Liver transplantation as an alternative for the treatment of intrahepatic cholangiocarcinoma: Past, present, and future directions

Intrahepatic cholangiocarcinoma(iCCA)is a rare biliary tract cancer with high mortality rate.Complete resection of the iCCA lesion is the first choice of treatment,with good prognosis after margin-negative resection.Unfortunately,only 12%-40% of patients are eligible for resection at presentation due to cirrhosis,portal hypertension,or large tumor size.Liver transplantation(LT)offers margin-negative iCCA extirpation for patients with unresectable tumors.Initially,iCCA was a contraindication for LT until size-based selection criteria were introduced to identify patients with satisfied post-LT outcomes.Recent studies have shown that tumor biology-based selection can yield high post-LT survival in patients with locally advanced iCCA.Another selection criterion is the tumor response to neoadjuvant therapy.Patients with response to neoadjuvant therapy have better outcomes after LT compared with those without tumor response to neoadjuvant therapy.Another index that helps predict the treatment outcome is the biomarker.Improved survival outcomes have also opened the door for living donor LT for iCCA.Patients undergoing LT for iCCA now have statistically similar survival rates as patients undergoing resection.The combination of surgery and locoregional and systemic therapies improves the prognosis of iCCA patients.

Liver transplantation as an alternative for the treatment of non-resectable liver colorectal cancer: Advancing the therapeutic algorithm

Colorectal cancer is a leading cause of cancerrelated mortality,with nearly half of the affected patients developing liver metastases.For three decades,liver resection(LR)has been the primary curative strategy,yet its applicability is limited to about 20%of cases.Liver transplantation(LT)for unresectable metastases was attempted unsuccessfully in the 1990s,with high rates of perioperative death and recurrence.There is now more interest in this strategy due to improvements in systemic therapies and surgical techniques.A significant study conducted by the Oslo group showed that patients receiving liver transplants had a 60%chance of survival after five years.Significantly better results have been achieved by using advanced imaging for risk stratification and further refining selection criteria,especially in the Norvegian SECA trials.This review carefully charts the development and history of LT as a treatment option for colorectal cancer liver metastases.The revolutionary path from the early days of exploratory surgery to the current situation of cautious optimism is traced,highlighting the critical clinical developments and improved patient selection standards that have made LT a potentially curative treatment for such challenging very well selected cases.

Liver transplantation and resection in patients with hepatocellular cancer and portal vein tumor thrombosis: Feasible and effective?

Patients with locally advanced hepatocellular cancer(HCC)and portal vein tumor thrombosis(PVTT)have a dismal prognosis since limited treatment options are available for them.In recent years,effective systemic therapy,and advances in the understanding of technicalities and effectiveness of ablative therapies especially radiotherapy,have given some hope to prolong survival in them.This review summarized recent evidence in literature regarding the possible role of liver resection(LR)and liver transplantation(LT)in patients with locally advanced HCC and PVTT with no extrahepatic disease.Downstaging therapies have helped make curative resection or LT a reality in selected patients.This review emphasizes on the key points to focus on when considering surgery in these patients,who are usually relegated to palliative systemic therapy alone.Meticulous patient selection based on tumor biology,documented downstaging based on imaging and decrease in tumor marker levels,and an adequate waiting period to demonstrate stable disease,may help obtain satisfactory long-term outcomes post LR or LT in an intention to treat strategy in patients with HCC and PVTT.

Liver transplantation as an alternative for the treatment of neuroendocrine liver metastasis: Appraisal of the current evidence

