Performance of pre-transplant criteria in prediction of hepatocellular carcinoma progression and waitlist dropout.

BACKGROUND & AIM: Liver transplantation (LT) selection models for hepatocellular carcinoma (HCC) have not been proposed to predict waitlist dropout because of tumour progression. The aim of this study was to compare the alpha-foetoprotein (AFP) model and other pre-LT models in their prediction of HCC dropout. METHODS: A multicentre cohort study was conducted in 20 Latin American transplant centres, including 994 listed patients for LT with HCC from 2012 to 2018. Longitudinal tumour characteristics, and patterns of progression were recorded at time of listing, after treatments and at last follow-up over the waitlist period. Competing risk regression models were performed, and model's discrimination was compared estimating Harrell's adapted c-statistics. RESULTS: HCC dropout rate was significantly higher in patients beyond (24% [95% CI 16-28]) compared to those within Milan criteria (8% [95% IC 5%-12%]; p < .0001), with a SHR of 3.01 [95% CI 2.03-4.47]), adjusted for waiting list time and bridging therapies (c-index 0.63 [95% CI 0.57; 0.69). HCC dropout rates were higher in patients with AFP scores >2 (adjusted SHR of 3.17 [CI 2.13-4.71]), c-index of 0.71 (95% CI 0.65-0.77; p = .09 vs Milan). Similar discrimination power for HCC dropout was observed between the AFP score and the Metroticket 2.0 model. In patients within Milan, an AFP score >2 points discriminated two populations with a higher risk of HCC dropout (SHR 1.68 [95% CI 1.08-2.61]). CONCLUSIONS: Pre-transplant selection models similarly predicted HCC dropout. However, the AFP model can discriminate a higher risk of dropout among patients within Milan criteria.

Recurrence of hepatocellular carcinoma after liver transplantation: Prognostic and predictive factors of survival in a Latin American cohort.

BACKGROUND & AIM: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) has a poor prognosis, and the adjusted effect of different treatments on post-recurrence survival (PRS) has not been well defined. This study aims to evaluate prognostic and predictive variables associated with PRS. METHODS: This Latin American multicenter retrospective cohort study included HCC patients who underwent LT between the years 2005-2018. We evaluated the effect of baseline characteristics at time of HCC recurrence diagnosis and PRS (Cox regression analysis). Early recurrences were those occurring within 12 months of LT. To evaluate the adjusted treatment effect for HCC recurrence, a propensity score matching analysis was performed to assess the probability of having received any specific treatment for recurrence. RESULTS: From a total of 1085 transplanted HCC patients, the cumulative incidence of recurrence was 16.6% (CI 13.5-20.3), with median time to recurrence of 13.0 months (IQR 6.0-26.0). Factors independently associated with PRS were early recurrence (47.6%), treatment with sorafenib and surgery/trans-arterial chemoembolization (TACE). Patients who underwent any treatment presented "early recurrences" less frequently, and more extrahepatic metastasis. This unbalanced distribution was included in the propensity score matching, with correct calibration and discrimination (receiving operator curve of 0.81 [CI 0.72;0.88]). After matching, the adjusted effect on PRS for any treatment was HR of 0.2 (0.10;0.33); P < .0001, for sorafenib therapy HR of 0.4 (0.27;0.77); P = .003, and for surgery/TACE HR of 0.4 (0.18;0.78); P = .009. CONCLUSION: Although early recurrence was associated with worse outcome, even in this population, systemic or locoregional treatments were associated with better PRS.

Liver transplantation for hepatocellular carcinoma: impact of expansion criteria in a multicenter cohort study from a high waitlist mortality region.

This study aimed to compare liver transplantation (LT) outcomes and evaluate the potential rise in numbers of LT candidates with hepatocellular carcinoma (HCC) of different allocation policies in a high waitlist mortality region. Three policies were applied in two Latin American cohorts (1085 HCC transplanted patients and 917 listed patients for HCC): (i) Milan criteria with expansion according to UCSF downstaging (UCSF-DS), (ii) the AFP score, and (iii) restrictive policy or Double Eligibility Criteria (DEC; within Milan + AFP score ≤2). Increase in HCC patient numbers was evaluated in an Argentinian prospective validation set (INCUCAI; NCT03775863). Expansion criteria in policy A showed that UCSF-DS [28.4% (CI 12.8-56.2)] or "all-comers" [32.9% (CI 11.9-71.3)] had higher 5-year recurrence rates compared to Milan, with 10.9% increase in HCC patients for LT. The policy B showed lower recurrence rates for AFP scores ≤2 points, even expanding beyond Milan criteria, with a 3.3% increase. Patients within DEC had lower 5-year recurrence rates compared with those beyond DEC [13.3% (CI 10.1-17.3) vs 24.2% (CI 17.4-33.1; P = 0.0006], without significant HCC expansion. In conclusion, although the application of a stricter policy may optimize the selection process, this restrictive policy may lead to ethical concerns in organ allocation (NCT03775863).

