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2.
Cancers (Basel) ; 16(9)2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38730631

RESUMO

(1) Background: The liver-first approach may be indicated for colorectal cancer patients with synchronous liver metastases to whom preoperative chemotherapy opens a potential window in which liver resection may be undertaken. This study aims to present the data of feasibility and short-term outcomes in the liver-first approach. (2) Methods: A prospective observational study was performed in Spanish hospitals that had a medium/high-volume of HPB surgeries from 1 June 2019 to 31 August 2020. (3) Results: In total, 40 hospitals participated, including a total of 2288 hepatectomies, 1350 for colorectal liver metastases, 150 of them (11.1%) using the liver-first approach, 63 (42.0%) in hospitals performing <50 hepatectomies/year. The proportion of patients as ASA III was significantly higher in centers performing ≥50 hepatectomies/year (difference: 18.9%; p = 0.0213). In 81.1% of the cases, the primary tumor was in the rectum or sigmoid colon. In total, 40% of the patients underwent major hepatectomies. The surgical approach was open surgery in 87 (58.0%) patients. Resection margins were R0 in 78.5% of the patients. In total, 40 (26.7%) patients had complications after the liver resection and 36 (27.3%) had complications after the primary resection. One-hundred and thirty-two (89.3%) patients completed the therapeutic regime. (4) Conclusions: There were no differences in the surgical outcomes between the centers performing <50 and ≥50 hepatectomies/year. Further analysis evaluating factors associated with clinical outcomes and determining the best candidates for this approach will be subsequently conducted.

3.
Liver Int ; 44(2): 279-285, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38100141

RESUMO

Recommended post-liver transplant (LT) prophylaxis in patients with hepatitis delta includes a nucleos(t)ide analogue (NA) and anti-hepatitis B immunoglobulin (HBIG) indefinitely. We analysed the use of HBIG in real-life clinical practice and its impact on HBV/HDV recurrence in 174 HDV-related LT patients from 10 Spanish liver transplant centres (1988-2018). Median post-LT follow-up was 7.8 (2.3-15.1) years and patient survival at 5 years was 90%. Most patients (97%) received HBIG in the immediate post-LT, but only 42% were on HBIG at the last control. Among those discontinuing HBIG, the median time on treatment was 18 (7-52) months. Post-LT HBsAg+ was detected in 16 (9%) patients and HBV-DNA in 12 (7%). Despite HBsAg positivity, HDV recurrence was reported only in three patients (1.7%), all of whom were not receiving NA and had discontinued HBIG. Our data suggest that a finite HBIG prophylaxis in HDV-LT is feasible, especially if high-barrier NAs are used.


Assuntos
Transplante de Fígado , Humanos , Antivirais/uso terapêutico , Antígenos de Superfície da Hepatite B , Resultado do Tratamento , Cirrose Hepática/complicações , Cirrose Hepática/cirurgia , Cirrose Hepática/tratamento farmacológico , Imunoglobulinas/uso terapêutico , Recidiva , Vírus da Hepatite B/genética
4.
Front Surg ; 10: 1048451, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37808255

RESUMO

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.

5.
Updates Surg ; 75(1): 115-131, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36376560

RESUMO

Very few surveys have been carried out of oncosurgical decisions made in patients with pancreatic cancer (PC), or of the possible differences in therapeutic approaches between low/medium and high-volume centers. A survey was sent out to centers affiliated to the Spanish Group of Pancreatic Surgery (GECP) asking about their usual pre-, intra- and post-operative management of PC patients and describing five imaginary cases of PC corresponding to common scenarios that surgeons regularly assess in oncosurgical meetings. A consensus was considered to have been reached when 80% of the answers coincided. We received 69 responses from the 72 GECP centers (response rate 96%). Pre-operative management: consensus was obtained on 7/16 questions (43.75%) with no significant differences between low- vs high-volume centers. Intra-operative: consensus was obtained on 11/28 questions (39.3%). D2 lymphadenectomy, biliary culture, intra-operative biliary margin study, pancreatojejunostomy, and two loops were significantly more frequent in high-volume hospitals (p < 0.05). Post-operative: consensus was obtained on 2/8 questions (25%). No significant differences were found between low-/medium- vs high-volume hospitals. Of the 41 questions asked regarding the cases, consensus was reached on 22 (53.7%). No differences in the responses were found according to the type of hospital. Management and cases: consensus was reached in 42/93 questions (45.2%). At GECP centers, consensus was obtained on 45% of the questions. Only 5% of the answers differed between low/medium and high-volume centers (all intra-operative). A more specific assessment of why high-volume centers obtain the best results would require the design of complex prospective studies able to measure the therapeutic decisions made and the effectiveness of their execution. Clinicaltrials.gov identifier: NCT04755036.