Background:Liver transplantation(LT)for neuroendocrine liver metastases(NELM)is still in debate.Studies comparing LT with liver resection(LR)for NELM are scarce,as patient selection is heterogeneous and experience is limited.The goal of this review was to provide a critical analysis of the evidence on LT versus LR in the treatment of NELM.Data sources:A scoping literature search on LT and LR for NELM was performed with PubMed,including English articles up to March 2023.Results:International guidelines recommend LR for NELM in resectable,well-differentiated tumors in the absence of extrahepatic metastatic disease with superior results of LR compared to systemic or liver-directed therapies.Advanced liver surgery has extended resectability criteria whilst entailing increased perioperative risk and short disease-free survival.In highly selected patients(based on the Milan criteria)with unresectable NELM,oncologic results of LT are promising.Prognostic factors include tumor biology(G1/G2)and burden,waiting time for LT,patient age and extrahepatic spread.Based on low-level evi-dence,LT for low-grade NELM within the Milan criteria resulted in improved disease-free survival and overall survival compared to LR.The benefits of LT were lost in patients beyond the Milan NELM-criteria.Conclusions:With adherence to strict selection criteria especially tumor biology,LT for NELM is becoming a valuable option providing oncologic benefits compared to LR.Recent evidence suggests even stricter selection criteria with regard to tumor biology.

Liver transplantation as an alternative for the treatment of perihilar cholangiocarcinoma: A critical review

Background:Perihilar cholangiocarcinoma(phCCC)is a dismal malignancy.There is no consensus regard-ing the best treatment for patients with unresectable phCCC.The present review aimed to gather the current pieces of evidence for liver transplantation and liver resection as a treatment for phCCC and to build better guidance for clinical practice.Data sources:The search was conducted in PubMed,Embase,Cochrane,and LILACS.The related references were searched manually.Inclusion criteria were:reports in English or Portuguese literature that a)patients with confirmed diagnosis of phCCC;b)patients treated with a curative intent;c)patients with the outcomes of liver resection and liver transplantation.Case reports,reviews,letters,editorials,conference abstracts and papers with full-text unavailability were excluded from the analysis.Results:Most of the current literature is based on observational retrospective studies with low grades of evidence.Liver resection has better long-term outcomes than systemic chemotherapy or palliation ther-apy and liver transplantation is a good alternative for selected patients with unresectable phCCC.All candidates for resection or transplantation should be medically fit and free of intrahepatic or extrahep-atic diseases.As a general rule,patients presenting with a tumor having a longitudinal size>3 cm or extending below the cystic duct,lymph node disease,confirmed extrahepatic dissemination;intraoper-atively diagnosed metastatic disease;a history of other malignancies within the last five years,and did not complete chemoradiation regimen and were medically unfit should not be considered for transplan-tation.Some of these criteria should be individually assessed.Liver transplantation or resection should only be considered in highly experienced hepatobiliary centers,and any decision-making must be based on a multidisciplinary evaluation.Conclusions:phCCC is a complex condition with high morbidity.Surgical therapies,including hepatec-tomy and liver transplantation,are the best option for better long-term disease-free survival.

Validation and performance of three scoring systems for predicting primary non-function and early allograft failure after liver transplantation

Background: Primary non-function(PNF) and early allograft failure(EAF) after liver transplantation(LT) seriously affect patient outcomes. In clinical practice, effective prognostic tools for early identifying recipients at high risk of PNF and EAF were urgently needed. Recently, the Model for Early Allograft Function(MEAF), PNF score by King's College(King-PNF) and Balance-and-Risk-Lactate(BAR-Lac) score were developed to assess the risks of PNF and EAF. This study aimed to externally validate and compare the prognostic performance of these three scores for predicting PNF and EAF. Methods: A retrospective study included 720 patients with primary LT between January 2015 and December 2020. MEAF, King-PNF and BAR-Lac scores were compared using receiver operating characteristic(ROC) and the net reclassification improvement(NRI) and integrated discrimination improvement(IDI) analyses. Results: Of all 720 patients, 28(3.9%) developed PNF and 67(9.3%) developed EAF in 3 months. The overall early allograft dysfunction(EAD) rate was 39.0%. The 3-month patient mortality was 8.6% while 1-year graft-failure-free survival was 89.2%. The median MEAF, King-PNF and BAR-Lac scores were 5.0(3.5–6.3),-2.1(-2.6 to-1.2), and 5.0(2.0–11.0), respectively. For predicting PNF, MEAF and King-PNF scores had excellent area under curves(AUCs) of 0.872 and 0.891, superior to BAR-Lac(AUC = 0.830). The NRI and IDI analyses confirmed that King-PNF score had the best performance in predicting PNF while MEAF served as a better predictor of EAD. The EAF risk curve and 1-year graft-failure-free survival curve showed that King-PNF was superior to MEAF and BAR-Lac scores for stratifying the risk of EAF. Conclusions: MEAF, King-PNF and BAR-Lac were validated as practical and effective risk assessment tools of PNF. King-PNF score outperformed MEAF and BAR-Lac in predicting PNF and EAF within 6 months. BAR-Lac score had a huge advantage in the prediction for PNF without post-transplant variables. Proper use of these scores will help early identify PNF, standardize grading of EAF and reasonably select clinical endpoints in relative studies.