Direct-Acting Antivirals and Hepatocellular Carcinoma: No Evidence of Higher Wait-List Progression or Posttransplant Recurrence.

The association between direct-acting antivirals (DAAs) and hepatocellular carcinoma (HCC) wait-list progression or its recurrence following liver transplantation (LT) remains uncertain. We evaluated the impact of DAAs on HCC wait-list progression and post-LT recurrence. This Latin American multicenter retrospective cohort study included HCC patients listed for LT between 2012 and 2018. Patients were grouped according to etiology of liver disease: hepatitis C virus (HCV) negative, HCV+ never treated with DAAs, and HCV+ treated with DAAs either before or after transplantation. Multivariate competing risks models were conducted for both HCC wait-list progression adjusted by a propensity score matching (pre-LT DAA effect) and for post-LT HCC recurrence (pre- or post-LT DAA effect). From 994 included patients, 50.6% were HCV-, 32.9% were HCV+ never treated with DAAs, and 16.5% were HCV+ treated with DAAs either before (n = 66) or after LT (n = 98). Patients treated with DAAs before LT presented similar cumulative incidence of wait-list tumor progression when compared with those patients who were HCV+ without DAAs (26.2% versus 26.9%; P = 0.47) and a similar HCC-related dropout rate (12.1% [95% CI, 0.4%-8.1%] versus 12.9% [95% CI, 3.8%-27.2%]), adjusted for baseline tumor burden, alpha-fetoprotein values, HCC diagnosis after listing, bridging therapies, and by the probability of having received or not received DAAs through propensity score matching (subhazard ratio [SHR], 0.9; 95% CI, 0.6-1.6; P = 0.95). A lower incidence of posttransplant HCC recurrence among HCV+ patients who were treated with pre- or post-LT DAAs was observed (SHR, 0.7%; 95% CI, 0.2%-4.0%). However, this effect was confounded by the time to DAA initiation after LT. In conclusion, in this multicenter cohort, HCV treatment with DAAs did not appear to be associated with an increased wait-list tumor progression and HCC recurrence after LT.

International and multicenter real-world study of sorafenib-treated patients with hepatocellular carcinoma under dialysis.

BACKGROUND & AIMS: Information on safety and efficacy of systemic treatment in patients with hepatocellular carcinoma (HCC) under dialysis are limited due to patient exclusion from clinical trials. Thus, we aimed to evaluate the rate, prevalence, tolerability, and outcome of sorafenib in this population. METHODS: We report a multicenter study comprising patients from Latin America and Europe. Patients treated with sorafenib were enrolled; demographics, dose modifications, adverse events (AEs), treatment duration, and outcome of patients undergoing dialysis were recorded. RESULTS: As of March 2018, 6156 HCC patients were treated in 44 centres and 22 patients were concomitantly under dialysis (0.36%). The median age was 65.5 years, 40.9% had hepatitis C, 75% had Child-Pugh A, and 85% were Barcelona Clinic Liver Cancer-C. The median time to first dose modification, treatment duration and overall survival rate were 2.4 months (interquartile ranges [IQR], 0.8-3.8), 10.8 months (IQR, 4.5-16.9), and 17.5 months (95% CI, 7.2-24.5), respectively. Seventeen patients required at least 1 dose modification. The main causes of first dose modification were asthenia/worsening of Eastern Cooperative Oncology Group-Performance Status and diarrhoea. At the time of death or last follow-up, four patients were still on treatment and 18 had discontinued sorafenib: 14 were due to tumour progression, 2 were sorafenib-related, and 2 were non-sorafenib-related AE. CONCLUSIONS: The outcomes observed in this cohort seem comparable to those in the non-dialysis population. Thus, to the best of our knowledge, this is the largest and most informative dataset regarding systemic treatment outcomes in HCC patients undergoing dialysis.

Results of Liver Transplantation for Hepatocellular Carcinoma in a Multicenter Latin American Cohort Study.