Assuntos
Neoplasias Pancreáticas , Humanos , Estudos Prospectivos , Neoplasias Pancreáticas/cirurgia , Pâncreas , Hospitais com Alto Volume de Atendimentos , Neoplasias Pancreáticas
6.
Cells ; 11(17)2022 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-36078082

RESUMO

BACKGROUND: Sorafenib constitutes a suitable treatment alternative for patients with advanced hepatocellular carcinoma (HCC) in whom atezolizumab + bevacizumab therapy is contraindicated. The aim of the study was the identification of a miRNA signature in liquid biopsy related to sorafenib response. METHODS: miRNAs were profiled in hepatoblastoma HepG2 cells and tested in animal models, extracellular vesicles (EVs), and plasma from HCC patients. RESULTS: Sorafenib altered the expression of 11 miRNAs in HepG2 cells. miR-200c-3p and miR-27a-3p exerted an anti-tumoral activity by decreasing cell migration and invasion, whereas miR-122-5p, miR-148b-3p, miR-194-5p, miR-222-5p, and miR-512-3p exerted pro-tumoral properties by increasing cell proliferation, migration, or invasion, or decreasing apoptosis. Sorafenib induced a change in EVs population with an increased number of larger EVs, and promoted an accumulation of miR-27a-3p, miR-122-5p, miR-148b-3p, miR-193b-3p, miR-194-5p, miR-200c-3p, and miR-375 into exosomes. In HCC patients, circulating miR-200c-3p baseline levels were associated with increased survival, whereas high levels of miR-222-5p and miR-512-3p after 1 month of sorafenib treatment were related to poor prognosis. The RNA sequencing revealed that miR-200c-3p was related to the regulation of cell growth and death, whereas miR-222-5p and miR-512-3p were related to metabolic control. CONCLUSIONS: The study showed that Sorafenib regulates a specific miRNA signature in which miR-200c-3p, miR-222-5p, and miR-512-3p bear prognostic value and contribute to treatment response.


Assuntos
Carcinoma Hepatocelular , MicroRNAs , Sorafenibe , Biomarcadores , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico
7.
Am J Transplant ; 22(4): 1169-1181, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34856070

RESUMO

Postmortem normothermic regional perfusion (NRP) is a rising preservation strategy in controlled donation after circulatory determination of death (cDCD). Herein, we present results for cDCD liver transplants performed in Spain 2012-2019, with outcomes evaluated through December 31, 2020. Results were analyzed retrospectively and according to recovery technique (abdominal NRP [A-NRP] or standard rapid recovery [SRR]). During the study period, 545 cDCD liver transplants were performed with A-NRP and 258 with SRR. Median donor age was 59 years (interquartile range 49-67 years). Adjusted risk estimates were improved with A-NRP for overall biliary complications (OR 0.300, 95% CI 0.197-0.459, p < .001), ischemic type biliary lesions (OR 0.112, 95% CI 0.042-0.299, p < .001), graft loss (HR 0.371, 95% CI 0.267-0.516, p < .001), and patient death (HR 0.540, 95% CI 0.373-0.781, p = .001). Cold ischemia time (HR 1.004, 95% CI 1.001-1.007, p = .021) and re-transplantation indication (HR 9.552, 95% CI 3.519-25.930, p < .001) were significant independent predictors for graft loss among cDCD livers with A-NRP. While use of A-NRP helps overcome traditional limitations in cDCD liver transplantation, opportunity for improvement remains for cases with prolonged cold ischemia and/or technically complex recipients, indicating a potential role for complimentary ex situ perfusion preservation techniques.


