoperative management is critical in this process.

Background:Lymph node status is a prominent prognostic factor for intrahepatic cholangiocarcinoma (ICC). However, the prognostic value of performing lymph node dissection (LND) in patients with clinical node-negative ICC remains controversial. The aim of this study was to evaluate the clinical value of LND on long-term outcomes in this subgroup of patients. Methods:We retrospectively analyzed patients who underwent radical liver resection for clinically node-negative ICC from three tertiary hepatobiliary centers. The propensity score matching analysis at 1:1 ratio based on clinicopathological data was conducted between patients with and without LND. Recurrence-free survival (RFS) and overall survival (OS) were compared in the matched cohort. Results:Among 303 patients who underwent radical liver resection for ICC, 48 patients with clinically positive nodes were excluded, and a total of 159 clinically node-negative ICC patients were finally eligible for the study, with 102 in the LND group and 57 in the non-LND group. After propensity score matching, two well-balanced groups of 51 patients each were analyzed. No significant difference of median RFS (12.0 vs. 10.0 months, P = 0.37) and median OS (22.0 vs. 26.0 months, P = 0.47) was observed between the LND and non-LND group. Also, LND was not identified as one of the independent risks for survival. Among 51 patients who received LND, 11 patients were with positive lymph nodes (lymph node metastasis (LNM) (+)) and presented significantly worse outcomes than those with LND (-). On the other hand, postoperative adjuvant therapy was the independent risk factor for both RFS (hazard ratio (HR): 0.623, 95% confidence interval (CI): 0.393 - 0.987, P = 0.044) and OS (HR: 0.585, 95% CI: 0.359 - 0.952, P = 0.031). Furthermore, postoperative adjuvant therapy was associated with prolonged survivals of non-LND patients (P = 0.02 for RFS and P = 0.03 for OS). Conclusions:Based on the data, we found that LND did not significantly improve the prognosis of patients with clinically node-negative ICC. Postoperative adjuvant therapy was associated with prolonged survival of ICC patients, especially in non-LND individuals.

Objectives Homozygous familial hypercholesterolemia (HoFH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and early-onset cardiovascular disease. To assess the therapeutic effects of liver transplantation (LT) on HoFH patients, we observed and analyzed the outcomes of HoFH children after LT. Study design This prospective cohort study included all LT candidates under 18 years old diagnosed with HoFH at Ren Ji Hospital between November 2017 and July 2021. The patients were followed until October 2023. They were treated according to the standard protocol at our center. We collected data on changes in lipid profiles, clinical manifestations, and cardiovascular complications at different time points, and recorded postoperative recipient and graft survival. Results Fourteen HoFH patients with a median age of 7 (2-12) years were included. Preoperatively, xanthomas and arcus corneas occurred in 14 and 3 patients, respectively, with 10 patients showing mild cardiovascular disease. All patients underwent LT. Recipient and graft survival rates were 100% over a median follow-up duration of 35 (27-71) months. Median LDL-C levels dropped from 11.83 (7.99-26.14) mmol/L preoperatively to 2.3 (1.49-3.39) mmol/L postoperative at the last measurement. Thirteen patients discontinued lipid-lowering treatment after LT, while only one patient resumed statins 6 months post-operation. Xanthomas and arcus corneas significantly improved. Cardiovascular complications regressed in five patients, with no progression observed in the others. Conclusions LT is a safe and effective treatment for severe HoFH patients beyond lipid-lowering control. Early LT improves prognosis and quality of life while minimizing the risk of cardiovascular complications.

