Role of protein induced by vitamin-K absence-II in transplanted patients with HCC not producing alpha-fetoprotein.

Elevated Protein Induced by Vitamin-K Absence-II (PIVKA-II) has been shown to be an adverse prognostic factor in HCC patients undergoing liver transplantation (LT). No definitive data are available about the impact of PIVKA-II concerning post-LT recurrence in patients not secreting (≤ 20 ng/mL) alpha-fetoprotein (AFP). An observational retrospective study of the East-West HCC-LT consortium is reported. Between 2000 and 2019, 639 HCC patients were enrolled in 5 collaborative European and Japanese centers. To minimize the initial selection bias, an inverse probability therapy weighting method was adopted to analyze the data. In the post-inverse probability therapy weighting population, PIVKA-II (HR = 2.00; 95% CI: 1.52-2.64; p < 0.001) and AFP (HR=1.82; 95% CI: 1.48-2.24; p < 0.001) were the most relevant independent risk factors for post-LT recurrence. A sub-analysis focusing only on patients who are AFP non-secreting confirmed the negative role of PIVKA-II (HR=2.06, 95% CI: 1.26-3.35; p =0.004). When categorizing the entire population into 4 groups according to the AFP levels (≤ or > 20 ng/mL) and PIVKA (≤ or > 300 mUA/mL) at the time of LT, the lowest recurrence rates were observed in the low AFP-PIVKA-II group (5-year recurrence rate = 8.0%). Conversely, the high AFP-PIVKA-II group had the worst outcome (5-year recurrence rate = 35.1%). PIVKA-II secretion is a relevant risk factor for post-LT HCC recurrence. The role of this marker is independent of the AFP status. Combining both tumor markers, especially in the setting of LT, should be of great relevance for adding information about predicting the post-LT risk of tumor recurrence and selecting these patients for transplantation.

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 solid-organ 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.

Controversy Over Liver Transplantation or Resection for Neuroendocrine Liver Metastasis: Tumor Biology Cuts the Deal.

BACKGROUND: In patients with neuroendocrine liver metastasis (NELM), liver transplantation (LT) is an alternative to liver resection (LR), although the choice of therapy remains controversial. In this multicenter study, we aim to provide novel insight in this dispute. METHODS: Following a systematic literature search, 15 large international centers were contacted to provide comprehensive data on their patients after LR or LT for NELM. Survival analyses were performed with the Kaplan-Meier method, while multivariable Cox regression served to identify factors influencing survival after either transplantation or resection. Inverse probability weighting and propensity score matching was used for analyses with balanced and equalized baseline characteristics. RESULTS: Overall, 455 patients were analyzed, including 230 after LR and 225 after LT, with a median follow-up of 97 months [95% confidence interval (CI): 85-110 months]. Multivariable analysis revealed G3 grading as a negative prognostic factor for LR [hazard ratio (HR)=2.22, 95% CI: 1.04-4.77, P =0.040], while G2 grading (HR=2.52, 95% CI: 1.15-5.52, P =0.021) and LT outside Milan criteria (HR=2.40, 95% CI: 1.16-4.92, P =0.018) were negative prognostic factors in transplanted patients. Inverse probability-weighted multivariate analyses revealed a distinct survival benefit after LT. Matched patients presented a median overall survival (OS) of 197 months (95% CI: 143-not reached) and a 73% 5-year OS after LT, and 119 months (95% CI: 74-133 months) and a 52.8% 5-year OS after LR (HR=0.59, 95% CI: 0.3-0.9, P =0.022). However, the survival benefit after LT was lost if patients were transplanted outside Milan criteria. CONCLUSIONS: This multicentric study in patients with NELM demonstrates a survival benefit of LT over LR. This benefit depends on adherence to selection criteria, in particular low-grade tumor biology and Milan criteria, and must be balanced against potential risks of LT.

