Cumulative exposure to tacrolimus and incidence of cancer after liver transplantation.

Cancer is the leading cause of death after liver transplantation (LT). This multicenter case-control nested study aimed to evaluate the effect of maintenance immunosuppression on post-LT malignancy. The eligible cohort included 2495 LT patients who received tacrolimus-based immunosuppression. After 13 922 person/years follow-up, 425 patients (19.7%) developed malignancy (cases) and were matched with 425 controls by propensity score based on age, gender, smoking habit, etiology of liver disease, and hepatocellular carcinoma (HCC) before LT. The independent predictors of post-LT malignancy were older age (HR = 1.06 [95% CI 1.05-1.07]; p < .001), male sex (HR = 1.50 [95% CI 1.14-1.99]), smoking habit (HR = 1.96 [95% CI 1.42-2.66]), and alcoholic liver disease (HR = 1.53 [95% CI 1.19-1.97]). In selected cases and controls (n = 850), the immunosuppression protocol was similar (p = .51). An increased cumulative exposure to tacrolimus (CET), calculated by the area under curve of trough concentrations, was the only immunosuppression-related predictor of post-LT malignancy after controlling for clinical features and baseline HCC (CET at 3 months p = .001 and CET at 12 months p = .004). This effect was consistent for de novo malignancy (after excluding HCC recurrence) and for internal neoplasms (after excluding non-melanoma skin cancer). Therefore, tacrolimus minimization, as monitored by CET, is the key to modulate immunosuppression in order to prevent cancer after LT.

Post-transplant lymphoproliferative disease in liver transplant recipients.

INTRODUCTION: Post-transplant lymphoproliferative syndrome (PTLD) is a rare and potentially life-threatening complication after liver transplantation. The aim of this study was to analyze the clinicopathologic features related to PTLD in a single institution after liver transplantation. METHODS: Observational study where we have retrospectively analyzed 851 cases who underwent liver transplantation. Ten cases have developed PTLD. Their clinical-pathological characteristics and the treatment received have been analyzed. RESULTS: PTLD incidence was 1.2% (10/851). The mean time from liver transplantation to PTLD diagnosis was 36 months (range 1.2 to 144 months). PTLD localization was extranodal in all cases, the most frequent location being intestinal. Seven cases showed a monomorphic lymphoma which in all cases was differentiated B cell lymphomas. Fifty per cent of the series were seropositive for Epstein-Barr virus. Five patients were alive at the time of the review. Among these patients, we observed three cases of complete remission and two cases of disease stabilization. The death rate was higher in the first year after diagnosis of PTLD. CONCLUSION: PTLD is a rare complication after liver transplantation, but it may pose a threat to the life of a liver transplant recipient. It is essential to identify patients at risk, to establish an early diagnosis and treatment that can change the outcome of the disease.

Is the sinusoidal obstructive syndrome post-liver transplantation a pathologic entity with a multifactorial etiology?

The sinusoidal obstructive syndrome is a complication typically associated with hematopoietic stem cell transplantation. This syndrome, more commonly known as veno-occlusive disease, has also been described after liver transplantation. It can have a life-threatening course. Herein, we describe the hepatic graft loss secondary to the development of a sinusoidal obstructive syndrome after a severe acute cellular rejection and toxic levels of once daily modified released tacrolimus (TAC). We discuss the role of the endotheliitis of acute rejection and toxic metabolites of some immunosuppressants such as azathioprine and TAC. Based on the current scientific evidence, we contemplate the possibility that the etiology of sinusoidal obstruction syndrome post-liver transplantation is multifactorial.

Development of a liver graft assessment expert machine-learning system: when the artificial intelligence helps liver transplant surgeons.

