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BACKGROUND: Recent introduction of direct antiviral agents (DAAs) has completely changed the scenario regarding hepatitis C virus (HCV) treatment. Certain countries' economic health programs prioritize DAAs according to specific clinical features of HCV-infected patients. The aim of this study was to define epidemiological, demographic and clinical characteristics of HCV-infected patients in the Tuscany region of central Italy. METHODS: We enrolled HCV patients with chronic viral hepatitis who were referred to the outpatient services of 16 hospitals in Tuscany from 1 January 2015 to 31 December 2015. Case report forms contained patient information including main demographic data, blood chemistry data, viral hepatitis markers, instrumental evaluations (liver biopsy or transient elastometry, liver ultrasound), eligibility for DAAs, and liver transplantation or therapy already in progress. RESULTS: Of all patients considered, 2919 HCV patients were enrolled (mean age: 57.44 ± 15.15; 54% males, 46% females). All routes of transmission were well represented (intravenous drug use in 20.7%; nosocomial/dental care in 20.6%; and coagulation factors/blood transfusions in 13.3%). Diabetes was the highest represented comorbidity (20.8%), followed by metabolic syndrome (15.5%) and ischemic heart disease (6.2%). The most prevalent HCV genotypes were 1b (47.4%) and 2 (16.5%). In the whole cohort of patients, 32.8% were cirrhotic (40 patients were listed for liver transplantation). Signs of portal hypertension were present mostly in the group older than 45 years (92.3%). Extrahepatic HCV-related diseases were present in 13.3% of cases (cryoglobulinemic syndrome in 58.3% and B-cell non-Hodgkin's lymphoma in 10.5%). CONCLUSIONS: Our study provides evidence of a high prevalence of epidemiological changes in HCV infection with a major prevalence of advanced liver disease, such as portal hypertension, in this elderly cohort of patients.
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Hepatitis C Crónica , Adulto , Anciano , Estudios de Cohortes , Comorbilidad , Femenino , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/epidemiología , Hepatitis C Crónica/virología , Humanos , Italia/epidemiología , Masculino , Persona de Mediana EdadRESUMEN
Several risk factors for ischaemic-type biliary lesions (ITBL) after liver transplantation (LT) have been identified, but the role of portal vein perfusion at graft procurement is still unclear. This was a prospective study on double aortic and portal perfusion (DP) of liver grafts stratified by donor's decade (<60 yo; 60-69 yo; 70-79 yo and ≥80 yo) versus similar historical cohorts of primary, adult grafts procured with single aortic perfusion (SP) only. The primary study aim was to assess the role of DP on the incidence of ITBL. There was no difference in the incidence of overall biliary complications according to procurement technique for recipients of grafts <80 years. A higher incidence of ITBL was observed for patients receiving grafts ≥80 years and perfused through the aorta only (1.9 vs. 13.4%; P = 0.008). When analysing octogenarian grafts, donor male gender (HR = 6.4; P = 0.001), haemodynamic instability (HR = 4.9; P = 0.008), and type-2 diabetes mellitus (DM2) (HR = 3.0; P = 0.03) were all independent risk factors for ITBL, while double perfusion at procurement (HR = 0.1; P = 0.04) and longer donor intensive care unit (ICU) stay (HR = 0.7; P = 0.04) were protective factors. Dual aortic and portal perfusion has the potential to reduce post-transplant ITBL incidence for recipients of octogenarian donor grafts. Larger series are needed to confirm this preliminary experience.
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Factores de Edad , Aorta/patología , Trasplante de Hígado/efectos adversos , Vena Porta/patología , Donantes de Tejidos , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Enfermedades de las Vías Biliares/etiología , Femenino , Supervivencia de Injerto , Hemodinámica , Humanos , Isquemia/etiología , Hígado/patología , Trasplante de Hígado/métodos , Masculino , Persona de Mediana Edad , Perfusión , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
Organ shortage and increasing donor age in liver transplant are stimulating transplant centers to accept otherwise discarded grafts due to donor age or vascular abnormalities; nevertheless, the use of nonagenarian donor grafts is uncommon because advanced age is associated with a higher risk of ischemic-type biliary lesions and worse long-term graft survival. We herein report the case of a 90-year-old donor with fully replaced right hepatic artery. After back-table vascular assessment, the donor right hepatic artery was anastomosed end-to-end with the gastroduodenal artery with 2 polypropylene 8/0 running sutures. Even if the back-table reconstruction of a replaced right hepatic artery is not associated with an enhanced risk of posttransplant vascular complications, vascular abnormalities might discourage the use of otherwise acceptable elderly grafts. The present case underscores that elderly liver grafts should not be discarded per se even in the presence of vascular variants.