Development and validation of a REcurrent Liver cAncer Prediction ScorE (RELAPSE) following liver transplantation in patients with hepatocellular carcinoma: Analysis of the US Multicenter HCC Transplant Consortium.

HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22-1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04-1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35-1.73, p < 0.001), microvascular (HR = 2.37, 95%-CI, 1.87-2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41-4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29-2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54-3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.

The optimal immunosuppression management to prevent early rejection after liver transplantation: A systematic review of the literature and expert panel recommendations.

BACKGROUND: The optimal immunosuppression protocol to prevent early acute cellular rejection (ACR) after liver transplantation (LT) avoiding prolonged hospitalization and early hospital readmission is undefined. OBJECTIVES: To identify the most suitable immunosuppression regimen for inclusion in ERAS programs in order to minimize early ACR after LT and to provide expert panel recommendations DATA SOURCES: Ovid MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Central. METHODS: Systematic review following PRISMA guidelines and recommendations using the GRADE approach derived from an international expert panel. Studies from January 2000 onward focusing on early ACR were included. Rates of early renal dysfunction and infection were evaluated. CRD42021245586 RESULTS: Thirty-seven studies met inclusion criteria; 23 randomized controlled trials, 14 retrospective or prospective observational comparative or noncomparative studies. Several sources of biases which potentially confound conclusions were identified: heterogeneity in immunosuppression protocols, higher serum tacrolimus levels than currently used in clinical practice, differences in the definition of ACR. CONCLUSIONS: Tacrolimus is the standard immunosuppression after LT and can be used in combination with other drugs such as corticosteroids and MMF, and in association with anti-IL2 receptor antibody (IL2Ra) induction. (Quality of Evidence; Low | Grade of Recommendation; Strong). Low dose or delayed introduction of tacrolimus in association with corticosteroids and MMF and/or anti-IL2Ra induction can be used to reduce acute kidney injury. (Quality of Evidence; Low | Grade of Recommendation; Strong). Use of tacrolimus in association with corticosteroids and MMF and/or anti-IL2Ra induction does not lead to increased infection rates. (Quality of Evidence; Low | Grade of Recommendation; Weak).

Three-dimensional modeling in complex liver surgery and liver transplantation.

Liver resection and transplantation are the most effective therapies for many hepatobiliary tumors and diseases. However, these surgical procedures are challenging due to the anatomic complexity and many anatomical variations of the vascular and biliary structures. Three-dimensional (3D) printing models can clearly locate and describe blood vessels, bile ducts and tumors, calculate both liver and residual liver volumes, and finally predict the functional status of the liver after resection surgery. The 3D printing models may be particularly helpful in the preoperative evaluation and surgical planning of especially complex liver resection and transplantation, allowing to possibly increase resectability rates and reduce postoperative complications. With the continuous developments of imaging techniques, such models are expected to become widely applied in clinical practice.

Meso-Rex bypass for the management of extrahepatic portal vein obstruction in adults (with video).

BACKGROUND: Extrahepatic portal vein obstruction (EHPVO) results in severe portal hypertension (PHT) leading to severely compromised quality of life. Often, pharmacological and endoscopic management is unable to solve this problem. Restoring hepatic portal flow using meso-Rex bypass (MRB) may solve it. This procedure, uncommon in adult patients, is considered the treatment of choice for EHPVO in children. METHODS: From 1997 to 2018, 8 male and 6 female adults, with a median age of 51 years (range 22-66) underwent MRB procedure for EHPVO at the University Hospitals Saint-Luc in Brussels, Belgium. Symptoms of PHT were life altering in all but one patient and consisted of repetitive gastro-intestinal bleedings, sepsis due to portal biliopathy, and/or severe abdominal discomfort. The surgical technique consisted in interposition of a free venous graft or of a prosthetic graft between the superior mesenteric vein and the Rex recess of the left portal vein. RESULTS: Median operative time was 500 min (range 300-730). Median follow-up duration was 22 months (range 2-169). One patient died due to hemorrhagic shock following percutaneous transluminal intervention for early graft thrombosis. Major morbidity, defined as Clavien-Dindo score ≥ III, was 35.7% (5/14). Shunt patency at last follow-up was 64.3% (9/14): 85.7% (6/7) of pure venous grafts and only 42.9% (3/7) of prosthetic graft. Symptom relief was achieved in 85.7% (12/14) who became asymptomatic after MRB. CONCLUSIONS: Adult EHPVO represents a difficult clinical condition that leads to severely compromised quality of life and possible life-threatening complications. In such patients, MRB represents the only and last resort to restore physiological portal vein flow. Although successful in a majority of patients, this procedure is associated with major morbidity and mortality and should be done in tertiary centers experienced with vascular liver surgery to get the best results.