Assuntos
Transplante de Fígado , Obtenção de Tecidos e Órgãos , Idoso , Morte , Sobrevivência de Enxerto , Humanos , Transplante de Fígado/efeitos adversos , Transplante de Fígado/métodos , Pessoa de Meia-Idade , Preservação de Órgãos/métodos , Perfusão/métodos , Estudos Retrospectivos , Fatores de Risco , Doadores de Tecidos
8.
Am J Transplant ; 21(1): 372-381, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32705768

RESUMO

Domino liver transplantation (DLT) has been used widely in patients with hereditary amyloid transthyretin (ATTR) amyloidosis. New-onset polyneuropathy in recipients of DLT has been reported, but there are few cases of cardiac involvement reported. We aimed to perform a cross-sectional study for ATTR amyloidosis with cardiomyopathy (ATTR-CM) in DLT recipients. We evaluated 23 living DLT recipients a median of 9 years since DLT at 2 referral centers with a systematic cardiac evaluation, including bone scintigraphy. Median age was 72 years, 91% had hypertension, 35% had diabetes mellitus, 67% had chronic renal failure, and 8 patients (35%) developed new-onset polyneuropathy. Only 13% had a normal electrocardiogram and a normal echocardiography, and most of them showed some conduction disturbance or increase in left ventricular wall thickness, but only 1 patient with a Glu89Lys mutation developed ATTR-CM diagnosed by bone scintigraphy and endomyocardial biopsy. None of the recipients of a DLT with Val30Met mutation showed cardiac involvement by bone scintigraphy. In conclusion, DLT from Val30Met donors seems to be safe regarding the development of ATTR-CM. Evaluation of cardiomyopathy in DLT recipients is challenging due to concomitant comorbidities and in this context, bone scintigraphy can be helpful to evaluate ATTR-CM.


Assuntos
Neuropatias Amiloides Familiares , Cardiomiopatias , Transplante de Fígado , Idoso , Neuropatias Amiloides Familiares/genética , Cardiomiopatias/etiologia , Estudos Transversais , Humanos , Transplante de Fígado/efeitos adversos
9.
Cell Physiol Biochem ; 54(3): 457-473, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32369692

RESUMO

BACKGROUND/AIMS: Orthotopic liver transplantation (OLT) is the recommended treatment for patients at early stages of hepatocarcinoma (HCC) with portal hypertension and/or increased bilirubinemia, but without vascular-associated diseases. Tumor recurrence, which is the main drawback for the survival of patients submitted to OLT for HCC, has been related to tumor-related variables and the immunosuppressive therapies. We have previously shown that Tacrolimus (FK506) exerts a more potent pro-apoptotic and anti-proliferative effects than the mammalian target of rapamycin (mTOR) inhibitors (Sirolimus and Everolimus) in liver cancer cells. This study identified the role of the immunosuppressant partners such as FK506-binding proteins (FKBPs) in the induction of cell death and arrest of cell proliferation by immunosuppressants in two representative liver cancer cells. METHODS: The regulation of endoplasmic reticulum (ER) stress, apoptosis/autophagy, cell proliferation, and FKBPs expression was determined in Tacrolimus-, Sirolimus- and Everolimus-treated primary human hepatocytes, and hepatoma HepG2 and Huh7 cell lines. The functional repercussion of FKBPs on cell death and proliferation was also addressed using the siRNA technology. The assessed antitumoral properties of the immunosuppressants were associated to microRNAs (miRNAs) pattern. RESULTS: The enhanced pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with increased protein kinase RNA-like endoplasmic reticulum kinase (PERK)-related ER stress, Ser15P-p53/p53 ratio and p21 protein expression that may counterbalance the risk of proliferative upregulation caused by enhanced Thr172P-Cdk4/Cdk4 activation in liver cancer cells. The inhibition of the mTOR pathway by Sirolimus and Everolimus was related to an induction of autophagy; and at a high dose, these drugs impaired translation likely at a very early step of the elongation phase. Tacrolimus and mTOR inhibitors increased the protein expression of FKBP12 and FKBP51 that appeared to play pro-survival role. Interestingly, the administration of immunosuppressants yields a specific pattern of miRNAs. Tacrolimus and mTOR inhibitors decreased miR-92a-1-5p, miR-197-3p, miR-483-3p and miR-720, and increased miR-22-3p, miR-376a-3p, miR-663b, miR-886-5p, miR-1300 and miR-1303 expressions in HepG2 cells. CONCLUSION: The more potent pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with an increased activation of PERK and p53 signaling, and p21 protein expression. FKBP12 and FKBP51 appeared to be the most relevant partners of Tacrolimus and mTOR inhibitors exerting a pro-survival effect in HepG2 cells. The observed effects of immunosuppressants were related to a specific miRNA signature in liver cancer cells.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Imunossupressores/farmacologia , Neoplasias Hepáticas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Tacrolimo/farmacologia , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Everolimo/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Interferente Pequeno , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Proteína 1A de Ligação a Tacrolimo/metabolismo , Proteína Supressora de Tumor p53/metabolismo , eIF-2 Quinase/metabolismo
10.
Cell Death Dis ; 11(5): 339, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32382022