HSP110 aggravates ischemia-reperfusion injury after liver transplantation by promoting NF-κB pathway

Background:Ischemia-reperfusion injury(IRI)poses a significant challenge to liver transplantation(LT).The underlying mechanism primarily involves overactivation of the immune system.Heat shock protein 110(HSP110)functions as a molecular chaperone that helps stabilize protein structures.Methods:An IRI model was established by performing LT on Sprague-Dawley rats,and HSP110 was silenced using siRNA.Hematoxylin-eosin staining,TUNEL,immunohistochemistry,ELISA and liver enzyme analysis were performed to assess IRI following LT.Western blotting and quantitative reverse transcription-polymerase chain reaction were conducted to investigate the pertinent molecular changes.Results:Our findings revealed a significant increase in the expression of HSP110 at both the mRNA and protein levels in the rat liver following LT(P<0.05).However,when rats were injected with siRNAHSP110,IRI subsequent to LT was notably reduced(P<0.05).Additionally,the levels of liver enzymes and inflammatory chemokines in rat serum were significantly reduced(P<0.05).Silencing HSP110 with siRNA resulted in a marked decrease in M1-type polarization of Kupffer cells in the liver and downregulated the NF-κB pathway in the liver(P<0.05).Conclusions:HSP110 in the liver promotes IRI after LT in rats by activating the NF-κB pathway and inducing M1-type polarization of Kupffer cells.Targeting HSP110 to prevent IRI after LT may represent a promising new approach for the treatment of LT-associated IRI.

Fecal microbiota transplantation for treatment of non-alcoholic fatty liver disease:Mechanism,clinical evidence,and prospect

The population of non-alcoholic fatty liver disease(NAFLD)patients along with relevant advanced liver disease is projected to continue growing,because currently no medications are approved for treatment.Fecal microbiota transplantation(FMT)is believed a novel and promising therapeutic approach based on the concept of the gut-liver axis in liver disease.There has been an increase in the number of pre-clinical and clinical studies evaluating FMT in NAFLD treatment,however,existing findings diverge on its effects.Herein,we briefly summarized the mechanism of FMT for NAFLD treatment,reviewed randomized controlled trials for evaluating its efficacy in NAFLD,and proposed the prospect of future trials on FMT.

Use of machine learning models for the prognostication of liver transplantation: A systematic review

BACKGROUND Liver transplantation(LT)is a life-saving intervention for patients with end-stage liver disease.However,the equitable allocation of scarce donor organs remains a formidable challenge.Prognostic tools are pivotal in identifying the most suitable transplant candidates.Traditionally,scoring systems like the model for end-stage liver disease have been instrumental in this process.Nevertheless,the landscape of prognostication is undergoing a transformation with the integration of machine learning(ML)and artificial intelligence models.AIM To assess the utility of ML models in prognostication for LT,comparing their performance and reliability to established traditional scoring systems.METHODS Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines,we conducted a thorough and standardized literature search using the PubMed/MEDLINE database.Our search imposed no restrictions on publication year,age,or gender.Exclusion criteria encompassed non-English studies,review articles,case reports,conference papers,studies with missing data,or those exhibiting evident methodological flaws.RESULTS Our search yielded a total of 64 articles,with 23 meeting the inclusion criteria.Among the selected studies,60.8%originated from the United States and China combined.Only one pediatric study met the criteria.Notably,91%of the studies were published within the past five years.ML models consistently demonstrated satisfactory to excellent area under the receiver operating characteristic curve values(ranging from 0.6 to 1)across all studies,surpassing the performance of traditional scoring systems.Random forest exhibited superior predictive capabilities for 90-d mortality following LT,sepsis,and acute kidney injury(AKI).In contrast,gradient boosting excelled in predicting the risk of graft-versus-host disease,pneumonia,and AKI.CONCLUSION This study underscores the potential of ML models in guiding decisions related to allograft allocation and LT,marking a significant evolution in the field of prognostication.

