A surgical model for isolating the pig liver in vivo for gene therapy.

Several studies report results that suggest the need of vascularization blocking for efficient gene transfer to the liver, especially in nonviral gene therapy. In this study, we describe a surgical strategy for in vivo isolation of the pig liver, resulting in a vascular watertight organ that allows the evaluation of several gene injection conditions. The hepatic artery and portal, suprahepatic and infrahepatic cava veins were dissected. Then, liver vascularization was excluded for 5-7 min. In that time, we first injected 200 ml saline solution containing the p3c-eGFP plasmid (20 µg/ml) simultaneously through two different catheters placed in the portal and cava veins, respectively. Vital co…

Results after 13 years of kidney-pancreas transplantation in type 1 diabetic patients in Comunidad Valenciana

INTRODUCTION Simultaneous pancreas-kidney (SPK) transplant is a proven option of treatment for patients with type 1 diabetes mellitus and related end-stage renal disease, who are candidates for kidney transplantation. The results from the beginning of SPK transplant program in Comunidad Valenciana are presented. METHODS Descriptive, retrospective, and single-center study of the pancreas transplant performed at the Hospital Universitari i Politecnic La Fe, from September 2002 to December 2015. Clinical variables from donors and recipients, peri-operative variables, patient survival, and pancreatic graft survival were collected. RESULTS Eighty-one patients with type 1 diabetes mellitus (48 ma…

Long-term outcome of ‘long-term liver transplant survivors’

There are few studies focusing on long-term complications in liver transplant (LT) recipients. The aim of this study was to define the outcome of LT recipients having survived at least 10 years from LT. Of 323 adult LT done between 1991 and 1997, the 167(52%) alive >10 years post-LT (baseline time) formed the study population. Long-term outcome measures included the following: immunosuppression, metabolic complications [obesity, arterial hypertension (AH), diabetes, dislypidemia], cardiovascular events (CVE), chronic renal dysfunction-CRD, and de novo tumors. Median age at LT was 50 years. Most common indication was postnecrotic cirrhosis (89%), mostly because of HCV (46%). At study-baselin…

Anemia is not predictive of sustained virological response in liver transplant recipients with hepatitis C virus who are treated with pegylated interferon and ribavirin

In the immunocompetent setting, antiviral therapy–related anemia has recently been shown to be associated with a sustained virological response (SVR). Our goal was to assess whether this is also true for liver transplantation (LT). We included 160 LT patients with recurrent hepatitis C virus (HCV) who were treated with pegylated interferon and ribavirin (RBV) between 2002 and 2010; 76% of the patients were men, the median age of the patients was 56 years (range = 33-75 years), 63% had advanced fibrosis, and 86% were infected with HCV genotype 1a or 1b. The baseline immunosuppression was tacrolimus in 56% of the patients. Mycophenolate mofetil (MMF) was used in 15%. Anemia was defined as a h…

Resultados tras 13 años del inicio del trasplante simultáneo de páncreas-riñón en pacientes con diabetes mellitus tipo 1 en la Comunidad Valenciana

Resumen Introduccion El trasplante simultaneo de pancreas-rinon (SPK, por simultaneous pancreas kidney) es una opcion terapeutica valida en pacientes afectos de diabetes mellitus tipo 1 con enfermedad renal cronica terminal que son candidatos a trasplante renal. Se presentan los resultados desde el inicio del programa de trasplante SPK en la Comunidad Valenciana. Metodos Estudio descriptivo, retrospectivo y unicentrico de los trasplantes de pancreas realizados en el Hospital Universitari i Politecnic La Fe, desde septiembre de 2002 a diciembre de 2015. Se recogieron variables clinicas de los donantes y receptores, variables peri-operatorias y supervivencia del paciente y del injerto pancrea…

Reply to the Letter «A challenge for medium and small pancreatic transplant groups: How can the learning curve from the retrieval team affect the pancreas graft thrombosis?»

Hydrodynamic IL10 Gene Transfer in Human Colon: Results from an "EX VIVO" Study with Potential Clinical Application in Crohn's Disease.

