Evolution of transplant oncology indications: a single-institution experience over 40 years.

Liver transplantation (LT) for uncommon tumoral indications has changed across the decades, with impaired results reported in the first historical series mainly for non-tumoral-related causes. Recently, renewed interest in liver transplant oncology has been reported. The study aims to analyze a mono-center experience exploring the evolution and the impact on patient survival of LT in uncommon tumoral indications. A retrospective analysis of 851 LT performed during 1982-2023 was investigated. 33/851 (3.9%) uncommon tumoral indications were reported: hepatocellular carcinoma (HCC) on non-cirrhotic liver (n = 14), peri-hilar (phCCA) (n = 8) and intrahepatic cholangiocarcinoma (i-CCA) (n = 3), metastatic disease (n = 4), hepatic hemangioendothelioma (n = 2), and benign tumor (n = 2). Uncommon tumoral indications were mainly transplanted during the period 1982-1989, with a complete disappearance after the year 2000 and a slight rise in the last years. Poor outcomes were reported: 5-year survival rates were 28.6%, 25.0%, 0%, and 0% in the case of HCC on non-cirrhotic liver, phCCA, i-CCA, and metastases, respectively. However, the cause of patient death was often related to non-tumoral conditions. LT for uncommon oncological diseases has increased worldwide in recent decades. Historical series report poor survival outcomes despite more recent data showing promising results. Hence, the decision to transplant these patients should be under the risk and overall benefit of the patient. The results of the ongoing protocol studies are expected to confirm the validity of the unconventional tumor indications.

Recipient hepatectomy technique may affect oncological outcomes of Liver Transplantation for hepatocellular carcinoma.

BACKGROUND: To date, caval sparing (CS) and total caval replacement (TCR) for recipient hepatectomy in liver transplantation (LT) have been compared only in terms of surgical morbidity. Nonetheless, CS technique is inherently associated with an increased manipulation of the native liver and later exclusion of the venous outflow, which may increase the risk of intraoperative shedding of tumor cells when LT is performed for hepatocellular carcinoma (HCC). METHODS: A multicenter, retrospective study was performed to assess the impact of recipient hepatectomy (CS vs. TCR) on the risk of post-transplant HCC recurrence, among 16 European Transplant Centers that used either TCR or CS recipient hepatectomy, as elective protocol technique. Exclusion criteria comprised cases of non-Center-protocol recipient hepatectomy technique, living-donor LT, HCC diagnosis suspected on preoperative imaging but not confirmed at pathological examination of the explanted liver, HCC in close contact with the inferior vena cava and previous liver resection for HCC. RESULTS: In 2420 patients, CS and TCR approaches were used in 1452 (60%) and 968 (40%) cases, respectively. Group adjustment with inverse probability weighting was performed for high volume center, recipient age, alcohol abuse, viral hepatitis, Child-Pugh class C, MELD score, cold ischemia time, clinical HCC stage within Milan criteria, pre-LT downstaging/bridging therapies, pre-LT AFP serum levels, number and size of tumor nodules, microvascular invasion and complete necrosis of all tumor nodules (matched cohort, TCR, n=938; CS, n=935). In a multivariate cause-specific hazard model, CS was associated with a higher risk of HCC recurrence(HR 1.536, p=0.007). CONCLUSIONS: TCR recipient hepatectomy, compared to CS approach, may be associated with some protective effect against post-LT tumor recurrence.

Portal vein thrombosis and liver transplantation: management, matching, and outcomes: a retrospective multicenter cohort study.