RESUMO

Sorafenib and Regorafenib are the recommended first- and second-line therapies in patients with advanced hepatocellular carcinoma (HCC). Lenvatinib and Cabozantinib have shown non-inferior antitumoral activities compared with the corresponding recommended therapies. The clinical trials have established recommended doses for each treatment that lead different blood concentrations in patients for Sorafenib (10 µM), Regorafenib (1 µM), Lenvatinib (0.1 µM), and Cabozantinib (1 µM). However, very low response rates are observed in patients attributed to intrinsic resistances or upregulation of survival signaling. The aim of the study was the comparative dose-response analysis of the drugs (0-100 µM) in well-differentiated (HepG2, Hep3B, and Huh7), moderately (SNU423), and poorly (SNU449) differentiated liver cancer cells in 2D/3D cultures. Cells harbors wild-type p53 (HepG2), non-sense p53 mutation (Hep3B), inframe p53 gene deletion (SNU423), and p53 point mutation (Huh7 and SNU449). The administration of regular used in vitro dose (10 µM) in 3D and 2D cultures, as well as the dose-response analysis in 2D cultures showed Sorafenib and Regorafenib were increasingly effective in reducing cell proliferation, and inducing apoptosis in well-differentiated and expressing wild-type p53 in HCC cells. Lenvatinib and Cabozantinib were particularly effective in moderately to poorly differentiated cells with mutated or lacking p53 that have lower basal oxygen consumption rate (OCR), ATP, and maximal respiration capacity than observed in differentiated HCC cells. Sorafenib and Regorafenib downregulated, and Lenvatinib and Cabozantinib upregulated epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor receptor (c-Met) in HepG2 cells. Conclusions: Sorafenib and Regorafenib were especially active in well-differentiated cells, with wild-type p53 and increased mitochondrial respiration. By contrast, Lenvatinib and Cabozantinib appeared more effective in moderately to poorly differentiated cells with mutated p53 and low mitochondrial respiration. The development of strategies that allow us to deliver increased doses in tumors might potentially enhance the effectiveness of the treatments.


Assuntos
Técnicas de Cultura de Células , Diferenciação Celular/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Mitocôndrias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Adulto , Anilidas/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Respiração Celular/efeitos dos fármacos , Feminino , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Masculino , Mitocôndrias/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Quinolinas/farmacologia , Sorafenibe/farmacologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia
11.
Transplant Proc ; 52(2): 509-511, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32035674