The impact of biological features for a better prediction of posttransplant hepatocellular cancer recurrence.

PURPOSE OF REVIEW: Morphological criteria (i.e., Milan Criteria) have been considered for a long time to be the best tool for selecting patients with hepatocellular cancer (HCC) waiting for liver transplantation (LT). In the last ten years, a refinement of the selection criteria has been observed, with the introduction of biological tumor characteristics enabling to enlarge the number of potential transplant candidates and to select LT candidates with a lower risk of posttransplant recurrence. RECENT FINDINGS: Several biological tumor aspects have been explored and validated in international cohorts to expand the ability to predict patients at high risk for recurrence. Alpha-fetoprotein, radiological response to locoregional treatments, and other more recently proposed markers have been principally explored. Moreover, more complex statistical approaches (i.e., deep learning) have been advocated to explore the nonlinear intercorrelations between the investigated features. SUMMARY: The addition of biological aspects to morphology has improved the ability to discriminate among high- and low-risk patients for recurrence. New prognostic algorithms based on the more sophisticated artificial intelligence approach are further improving the capability to select LT candidates with HCC.

Expert Consensus Guidelines on Minimally Invasive Donor Hepatectomy for Living Donor Liver Transplantation From Innovation to Implementation: A Joint Initiative From the International Laparoscopic Liver Society (ILLS) and the Asian-Pacific Hepato-Pancreato-Biliary Association (A-PHPBA).

OBJECTIVE: The Expert Consensus Guidelines initiative on MIDH for LDLT was organized with the goal of safe implementation and development of these complex techniques with donor safety as the main priority. BACKGROUND: Following the development of minimally invasive liver surgery, techniques of MIDH were developed with the aim of reducing the short- and long-term consequences of the procedure on liver donors. These techniques, although increasingly performed, lack clinical guidelines. METHODS: A group of 12 international MIDH experts, 1 research coordinator, and 8 junior faculty was assembled. Comprehensive literature search was made and studies classified using the SIGN method. Based on literature review and experts opinions, tentative recommendations were made by experts subgroups and submitted to the whole experts group using on-line Delphi Rounds with the goal of obtaining >90% Consensus. Pre-conference meeting formulated final recommendations that were presented during the plenary conference held in Seoul on September 7, 2019 in front of a Validation Committee composed of LDLT experts not practicing MIDH and an international audience. RESULTS: Eighteen Clinical Questions were addressed resulting in 44 recommendations. All recommendations reached at least a 90% consensus among experts and were afterward endorsed by the validation committee. CONCLUSIONS: The Expert Consensus on MIDH has produced a set of clinical guidelines based on available evidence and clinical expertise. These guidelines are presented for a safe implementation and development of MIDH in LDLT Centers with the goal of optimizing donor safety, donor care, and recipient outcomes.

Charting the Path Forward for Risk Prediction in Liver Transplant for Hepatocellular Carcinoma: International Validation of HALTHCC Among 4,089 Patients.