Background: The complex process of liver graft assessment is one point for improvement in liver transplantation. The main objective of this study is to develop a tool that supports the surgeon who is responsible for liver donation in the decision-making process whether to accept a graft or not using the initial variables available to it. Material and method: Liver graft samples candidate for liver transplantation after donor brain death were studied. All of them were evaluated "in situ" for transplantation, and those discarded after the "in situ" evaluation were considered as no transplantable liver grafts, while those grafts transplanted after "in situ" evaluation were considered as transplantable liver grafts. First, a single-center, retrospective and cohort study identifying the risk factors associated with the no transplantable group was performed. Then, a prediction model decision support system based on machine learning, and using a tree ensemble boosting classifier that is capable of helping to decide whether to accept or decline a donor liver graft, was developed. Results: A total of 350 liver grafts that were evaluated for liver transplantation were studied. Steatosis was the most frequent reason for classifying grafts as no transplantable, and the main risk factors identified in the univariant study were age, dyslipidemia, personal medical history, personal surgical history, bilirubinemia, and the result of previous liver ultrasound (p < 0.05). When studying the developed model, we observe that the best performance reordering in terms of accuracy corresponds to 76.29% with an area under the curve of 0.79. Furthermore, the model provides a classification together with a confidence index of reliability, for most cases in our data, with the probability of success in the prediction being above 0.85. Conclusion: The tool presented in this study obtains a high accuracy in predicting whether a liver graft will be transplanted or deemed non-transplantable based on the initial variables assigned to it. The inherent capacity for improvement in the system causes the rate of correct predictions to increase as new data are entered. Therefore, we believe it is a tool that can help optimize the graft pool for liver transplantation.

Impact of a Donor Age >75 Years on the Survival of Liver Transplant Recipients.

BACKGROUND: An organ shortage is the reason why it is necessary to expand the pool of donors, which can be achieved by using elderly donors. The main goal of this study is to analyze the outcomes of liver transplant (LT) when it is performed with donors older than 75 years. METHODS: We carried out a retrospective case-control study (N = 212) that included LTs with donors older than 75 years (group A, n = 106 cases) that were performed in our center between the years 2010 and 2020. This cohort has been paired off with a similar control group (group B, n = 106) whose donors were significantly younger. A survival analysis using the Kaplan-Meier model was performed. RESULTS: Average (SD) age of donors in group A was statistically greater than group B (A, 79.1 [3.0] years vs B, 54.4 [15.3], P < .001). There were no differences either in the average age of the recipients or in the Model for End-Stage Liver Disease score of both groups. Indications for LT were distributed equally in both groups: the most common was cellular hepatocarcinoma followed by alcohol-related cirrhosis. Survival rates for group A were 81%, 78%, and 67%, in 1, 3, and 5 years, respectively, while in group B they were 85%, 76%, and 71%, respectively, without differences found between the groups (P = .57). CONCLUSIONS: Using elderly liver donors is safe, achieving good outcomes in terms of short- and midterm rates of survival.

Risk Factors for No Valid Liver Graft. Multivariate Study Based on the Variables Included in the Donation Protocol of the National Trasplant Organisation. / Factores de riesgo para injertos hepáticos no válidos. Estudio multivariante a partir de las variables recogidas en el protocolo de donación de la Organización Nacional de Trasplantes.

INTRODUCTION: Among the strategies designed to optimize the number of existing liver grafts for transplantation, the implementation of the graft assessment process is one of the least explored. The main objective is to identify the risk factors presented by liver donors for «NO validity¼. Secondly, we analyzed the coincidence between the surgeon's assessment and that of the anatomo-pathologist in the invalid donors. MATERIAL AND METHOD: Retrospective study conducted from a prospective database that analyzes 190 liver donors, 95 valid and 95 NOT valid. The variables of each of them corresponding to the donation protocol of the National Transplant Organization are studied. Through a multivariate study we determine the independent risk factors of NO validity. We checked the causes of NO validity argued with the histopathological findings of these grafts. RESULTS: The independent risk factors of non-validity in the multivariate study (P < .05) were: dyslipidemia, personal medical history other than cardiovascular and abdominal surgical risk factors, GGT, BrT, and the result of previous liver ultrasound. The 3 most frequent causes of NO validity were: steatosis, fibrosis and macroscopic appearance of the organ. 78% of the biopsies confirmed the NO validity of the graft (in 57.9% of the cases the histological findings coincided with those described by the surgeon). The 22.1% of the biopsies hadnt pathological findings. CONCLUSIONS: The determination of the risk factors of NO validity will contribute to the design of future assessment scores that are useful tools in the process of liver graft assessment.).