Background: The aim of this work is to evaluate the efficacy of hydrodynamic venous IL10 gene delivery to "ex vivo" human colon segments and to determine its potential interest in Crohn's disease treatment. Methods: Twenty human colon segments were obtained from surgical resections. Hydrodynamic transfection through the main vein of the pedicle with 50 mL of hIL10 plasmid (20 mu g/mL) solution was performed on 13 of them. Tissue sections were cultured and DNA, RNA, and protein copies were determined after 1, 2, and 4 days. Data obtained were compared with 6 nontransfected specimens. Finally, 1 specimen was injected with gold nanoparticles, and their distribution was examined under electron …

Estimating the Patient-Specific Relative Stiffness Between a Hepatic Lesion and the Liver Parenchyma

This paper presents a novel non-invasive methodology to obtain the patient-specific relative stiffness between a hepatic lesion and the liver parenchyma in vivo. This relative stiffness can be used as a biomarker about the type of lesion. This biomarker together with the rest of pathological information can be used to plan a biopsy, an image-guide intervention or a radiation therapy. This relative stiffness is estimated by means of the finite element simulation of the breathing process, which is embedded in an optimization routine based on genetic algorithms. This routine was aimed at finding the patient-specific relative stiffness between a hepatic lesion and the liver parenchyma for the p…

Simultaneous Pancreas Kidney Transplantation Improves Cardiovascular Autonomic Neuropathy with Improved Valsalva Ratio as the Most Precocious Test

Background. Simultaneous pancreas-kidney (SPK) transplantation is a proven option of treatment for patients with type 1 diabetes mellitus (T1DM) and related end-stage renal disease. There is discrepancy between the results of different studies about the impact of prolonged normalization of glucose metabolism achieved by SPK on the course of diabetic complications including severe forms of diabetic neuropathy. The objective of the study was to evaluate the prevalence of cardiovascular autonomic neuropathy (CAN) in patients undergoing SPK transplantation and its evolution 10 years after transplantation. Methods. Prospective study of 81 patients transplanted in a single center from year 2002 t…

Estimation of the elastic parameters of human liver biomechanical models by means of medical images and evolutionary computation.

This paper presents a method to computationally estimate the elastic parameters of two biomechanical models proposed for the human liver. The method is aimed at avoiding the invasive measurement of its mechanical response. The chosen models are a second order Mooney–Rivlin model and an Ogden model. A novel error function, the geometric similarity function (GSF), is formulated using similarity coefficients widely applied in the field of medical imaging (Jaccard coefficient and Hausdorff coefficient). This function is used to compare two 3D images. One of them corresponds to a reference deformation carried out over a finite element (FE) mesh of a human liver from a computer tomography image, …

Is Physical Exercise Harmful to Liver Transplantation Recipients? Review of Literature

Liver transplantation is a treatment that significantly improves the patients' quality of life. However, we should be more ambitious and seek an improvement in their fitness through training protocols allowing them to fully return to daily activities. English and Spanish-language articles on PubMed and the Cochrane Library were searched untill 2014. Articles were reviewed by 2 of the authors to determine if they were suitable for inclusion. It is shown a compilation of studies that included patients who have participated in aerobic, strength, or both combined training programs, without implying a risk for the graft function. There is a lack of studies with high scientific evidence that stab…

Efficacy of interleukin 10 gene hydrofection in pig liver vascular isolated ‘in vivo’ by surgical procedure with interest in liver transplantation

AIM Liver transplantation is the only curative strategy for final stage liver diseases. Despite the great advances achieved during the last 20 years, the recipient immune response after transplantation is not entirely controlled. This results in high rates of acute cell rejection and, approximately, 10% of early mortality. Therapeutic treatment could be improved by efficiently transfecting genes that encode natural immunosuppressant proteins, employing safe procedures that could be transferred to clinical setting. In this sense, interleukin 10 plays a central role in immune tolerance response by acting at different levels. METHODS hIL10 gene was hydrofected by retrograde hydrodynamic inject…

Expanded criteria for liver transplantation in patients with cirrhosis and hepatocellular carcinoma