Comparison of different preoperative objective nutritional indices for evaluating 30-d mortality and complications after liver transplantation

BACKGROUND The nutritional status is closely related to the prognosis of liver transplant re-cipients,but few studies have reported the role of preoperative objective nutri-tional indices in predicting liver transplant outcomes.AIM To compare the predictive value of various preoperative objective nutritional indicators for determining 30-d mortality and complications following liver transplantation(LT).METHODS A retrospective analysis was conducted on 162 recipients who underwent LT at our institution from December 2019 to June 2022.RESULTS This study identified several independent risk factors associated with 30-d mor-tality,including blood loss,the prognostic nutritional index(PNI),the nutritional risk index(NRI),and the control nutritional status.The 30-d mortality rate was 8.6%.Blood loss,the NRI,and the PNI were found to be independent risk factors for the occurrence of severe postoperative complications.The NRI achieved the highest prediction values for 30-d mortality[area under the curve(AUC)=0.861,P<0.001]and severe complications(AUC=0.643,P=0.011).Compared to those in the high NRI group,the low patients in the NRI group had lower preoperative body mass index and prealbumin and albumin levels,as well as higher alanine aminotransferase and total bilirubin levels,Model for End-stage Liver Disease scores and prothrombin time(P<0.05).Furthermore,the group with a low NRI exhibited significantly greater incidences of intraabdominal bleeding,primary graft nonfunction,and mortality.CONCLUSION The NRI has good predictive value for 30-d mortality and severe complications following LT.The NRI could be an effective tool for transplant surgeons to evaluate perioperative nutritional risk and develop relevant nutritional therapy.

Klebsiella pneumoniae infections after liver transplantation:Drug resistance and distribution of pathogens,risk factors,and influence on outcomes

BACKGROUND Liver transplantation(LT)is the only curative treatment for end-stage liver disease.However,LT recipients are susceptible to infection,which is the leading cause of early mortality after LT.Klebsiella pneumoniae infections(KPIs)in the bloodstream are common in LT recipients.We hypothesized that KPIs and carbapenemresistant Klebsiella pneumoniae(CRKP)infections may affect the outcomes of LT recipients.AIM To assess KPI incidence,timing,distribution,drug resistance,and risk factors following LT and its association with outcomes.METHODS This retrospective study included 406 patients undergoing LT at The Third Xiangya Hospital of Central South University,a tertiary hospital,from January 2015 to January 2023.We investigated the risk factors for KPIs and assessed the impact of KPIs and CRKP infections on the prognosis of LT recipients using logistic regression analysis.RESULTS KPI incidence was 7.9%(n=32),with lung/thoracic cavity the most frequent site of infection;the median time from LT to KPI onset was 7.5 d.Of 44 Klebsiella pneumoniae isolates,43(97.7%)and 34(77.3%)were susceptible to polymyxin B or ceftazidime/avibactam and tigecycline,respectively;>70%were resistant to piperacillin/tazobactam,ceftazidime,cefepime,aztreonam,meropenem,and levofloxacin.Female sex[odds ratio(OR)=2.827,95%confidence interval(CI):1.256-6.364;P=0.012],pre-LT diabetes(OR=2.794,95%CI:1.070-7.294;P=0.036),day 1 post-LT alanine aminotransferase(ALT)levels≥1500 U/L(OR=3.645,95%CI:1.671-7.950;P=0.001),and post-LT urethral catheter duration over 4 d(OR=2.266,95%CI:1.016-5.054;P=0.046)were risk factors for KPI.CRKP infections,but not KPIs,were risk factors for 6-month all-cause mortality post-LT.CONCLUSION KPIs occur frequently and rapidly after LT.Risk factors include female sex,pre-LT diabetes,increased post-LT ALT levels,and urethral catheter duration.CRKP infections,and not KPIs,affect mortality.