1000 consecutive liver transplants. Descriptive analysis and evolution of a single center. / 1000 trasplantes hepáticos consecutivos. Análisis descriptivo y evolución de un centro.

Between 1991 and 2013, 1,000 liver transplantations were performed at Virgen del Rocio Hospital (Seville, Spain). A retrospective study was conducted, analyzing the characteristics of recipients and donors, indications, surgical technique, complications and survival in 2 different stages (1991-2002 vs. 2003-2013) coinciding with the implementation of the MELD scale as a prioritization model. The most frequent indication were of hepatopathy of hepatocellular origin in 48.8%. There was a significant increase in the indications for hepatocarcinoma (8.6% and 24.1% P=0.03), and the rate of retransplantation (5.9% vs 9.6%, P=0.04). There was a change in the age of donation, going from 27.7 years in 1990 to 62.9 years in 2012 (P=0.001). The percentage of patients who did not require blood transfusion doubled (6.16 vs. 14.31%, P=.001). Survival of all patients after one, 5 and 10 years was 77, 63.5 and 51.3%, respectively.

Incidence and survival rate of de novo tumors in liver transplants. / Incidencia y supervivencia de los tumores de novo en el trasplante hepático.

INTRODUCTION: The greater survival of transplanted patients is accompanied by an increase in the rate of de novo malignancies (NM), which are the most frequent late-onset complication. We can distinguish between non-melanoma skin cancers (NMSC), post-transplant lymphoproliferative disorders (PTLD) and solid organ cancers (SOC). Our objective is to determine the incidence of the different types of NM, the time elapsed until diagnosis and survival rates in our setting. METHODS: We conducted a retrospective study of 1071 liver transplant patients from 1990 to 2015 at our center. We analyzed the demographic variables, incidence of NM and survival. RESULTS: 184 NM developed in 1071 transplant patients (17%), specifically 19% of the males and 13% of the females (P=.004). The most frequent NM were NMSC (29%), lung (18%), head and neck (16%), PTLD (10%) and gastrointestinal (8%). The median time of diagnosis was 7.9 years in NMSC, 3.9 years in PTLD and 9.8 years in SOC. Patients with NMSC had significantly better survival than those with PTLD or SOC. The incidence of de novo tumors (excluding NMSC) was 1889/100,000 transplants/year. By gender, lung cancer was the most common TOS in men and breast cancer in women. CONCLUSION: In our setting, excluding NMSC, the incidence is 8.8 times greater than estimations for the general population, with a high rate of lung cancer, so we should implement preventive and diagnostic strategies.

Monitoring of transplanted liver health by quantification of organ-specific genomic marker in circulating DNA from receptor.

BACKGROUND: Health assessment of the transplanted organ is very important due to the relationship of long-term survival of organ transplant recipients and health organ maintenance. Nowadays, the measurement of cell-free DNA from grafts in the circulation of transplant recipients has been considered a potential biomarker of organ rejection or transplant associated complications in an attempt to replace or reduce liver biopsy. However, methods developed to date are expensive and extremely time-consuming. Our approach was to measure the SRY gene, as a male organ biomarker, in a setting of sex-mismatched female recipients of male donor organs. METHODS: Cell-free DNA quantization of the SRY gene was performed by real-time quantitative PCR beforehand, at the moment of transplantation during reperfusion (day 0) and during the stay at the intensive care unit. Beta-globin cell-free DNA levels, a general cellular damage marker, were also quantified. RESULTS: Beta-globin mean values of patients, who accepted the graft without any complications during the first week after surgery, diminished from day 0 until patient stabilization. This decrease was not so evident in patients who suffered some kind of post-transplantation complications. All patients showed an increase in SRY levels at day 0, which decreased during hospitalization. Different complications that did not compromise donated organs showed increased beta-globin levels but no SRY gene levels. However, when a donated organ was damaged the patients exhibited high levels of both genes. CONCLUSION: Determination of a SRY gene in a female recipient's serum is a clear and specific biomarker of donated organs and may give us important information about graft health in a short period of time by a non-expensive technique. This approach may permit clinicians to maintain a close follow up of the transplanted patient.