Prognosticating outcomes in liver transplant (LT) for hepatocellular carcinoma (HCC) continues to challenge the field. Although Milan Criteria (MC) generalized the practice of LT for HCC and improved outcomes, its predictive character has degraded with increasing candidate and oncological heterogeneity. We sought to validate and recalibrate a previously developed, preoperatively calculated, continuous risk score, the Hazard Associated with Liver Transplantation for Hepatocellular Carcinoma (HALTHCC), in an international cohort. From 2002 to 2014, 4,089 patients (both MC in and out [25.2%]) across 16 centers in North America, Europe, and Asia were included. A continuous risk score using pre-LT levels of alpha-fetoprotein, Model for End-Stage Liver Disease Sodium score, and tumor burden score was recalibrated among a randomly selected cohort (n = 1,021) and validated in the remainder (n = 3,068). This study demonstrated significant heterogeneity by site and year, reflecting practice trends over the last decade. On explant pathology, both vascular invasion (VI) and poorly differentiated component (PDC) increased with increasing HALTHCC score. The lowest-risk patients (HALTHCC 0-5) had lower rates of VI and PDC than the highest-risk patients (HALTHCC > 35) (VI, 7.7%[ 1.2-14.2] vs. 70.6% [48.3-92.9] and PDC:4.6% [0.1%-9.8%] vs. 47.1% [22.6-71.5]; P < 0.0001 for both). This trend was robust to MC status. This international study was used to adjust the coefficients in the HALTHCC score. Before recalibration, HALTHCC had the greatest discriminatory ability for overall survival (OS; C-index = 0.61) compared to all previously reported scores. Following recalibration, the prognostic utility increased for both recurrence (C-index = 0.71) and OS (C-index = 0.63). Conclusion: This large international trial validated and refined the role for the continuous risk metric, HALTHCC, in establishing pre-LT risk among candidates with HCC worldwide. Prospective trials introducing HALTHCC into clinical practice are warranted.

The real incidence of biliary tract complications after adult liver transplantation: the role of the prospective routine use of cholangiography during post-transplant follow-up.

Biliary tract complications (BTCs) still burden liver transplantation (LT). The wide reporting variability highlights the absence of systematic screening. From 2000 to 2009, simultaneous liver biopsy and direct biliary visualization were prospectively performed in 242 recipients at 3 and 6 months (n = 212, 87.6%) or earlier when indicated (n = 30, 12.4%). Median follow-up was 148 (107-182) months. Seven patients (2.9%) experienced postprocedural morbidity. BTCs were initially diagnosed in 76 (31.4%) patients; 32 (42.1%) had neither clinical nor biological abnormalities. Acute cellular rejection (ACR) was present in 27 (11.2%) patients and in 6 (22.2%) BTC patients. Nine (3.7%) patients with normal initial cholangiography developed BTCs after 60 (30-135) months post-LT. BTCs directly lead to 7 (2.9%) re-transplantations and 14 (5.8%) deaths resulting in 18 (7.4%) allograft losses. Bile duct proliferation at 12-month biopsy proved an independent risk factor for graft loss (P = 0.005). Systematic biliary tract and allograft evaluation allows the incidence and extent of biliary lesions to be documented more precisely and to avoid erroneous treatment of ACR. The combination 'abnormal biliary tract-canalicular proliferation' is an indicator of worse graft outcome. BTCs are responsible for important delayed allograft and patient losses. These results underline the importance of life-long follow-up and appropriate timing for re-transplantation.

Symptomatic Val122del mutated hereditary transthyretin amyloidosis: Need for early diagnosis and prioritization for heart and liver transplantation.