Predicting major adverse cardiovascular events after orthotopic liver transplantation using a supervised machine learning model:A cohort study

BACKGROUND Liver transplant(LT)patients have become older and sicker.The rate of post-LT major adverse cardiovascular events(MACE)has increased,and this in turn raises 30-d post-LT mortality.Noninvasive cardiac stress testing loses accuracy when applied to pre-LT cirrhotic patients.AIM To assess the feasibility and accuracy of a machine learning model used to predict post-LT MACE in a regional cohort.METHODS This retrospective cohort study involved 575 LT patients from a Southern Brazilian academic center.We developed a predictive model for post-LT MACE(defined as a composite outcome of stroke,new-onset heart failure,severe arrhythmia,and myocardial infarction)using the extreme gradient boosting(XGBoost)machine learning model.We addressed missing data(below 20%)for relevant variables using the k-nearest neighbor imputation method,calculating the mean from the ten nearest neighbors for each case.The modeling dataset included 83 features,encompassing patient and laboratory data,cirrhosis complications,and pre-LT cardiac assessments.Model performance was assessed using the area under the receiver operating characteristic curve(AUROC).We also employed Shapley additive explanations(SHAP)to interpret feature impacts.The dataset was split into training(75%)and testing(25%)sets.Calibration was evaluated using the Brier score.We followed Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis guidelines for reporting.Scikit-learn and SHAP in Python 3 were used for all analyses.The supplementary material includes code for model development and a user-friendly online MACE prediction calculator.RESULTS Of the 537 included patients,23(4.46%)developed in-hospital MACE,with a mean age at transplantation of 52.9 years.The majority,66.1%,were male.The XGBoost model achieved an impressive AUROC of 0.89 during the training stage.This model exhibited accuracy,precision,recall,and F1-score values of 0.84,0.85,0.80,and 0.79,respectively.Calibration,as assessed by the Brier score,indicated excellent model calibration with a score of 0.07.Furthermore,SHAP values highlighted the significance of certain variables in predicting postoperative MACE,with negative noninvasive cardiac stress testing,use of nonselective beta-blockers,direct bilirubin levels,blood type O,and dynamic alterations on myocardial perfusion scintigraphy being the most influential factors at the cohort-wide level.These results highlight the predictive capability of our XGBoost model in assessing the risk of post-LT MACE,making it a valuable tool for clinical practice.CONCLUSION Our study successfully assessed the feasibility and accuracy of the XGBoost machine learning model in predicting post-LT MACE,using both cardiovascular and hepatic variables.The model demonstrated impressive performance,aligning with literature findings,and exhibited excellent calibration.Notably,our cautious approach to prevent overfitting and data leakage suggests the stability of results when applied to prospective data,reinforcing the model’s value as a reliable tool for predicting post-LT MACE in clinical practice.

Association of donor hepatectomy time with liver transplantation outcomes: A multicenter retrospective study

BACKGROUND Prolonged donor hepatectomy time may be implicated in early and late complications of liver transplantation.AIM To evaluate the impact of donor hepatectomy time on outcomes of liver transplant recipients,mainly early allograft dysfunction.METHODS This multicenter retrospective study included brain-dead donors and adult liver graft recipients.Donor-recipient matching was obtained through a crossover list.Clinical and laboratory data were recorded for both donors and recipients.Donor hepatectomy,cold ischemia,and warm ischemia times were recorded.Primary outcome was early allograft dysfunction.Secondary outcomes included need for retransplantation,length of intensive care unit and hospital stay,and patient and graft survival at 12 months.RESULTS From January 2019 to December 2021,a total of 243 patients underwent a liver transplant from a brain-dead donor.Of these,57(25%)developed early allograft dysfunction.The median donor hepatectomy time was 29(23–40)min.Patients with early allograft dysfunction had a median hepatectomy time of 25(22–38)min,whereas those without it had a median time of 30(24–40)min(P=0.126).CONCLUSION Donor hepatectomy time was not associated with early allograft dysfunction,graft survival,or patient survival following liver transplantation.