RESUMO

BACKGROUND: Health care-associated infection (HAI) represent a global health problem with an increase in hospital stays, deaths, and monetary costs. Recipients of solid organ transplants are a population at risk. The objectives of the study were to characterize the incidence of HAI in renal and hepatic transplant recipients as well as to compare them with the population without transplants in intensive care units (ICU). METHODS: The data on the incidence of HAI, localization, microorganisms, and demographics were taken from the patients admitted between the years 2013 to 2018 (n = 4307) from the registration of the Project for the Reduction of Nosocomial Infection in Intensive Care Units. The variables were compared with those of renal transplant (n = 96) and liver transplants (n = 68) recipients. RESULTS: Renal transplant recipients showed 26% incidence of HAI. The most frequent were surgical site infection (SSI), urinary tract infection, and primary bacteremia; the most frequent microorganism was Staphylococcus spp, mortality 3.8%. Liver transplant recipients showed 41% incidence of HAI. The most frequent were tracheobronchitis associated with mechanical ventilation, SSI, and primary bacteremia; the most frequent microorganism was Staphylococcus spp, mortality 37%. The population without transplants in the ICU showed 17% incidence of HAI. The most frequent were respiratory infections associated with mechanical ventilation, primary bacteremia, and SSI; the most frequent microorganism was Acinetobacter spp, mortality 21%. CONCLUSIONS: HAI in recipients of solid organ transplants (renal and hepatic) have a higher incidence than in a population without transplants. The location and causal microorganisms have particularities that must be taken into account for the development of prevention protocols.


Assuntos
Infecção Hospitalar/epidemiologia , Transplante de Rim/efeitos adversos , Transplante de Fígado/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Adulto , Bacteriemia/epidemiologia , Feminino , Humanos , Incidência , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Infecção da Ferida Cirúrgica/epidemiologia , Infecções Urinárias/epidemiologia
13.
Clin Chem Lab Med ; 57(6): 883-890, 2019 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-30530897

RESUMO

Background Optimal haemostasis management in orthotropic liver transplant (OLT) could reduce blood loss and transfusion volume, improve patient outcomes and reduce cost. Methods We performed a study including 336 OLTs to evaluate the clinical and cost effectiveness of a new point-of-care (POC)-based haemostatic management approach in OLT patients. Results In terms of health benefit we found that the new approach showed a significant reduction in transfusion requirements (red blood cell transfusion units were reduced from 5.3±4.6 to 2.8±2.9 [p<0.001], free frozen plasma from 3.1±3.3 to 0.4±1.0 [p<0.001] and platelets from 2.9±3.9 to 0.4±0.9 [p<0.001], transfusion avoidance, 9.7% vs. 29.1% [p<0.001] and massive transfusion, 14.5% vs. 3.8% [p=0.001]); we also found a significant improvement in patient outcomes, such, reoperation for bleeding or acute-kidney-failure (8.3% vs. 2.4%, p=0.015; 33.6% vs. 5.4%, p<0.001), with a significant reduction in the length of the hospital total stay (40.6±13.8 days vs. 38.2±14.4 days, p=0.001). The lowest cost incurred was observed with the new approach (€73,038.80 vs. €158,912.90) with significant patient saving associated to transfusion avoidance (€1278.36), ICU-stay (€3037.26), total-stay (€3800.76) and reoperation for bleeding (€80,899.64). Conclusions POC haemostatic monitoring during OLT is cost effective.


Assuntos
Análise Custo-Benefício , Doença Hepática Terminal/terapia , Transplante de Fígado , Sistemas Automatizados de Assistência Junto ao Leito/economia , Testes de Coagulação Sanguínea , Transfusão de Eritrócitos , Humanos , Tempo de Internação
14.
Transplantation ; 102(12): 2056-2064, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29757893

RESUMO

BACKGROUND: Many centers implement everolimus-based immunosuppression in liver transplant patients with hepatocellular carcinoma. We aimed to explore the potential impact of early initiated everolimus on tumor recurrence after liver transplantation. METHODS: This study included 192 patients with hepatocellular carcinoma undergoing liver transplantation among who 64 individuals were prospectively enrolled (2012-2015) and received early initiated everolimus (ie, started between postoperative day 15 to 21), whereas the remaining 128 patients acted as historical controls without everolimus. Propensity score matching was performed to ensure comparability. Multivariate Cox regression and competing risks analysis were used to control for potential confounders. RESULTS: Patients with and without everolimus were comparable in terms of number of nodules (P = 0.37), total tumor diameter (P = 0.44), Milan criteria fulfillment (P = 0.56), and histological differentiation (P = 0.61), but there were increased microvascular invasion rates in the everolimus group (26.5% vs 13.3%; P = 0.026). Tumor recurrence rates were similar with and without everolimus (10.9% vs 9.9% at 36 months respectively; P = 0.18). After controlling for microvascular invasion among other potential confounders, everolimus had no significant impact on tumor recurrence, neither in the multivariate Cox regression (relative risk = 3.23; P = 0.09), nor in the competing risks analysis for tumor recurrence-death (relative risk = 1.02; P = 0.94). Patients receiving everolimus had reduced tacrolimus trough concentrations and lower serum creatinine within the first 18 months postliver transplantation. CONCLUSION: Everolimus may not be universally prescribed to prevent tumor recurrence in liver transplant patients with hepatocellular carcinoma. Future randomized trials should be focused on patients with histological features of increased tumor aggressiveness, in whom the potential benefit would be higher.