BACKGROUND: Hereditary transthyretin (ATTRv) amyloidosis is an autosomal dominant disease linked to transthyretin gene mutations which cause instability of the transthyretin tetramer. After dissociation and misfolding they reassemble as insoluble fibrils (i.e. amyloid). Apart from the common Val30Met mutation there is a very heterogeneous group of non-Val30Met mutations. In some cases, the clinical picture is dominated by a rapidly evolving restrictive and hypertrophic cardiomyopathy. METHODS: A case series of four liver recipients with the highly clinically relevant, rare and particularly aggressive Val122del mutation is presented. Medical and surgical therapeutic options, waiting list policy for ATTRv-amyloidosis, including the need for heart transplantation, and status of heart-liver transplantation are discussed. RESULTS: Three patients needed a staged (1 patient) or simultaneous (2 patients) heart-liver transplant due to rapidly progressing cardiac failure and/or neurologic disability. Domino liver transplantation was impossible in two due to fibrotic hepatic transformation caused by cardiomyopathy. After a follow-up ranging from 3.5 to 9.5 years, cardiac (allograft) function was maintained in all patients, but neuropathy progressed in three patients, one of whom died after 80 months. CONCLUSIONS: This is the first report in (liver) transplant literature about the rare Val122del ATTRv mutation. Due to its aggressiveness, symptomatic patients should be prioritized on the liver and, in cases with cardiomyopathy, heart waiting lists in order to avoid the irreversible neurological and cardiac damage that leads to a rapid lethal outcome.

Solitary prostate cancer liver metastasis: an exceptional indication for liver resection.

INTRODUCTION: Prostatic cancer metastases (PCM) are usually systemic. Isolated PCM liver metastases (PCLM) are very rare. The treatment of PCM consists of hormono- and chemotherapy eventually combined with stereotactic radiation. PATIENT AND DISCUSSION: A case of a 67-year old man presenting with a solitary, metachronous PCLM undergoing a left extended hepatectomy due to resistance to hormono- and chemotherapy is reported. He died of recurrent systemic disease 31 months later. CONCLUSIONS: The very rare indication and possible role of liver resection in the treatment of PCLM is discussed.

mTOR Inhibition Is Most Beneficial After Liver Transplantation for Hepatocellular Carcinoma in Patients With Active Tumors.

OBJECTIVE: The aim of this study was to evaluate the survival benefit of sirolimus in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) (exploratory analysis of the SiLVER-trial). SUMMARY AND BACKGROUND DATA: Patients receiving LT) for HCC are at a high risk for tumor recurrence. Calcineurin inhibitors have shown evidence to promote cancer growth, whereas mammalian target of rapamycin (mTOR) inhibitors like sirolimus have anticancer effects. In the SiLVER-trial (Clinicaltrials.gov: NCT00355862), the effect of sirolimus on the recurrence of HCC after LT was investigated in a prospective randomized trial. Although the primary endpoint of improved disease-free survival (DFS) with sirolimus was not met, outcomes were improved for patients in the sirolimus-treatment arm in the first 3 to 5 years. To learn more about the key variables, a multivariate analysis was performed on the SiLVER-trial data. PATIENTS AND METHODS: Data from 508 patients of the intention-to-treat analysis were included in exploratory univariate and multivariate models for overall survival (OS), DFS and a competing risk analysis for HCC recurrence. RESULTS: Sirolimus use for ≥3 months after LT for HCC independently reduced the hazard for death in the multivariate analysis [hazard ratio (HR): 0.7 (95% confidence interval, CI: 0.52-0.96, P = 0.02). Most strikingly, patients with an alpha-fetoprotein (AFP) ≥10 ng/mL and having used sirolimus for ≥3 months, benefited most with regard to OS, DFS, and HCC-recurrence (HR: 0.49-0.59, P = 0.0079-0.0245). CONCLUSIONS: mTOR-inhibitor treatment with sirolimus for ≥3 months improves outcomes in LT for HCC, especially in patients with AFP-evidence of higher tumor activity, advocating particularly for mTOR inhibitor use in this subgroup of patients. CLINICAL TRIAL REGISTRATION: EudraCT: 2005-005362-36 CLINICALTRIALS.GOV:: NCT00355862.

Cavoportal Hemitransposition in Liver Transplantation: Toward a More Safe and Efficient Technique.