BACKGROUND AND AIMS: Besides the increased risk of perioperative morbidity, graft failure, and mortality, the majority of PVT are diagnosed at liver transplantation (LT). Improving preoperative management and patient selection may lead to better short-term and long-term outcomes and reduce the risk of a futile LT. The authors aimed to identify predictors of adverse outcomes after LT in patients with nonmalignant portal vein thrombosis (PVT) and improve donor to recipient matching by analyzing the results of the Italian cohort of LT recipients. METHODS: Adult patients who underwent LT in Italy between January 2000 and February 2020 diagnosed with PVT pre-LT or at time of LT were considered eligible for inclusion. Based on a survey encompassing all 26 surgeons participating in the study, a binary composite outcome was defined. Patients were classified as having the composite event if at least one of these conditions occurred: operative time more than 600 min, estimated blood loss greater than 5000 ml, more than 20 ICU days, 90 days mortality, 90 days retransplant. RESULTS: Seven hundred fourteen patients were screened and 698 met the inclusion criteria. The analysis reports the results of 568 patients that fulfilled the criteria to enter the composite outcome analysis.Overall, 156 patients (27.5%) developed the composite outcome. PVT stage 3/4 at transplant and need for any surgical correction of PVT are independent predictors of the composite outcome occurrence. When stratified by PVT grade, overall survival at 1-year ranges from 89.0% with PVT grade 0/1 to 67.4% in patients with PVT grade 3/4 at LT (P<0.001). Nevertheless, patients with severe PVT can improve their survival when identified risk factors are not present. CONCLUSIONS: Potential LT candidates affected by PVT have a benefit from LT that should be adequately balanced on liver function and type of inflow reconstruction needed to mitigate the incidence of adverse events. Nonetheless, the absence of specific risk factors may improve the outcomes even in patients with PVT grades 3-4.

The role of echocardiographic assessment for the risk of adverse events in liver transplant recipients: A systematic review and meta-analysis.

BACKGROUND & AIMS: Echocardiographic findings may provide valuable information about the cardiac conditions in cirrhotic patients waiting for liver transplantation (LT). However, data on the ability of the different echocardiographic parameters to predict post-transplant risk of mortality are scarce and heterogeneous. This systematic review evaluates the role of different echocardiographic features as predictors of post-LT mortality. A meta-analysis was also performed according to the observed results. METHODS: A systematic review was conducted according to PRISMA guidelines. Medline (PubMed) database was searched through February 2023 for relevant published original articles reporting the prognostic value of echocardiographic findings associated with outcomes of adult LT recipients. The risk of bias in included articles was assessed using ROBINS-E tool. Methodological quality varied from low to high across the risk of bias domains. RESULTS: Twenty-three studies were identified after the selection process; ten were enrollable for the meta-analyses. According to the results observed, the E/A ratio fashioned as a continuous value (HR = 0.43, 95%CI = 0.25-0.76; P = 0.003), and tricuspid regurgitation (HR = 2.36, 95%CI = 1.05-5.31; P = 0.04) were relevant predicting variables for post-LT death. Other echocardiographic findings failed to merge with statistical relevance. CONCLUSION: Tricuspid regurgitation and left ventricular diastolic dysfunction play a role in the prediction of post-LT death. More studies are needed to clarify further the impact of these echocardiographic features in the transplantation setting.

Superiority of the new sex-adjusted models to remove the female disadvantage restoring equity in liver transplant allocation.

BACKGROUND AND AIMS: Model for End-stage Liver Disease (MELD) and MELDNa are used worldwide to guide graft allocation in liver transplantation (LT). Evidence exists that females are penalized in the present allocation systems. Recently, new sex-adjusted scores have been proposed with improved performance respect to MELD and MELDNa. GEMA-Na, MELD 3.0, and sex-adjusted MELDNa were developed to improve the 90-day dropout prediction from the list. The present study aimed at evaluating the accuracy and calibration of these scores in an Italian setting. METHODS: The primary outcome of the present study was the dropout from the list up to 90 days because of death or clinical deterioration. We retrospectively analysed data from 855 adults enlisted for liver transplantation in the Lazio region (Italy) (2012-2018). Ninety-day prediction of GEMA-Na, MELD 3.0 and sex-adjusted MELDNa with respect to MELD and MELDNa was analysed. Brier score and Brier Skill score were used for accuracy, and the Greenwood-Nam-D'Agostino test was used to evaluate the calibration of the models. RESULTS: GEMA-Na (concordance = .82, 95% CI = .75-.89), MELD 3.0 (concordance = .81, 95% CI = .74-.87) and sex-adjusted MELDNa (concordance = .81, 95% CI = .74-.88) showed the best 90-day dropout prediction. GEMA-Na showed a higher increase in accuracy with respect to MELD (p = .03). No superiority was shown with respect to MELDNa. All the tested scores showed a good calibration of the models. Using GEMA-Na instead of MELD would potentially save one in nine dropouts and could save one dropout per 285 patients listed. CONCLUSIONS: Validation and reclassification of the sex-adjusted score GEMA-Na confirm its superiority in predicting short-term dropout also in an Italian setting when compared with MELD.