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Carcinoma Hepatocelular/cirugía , Selección de Donante , Arteria Hepática/cirugía , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/métodos , Procedimientos de Cirugía Plástica/métodos , Donantes de Tejidos , Procedimientos Quirúrgicos Vasculares/métodos , Factores de Edad , Anciano de 80 o más Años , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Angiografía por Tomografía Computarizada , Femenino , Arteria Hepática/diagnóstico por imagen , Hepatitis B/complicaciones , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Persona de Mediana Edad , Estadificación de Neoplasias , Resultado del Tratamiento , Ultrasonografía DopplerRESUMEN
BACKGROUND: The most appropriate endo-therapeutic approach to biliary anastomotic strictures is yet to be defined. AIM: To retrospectively report on the endo-therapy of duct-to-duct anastomotic strictures during 2013 in Italy. METHODS: Data were collected from 16 Endoscopy Units at the Italian Liver Transplantation Centers (BASALT study group). RESULTS: Complete endo-therapy and follow-up data are available for 181 patients: 101 treated with plastic multistenting, 26 with fully covered self-expandable metal stenting and 54 with single stenting. Radiological success was achieved for 145 patients (80%), that is, 88% of plastic multistenting, 88% of self-expandable metal stenting and 61% of single stenting (P < 0.001 vs plastic multistenting; P < 0.05 vs self-expandable metal stenting). After first-line endo-therapy failure, the patients underwent a second-line endo-therapy with plastic multistenting for 25%, fully covered self-expandable metal stenting for 53% and single stenting for 22% of cases, and radiological success was achieved for 84%, that is, 100%, 85% and 63% with plastic multistenting, self-expandable metal stenting and single stenting (P < 0.05 vs plastic multistenting or self-expandable metal stenting) respectively. Procedure-related complications occurred in 7.8% of endoscopic retrograde cholangiopancreatographies. Overall, clinical success was achieved in 87% of patients after a median follow-up of 25 months. CONCLUSION: Plastic multistenting is confirmed as the preferred first-line treatment, while fully covered self-expandable metal stenting as rescue option for biliary anastomotic strictures. Single stenting has sub-optimal results and should be abandoned.
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Colangiopancreatografia Retrógrada Endoscópica/instrumentación , Constricción Patológica/cirugía , Trasplante de Hígado/efectos adversos , Stents Metálicos Autoexpandibles , Stents/clasificación , Adulto , Anciano , Enfermedades de las Vías Biliares/etiología , Enfermedades de las Vías Biliares/cirugía , Colestasis/etiología , Constricción Patológica/etiología , Femenino , Humanos , Italia , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , Plásticos , Estudios Retrospectivos , Encuestas y Cuestionarios , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
To improve the efficiency of pancreatic islet transplantation, we performed in-vitro and in-vivo experiments with isolated human pancreatic islets coated by multi-layer nano-encapsulation using differently charged polymers [chitosan and poly(sodium styrene sulfonate)] to obtain up to 9 layers. The islet coating (thickness: 104.2⯱â¯4.2â¯nm) was uniform, with ≥ 90% cell viability and well preserved beta- and alpha-cell ultrastructure. Nano-encapsulated islets maintained physiological glucose-stimulated insulin secretion by both static incubation and perifusion studies. Notably, palmitate- or cytokine-induced toxicity was significantly reduced in nano-coated islets. Xenotransplantation of nano-encapsulated islets under the kidney capsule of streptozotocin-induced C57Bl/6J diabetic mice allowed long term normal or near normal glycemia, associated with minimal infiltration of immune cell into the grafts, well preserved islet morphology and signs of re-vascularization. In summary, the multi-layer nano-encapsulation approach described in the present study provides a promising tool to effectively protect human islets both in-vitro andin-vivo conditions.