Assuntos
Carcinoma Hepatocelular/cirurgia , Everolimo/administração & dosagem , Imunossupressores/administração & dosagem , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/efeitos adversos , Recidiva Local de Neoplasia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Esquema de Medicação , Everolimo/efeitos adversos , Feminino , Humanos , Imunossupressores/efeitos adversos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
15.
Front Psychiatry ; 9: 148, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29720952

RESUMO

The valid assessment of the impact of transplantation on psychological well-being is highly relevant to optimize treatment. However, to date there is no standardized instrument available in Spain. The Transplant Effects Questionnaire (TxEQ) evaluates the specific problems associated with organ transplantation, such as worry about transplant, guilt regarding the donor, disclosure of having undergone transplantation, adherence to medical treatment and responsibility toward the donor, family, friends, or medical staff. Against this backdrop the English original version of the TxEQ was translated into Spanish and validated in a sample of 240 liver transplant recipients. Participants also filled in the Posttraumatic Growth Inventory (PTGI), and the 12-Item Short Form Health Survey (SF-12v.2). Confirmatory factor analysis of the TxEQ-Spanish revealed a five-factor structure equivalent to the English original version, and satisfactory internal consistency (Cronbach's alpha: worry α = 0.82, guilt α = 0.77, disclosure α = 0.91, adherence α = 0.82, responsibility α = 0.83). Results showed that better mental quality of life was associated with higher adherence and disclosure, as well as less worry and guilt. Higher posttraumatic growth was significantly associated with worry, guilt, and responsibility. Interestingly, the most powerful predictor of posttraumatic growth was worry. Analysis of variance showed an interaction effect of PTG and mental quality of life on adherence, with medium PTG being associated with significantly stronger adherence in participants with better mental quality of life. In conclusion our study could successfully adapt and validate the Spanish version of the TxEQ in a large sample of liver transplant recipients. Our findings show a complex relationship between emotional reactions to transplantation, mental quality of life, and posttraumatic growth, which give further insight into inner processes supporting psychological well-being and adherence after liver transplantation.

16.
HPB (Oxford) ; 20(8): 768-775, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29622402

RESUMO

BACKGROUND: Studies suggest that vascular invasion may be a superior prognostic marker compared with traditional selection criteria, e.g. Milan criteria. This study aimed to investigate the prognostic value of micro and macrovascular invasion in a large database material. METHODS: Patients liver transplanted for HCC and cirrhosis registered in the European Liver Transplant Registry (ELTR) database were included. The association between the Milan criteria, Up-to-seven criteria and vascular invasion with overall survival and HCC specific survival was investigated with univariate and multivariate Cox regression analyses. RESULTS: Of 23,124 patients transplanted for HCC, 9324 had cirrhosis and data on explant pathology. Patients without microvascular invasion, regardless of number and size of HCC nodules, had a five-year overall survival of 73.2%, which was comparable with patients inside both Milan and Up-to-seven criteria. Patients without macrovascular invasion had an only marginally reduced survival of 70.7% after five years. Patients outside both Milan and Up-to-seven criteria without micro or macrovascular invasion still had a five-year overall survival of 65.8%. CONCLUSION: Vascular invasion as a prognostic indicator remains superior to criteria based on size and number of nodules. With continuously improving imaging studies, microvascular invasion may be used for selecting patients for transplantation in the future.