Rifaximin Reduces Risk of All-Cause Hospitalization in Cirrhotic Liver Transplant Candidates with Hepatic Encephalopathy.

In cirrhotic patients listed for liver transplantation (LT) with a history of hepatic encephalopathy (HE), rifaximin reduces the number of hospitalizations, but whether it influences the time to first hospitalization is unknown. AIMS: to evaluate the time-dependent impact of rifaximin on the risk of all-cause hospitalization and dropout in patients on the LT waiting list. METHODS: Consecutive patients listed for LT were retrospectively enrolled. After balancing populations with and without rifaximin treatment using the inverse probability therapy weighting analysis, Fine-Gray multivariable competing risk analyses were run to explore risk factors for the first episode of hospitalization and dropout. RESULTS: When comparing 92 patients taking rifaximin to the untreated group of 152, rifaximin treatment was not associated with any of the study outcomes. In the subset of patients with a history of HE at waitlist entry (N = 81 rifaximin-treated and N = 39 untreated), rifaximin intake was independently associated with a lower risk of hospitalization for all causes (SHR 0.638; 95.0% CI 0.418-0.973; p = 0.037) and for HE (SHR 0.379; 95.0% CI 0.207-0.693; p = 0.002). CONCLUSIONS: cirrhotic LT candidates with a prior history of HE rifaximin treatment are associated with a lower risk of time-dependent all-cause hospitalization, likely due to its unique effect on gut microbiome composition/function.

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.

The Role of Donor Gamma-Glutamyl Transferase as a Risk Factor for Early Graft Function after Liver Transplantation.

BACKGROUND: Growing interest has been recently reported in the potential detrimental role of donor gamma-glutamyl transferase (GGT) peak at the time of organ procurement regarding the risk of poor outcomes after liver transplantation (LT). However, the literature on this topic is scarce and controversial data exist on the mechanisms justifying such a correlation. This study aims to demonstrate the adverse effect of donor GGT in a large European LT cohort regarding 90-day post-transplant graft loss. METHODS: This is a retrospective international study investigating 1335 adult patients receiving a first LT from January 2004 to September 2018 in four collaborative European centers. RESULTS: Two different multivariable logistic regression models were constructed to evaluate the risk factors for 90-day post-transplant graft loss, introducing donor GGT as a continuous or dichotomous variable. In both models, donor GGT showed an independent role as a predictor of graft loss. In detail, the log-transformed continuous donor GGT value showed an odds ratio of 1.46 (95% CI = 1.03-2.07; p = 0.03). When the donor GGT peak value was dichotomized using a cut-off of 160 IU/L, the odds ratio was 1.90 (95% CI = 1.20-3.02; p = 0.006). When the graft-loss rates were investigated, significantly higher rates were reported in LT cases with donor GGT ≥160 IU/L. In detail, 90-day graft-loss rates were 23.2% vs. 13.9% in patients with high vs. low donor GGT, respectively (log-rank p = 0.004). Donor GGT was also added to scores conventionally used to predict outcomes (i.e., MELD, D-MELD, DRI, and BAR scores). In all cases, when the score was combined with the donor GGT, an improvement in the model accuracy was observed. CONCLUSIONS: Donor GGT could represent a valuable marker for evaluating graft quality at transplantation. Donor GGT should be implemented in scores aimed at predicting post-transplant clinical outcomes. The exact mechanisms correlating GGT and poor LT outcomes should be better clarified and need prospective studies focused on this topic.

Adult 10-year survivors after liver transplantation: a single-institution experience over 40 years.