1000 trasplantes hepáticos consecutivos. Análisis descriptivo y evolución de un centro / 1000 consecutive liver transplants. Descriptive analysis and evolution of a single center

Desde 1991 a 2013 se realizaron en el Hospital Virgen del Rocío 1.000 trasplantes hepáticos. Se realizó un estudio retrospectivo, en el que se analizaron las características de los donantes y los receptores, las indicaciones, la técnica quirúrgica, las complicaciones y la supervivencia en 2 etapas diferentes (1991-2002 vs. 2003-2013), coincidiendo con la implantación del MELD como modelo de priorización. La indicación más frecuente fue la hepatopatía de origen hepatocelular en 48,8%. Hubo un incremento significativo en las indicaciones por hepatocarcinoma (8,6% y 24,1% p = 0,03), y de la tasa retrasplantes (5,9% Vs 9,6%, p = 0,04). Se apreció un cambio en la edad de donación, pasando de 27,7 años en 1990 a 62,9 años en 2012 (p = 0,001). El porcentaje de pacientes que no precisaron transfusión de hemoderivados se duplicó (6,16 vs. 14,31%, p = 0,001). La supervivencia de todos los pacientes a uno, 5 y 10 años fue del 77, 63,5 y 51,3%, respectivamente

Between 1991 and 2013, 1,000 liver transplantations were performed at Virgen del Rocio Hospital (Seville, Spain). A retrospective study was conducted, analyzing the characteristics of recipients and donors, indications, surgical technique, complications and survival in 2 different stages (1991-2002 vs. 2003-2013) coinciding with the implementation of the MELD scale as a prioritization model. The most frequent indication were of hepatopathy of hepatocellular origin in 48.8%. There was a significant increase in the indications for hepatocarcinoma (8.6% and 24.1% P = 0.03), and the rate of retransplantation (5.9% vs 9.6%, P = 0.04). There was a change in the age of donation, going from 27.7 years in 1990 to 62.9 years in 2012 (P = 0.001). The percentage of patients who did not require blood transfusion doubled (6.16 vs. 14.31%, P = .001). Survival of all patients after one, 5 and 10 years was 77, 63.5 and 51.3%, respectively

Incidencia y supervivencia de los tumores de novo en el trasplante hepático / Incidence and survival rate of de novo tumors in liver transplants

INTRODUCCIÓN: La mayor supervivencia del paciente trasplantado viene acompañada del aumento en la tasa de tumores de novo (TN) que representan la complicación tardía más frecuente. Podemos distinguir entre tumores de piel no melanoma (TPNM), síndrome linfoproliferativo postrasplante (SLPT) y tumores de órgano sólido (TOS). Nuestro objetivo es determinar la incidencia de los distintos TN, el tiempo trascurrido hasta su diagnóstico y su supervivencia en nuestro medio. MATERIAL Y MÉTODO: Realizamos un estudio retrospectivo de 1.071 trasplantados hepáticos desde 1990 hasta 2015 en nuestro centro. Analizamos las variables demográficas, la incidencia de TN y la supervivencia. RESULTADOS: Se desarrollaron 184 TN en 1.071 pacientes trasplantados (17%), en el 19% de los varones y en el 13% de las mujeres (p = 0,004). Los TN más frecuentes fueron los TPNM (29%), pulmón (18%), cabeza y cuello (16%), SLPT (10%) y gastrointestinales (8%). La mediana del tiempo de diagnóstico fue de 7,9 años en los TPNM, 3,9 años en SLPT y de 9,8 años en TOS. Los pacientes con TPNM tuvieron significativamente mejor supervivencia que aquellos con SLPT o TOS. La incidencia de los tumores de novo (excluidos TPNM) fue 1.889/100.000 trasplantados/año. Por género, el cáncer de pulmón fue el TOS más común en varones y el cáncer de mama en mujeres. CONCLUSIÓN: En nuestro medio, excluidos los TPNM, la incidencia es 8,8 veces la estimada para la población general, con una alta tasa de cáncer de pulmón por lo que deberíamos implementar estrategias preventivas y diagnósticas