BACKGROUND AND AIMS: Heterogeneous data has been reported regarding liver transplantation (LT) for hepatocellular carcinoma (HCC) in Latin America. We aimed to describe treatment during waiting list, survival and recurrence of HCC after LT in a multicenter study from Latin America. MATERIAL AND METHODS: Patients with HCC diagnosed prior to transplant (cHCC) and incidentally found in the explanted liver (iHCC) were included. Imaging-explanted features were compared in cHCC (non-discordant if pre and post-LT were within Milan, discordant if pre-LT was within and post-LT exceeding Milan). RESULTS: Overall, 435 patients with cHCC and 92 with iHCC were included. At listing, 81% and 91% of cHCC patients were within Milan and San Francisco criteria (UCSF), respectively. Five-year survival and recurrence rates for cHCC within Milan, exceeding Milan/within UCSF and beyond UCSF were 71% and 16%; 66% and 26%; 46% and 55%, respectively. Locoregional treatment prior to LT was performed in 39% of cHCC within Milan, in 53% beyond Milan/within UCSF and in 83% exceeding UCSF (p < 0.0001). This treatment difference was not observed according to AFP values (≤100, 44%; 101-1,000, 39%, and > 1,000 ng/mL 64%; p = 0.12). Discordant imaging-explanted data was observed in 29% of cHCC, showing lower survival HR 2.02 (CI 1.29; 3.15) and higher recurrence rates HR 2.34 when compared to AFP <100 ng/mL. Serum AFP > 1,000 ng/mL at listing was independently associated with a higher 5-year recurrence rate and a HR of 3.24 when compared to AFP <100 ng/mL. CONCLUSION: Although overall results are comparable to other regions worldwide, pre-LT treatment not only considering imaging data but also AFP values should be contemplated during the next years.

Liver transplantation for hepatocellular carcinoma: evaluation of the alpha-fetoprotein model in a multicenter cohort from Latin America.

BACKGROUND & AIMS: The French alpha-fetoprotein (AFP) model has recently shown superior results compared to Milan criteria (MC) for prediction of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) in European populations. The aim of this study was to explore the predictive capacity of the AFP model for HCC recurrence in a Latin-American cohort. METHODS: Three hundred twenty-seven patients with HCC were included from a total of 2018 patients transplanted at 15 centres. Serum AFP and imaging data were both recorded at listing. Predictability was assessed by the Net Reclassification Improvement (NRI) method. RESULTS: Overall, 82 and 79% of the patients were within MC and the AFP model respectively. NRI showed a superior predictability of the AFP model against MC. Patients with an AFP score >2 points had higher risk of recurrence at 5 years Hazard Ratio (HR) of 3.15 (P = 0.0001) and lower patient survival (HR = 1.51; P = 0.03). Among patients exceeding MC, a score ≤2 points identified a subgroup of patients with lower recurrence (5% vs 42%; P = 0.013) and higher survival rates (84% vs 45%; P = 0.038). In cases treated with bridging procedures, following restaging, a score >2 points identified a higher recurrence (HR 2.2, P = 0.12) and lower survival rate (HR 2.25, P = 0.03). A comparative analysis between HBV and non-HBV patients showed that the AFP model performed better in non-HBV patients. CONCLUSIONS: The AFP model could be useful in Latin-American countries to better select patients for LT in subgroups presenting with extended criteria. However, particular attention should be focused on patients with HBV.

Predictive Cardiometabolic Risk Profiling of Patients Using Vascular Age in Liver Transplantation.

Liver transplantation is the last therapeutic option in patients with end-stage liver diseases. The adequate clinical management of transplant-patients impacts their vital prognosis and decisions on many occasions are made from the interaction of multiple variables involved in the process. This work is based on the National Liver Transplantation Program in Uruguay. We performed predictive analysis of cardiometabolic diseases on the transplanted cohort between 2014 and 2019, considering vascular age as a key factor. This aims at classification of the cohort based on the vascular age of the evaluated patients before transplantation for risk-profiling. Predicted high-risk group of the patients showed substantial deterioration of post-transplant health-conditions, including higher mortality rate. In our knowledge, this is the first study in Latin America incorporating vascular age toward predictive analysis of cardiometabolic risk factors in liver transplantations. Predictive risk-modeling using vascular age in a pre-transplantation scenario provides significant opportunity for early prediction of post-transplant risk factors, leading to efficient treatment with anticipation.