Liver transplantation (LT) represents the best cure for several acute and chronic liver diseases. Several studies reported excellent mid-term survivals after LT. However, lesser evidence has been reported on very long (10- and 20-year) follow-up results. This study aims to analyze the monocentric LT experience of the Sapienza University of Rome to identify the pre-operatively available parameters limiting a 10-year post-transplant survival. A total of 491 patients transplanted between 1982 and 2012 were enrolled. The cohort was split into two groups, namely the Short Surviving Group (< 10 years; n = 228, 46.4%) and the Long Surviving Group (≥ 10 years; n = 263, 53.6%). Several differences were reported between the two groups regarding initial liver function, surgical techniques adopted, and immunosuppression. Four variables emerged as statistically relevant as independent risk factors for not reaching at least 10 years of follow-up: recipient age (OR = 1.02; P = 0.01), donor age (OR = 1.01; P = 0.03), being transplanted during the eighties (OR = 6.46; P < 0.0001) and nineties (OR = 2.63; P < 0.0001), and the UNOS status 1-2A (OR = 2.62; P < 0.0001). LT confirms to be an extraordinary therapy for several severe liver diseases, consenting to reach in half of the transplanted cases even more than 20 years of follow-up. The initial liver function and the donor and recipient ages are relevant in impacting long-term survival after transplantation. A broad commitment from many professional groups, including surgeons, hepatologists, and anesthesiologists, is necessary. The achievement of excellent results in terms of long-term survival is proof of the effectiveness of this multidisciplinary collaboration.

Improving outcomes of in situ split liver transplantation in Italy over the last 25 years.

BACKGROUND & AIMS: Split liver transplant(ation) (SLT) is still considered a challenging procedure that is by no means widely accepted. We aimed to present data on 25-year trends in SLT in Italy, and to investigate if, and to what extent, outcomes have improved nationwide during this time. METHODS: The study included all consecutive SLTs performed from May 1993 to December 2019, divided into three consecutive periods: 1993-2005, 2006-2014, and 2015-2019, which match changes in national allocation policies. Primary outcomes were patient and graft survival, and the relative impact of each study period. RESULTS: SLT accounted for 8.9% of all liver transplants performed in Italy. A total of 1,715 in situ split liver grafts were included in the analysis: 868 left lateral segments (LLSs) and 847 extended right grafts (ERGs). A significant improvement in patient and graft survival (p <0.001) was observed with ERGs over the three periods. Predictors of graft survival were cold ischaemia time (CIT) <6 h (p = 0.009), UNOS status 2b (p <0.001), UNOS status 3 (p = 0.009), and transplant centre volumes: 25-50 cases vs. <25 cases (p = 0.003). Patient survival was significantly higher with LLS grafts in period 2 vs. period 1 (p = 0.008). No significant improvement in graft survival was seen over the three periods, where predictors of graft survival were CIT <6 h (p = 0.007), CIT <6 h vs. ≥10 h (p = 0.019), UNOS status 2b (p = 0.038), and UNOS status 3 (p = 0.009). Retransplantation was a risk factor in split liver graft recipients, with significantly worse graft and patient survival for both types of graft (p <0.001). CONCLUSIONS: Our analysis showed Italian SLT outcomes to have improved over the last 25 years. These results could help to dispel reservations regarding the use of this procedure. IMPACT AND IMPLICATIONS: Split liver transplant(ation) (SLT) is still considered a challenging procedure and is by no means widely accepted. This study included all consecutive in situ SLTs performed in Italy from May 1993 to December 2019. With more than 1,700 cases, it is one of the largest series, examining long-term national trends in in situ SLT since its introduction. The data presented indicate that the outcomes of SLT improved during this 25-year period. Improvements are probably due to better recipient selection, refinements in surgical technique, conservative graft-to-recipient matching, and the continuous, yet carefully managed, expansion of donor selection criteria under a strict mandatory split liver allocation policy. These results could help to dispel reservations regarding the use of this procedure.

The Italian data on SARS-CoV-2 infection in transplanted patients support an organ specific immune response in liver recipients.