Development of a nomogram for predicting liver transplantation prognosis in hepatocellular carcinoma

BACKGROUND At present,liver transplantation(LT)is one of the best treatments for hepatocellular carcinoma(HCC).Accurately predicting the survival status after LT can significantly improve the survival rate after LT,and ensure the best way to make rational use of liver organs.AIM To develop a model for predicting prognosis after LT in patients with HCC.METHODS Clinical data and follow-up information of 160 patients with HCC who underwent LT were collected and evaluated.The expression levels of alphafetoprotein(AFP),des-gamma-carboxy prothrombin,Golgi protein 73,cytokeratin-18 epitopes M30 and M65 were measured using a fully automated chemiluminescence analyzer.The best cutoff value of biomarkers was determined using the Youden index.Cox regression analysis was used to identify the independent risk factors.A forest model was constructed using the random forest method.We evaluated the accuracy of the nomogram using the area under the curve,using the calibration curve to assess consistency.A decision curve analysis(DCA)was used to evaluate the clinical utility of the nomograms.RESULTS The total tumor diameter(TTD),vascular invasion(VI),AFP,and cytokeratin-18 epitopes M30(CK18-M30)were identified as important risk factors for outcome after LT.The nomogram had a higher predictive accuracy than the Milan,University of California,San Francisco,and Hangzhou criteria.The calibration curve analyses indicated a good fit.The survival and recurrence-free survival(RFS)of high-risk groups were significantly lower than those of low-and middle-risk groups(P<0.001).The DCA shows that the model has better clinical practicability.CONCLUSION The study developed a predictive nomogram based on TTD,VI,AFP,and CK18-M30 that could accurately predict overall survival and RFS after LT.It can screen for patients with better postoperative prognosis,and improve longterm survival for LT patients.

Influence of sex on outcomes of liver transplantation for hepatocellular carcinoma:a multicenter cohort study in China

Objective:Sex-specific differences are observed in various liver diseases,but the influence of sex on the outcomes of hepatocellular carcinoma(HCC)after liver transplantation(LT)remains to be determined.This study is the first Chinese nationwide investigation of the role of sex in post-LT outcomes in patients with HCC.Methods:Data for recipients with HCC registered in the China Liver Transplant Registry between January 2015 and December 2020 were analyzed.The associations between donor,recipient,or donor-recipient transplant patterns by sex and the post-LT outcomes were studied with propensity score matching(PSM).The survival associated with different sex-based donor-recipient transplant patterns was further studied.Results:Among 3,769 patients enrolled in this study,the 1-,3-,and 5-year overall survival(OS)rates of patients with HCC after LT were 96.1%,86.4%,and 78.5%,respectively,in female recipients,and 95.8%,79.0%,and 70.7%,respectively,in male recipients after PSM(P=0.009).However,the OS was comparable between recipients with female donors and male donors.Multivariate analysis indicated that male recipient sex was a risk factor for post-LT survival(HR=1.381,P=0.046).Among the donor-recipient transplant patterns,the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival(P<0.05).Conclusions:Our findings highlighted that the post-LT outcomes of female recipients were significantly superior to those of male recipients,and the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival.Livers from male donors may provide the most benefit to female recipients.Our results indicate that sex should be considered as a critical factor in organ allocation.

