Millorar la qualitat de vida després d'un trasplantament de fetge

Després d'un trasplantament de fetge, s'utilitzen fàrmacs immunosupressors per evitar que el cos rebutgi l'organ. Els medicaments que s'utilitzen habitualment poden provocar, al llarg dels anys, efectes adversos com toxicitat als ronyons, hipertensió arterial o diabetis. En aquesta recerca s'ha examinat com evolucionen els pacients que passen del fàrmac habitual a un altre d'alternatiu.Después de un transplante de hígado, se utilizan fármacos inmunosupresores para evitar que el cuerpo rechace el órgano. Los medicamentos que se utilizan habitualmente pueden provocar, a lo largo de los años, efectos adversos como toxicidad en los riñones, hipertensión arterial o diabetes. En esta investigación se ha examinado cómo evolucionan los pacientes que pasan del fármaco habitual a otro alternativo

Un tractament més benèvol per al pacient amb trasplantament hepàtic

Als anys 80, l'Hospital Universitari de la Vall d'Hebron es va convertir en el primer indret d'Espanya on es va realitzar un trasplantament hepàtic. Des d'aleshores, l'equip de metges investigadors dirigit pel Dr. Carlos Margarit -recentment traspassat-, ha realitzat un seguiment del curs clínic d'aquesta operació. D'aquí sorgeix una nova proposta: eliminar els esteroides del tractament degut als agressius efectes adversos.En los años 80 el hospital universitario Vall d'Hebrón se convierte en el primer lugar de España donde se realiza un transplante hepático. Desde entonces, el equipo de médicos investigadores dirigido por el Dr. Carlos Margarit -recientemente desaparecido-, ha realizado un seguimiento del curso clínico de esta operación. De aquí surge una nueva propuesta: eliminar a los esteroides del tratamiento debido a los agresivos efectos adversos.In the 80s the university hospital Vall d'Hebrón was the first hospital in Spain to carry out a liver transplant. Since then, the team of research doctors led by Dr. Carlos Margarit -who passed away recently-, has followed up the clinical course of this operation. Results suggest a new type of treatment: the elimination of steroids due to their aggressive side effects

Carlos Margarit, la força de la muntanya

El doctor Carlos Margarit, responsable del programa de Trasplantament Hepàtic d'Adults i Pediàtric de l'Hospital Vall d'Hebron, ens va deixar el propassat mes de desembre víctima d'un accident de muntanya. La doctora Itxarone Bilbao, que va treballar amb ell al llarg de 15 anys, descriu els trets més destacats de la seva trajectòria.El doctor Carlos Margarit, responsable del programa de Transplante Hepático de Adultos y Pediátrico del Hospital Vall d'Hebron, nos dejó el pasado mes de diciembre víctima de un accidente de montaña. La doctora Itxarone Bilbao, que trabajó con él durante 15 años, hace un repaso de su trayectoria

High intrapatient variability of tacrolimus exposure associated with poorer outcomes in liver transplantation

Liver transplantation; Tacrolimus; Liver diseasesTrasplante de hígado; Tacrolimús; Enfermedades del hígadoTrasplantament hepàtic; Tacrolimús; Malalties del fetgeTacrolimus (TAC) is a dose-dependent immunosuppressor with considerable intrapatient variability (IPV) in its pharmacokinetics. The aim of this work is to ascertain the association between TAC IPV at 6 months after liver transplantation (LT) and patient outcome. This single-center cohort study retrospectively analyzed adult patients who underwent transplantation from 2015 to 2019 who survived the first 6 months with a functioning graft. The primary end point was the patient’s probability of death and the secondary outcome was the loss of renal function between month 6 and the last follow-up. TAC IPV was estimated by calculating the coefficient of variation (CV) of the dose-corrected concentration (C0/D) between the third and sixth months post-LT. Of the 140 patients who underwent LT included in the study, the low-variability group (C0/D CV < 27%) comprised 105 patients and the high-variability group (C0/D CV ≥ 27%) 35 patients. One-, 3-, and 5-year patient survival rates were 100%, 82%, and 72% in the high-variability group versus 100%, 97%, and 93% in the low-variability group, respectively (p = 0.005). Moreover, significant impaired renal function was observed in the high-variability group at 1 year (69 ± 16 ml/min/1.73 m2 vs. 78 ± 16 ml/min/1.73 m2, p = 0.004) and at 2 years post-LT (69 ± 17 ml/min/1.73 m2 vs. 77 ± 15 ml/min/1.73 m2, p = 0.03). High C0/D CV 3–6 months remained independently associated with worse survival (hazard ratio = 3.57, 95% CI = 1.32–9.67, p = 0.012) and loss of renal function (odds ratio = 3.47, 95% CI = 1.30–9.20, p = 0.01). Therefore, high IPV between the third and sixth months appears to be an early and independent predictor of patients with poorer liver transplant outcomes.Isabel Campos-Varela’s research activity is funded by grant PI19/00330 from Instituto de Salud Carlos III. CIBERehd is supported by Instituto de Salud Carlos III. The work was independent of all funding

Study of Quasispecies Complexity and Liver Damage Progression after Liver Transplantation in Hepatitis C Virus Infected Patients