Extended splanchnic venous thrombosis represents a challenge for the liver transplantation (LT) surgeon. In the absence of large venous tributaries, the cavoportal hemitransposition (CPHTr) and the combined liver-intestinal or multivisceral transplantation are the only technical solutions. Because of the reported high morbidity and mortality rates due to infrequent use and a lack of standardization, the former technique has been almost abandoned by the transplant community. A newly designed technique of CPHTr is presented that is based on the combination of an inferior vena cava (IVC)-sparing hepatectomy and large laterolateral cavocaval and end-to-side cavoportal anastomoses separated only by a double vascular stapler line. This technique allows the splanchnic blood to be completely diverted toward the allograft and to eliminate low-flow IVC areas, which possibly lead to complications. The modified CPHTr technique proposed here offers a valuable alternative to much more complex and invasive intestinal transplantation procedures.

Influence of donor and recipient gender on liver transplantation outcomes in Europe.

BACKGROUND & AIMS: The impact of gender and donor/recipient gender mismatch on LT outcomes is controversial. The aim of this study was to compare outcomes of LT in Europe, using the ELTR database, between male and female recipients, including donor/recipient gender mismatch. METHODS: Recipient, donor and transplant characteristics were compared between male and female patients. Patient survival was compared between groups, and the impact of donor/recipient gender matching as well as donor and recipient anthropometric characteristics were evaluated as potential risk factors for post-LT death/graft loss. RESULTS: A total of 46,334 LT patients were evaluated (70.5% men and 29.5% women). Ten-year survival rate was significantly higher in female than in male recipients (66% vs 59%, P < .0001). At multivariate analysis, adjusted for indication to LT and type of graft, donor/recipient gender mismatch (HR 1.12, 95% CI 1.04-1.2; P = .003), donor age > 60 years (HR 1.09, 95% CI 1.01-1.18; P = .027) and recipient age (HR 1.02, 95% CI 1.1-1.02; P < .0001) were significantly associated with post-LT lower survival rate in men. Conversely in female recipients, donor BMI > 30 (HR 1.32, 95% CI 1.09-1.6; P = .005), donor age > 60 years (HR 1.15, 95% CI 1.01-1.32; P = .027) and recipient age (HR 1.02, 95% CI 1.01-1.02; P < .0001) were significantly associated with lower post-LT survival rate. CONCLUSIONS: Donor/recipient gender mismatch in male recipients and the use of obese donor in female recipients are associated with reduced survival after LT. Therefore, the incorporation of donor and recipient anthropometric quantities in the allocation process should be a matter of further studies, as their matching can significantly influence long-term outcomes.

What did the European Liver Transplant Registry bring to liver transplantation?

Since its foundation in 1985, the European Liver Transplant Registry has evolved to become an important tool to monitor the liver transplantation activity in Europe. The vast amount of data collected on 169 473 liver transplantations performed in 153 238 recipients has also resulted in scientific publications. Without doubt, several of these have influenced the daily practice of liver transplantation. This paper gives an overview of the development, the functioning, and the scientific activity of the European Liver Transplant Registry during more than three decades. Indeed, it can be said that the registry helped to advance the practice of liver transplantation not only in Europe but also worldwide.

SARS-CoV2 and immunosuppression: A double-edged sword.

Severe acute respiratory syndrome Coronavirus 2 (SARS-Cov2) outbreak has caused a pandemic rapidly impacting on the way of life of the entire world. This impact in the specific setting of transplantation and immunosuppression has been poorly explored to date. Discordant data exist on the impact of previous coronavirus outbreaks on immunosuppressed patients. Overall, only a very limited number of cases have been reported in literature, suggesting that transplanted patients not necessarily present an increased risk of severe SARS-Cov2-related disease compared to the general population. We conducted a literature review related to the impact of immunosuppression on coronavirus infections including case reports and series describing immunosuppression management in transplant recipients. The role of steroids, calcineurin inhibitors, and mycophenolic acid has been explored more in detail. A point-in-time snapshot of the yet released literature and some considerations in relation to the use of immunosuppression in SARS-Cov2 infected transplant recipients are provided here for the physicians dealing with immunocompromised patients.