INTRODUCTION: The greater survival of transplanted patients is accompanied by an increase in the rate of de novo malignancies (NM), which are the most frequent late-onset complication. We can distinguish between non-melanoma skin cancers (NMSC), post-transplant lymphoproliferative disorders (PTLD) and solid organ cancers (SOC). Our objective is to determine the incidence of the different types of NM, the time elapsed until diagnosis and survival rates in our setting. METHODS: We conducted a retrospective study of 1071 liver transplant patients from 1990 to 2015 at our center. We analyzed the demographic variables, incidence of NM and survival. RESULTS: 184 NM developed in 1071 transplant patients (17%), specifically 19% of the males and 13% of the females (P=.004). The most frequent NM were NMSC (29%), lung (18%), head and neck (16%), PTLD (10%) and gastrointestinal (8%). The median time of diagnosis was 7.9 years in NMSC, 3.9 years in PTLD and 9.8 years in SOC. Patients with NMSC had significantly better survival than those with PTLD or SOC. The incidence of de novo tumors (excluding NMSC) was 1889/100,000 transplants/year. By gender, lung cancer was the most common TOS in men and breast cancer in women. CONCLUSION: In our setting, excluding NMSC, the incidence is 8.8 times greater than estimations for the general population, with a high rate of lung cancer, so we should implement preventive and diagnostic strategies

Tumor de Masson intrahepático (hiperplasia endotelial papilar intravascular) / Intrahepatic Masson tumor (intravascular papillary endothelial hyperplasia)

No disponible

Síndrome linfoproliferativo en el trasplante hepático / Post-transplant lymphoproliferative disease in liver transplant recipients

Introducción: el síndrome linfoproliferativo postrasplante (SLPT) es una complicación infrecuente que ensombrece el pronóstico de los pacientes sometidos a un trasplante hepático (TH). Su patogenia es multifactorial, siendo sus dos principales factores de riesgo la inmunodepresión y la infección del virus de Epstein- Barr (VEB); sin embargo, en actualidad se piensa que puede estar relacionada con otros factores. Métodos: estudio observacional en el que hemos analizado de forma retrospectiva 851 casos que fueron sometidos a un trasplante hepático, de los cuales diez casos han desarrollado un SLPT. Se han analizado sus características clinicopatológicas y el tratamiento recibido. Resultados: la incidencia del SLPT ha sido del 1,2% (10/851) y el tiempo medio de presentación desde el TH hasta el diagnóstico, de 36 meses (rango 1,2-144 meses). El lugar de presentación ha sido extranodal en todos los casos, siendo más frecuente la localización intestinal. Siete casos presentaron un SLPT monomorfo, todos ellos linfomas diferenciados de células B. El 50% de la serie presentó seronegatividad para el virus de Epstein-Barr. La supervivencia global ha sido del 50%. Entre estos pacientes, hemos observado tres casos de curación completa, un caso de estabilización de la enfermedad y otro caso de recurrencia. Conclusión: el SLPT es una complicación infrecuente que supone una amenaza para la vida del paciente. Para poder instaurar un diagnóstico precoz y un tratamiento que pueda modificar el curso de la enfermedad, es fundamental la identificación de los pacientes en riesgo (AU)