A changing etiologic scenario in liver transplantation for hepatocellular carcinoma in a multicenter cohort study from Latin America.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of hepatocellular carcinoma (HCC) and liver transplantation (LT). Our study focused on changing trends of liver related HCC etiologies during the last years in Latin America. METHODS: From a cohort of 2761 consecutive adult LT patients between 2005 and 2012 in 17 different centers, 435 with HCC were included. Different periods including years 2005-2006, 2007-2008, 2009-2010 and 2011-2012 were considered. Etiology of liver disease was confirmed in the explant. RESULTS: Participating LT centers per country included 2 from Brazil (n=191), 5 transplant programs from Argentina (n=98), 2 from Colombia (n=65), 4 from Chile (n=49), 2 from Mexico (n=12), and 1 from Peru (n=11) and Uruguay (n=9). Chronic hepatitis C infection was the leading cause of HCC in the overall cohort (37%), followed by HBV (25%) and alcoholic liver disease (17%). NAFLD and cryptogenic cirrhosis accounted for 6% and 7%, respectively. While HCV decreased from 48% in 2005-06 to 26% in 2011-12, NAFLD increased from 1.8% to 12.8% during the same period, accounting for the third cause of HCC. This represented a 6-fold increase in NAFLD-HCC, whereas HCV had a 2-fold decrease. Patients with NAFLD were older, had lower pre-LT serum AFP values and similar 5-year survival and recurrence rates than non-NAFLD. CONCLUSION: There might be a global changing figure regarding etiologies of HCC in Latin America. This epidemiological change on the incidence of HCC in the world, although it has been reported, should still be confirmed in prospective studies.

Resultados del Programa Nacional de Trasplante Hepático del Uruguay a 10 años de su inicio / Results of the National Program of Liver Transplantation in Uruguay 10 years after it was initiated / Resultados do Programa Nacional de Transplante de Fígado do Uruguai 10 anos após seu início

Resumen: Introducción: el trasplante hepático (TH) constituye el tratamiento de elección en pacientes con enfermedades hepáticas severas e irreversibles, sin opción de tratamientos alternativos eficaces. La medición de indicadores de calidad permite detectar problemáticas susceptibles de ser mejoradas a fin de optimizar los resultados. Objetivo: presentar los resultados del Programa Nacional de Trasplante Hepático (PNTH) del Uruguay a 10 años de su implementación y compararlos con los estándares de calidad internacionales. Material y método: estudio retrospectivo de los TH realizados del 14/7/2009 al 14/7/2019. Resultados: N: 190 TH. Edad promedio: 45 años. Sexo: 60% hombres. MELD promedio al TH: 21. Principales indicaciones: cirrosis (59%) y hepatocarcinoma (21%). Mortalidad posoperatoria: 7,4% y perioperatoria: 2,1% (estándares <10% y 1%). Tasa de retrasplante: precoz 3,7% y tardío 4,2% (estándares <5% y 8%). Tasa de reintervención: 13,1% (estándar <10%) y de no función primaria: 2,6% (estándar <2%). Sobrevida: 86,6% al año, 81,8% a 3, 77,4% a 5 y 63,2% a 10 años (estándares >80, 75, 70 y 60%). Pacientes evaluados en menos de 30 días: 47% (estándar >75%). Tasa de hígados no implantados sin causa objetiva: 0,5% (estándar <1%). El 86% de los usuarios expresaron satisfacción (estándar >80%). Mortalidad en lista: 19% (estándar <15%). Mortalidad precoz con hígado funcionante: 1% (estándar <1%). Conclusiones: el PNTH del Uruguay cumple con la mayoría de los indicadores de calidad, presentando resultados en sobrevida por encima de los estándares internacionales.

Summary: Introduction: liver transplantation constitutes the first therapy chosen by patients with severe and irreversible liver conditions, when no effective alternative options are available. Measurement of quality indicators allow for the detection of problems that may be solved in order to optimize results. Objective: to present the results obtained in the National Program of Liver Transplantation in Uruguay, 10 years after its implementation and to compare them to international quality standards. Method: retrospective study of liver transplantations performed from July 14, 2009 through July 14, 2019. Results: N: 190 Liver transplantations (LT). Average age: 45 years old. Gender: 60% male. MELD average MELD (Model for End-stage Liver Disease) upon LT: 21. Main indications: cirrhosis he(59%) y hepatocarcinoma (21%). Post-surgery mortality: 7.4% and peri-operative mortality 2.1% (standards <10 and 1%). Re-transplantation rate: early 3.7% and late 4.2% (standards <5% and 8%). Reoperation rate: 13.1% (standard <10%) and of non-primary function: 2.6% (standard <2%). Survival: 86.6% per year, 81.8% after 3 years, 77.4% after 5 and 63.2% after 10 years (standards >80, 75, 70 and 60%). Patients assessed in less than 30 days: 47% (standard >75%). Non-implanted livers with no objective cause rate: 0.5% (standard <1%). 86% of users stated they were satisfied (standard >80%). Mortality in the waiting list: 19% (standard <15%). Early mortality with functioning liver: 1% (standard <1%). Conclusions: national Program of Liver Transplantation in Uruguay meets most quality indicators standards, evidencing survival results that are above international standards.