Alpha-fetoprotein and 18F-FDG standard uptake value predict tumor recurrence after liver transplantation for hepatocellular carcinoma with portal vein tumor thrombosis: Preliminary experience.

BACKGROUND: Portal vein tumor thrombosis (PVTT) is regarded as a contraindication for liver transplantation (LT) in hepatocellular carcinoma (HCC). However, some of these patients may have a favorable prognosis after LT. In this study, we evaluated the biological behavior of HCC with PVTT using tumor biomarker (alpha-fetoprotein, AFP) and 18F-FDG positron emission tomography (tumor standard uptake value) to identify a subset of patients who may be suitable for LT. METHODS: Seventy-five HCC-PVTT liver recipients transplanted during February 2016 and June 2018 were analyzed. Different pre-transplant prognostic factors were identified by univariate and multivariate analyses. PVTT status was identified following Vp classification (Vp1-Vp4). RESULTS: Three-year recurrence-free survival and overall survival rates were 40% and 65.4% in Vp2-Vp3 PVTT patients, 21.4% and 30.6% in Vp4 PVTT patients (P < 0.05). Total tumor diameter >8 cm, pre-transplant AFP level >1000 ng/mL and intrahepatic tumor maximal standard uptake value (SUVmax-tumor >5) were independent risk factors for HCC recurrence and overall survival after LT in Vp2-3 PVTT patients. Low risk patients were defined as total tumor diameter ≤8 cm; or if total tumor diameter more than 8 cm, with both pre-transplant AFP level less than 1000 ng/mL and intrahepatic tumor SUVmax less than 5, simultaneously. Twenty-two Vp2-3 PVTT HCC patients (46.8%) were identified as low risk patients, and their 3-year recurrence-free and overall survival rates were 67.6% and 95.2%, respectively. CONCLUSIONS: Patients with segmental or lobar PVTT and biologically favorable tumors defined by AFP and 18F-FDG SUVmax might be suitable for LT.

Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma.

OBJECTIVE: To characterise gut microbiome in patients with hepatocellular carcinoma (HCC) and evaluate the potential of microbiome as non-invasive biomarkers for HCC. DESIGN: We collected 486 faecal samples from East China, Central China and Northwest China prospectively and finally 419 samples completed Miseq sequencing. We characterised gut microbiome, identified microbial markers and constructed HCC classifier in 75 early HCC, 40 cirrhosis and 75 healthy controls. We validated the results in 56 controls, 30 early HCC and 45 advanced HCC. We further verified diagnosis potential in 18 HCC from Xinjiang and 80 HCC from Zhengzhou. RESULTS: Faecal microbial diversity was increased from cirrhosis to early HCC with cirrhosis. Phylum Actinobacteria was increased in early HCC versus cirrhosis. Correspondingly, 13 genera including Gemmiger and Parabacteroides were enriched in early HCC versus cirrhosis. Butyrate-producing genera were decreased, while genera producing-lipopolysaccharide were increased in early HCC versus controls. The optimal 30 microbial markers were identified through a fivefold cross-validation on a random forest model and achieved an area under the curve of 80.64% between 75 early HCC and 105 non-HCC samples. Notably, gut microbial markers validated strong diagnosis potential for early HCC and even advanced HCC. Importantly, microbial markers successfully achieved a cross-region validation of HCC from Northwest China and Central China. CONCLUSIONS: This study is the first to characterise gut microbiome in patients with HCC and to report the successful diagnosis model establishment and cross-region validation of microbial markers for HCC. Gut microbiota-targeted biomarkers represent potential non-invasive tools for early diagnosis of HCC.