Fibrosis; Hepatitis C virus; Viral loadFibrosis; Virus de la hepatitis C; Carga viralFibrosi; Virus de l'hepatitis C; Càrrega viralCirrhosis derived from chronic hepatitis C virus (HCV) infection is still a common indication for liver transplantation (LT). Reinfection of the engrafted liver is universal in patients with detectable viral RNA at the time of transplant and causes fast progression of cirrhosis (within 5 years) in around one-third of these patients. To prevent damage to the liver graft, effective direct-acting antiviral (DAA) therapy is required as soon as possible. However, because of post-LT clinical instability, it is difficult to determine the optimal time to start DAAs with a low risk of complications. Evaluate changes in quasispecies complexity following LT and seek a predictive index of fast liver damage progression to determine the timing of DAA initiation. HCV genomes isolated from pre-LT and 15-day post-LT serum samples of ten patients, who underwent orthotopic LT, were quantified and sequenced using a next-generation sequencing platform. Sequence alignments, phylogenetic trees, quasispecies complexity measures, biostatistics analyses, adjusted R2 values, and analysis of variance (ANOVA) were carried out. Three different patterns of reinfection were observed (viral bottlenecking, conserved pre-LT population, and mixed populations), suggesting that bottlenecking or homogenization of the viral population is not a generalized effect after liver graft reinfection. None of the quasispecies complexity measures predicted the future degree of liver damage. Higher and more uniform viral load (VL) values were observed in all pre-LT samples, but values were more dispersed in post-LT samples. However, VL increased significantly from the pre-LT to 15-day post-LT samples in patients with advanced fibrosis at 1-year post-LT, suggesting that a VL increase on day 15 may be a predictor of fast liver fibrosis progression. HCV kinetics after LT differ between patients and are not fibrosis-dependent. Higher VL at day 15 post-LT versus pre-LT samples may predict fast liver fibrosis progression.This study was supported by grants from Instituto de Salud Carlos III cofinanced by the European Regional Development Fund (ERDF) with grant numbers PI19/00533, PI19/00301, Clinical Trial Gov. Identifier: NCT01707849, and from Centro para el Desarrollo Tecnológico Industrial-CDTI of the Spanish Ministry of Economics and Competitiveness (MINECO) grant number, IDI-20200297. C.P. is supported by the Miguel Servet program of Instituto de Salud Carlos III, grant CP14/00121, cofinanced by the ERDF. Astellas Pharma Inc and Novartis Pharma also provided funding for the study, but these companies had had no role in the study design, data collection or analysis, decision to publish, or preparation of the manuscript

Ultra Deep Sequencing of Circulating Cell-Free DNA as a Potential Tool for Hepatocellular Carcinoma Management

Biomarkers; cfDNA; Liquid biopsyBiomarcadores; cfDNA; Biopsia líquidaBiomarcadors; cfDNA; Biòpsia líquidaBackground: Cell-free DNA (cfDNA) concentrations have been described to be inversely correlated with prognosis in cancer. Mutations in HCC-associated driver genes in cfDNA have been reported, but their relation with patient’s outcome has not been described. Our aim was to elucidate whether mutations found in cfDNA could be representative from those present in HCC tissue, providing the rationale to use the cfDNA to monitor HCC. Methods: Tumoral tissue, paired nontumor adjacent tissue and blood samples were collected from 30 HCC patients undergoing curative therapies. Deep sequencing targeting HCC driver genes was performed. Results: Patients with more than 2 ng/µL of cfDNA at diagnosis had higher mortality (mean OS 24.6 vs. 31.87 months, p = 0.01) (AUC = 0.782). Subjects who died during follow-up, had a significantly higher number of mutated genes (p = 0.015) and number of mutations (p = 0.015) on cfDNA. Number of mutated genes (p = 0.001), detected mutations (p = 0.001) in cfDNA and ratio (number of mutations/cfDNA) (p = 0.003) were significantly associated with recurrence. However, patients with a ratio (number of mutations/cfDNA) above 6 (long-rank p = 0.0003) presented a higher risk of recurrence than those with a ratio under 6. Detection of more than four mutations in cfDNA correlated with higher risk of death (long-rank p = 0.042). Conclusions: In summary, cfDNA and detection of prevalent HCC mutations could have prognostic implications in early-stage HCC patientsThis research was funded by Instituto de Salud Carlos III (ISCIII) (PI18/00961) and (PI21/00714) to B.M. PI19/00301 by Instituto de Salud Carlos III (ISCIII) and Centro para el Desarrollo Tecnológico Industrial (CDTI) from the Spanish Ministry of Economy and Business, grant number IDI-20200297 to J.Q., E.V.-A. is a recipient of a predoctoral fellowship from Instituto de Salud Carlos III (ISCIII) (FI18/00027)

A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC.</p> <p>Methods/Design</p> <p>The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 2^1/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating.</p> <p>Discussion</p> <p>If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC.</p> <p>Trial Register</p> <p>Trial registered at <url>http://www.clinicaltrials.gov</url>: NCT00355862</p> <p>(EudraCT Number: 2005-005362-36)</p

A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma

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