Assuntos
Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Idoso , Biópsia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Tomada de Decisão Clínica , Bases de Dados Factuais , Europa (Continente) , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Transplante de Fígado/efeitos adversos , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Seleção de Pacientes , Sistema de Registros , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
17.
Pharmacogenet Genomics ; 28(2): 41-48, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29256966

RESUMO

OBJECTIVE: Cytochrome P450 3A4 (CYP3A4) metabolizes about half of all drugs on the market; however, the impact of CYP3A4 loss-of-function variants on drug exposures remains poorly characterized. Here, we report the effect of the CYP3A4*20 frameshift allele in two Spanish liver transplant patients treated with tacrolimus. PATIENTS AND METHODS: A series of 90 transplanted patients (with DNA available for 89 of the recipients and 76 of the liver donors) treated with tacrolimus were included in the study. The genotypes of liver donors and of the recipients for CYP3A4*20 (rs67666821), CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746) were compared with weight-adjusted tacrolimus dose (D), tacrolimus trough concentration (C0), and dose-adjusted tacrolimus trough concentrations (C0/D) using the Mann-Whitney U-nonparametric test. RESULTS: The CYP3A4*20 allele was detected in two of the liver donors. This genotype yielded at all times higher C0/D (2.6-fold, average) than intermediate CYP3A metabolizers (CYP3A4*1/*1 and CYP3A5*3/*3) (P=0.045, 90 days after transplantation). CYP3A4*22 carriers showed a 1.9-fold average increase in C0/D (P=0.047, 0.025, and 0.053; at days 7, 14, and 30 after transplantation, respectively) compared with intermediate metabolizers. In terms of recipients' genotype, CYP3A5*1 had reduced (P=0.025) and CYP3A4*22 increased C0/D (P=0.056) 7 days after transplantation. The incidence of biopsy-proven acute rejection was 0, 12, and 20% for livers with poor, intermediate, and extensive CYP3A-metabolizing capacity, respectively (P=0.0995). CONCLUSION: This first description of CYP3A4*20 null genotype in liver-transplanted patients, supports the relevance of CYP3A genotyping in tacrolimus therapy.


Assuntos
Citocromo P-450 CYP3A/genética , Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/administração & dosagem , Tacrolimo/administração & dosagem , Adulto , Idoso , Alelos , Relação Dose-Resposta a Droga , Feminino , Genótipo , Rejeição de Enxerto/genética , Rejeição de Enxerto/patologia , Humanos , Imunossupressores/farmacocinética , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Tacrolimo/farmacocinética , Doadores de Tecidos
18.
PLoS One ; 12(3): e0174326, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28350813

RESUMO

BACKGROUND & AIMS: Patients with hepatocellular carcinoma (HCC) submitted to orthotopic liver transplantation (OLT) have a variable 5-year survival rate limited mostly by tumor recurrence. The etiology, age, sex, alcohol, Child-Pugh, and the immunesuppressor have been associated with tumour recurrence. The expression of ΔNp73 is related to the reduced survival of patients with HCC. The study evaluated the expression of p63 and p73 isoforms and cell death receptors, and their relation to tumour recurrence and survival. The results were in vitro validated in HCC cell lines. METHODS: HCC sections from patients submitted to OLT were used. The in vitro study was done in differentiated hepatitis B virus (HBV)-expressing Hep3B and control HepG2 cells. The expression of cell death receptors and cFLIPS/L, caspase-8 and -3 activities, and cell proliferation were determined in control and p63 and p73 overexpressing HCC cells. RESULTS: The reduced tumor expression of cell death receptors and TAp63 and TAp73, and increased ΔNp63 and ΔNp73 expression were associated with tumor recurrence and reduced survival. The in vitro study demonstrated that HBV-expressing Hep3B vs HepG2 cells showed reduced expression of p63 and p73, cell death receptors and caspase activation, and increased cFLIPL/cFLIPS ratio. The overexpression of TAp63 and TAp73 exerted a more potent pro-apoptotic and anti-proliferative effects in Hep3B than HepG2-transfected cells which was related to cFLIPL upregulation. CONCLUSIONS: The reduction of TAp63 and TAp73 isoforms, rather than alteration of ΔN isoform expression, exerted a significant functional repercussion on cell death and proliferation in HBV-expressing HepB cells.