Current status of liver transplantation for human immunodeficiency virus-infected patients in China's Mainland

According to the report from the Chinese Center for Disease Control and Prevention,the prevalence of human immunodeficiency virus(HIV)infection exceeded 1.2 million individuals by the year 2022,with an annual increase of about 80000 cases.The overall prevalence of hepatitis B surface antigen among individuals co-infected with HIV reached 13.7%,almost twice the rate of the general population in China.In addition to the well-documented susceptibility to opportunistic infections and new malignancies,HIV infected patients frequently experience liver-related organ damage,with the liver and kidneys being the most commonly affected.This often leads to the development of end-stage liver and kidney diseases.Therefore,organ transplantation has emerged as an important part of active treatment for HIV infected patients.However,the curative effect is not satisfactory.HIV infection has been considered a contraindication for organ transplantation.Until the emergence of highly active anti-retroviral therapy in 1996,the once intractable replication of retrovirus was effectively inhibited.With prolonged survival,the failure of important organs has become the main cause of death among HIV patients.Therefore,transplant centers worldwide have resu-med exploration of organ transplantation for HIV-infected individuals and reached a positive conclusion.This study provides an overview of the current landscape of HIV-positive patients receiving liver transplantation(LT)in main-land China.To date,our transplant center has conducted LT for eight end-stage liver disease patients co-infected with HIV,and all but one,who died two months postoperatively due to sepsis and progressive multi-organ failure,have survived.Comparative analysis with hepatitis B virus-infected patients during the same period revealed no statistically significant differences in acute rejection reactions,cytomegalovirus infection,bacteremia,pulmonary infections,acute kidney injury,new-onset cancers,or vascular and biliary complications.

How to apply ex-vivo split liver transplantation safely and feasibly: A three-step approach

BACKGROUND Given the current organ shortage crisis,split liver transplantation(SLT)has emerged as a promising alternative for select end-stage liver disease patients.AIM To introduce an ex-vivo liver graft splitting approach and evaluate its safety and feasibility in SLT.METHODS A retrospective analysis was conducted on the liver transplantation data from cases performed at our center between April 1,2022,and May 31,2023.The study included 25 SLT cases and 81 whole liver transplantation(WLT)cases.Total ex-vivo liver splitting was employed for SLT graft procurement in three steps.Patient outcomes were determined,including liver function parameters,postoperative complications,and perioperative mortality.Group comparisons for categorical variables were performed using theχ²-test.RESULTS In the study,postoperative complications in the 25 SLT cases included hepatic artery thrombosis(n=1)and pulmonary infections(n=3),with no perioperative mortality.In contrast,among the 81 patients who underwent WLT,complications included perioperative mortality(n=1),postoperative pulmonary infections(n=8),abdominal infection(n=1),hepatic artery thromboses(n=3),portal vein thrombosis(n=1),and intra-abdominal bleeding(n=5).Comparative analysis demonstrated significant differences in alanine aminotransferase(176.0 vs 73.5,P=0.000)and aspartate aminotransferase(AST)(42.0 vs 29.0,P=0.004)at 1 wk postoperatively,and in total bilirubin(11.8 vs 20.8,P=0.003)and AST(41.5 vs 26.0,P=0.014)at 2 wk postoperatively.However,the overall incidence of complications was comparable between the two groups(P>0.05).CONCLUSION Our findings suggest that the total ex-vivo liver graft splitting technique is a safe and feasible approach,especially under the expertise of an experienced transplant center.The approach developed by our center can serve as a valuable reference for other transplantation centers.

Advancing immunosuppression in liver transplantation: A narrative review

Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation(LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive therapy cannot selectively inhibit the graft-specific immune response and entails a significant risk of serious side effects, i.e., among others, de novo cancers, infections, cardiovascular events, renal failure, metabolic syndrome, and late graft fibrosis, with progressive loss of graft function. Pharmacological research, aimed to develop alternative immunosuppressive agents in LT, is behind other solidorgan transplantation subspecialties, and, therefore, the development of new compounds and strategies should get priority in LT. The research trajectories cover mechanisms to induce T-cell exhaustion, to inhibit co-stimulation, to mitigate non-antigen-specific inflammatory response, and, lastly, to minimize the development and action of donor-specific antibodies. Moreover, while cellular modulation techniques are complex, active research is underway to foster the action of T-regulatory cells, to induce tolerogenic dendritic cells, and to promote the function of B-regulatory cells. We herein discuss current lines of research in clinical immunosuppression, particularly focusing on possible applications in the LT setting.