Introduction: Post-transplant lymphoproliferative syndrome (PTLD) is a rare and potentially life-threatening complication after liver transplantation. The aim of this study was to analyze the clinicopathologic features related to PTLD in a single institution after liver transplantation. Methods: Observational study where we have retrospectively analyzed 851 cases who underwent liver transplantation. Ten cases have developed PTLD. Their clinical-pathological characteristics and the treatment received have been analyzed. Results: PTLD incidence was 1.2% (10/851). The mean time from liver transplantation to PTLD diagnosis was 36 months (range 1.2 to 144 months). PTLD localization was extranodal in all cases, the most frequent location being intestinal. Seven cases showed a monomorphic lymphoma which in all cases was differentiated B cell lymphomas. Fifty per cent of the series were seropositive for Epstein-Barr virus. Five patients were alive at the time of the review. Among these patients, we observed three cases of complete remission and two cases of disease stabilization. The death rate was higher in the first year after diagnosis of PTLD. Conclusion: PTLD is a rare complication after liver transplantation, but it may pose a threat to the life of a liver transplant recipient. It is essential to identify patients at risk, to establish an early diagnosis and treatment that can change the outcome of the disease (AU)

Factores de riesgo para injertos hepáticos no válidos. Estudio multivariante a partir de las variables recogidas en el protocolo de donación de la Organización Nacional de Trasplantes / Risk Factors for No Valid Liver Graft. Multivariate Study Based on the Variables Included in the Donation Protocol of the National Trasplant Organisation

INTRODUCCIÓN: Entre las estrategias diseñadas para optimizar el número de injertos hepáticos existentes para trasplante, la implementación del proceso de valoración de injertos constituye una de las menos exploradas. El objetivo principal es identificar los factores de riesgo que presentan los donantes hepáticos para la «NO validez». Secundariamente analizamos la coincidencia entre la valoración del cirujano y la del anatomopatólogo en los donantes NO válidos. MATERIAL Y MÉTODO: Estudio retrospectivo realizado a partir de una base de datos prospectiva que analiza 190 donantes hepáticos, 95 válidos y 95 NO válidos. Se estudian las variables de cada uno de ellos correspondientes al protocolo de donación de la Organización Nacional de Trasplantes. Mediante el estudio multivariante determinamos los factores de riesgo independientes de NO validez. Cotejamos las causas de NO validez argumentadas con los hallazgos histopatológicos de dichos injertos. RESULTADOS: Los factores de riesgo independientes de NO validez en el estudio multivariante (p < 0,05) fueron: dislipemia, antecedentes personales médicos distintos a factores de riesgo cardiovascular y quirúrgicos abdominales, GGT, BrT, y el resultado de la ecografía hepática previa. Las dos causas más frecuentes de NO validez fueron: esteatosis y fibrosis. El 78% de las biopsias confirmaron la NO validez del injerto (en 57,9% del total coincidían los hallazgos histológicos con los descritos por el cirujano). El 22% restante de las biopsias no presentaban hallazgos patológicos. CONCLUSIONES: La determinación de los factores de riesgo de NO validez contribuirá al diseño de futuros scores de valoración que constituyan herramientas útiles en el proceso de valoración de injertos hepáticos

INTRODUCTION: Among the strategies designed to optimize the number of existing liver grafts for transplantation, the implementation of the graft assessment process is one of the least explored. The main objective is to identify the risk factors presented by liver donors for «NO validity». Secondly, we analyzed the coincidence between the surgeon's assessment and that of the anatomo-pathologist in the invalid donors. MATERIAL AND METHOD: Retrospective study conducted from a prospective database that analyzes 190 liver donors, 95 valid and 95 NOT valid. The variables of each of them corresponding to the donation protocol of the National Transplant Organization are studied. Through a multivariate study we determine the independent risk factors of NO validity. We checked the causes of NO validity argued with the histopathological findings of these grafts. RESULTS: The independent risk factors of non-validity in the multivariate study (P < .05) were: dyslipidemia, personal medical history other than cardiovascular and abdominal surgical risk factors, GGT, BrT, and the result of previous liver ultrasound. The 3 most frequent causes of NO validity were: steatosis, fibrosis and macroscopic appearance of the organ. 78% of the biopsies confirmed the NO validity of the graft (in 57.9% of the cases the histological findings coincided with those described by the surgeon). The 22.1% of the biopsies hadńt pathological findings. CONCLUSIONS: The determination of the risk factors of NO validity will contribute to the design of future assessment scores that are useful tools in the process of liver graft assessment)