Assuntos
Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Transplante de Fígado , Fígado/patologia , Fatores de Transcrição/genética , Proteína Tumoral p73/genética , Proteínas Supressoras de Tumor/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Morte Celular , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Hepatite B/complicações , Vírus da Hepatite B/isolamento & purificação , Humanos , Fígado/metabolismo , Fígado/virologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Transplante de Fígado/métodos , Masculino , Isoformas de Proteínas/genética , Receptores de Morte Celular/genética
19.
Transplantation ; 100(11): 2372-2381, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27780185

RESUMO

BACKGROUND: Liver transplantation is the most extreme form of surgical management of patients with hepatic trauma, with very limited literature data supporting its use. The aim of this study was to assess the results of liver transplantation for hepatic trauma. METHODS: This retrospective analysis based on European Liver Transplant Registry comprised data of 73 recipients of liver transplantation for hepatic trauma performed in 37 centers in the period between 1987 and 2013. Mortality and graft loss rates at 90 days were set as primary and secondary outcome measures, respectively. RESULTS: Mortality and graft loss rates at 90 days were 42.5% and 46.6%, respectively. Regarding general variables, cross-clamping without extracorporeal veno-venous bypass was the only independent risk factor for both mortality (P = 0.031) and graft loss (P = 0.034). Regarding more detailed factors, grade of liver trauma exceeding IV increased the risk of mortality (P = 0.005) and graft loss (P = 0.018). Moreover, a tendency above the level of significance was observed for the negative impact of injury severity score (ISS) on mortality (P = 0.071). The optimal cut-off for ISS was 33, with sensitivity of 60.0%, specificity of 80.0%, positive predictive value of 75.0%, and negative predictive value of 66.7%. CONCLUSIONS: Liver transplantation seems to be justified in selected patients with otherwise fatal severe liver injuries, particularly in whom cross-clamping without extracorporeal bypass can be omitted. The ISS cutoff less than 33 may be useful in the selection process.


Assuntos
Transplante de Fígado , Fígado/lesões , Feminino , Rejeição de Enxerto/etiologia , Humanos , Escala de Gravidade do Ferimento , Transplante de Fígado/efeitos adversos , Transplante de Fígado/mortalidade , Masculino , Sistema de Registros , Estudos Retrospectivos
20.
PLoS One ; 11(8): e0160979, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27518575

RESUMO

Orthotopic liver transplantation (OLT) is the recommended treatment for patients at early stages of hepatocarcinoma (HCC) with potential portal hypertension and/or bilirubinemia, but without vascular-associated diseases. The patients are receiving immunosuppressive therapy to reduce graft rejection, but differential side effects have been related to calcineurin and mTOR inhibitor administration regarding tumor recurrence and nephrotoxicity. The in vitro studies showed that Tacrolimus exerted a more potent pro-apoptotic effect than Everolimus (Huh 7>Hep 3B>HepG2), being sirolimus only active in Hep3B cell line. Tacrolimus and Everolimus exerted potent antiproliferative properties in Huh 7 and Hep3B in which cells Sirolimus was inactive. Interestingly, Tacrolimus- and Everolimus-dependent G0/G1 cell accumulation occurred as a consequence of drastic reduction in S, as well as in S and G2+M phases, respectively. The in vivo studies support data on the more effective antitumoral properties of Everolimus, eventual risk of pro-angiogenic tumoral properties and nephrotoxicity of Tacrolimus, and pro-proliferative properties of Sirolimus in tumors developed in nude mice.


Assuntos
Carcinoma Hepatocelular/patologia , Rim/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Tacrolimo/efeitos adversos , Tacrolimo/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Everolimo/efeitos adversos , Everolimo/farmacologia , Everolimo/uso terapêutico , Fibrose , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Rim/patologia , Masculino , Camundongos , Neovascularização Patológica/tratamento farmacológico , Tacrolimo/uso terapêutico
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