Relative carcinogenicity of tacrolimus vs mycophenolate after solid organ transplantation and its implications for liver transplant care

BACKGROUND De novo malignancy is a leading cause of late morbidity and mortality in liver transplant recipients.Cumulative immunosuppression has been shown to contribute to post-transplant malignancy(PTM)risk.There is emerging evidence on the differential carcinogenic risk profile of individual immunosuppressive drugs,independent of the net effect of immunosuppression.Calcineurin inhibitors such as tacrolimus may promote tumourigenesis,whereas mycophenolic acid(MPA),the active metabolite of mycophenolate mofetil,may limit tumour progression.Liver transplantation(LT)is relatively unique among solid organ transplantation in that immunosuppression monotherapy with either tacrolimus or MPA is often achievable,which makes careful consideration of the risk-benefit profile of these immunosuppression agents particularly relevant for this cohort.However,there is limited clinical data on this subject in both LT and other solid organ transplant recipients.AIM To investigate the relative carcinogenicity of tacrolimus and MPA in solid organ transplantation.METHODS A literature search was conducted using MEDLINE and Embase databases using the key terms“solid organ transplantation”,“tacrolimus”,“mycophenolic acid”,and“carcinogenicity”,in order to identify relevant articles published in English between 1st January 2002 to 11th August 2022.Related terms,synonyms and explosion of MeSH terms,Boolean operators and truncations were also utilised in the search.Reference lists of retrieved articles were also reviewed to identify any additional articles.Excluding duplicates,abstracts from 1230 records were screened by a single reviewer,whereby 31 records were reviewed in detail.Full-text articles were assessed for eligibility based on pre-specified inclusion and exclusion criteria.RESULTS A total of 6 studies were included in this review.All studies were large population registries or cohort studies,which varied in transplant era,type of organ transplanted and immunosuppression protocol used.Overall,there was no clear difference demonstrated between tacrolimus and MPA in de novo PTM risk following solid organ transplantation.Furthermore,no study provided a direct comparison of carcinogenic risk between tacrolimus and MPA monotherapy in solid organ transplantation recipients.CONCLUSION The contrasting carcinogenic risk profiles of tacrolimus and MPA demonstrated in previous experimental studies,and its application in solid organ transplantation,is yet to be confirmed in clinical studies.Thus,the optimal choice of immunosuppression drug to use as maintenance monotherapy in LT recipients is not supported by a strong evidence base and remains unclear.

A Single-Cell Landscape of Human Liver Transplantation Reveals a Pathogenic Immune Niche Associated with Early Allograft Dysfunction

Liver transplantation(LT)is the standard therapy for individuals afflicted with end-stage liver disease.Despite notable advancements in LT technology,the incidence of early allograft dysfunction(EAD)remains a critical concern,exacerbating the current organ shortage and detrimentally affecting the prognosis of recipients.Unfortunately,the perplexing hepatic heterogeneity has impeded characterization of the cellular traits and molecular events that contribute to EAD.Herein,we constructed a pioneering single-cell transcriptomic landscape of human transplanted livers derived from non-EAD and EAD patients,with 12 liver samples collected from 7 donors during the cold perfusion and portal reperfusion stages.Comparison of the 75231 cells of non-EAD and EAD patients revealed an EAD-associated immune niche comprising mucosal-associated invariant T cells,granzyme B^(+)(GZMB^(+))granzyme K^(+)(GZMK^(+))natural killer cells,and S100 calcium binding protein A12^(+)(S100A12^(+))neutrophils.Moreover,we verified this immune niche and its association with EAD occurrence in two independent cohorts.Our findings elucidate the cellular characteristics of transplanted livers and the EAD-associated pathogenic immune niche at the single-cell level,thus,offering valuable insights into EAD onset.