Introduction: The study of immune response to SARSCoV-2 infection in different solid organ transplant settings represents an opportunity for clarifying the interplay between SARS-CoV-2 and the immune system. In our nationwide registry study from Italy, we specifically evaluated, during the first wave pandemic, i.e., in non-vaccinated patients, COVID-19 prevalence of infection, mortality, and lethality in liver transplant recipients (LTRs), using non-liver solid transplant recipients (NL-SOTRs) and the Italian general population (GP) as comparators. Methods: Case collection started from February 21 to June 22, 2020, using the data from the National Institute of Health and National Transplant Center, whereas the data analysis was performed on September 30, 2020.To compare the sex- and age-adjusted distribution of infection, mortality, and lethality in LTRs, NL-SOTRs, and Italian GP we applied an indirect standardization method to determine the standardized rate. Results: Among the 43,983 Italian SOTRs with a functioning graft, LTRs accounted for 14,168 patients, of whom 89 were SARS-CoV-2 infected. In the 29,815 NL-SOTRs, 361 cases of SARS-CoV-2 infection were observed. The geographical distribution of the disease was highly variable across the different Italian regions. The standardized rate of infection, mortality, and lethality rates in LTRs resulted lower compared to NL-SOTRs [1.02 (95%CI 0.81-1.23) vs. 2.01 (95%CI 1.8-2.2); 1.0 (95%CI 0.5-1.5) vs. 4.5 (95%CI 3.6-5.3); 1.6 (95%CI 0.7-2.4) vs. 2.8 (95%CI 2.2-3.3), respectively] and comparable to the Italian GP. Discussion: According to the most recent studies on SOTRs and SARS-CoV-2 infection, our data strongly suggest that, in contrast to what was observed in NL-SOTRs receiving a similar immunosuppressive therapy, LTRs have the same risk of SARS-CoV-2 infection, mortality, and lethality observed in the general population. These results suggest an immune response to SARS-CoV-2 infection in LTRS that is different from NL-SOTRs, probably related to the ability of the grafted liver to induce immunotolerance.

Survival benefit of second line therapies for recurrent hepatocellular carcinoma: repeated hepatectomy, thermoablation and second-line transplant referral in a real life national scenario.

BACKGROUND: Despite second-line transplant(SLT) for recurrent hepatocellular carcinoma(rHCC) leads to the longest survival after recurrence(SAR), its real applicability has never been reported. The aim was to compare the SAR of SLT versus repeated hepatectomy and thermoablation(CUR group). METHODS: Patients were enrolled from the Italian register HE.RC.O.LE.S. between 2008 and 2021. Two groups were created: CUR versus SLT. A propensity score matching (PSM) was run to balance the groups. RESULTS: 743 patients were enrolled, CUR = 611 and SLT = 132. Median age at recurrence was 71(IQR 6575) years old and 60(IQR 53-64, p < 0.001) for CUR and SLT respectively. After PSM, median SAR for CUR was 43 months(95%CI = 37 - 93) and not reached for SLT(p < 0.001). SLT patients gained a survival benefit of 9.4 months if compared with CUR. MilanCriteria(MC)-In patients were 82.7% of the CUR group. SLT(HR 0.386, 95%CI = 0.23 - 0.63, p < 0.001) and the MELD score(HR 1.169, 95%CI = 1.07 - 1.27, p < 0.001) were the only predictors of mortality. In case of MC-Out, the only predictor of mortality was the number of nodules at recurrence(HR 1.45, 95%CI= 1.09 - 1.93, p = 0.011). CONCLUSION: It emerged an important transplant under referral in favour of repeated hepatectomy or thermoablation. In patients with MC-Out relapse, the benefit of SLT over CUR was not observed.

Severity of Hepatocyte Damage and Prognosis in Cirrhotic Patients Correlate with Hepatocyte Magnesium Depletion.