Early allograft dysfunction (EAD) is a frequent phenomenon, leading to increased graft loss and higher mortality after liver transplantation (LT). Despite significant efforts for early diagnosis of EAD, there is no existing approach that can predict EAD on the first post-operative day. The aim is to define a metabolite-based biomarker on the first day after LT complicated with EAD. Ten patients diagnosed with EAD and 26 non-EAD are recruited for the study. A HPLC-MS/MS is used to determine 14 amino acids and 15 bile acids serum concentration. Comparative analyses are conducted between EAD and non-EAD groups. Arginine is identified as the most significant metabolite distinguishing the EAD and non-EAD groups, and therefore, is identified as a potential biomarker of EAD. The optimal cut-off value for arginine is 52.09 µmol L-1, with an AUROC of 0.804 (95% confidence interval: 0.638-0.917, p < 0.001), yielding a sensitivity of 100%, specificity of 53.8%, and Youden index of 0.54, NPVof 100%, and PPV of 45.45%. In summary, the study indicated that targeted metabolomics analysis would be a promising strategy for discovering novel biomarkers to predict EAD. The identified arginine may be helpful in developing an objective diagnostic method for EAD.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated death globally. Liver transplantation (LT) has emerged as a key treatment for patients with HCC, and the Milan criteria have been adopted as the cornerstone of the selection policy. To allow more patients to benefit from LT, a number of expanded criteria have been proposed, many of which use radiologic morphological characteristics with larger and more tumors as surrogates to predict outcomes. Other groups developed indices incorporating biological variables and dynamic markers of response to locoregional treatment. These expanded selection criteria achieved satisfactory results with limited liver supplies. In addition, a number of prognostic models have been developed using clinicopathological characteristics, imaging radiomics features, genetic data, and advanced techniques such as artificial intelligence. These models could improve prognostic estimation, establish surveillance strategies, and bolster long-term outcomes in patients with HCC. In this study, we reviewed the latest findings and achievements regarding the selection criteria and post-transplant prognostic models for LT in patients with HCC.

Background: The optimal timing to discontinue immune checkpoint inhibitor (ICI) therapy in hepatocellular carcinoma (HCC) patients with clinical benefits remains unclear. This study aimed to assess the outcomes of HCC patients after ICI discontinuation. Methods: Patients with HCC were retrospectively screened and those discontinued ICI therapy in the absence of progressive disease (PD) were included. Responses at discontinuation were evaluated per response evaluation criteria in solid tumors (RECIST) version 1.1 and modified RECIST (mRECIST). Patients were classified into five subgroups according to the cause of discontinuation: complete response (CR), partial response (PR), stable disease (SD) per RESICT version 1.1, adverse event (AE), or others. Progression-free survival (PFS) and overall survival (OS) since ICI start or after ICI discontinuation were assessed. Results: A total of 66 patients were included. The median follow-up was 29.33 months. The median PFS since ICI start was 30.83 months [95% confidence interval (CI): 24.93-36.72], and the median OS was not reached. The median PFS after discontinuation was 20.6 months (95% CI: 7.63-33.56), and the median OS after discontinuation was not reached. Univariate analysis showed that age, treatment after discontinuation, Response (RECIST version 1.1) at discontinuation and modified response (mResponse per mRECIST) at discontinuation were significantly associated with PFS after discontinuation, while age and mResponse at discontinuation were significantly associated with OS after discontinuation. Multivariate analysis further demonstrated that mResponse at discontinuation and treatment after discontinuation were independently associated with PFS after discontinuation, while age was independently associated with OS after discontinuation. Conclusions: ICIs might be discontinued in HCC patients with a response of CR per mRECIST. Patients with a response of PR/SD per mRECIST or elder age could continue ICI therapy after achieving clinical benefits. Tyrosine kinase inhibitor (TKI) maintenance therapy might help to prevent progression after ICI discontinuation.