Orthotopic liver transplantation (OLT) selection for patients with hepatocellular carcinoma (HCC) is a matter of debate. The Milan criteria (MC) have been largely adopted by the international community. The main aim of this study was to evaluate the survival rates and recurrence probabilities of a new proposal for criteria (up to 3 tumors, each no larger than 5 cm, and a cumulative tumor burden </= 10 cm). Patients with cirrhosis and HCC included on the waiting list (WL) from 1991 to 2006 were retrospectively analyzed. Outcomes in patients who had tumors within and beyond the MC were compared. The survival analysis was done (1) with the intention-to-treat principle and (2) among transplante…

¿Es perjudicial el ejercicio físico para el trasplantado de hígado? Revisión de la literatura

Resumen El trasplante hepatico es un tratamiento que ha permitido mejorar de manera significativa la calidad de vida de los pacientes. Sin embargo, se debe ser mas ambiciosos y buscar una mejora de su condicion fisica a traves de protocolos de entrenamiento que permitan una reincorporacion total a las actividades de la vida diaria. Se buscaron articulos en los idiomas espanol e ingles, en las bases de datos PubMed y Cochrane, hasta el ano 2014. Todos los articulos fueron revisados por 2 autores para determinar si eran apropiados para su inclusion. Se muestra una recopilacion de estudios donde se consiguen mejoras en el estado fisico de pacientes que han participado en programas de entrenami…

Post-transplant lymphoproliferative disorders after solid organ and hematopoietic stem cell transplantation.

Post-transplant lymphoproliferative disorders (PTLD) are a rare complication after both solid organ (SOT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this single center retrospective study, we compared clinical, biological, and histological features, and outcomes of PTLD after both types of transplant. We identified 82 PTLD (61 after SOT and 21 after allo-HSCT). The presence of B symptoms, Waldeyer ring, spleen, central nervous system, and liver involvement, and advanced Ann-Arbor stage were more frequent in allo-HSCT recipients. PTLD had an earlier onset in allo-HSCT than in SOT cohort (4 vs. 64 months, p  .0001). PTLD was EBV-positive in 100% of allo-HSCT, in co…

Studying Closed Hydrodynamic Models of "In Vivo" DNA Perfusion in Pig Liver for Gene Therapy Translation to Humans.

17 páginas, 6 figuras. En la versión online contiene 3 figuras y 1 tabla en información suplemetaria

Efficacy of hydrodynamic interleukin 10 gene transfer in human liver segments with interest in transplantation.

Different diseases lead, during their advanced stages, to chronic or acute liver failure, whose unique treatment consists in organ transplantation. The success of intervention is limited by host immune response and graft rejection. The use of immunosuppressant drugs generally improve organ transplantation, but they cannot completely solve the problem. Also, their management is delicate, especially during the early stages of treatment. Thus, new tools to set an efficient modulation of immune response are required. The local expression of interleukin (IL) 10 protein in transplanted livers mediated by hydrodynamic gene transfer could improve the organ acceptance by the host because it presents…

Framingham score, renal dysfunction, and cardiovascular risk in liver transplant patients

Cardiovascular (CV) events represent major impediments to the long-term survival of liver transplantation (LT) patients. The aim of this study was to assess whether the Framingham risk score (FRS) at transplantation can predict the development of post-LT cardiovascular events (CVEs). Patients transplanted between 2006 and 2008 were included. Baseline features, CV risk factors, and CVEs occurring after LT (ischemic heart disease, stroke, heart failure, de novo arrhythmias, and peripheral arterial disease) were recorded. In total, 250 patients (69.6% men) with a median age of 56 years (range, 18-68 years) were included. At transplantation, 34.4%, 34.4%, and 33.2% of patients, respectively, ha…

Low RNA translation activity limits the efficacy of hydrodynamic gene transfer to pig liver “in vivo”

Background Hydrodynamic gene delivery has proved an efficient strategy for nonviral gene therapy in the murine liver but it has been less efficient in pigs. The reason for such inefficiency remains unclear. The present study used a surgical strategy to seal the whole pig liver in vivo. Methods A solution of enhanced green fluorescent protein (eGFP) DNA was injected under two different venous injection conditions (anterograde and retrograde), employing flow rates of 10 and 20 ml/s in each case, with the aim of identifying the best gene transfer conditions. The gene delivery and information decoding steps were evaluated by measuring the eGFP DNA, mRNA and protein copy number 24 h after transf…