Resumo: Introdução: o transplante de fígado (TH) é o tratamento de escolha em pacientes com doenças hepáticas graves e irreversíveis, sem a opção de tratamentos alternativos eficazes. A medição de indicadores de qualidade permite detectar problemas que podem ser melhorados para otimizar os resultados. Objetivo: apresentar os resultados do Programa Nacional de Transplante de Fígado (PNTH) do Uruguai 10 anos após sua implantação e compará-los com os padrões internacionais de qualidade. Materiais e métodos: estudo retrospectivo do HT realizado de 14/07/2009 a 14/07/2019. Resultados: N: 190 TH. Idade média: 45 anos. Sexo: 60% homens. Escala MELD média no TH: 21. Principais indicações: cirrose (59%) e hepatocarcinoma (21%). Mortalidade pós-operatória: 7,4% e peri-operatória 2,1% (padrões <10 e 1%). Taxa de retransplante: 3,7% inicial e 4,2% tardio (padrão <5% e 8%). Taxa de reintervenção: 13,1% (padrão <10%) e não função primária: 2,6% (padrão <2%). Sobrevivência: 86,6% em 1 ano, 81,8% em 3, 77,4% em 5 e 63,2% em 10 anos (padrões> 80, 75, 70 e 60%). Pacientes avaliados em menos de 30 dias: 47% (padrão> 75%). Taxa de fígados não implantados sem causa objetiva: 0,5% (padrão <1%). 86% dos usuários expressaram satisfação (padrão> 80%). Mortalidade em lista de espera: 19% (padrão <15%). Mortalidade precoce com fígado funcionante: 1% (padrão <1%). Conclusões: o PNTH do Uruguai cumpre a maioria dos indicadores de qualidade, apresentando resultados de sobrevivência acima dos padrões internacionais.

Infección de sitio quirúrgico en el Programa de Trasplante Hepático en Uruguay: alta incidencia de bacilos gramnegativos multirresistentes y extremadamente resistentes / Surgical site infection in the Liver Transplant Program in Uruguay: high incidence of multiresistant and extremely resistant gram-negative bacilli

Introducción: la infección de sitio quirúrgico (ISQ) en trasplante hepático (TH) significa para estos pacientes una importante causa de morbimortalidad. Objetivo: conocer la incidencia de ISQ, identificar microorganismos involucrados y factores favorecedores en vistas de optimizar nuestras estrategias de profilaxis. Material y método: estudio de cohorte en el cual los pacientes con trasplante hepático fueron incluidos prospectivamente en nuestra base de datos nacional, BaDaInTOS. Período de estudio: 14 de julio de 2009 a 31 de mayo 2013. Análisis estadístico: se utilizó chi cuadrado. Si el valor en tabla de contingencia fue menor o igual a 5 se usó el test exacto de Fisher. Se consideró significativo un valor de p < 0,05. Resultados: se trasplantaron 65 pacientes en este período. La frecuencia relativa acumulada de ISQ fue de 12 pacientes (18,46%); la distribución temporal muestra un aumento en su incidencia en los últimos 12 meses donde se presentaron siete episodios (58%) de todos los episodios de ISQ. La mediana de presentación fue de 17 días. Del total de pacientes con ISQ, 7 presentaron factores de riesgo para microorganismos multirresistentes en el pretrasplante. Se aislaron 16 microorganismos, 12 correspondieron a bacilos gramnegativos (BGN): (Klebsiella spp, n = 6), (Acinetobacter baumannii, n = 2), (Enterobacter cloacae, n = 1), (Aeromonas spp, n = 1), (Pseudomonas aeruginosa, n = 1), (E. coli, n = 1). En cuanto al perfil de resistencia: diez pacientes presentaron perfil de multirresistencia (MDR) y extremada resistencia (XDR). Conclusiones: uno de cada cinco pacientes presentó ISQ en nuestro centro, con una alta incidencia de BGN, MDR y XDR.