We aimed to evaluate the magnesium content in human cirrhotic liver and its correlation with serum AST levels, expression of hepatocellular injury, and MELDNa prognostic score. In liver biopsies obtained at liver transplantation, we measured the magnesium content in liver tissue in 27 cirrhotic patients (CIRs) and 16 deceased donors with healthy liver (CTRLs) by atomic absorption spectrometry and within hepatocytes of 15 CIRs using synchrotron-based X-ray fluorescence microscopy. In 31 CIRs and 10 CTRLs, we evaluated the immunohistochemical expression in hepatocytes of the transient receptor potential melastatin 7 (TRPM7), a magnesium influx chanzyme also involved in inflammation. CIRs showed a lower hepatic magnesium content (117.2 (IQR 110.5-132.9) vs. 162.8 (IQR 155.9-169.8) µg/g; p < 0.001) and a higher percentage of TRPM7 positive hepatocytes (53.0 (IQR 36.8-62.0) vs. 20.7 (10.7-32.8)%; p < 0.001) than CTRLs. In CIRs, MELDNa and serum AST at transplant correlated: (a) inversely with the magnesium content both in liver tissue and hepatocytes; and (b) directly with the percentage of hepatocytes stained intensely for TRPM7. The latter also directly correlated with the worsening of MELDNa at transplant compared to waitlisting. Magnesium depletion and overexpression of its influx chanzyme TRPM7 in hepatocytes are associated with severity of hepatocyte injury and prognosis in cirrhosis. These data represent the pathophysiological basis for a possible beneficial effect of magnesium supplementation in cirrhotic patients.

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.

A Low Daily Intake of Simple Sugars in the Diet Is Associated with Improved Liver Function in Cirrhotic Liver Transplant Candidates.

(1) Background: We investigated, for the first time, whether dietary simple sugar intake affects MELD score changes over time in a cohort of cirrhotic liver transplant candidates. (2) Methods: the MELD score, dietary habits using a 3-day food diary, and visceral adipose tissue index (VATI) measured with CT scan were assessed in 80 consecutive outpatient cirrhotic patients at baseline, after counseling to follow current nutritional guidelines. The MELD score was reassessed after six months and the DELTA-MELD was calculated as the MELD at the second assessment minus the MELD at baseline. (3) Results: Compared with the baseline, the MELD score of cirrhotic patients at the end of the study was decreased, stable, or increased in 36%, 8% and 56% of patients, respectively. In separate multiple linear regression models, DELTA-MELD was positively and independently correlated with the daily intake of simple sugars expressed in g/kg body weight (p = 0.01) or as a percentage of total caloric intake (p = 0.0004) and with the number of daily portions of fruit, added sugar, jam, and honey (p = 0.003). These associations were present almost exclusively in patients with VATI above the median value. (4) Conclusions: In cirrhotic patients with high amounts of visceral adipose tissue the consumption of simple sugars and fructose should be limited to improve their clinical outcome.

Outcome of liver transplantation in elderly patients: an Italian multicenter case-control study.

Despite the controversial results of liver transplantation (LT) in elderly recipients, the proportion of patients continues to increase. This study investigated the outcome of LT in elderly patients (≥ 65 years) in an Italian, multicenter cohort. Between January 2014 and December 2019, 693 eligible patients were transplanted, and two groups were compared: recipients ≥ 65 years (n = 174, 25.1%) versus 50-59 years (n = 519, 74.9%). Confounders were balanced using a stabilized inverse probability therapy weighting (IPTW). Elderly patients showed more frequent early allograft dysfunction (23.9 versus 16.8%, p = 0.04). Control patients had longer posttransplant hospital stays (median: 14 versus 13 days; p = 0.02), while no difference was observed for posttransplant complications (p = 0.20). At multivariable analysis, recipient age ≥ 65 years was an independent risk factor for patient death (HR 1.76; p = 0.002) and graft loss (HR 1.63; p = 0.005). The 3-month, 1-year, and 5-year patient survival rates were 82.6, 79.8, and 66.4% versus 91.1, 88.5, and 82.0% in the elderly and control group, respectively (log-rank p = 0.001). The 3-month, 1-year, and 5-year graft survival rates were 81.5, 78.7, and 66.0% versus 90.2, 87.2, and 79.9% in the elderly and control group, respectively (log-rank p = 0.003). Elderly patients with CIT > 420 min showed 3-month, 1-year, and 5-year patient survival rates of 75.7%, 72.8%, and 58.5% versus 90.4%, 86.5%, and 79.4% for controls (log-rank p = 0.001). LT in elderly (≥ 65 years) recipients provides favorable results, but inferior to those achieved in younger patients (50-59), especially when CIT > 7 h. Containment of cold ischemia time seems pivotal for favorable outcomes in this class of patients.