Abstract Background The Omicron variant BA.2 was the dominant variant in the COVID-19 outbreak in Shanghai since March 2022. We aim to investigate the characteristics of SARS-CoV-2 Omicron variant infection in pediatric liver-transplanted recipients. Methods We conducted a single-center, prospective, observational, single-arm study. We enrolled pediatric liver-transplanted patients infected with the Omicron variant BA.2 from March 19th to October 1st, 2022 and analyzed their demographic, clinical, laboratory, and outcome data. The management of COVID-19 was conducted according to the 9th trial edition of the Chinese guideline. The immunosuppressive therapy was tailored considering the patients’ infection developments and liver functions. Results Five children were included. The primary diseases included Niemann-Pick disease, propionic acidemia, decompensated cirrhosis, biliary atresia, and Crigler-Najjar syndrome type I. All of the patients were onset with fever before or when getting RNA-positive results at the age of 3 (Range: 1–13) years. The infection duration was 29 (Range: 18–40) days. Three and two children were diagnosed with mild and moderate COVID-19 respectively. Two patients were tested RNA-positive within 14 days after having been tested negative. The immunosuppressants were paused or extenuated in four patients. Eight of all nine cohabitants were injected with at least two doses of inactivated SARS-CoV-2 vaccine. The disease courses were significantly longer than the patients (P < 0.05). Conclusions Post-transplant immunosuppression slows down the virus clearance and increases the risk of relapse but does not affect symptom duration or infection severity in pediatric patients. Patients can usually gain a favorable outcome and prognosis by extenuating immunosuppressants.

Background:Tacrolimus (TAC) is the preferred calcineurin inhibitor (CNI) for pediatric liver transplant recipients. However, some recipients may not achieve the desired therapeutic window concentration of TAC, leading to poor prognosis. This study aimed to develop a clinical model that can predict the effectiveness of TAC in pediatric liver transplant recipients and help clinicians quickly identify cyclosporin as an alternative.Methods:We retrospectively analyzed data from 2,032 pediatric liver transplant recipients who underwent surgery at Renji Hospital, Shanghai Jiaotong University School of Medicine between 2006 and 2019. Demographic, comorbidity and pre-operative laboratory data were collected, and a nomogram was constructed using multivariate logistic regression analysis to estimate the risk of poor therapeutic outcomes for TAC-based immunosuppression.Results:The constructed nomogram included seven parameters, namely recipient CYP3A4 genotype, pre-transplant cholangitis, GRWR, spleen long diameter, serum albumin, graft volume reduction, and donor CYP genotype. The nomogram showed good discriminative ability with an area under the receiver operating characteristic curve (AUC) of 74.5% and good calibration. Decision curve analysis indicated a high potential clinical application of the model.Conclusion:This simple clinical model effectively predicts the risk of poor therapeutic outcomes in pediatric liver transplant recipients who receive TAC-based immunosuppression. Clinicians can use the model to identify cyclosporin as an alternative quickly, potentially improving patient prognosis.

Abstract Background Kasai portoenterostomy (KPE) is widely accepted for biliary atresia (BA) when diagnosed timely. However, the outcomes for many patients were not satisfactory and required liver transplantation (LT) subsequently. The aim of our study was to determine whether KPE could improve the post-transplant outcomes of BA children. Methods In this retrospective cohort study from 2006 to 2019, 1647 BA children were included and divided into two cohorts: those who underwent primary liver transplantation (pLT) (n = 599) and those who received KPE followed by LT (n = 1048). Propensity score matching (PSM) was conducted in a 1:1 ratio to balance basic characteristics and minimize the selection bias. Results Of 954 recipients after PSM, pLT group (n = 477) showed poor survival rate than KPE + LT group (n = 477) (p < 0.001), with 1-year survival rate of 87.2% and 94.7%, 5-year survival rate of 82.4% and 91.9% respectively. 59.2% of deaths happened within post-operative day 90, especially the first month (41.7%) after LT. pLT group had a significant higher mortality rate than KPE + LT group (15.5% vs 6.1%, p < 0.001). Pulmonary infection and post-LT liver failure were leading causes of death in pLT group compared with KPE + LT group. Conclusions KPE could improve the post-transplant survival for BA children. If diagnosed within 3 months, it is advisable to try KPE before considering LT for BA children.