Human duodenal submucosal glands contain a defined stem/progenitor subpopulation with liver-specific regenerative potential.

BACKGROUND & AIMS: Common precursors for the liver, biliary tree, and pancreas exist at an early stage of development in the definitive endoderm forming the foregut. We have identified and characterised endodermal stem/progenitor cells with regenerative potential persisting in the adult human duodenum. METHODS: Human duodena were obtained from organ donors, and duodenal submucosal gland cells were isolated after removal of the mucosa layer. Cells were cultured on plastic or as organoids and were transplanted into severe combined immunodeficient (SCID) mouse livers. RESULTS: In situ studies of submucosal glands in the human duodenum revealed cells expressing stem/progenitor cell markers that had unique phenotypic traits distinguishable from intestinal crypt cells. Genetic signature studies indicated that the cells are closer to biliary tree stem cells and to definitive endodermal cells than to adult hepatocytes, supporting the interpretation that they are endodermal stem/progenitor cells. In vitro, human duodenal submucosal gland cells demonstrated clonal growth, capability to form organoids, and ability to acquire functional hepatocyte traits. In vivo, transplanted cells engrafted into the livers of immunocompromised mice and differentiated to mature liver cells. In an experimental model of fatty liver, human duodenal submucosal gland cells were able to rescue hosts from liver damage by supporting repopulation and regeneration of the liver. CONCLUSIONS: A cell population with clonal growth and organoid formation capability, which has liver differentiation potency in vitro and in vivo in murine experimental models, is present within adult duodenal submucosal glands. These cells can be isolated, do not require reprogramming, and thus could potentially represent a novel cell source for regenerative medicine of the liver. IMPACT AND IMPLICATIONS: Cell therapies for liver disease could represent an option to support liver function, but the identification of sustainable and viable cell sources is critical. Here, we describe a cell population with organoid formation capability and liver-specific regenerative potential in submucosal glands of the human duodenum. Duodenal submucosal gland cells are isolated from adult organs, do not require reprogramming, and could rescue hepatocellular damage in preclinical models of chronic, but not acute, liver injury. Duodenal submucosal gland cells could represent a potential candidate cell source for regenerative medicine of the liver, but the determination of cell dose and toxicity is needed before clinical testing in humans.

The Effect of a Liver Transplant Program on the Outcomes of Resectable Hepatocellular Carcinoma: A Nationwide Multicenter Analysis.

OBJECTIVE: To evaluate the effect of a liver transplantation (LT) program on the outcomes of resectable hepatocellular carcinoma (HCC). BACKGROUND: Surgical treatment of HCC includes both hepatic resection (HR) and LT. However, the presence of cirrhosis and the possibility of recurrence make the management of this disease complex and probably different according to the presence of a LT program. METHODS: Patients undergoing HR for HCC between January 2005 and December 2019 were identified from a national database of HCC. The main study outcomes were major surgical complications according to the Comprehensive Complication Index, posthepatectomy liver failure (PHLF), 90-day mortality, overall survival, and disease-free survival. Secondary outcomes were salvage liver transplantation (SLT) and postrecurrence survival. RESULTS: A total of 3202 patients were included from 25 hospitals over the study period. Three of 25 (12%) had an LT program. The presence of an LT program within a center was associated with a reduced probability of PHLF (odds ratio=0.38) but not with overall survival and disease-free survival. There was an increased probability of SLT when HR was performed in a transplant hospital (odds ratio=12.05). Among transplant-eligible patients, those who underwent LT had a significantly longer postrecurrence survival. CONCLUSIONS: This study showed that the presence of a LT program was associated with decreased PHLF rates and an increased probability to receive SLT in case of recurrence.