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Materiales Biocompatibles Revestidos/química , Diabetes Mellitus Experimental/prevención & control , Trasplante de Islotes Pancreáticos , Islotes Pancreáticos/citología , Nanoestructuras/administración & dosificación , Animales , Glucemia/análisis , Células Cultivadas , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Nanoestructuras/química , Trasplante HeterólogoRESUMEN
We report a case of post-transplant liver graft infection with Schistosoma spp in a migrant from sub-Saharan Africa transplanted for HBV-related cirrhosis and with undiagnosed schistosomiasis pre-transplantation. The occurrence of tropical diseases in non-endemic areas warrants screening protocols for organ donors and recipients with a history of exposure in endemic areas.
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Trasplante de Hígado/efectos adversos , Schistosoma haematobium/aislamiento & purificación , Esquistosomiasis Urinaria/diagnóstico , Adulto , África del Sur del Sahara , Aloinjertos/parasitología , Animales , Antihelmínticos/uso terapéutico , Humanos , Hígado/parasitología , Cirrosis Hepática/cirugía , Masculino , Esquistosomiasis Urinaria/tratamiento farmacológico , Esquistosomiasis Urinaria/parasitología , MigrantesRESUMEN
AIM: To build a regional database of chronic patients to define the clinical epidemiology of hepatitis B virus (HBV)-infected patients in the Tuscan public health care system. METHODS: This study used a cross-sectional cohort design. We evaluated chronic viral hepatitis patients with HBV referred to the outpatient services of 16 hospital units. Information in the case report forms included main demographic data, blood chemistry data, viral hepatitis markers, instrumental evaluations, and eligibility for treatment or ongoing therapy and liver transplantation. RESULTS: Of 4015 chronic viral hepatitis patients, 1096 (27.3%) were HBV infected. The case report form was correctly completed for only 833 patients (64% males, 36% females; mean age 50.1 ± 15.4). Of these HBV-infected patients, 73% were Caucasian, 21% Asian, 4% Central African, 1% North African and 1% American. Stratifying patients by age and nationality, we found that 21.7% of HBV-infected patients were aged < 34 years (only 2.8% were Italian). The most represented routes of transmission were nosocomial/dental procedures (23%), mother-to-child (17%) and sexual transmission (12%). The most represented HBV genotypes were D (72%) and A (14%). Of the patients, 24.7% of patients were HBeAg positive, and 75.3% were HBeAg negative. Of the HBV patients 7% were anti-HDV positive. In the whole cohort, 26.9% were cirrhotic (35.8% aged < 45 years), and 47% were eligible for or currently undergoing treatment, of whom 41.9 % were cirrhotic. CONCLUSION: Only 27.3% of chronic viral hepatitis patients were HBV infected. Our results provide evidence of HBV infection in people aged < 34 years, especially in the foreign population not protected by vaccination. In our cohort of patients, liver cirrhosis was also found in young adults.
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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.
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Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/cirugía , Trasplante de Hígado , Anciano , Biopsia , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Toma de Decisiones Clínicas , Bases de Datos Factuales , Europa (Continente) , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Selección de Paciente , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
It has been reported that the incretin system, including regulated GLP-1 secretion and locally expressed DPP-4, is present in pancreatic islets. In this study we comprehensively evaluated the expression and role of DPP-4 in islet alpha and beta cells from non-diabetic (ND) and type 2 diabetic (T2D) individuals, including the effects of its inhibition on beta cell function and survival. Isolated islets were prepared from 25 ND and 18 T2D organ donors; studies were also performed with the human insulin-producing EndoC-ßH1 cells. Morphological (including confocal microscopy), ultrastructural (electron microscopy, EM), functional (glucose-stimulated insulin secretion), survival (EM and nuclear dyes) and molecular (RNAseq, qPCR and western blot) studies were performed under several different experimental conditions. DPP-4 co-localized with glucagon and was also expressed in human islet insulin-containing cells. Furthermore, DPP-4 was expressed in EndoC-ßH1 cells. The proportions of DPP-4 positive alpha and beta cells and DPP-4 gene expression were significantly lower in T2D islets. A DPP-4 inhibitor protected ND human beta cells and EndoC-ßH1 cells against cytokine-induced toxicity, which was at least in part independent from GLP1 and associated with reduced NFKB1 expression. Finally, DPP-4 inhibition augmented glucose-stimulated insulin secretion, reduced apoptosis and improved ultrastructure in T2D beta cells. These results demonstrate the presence of DPP-4 in human islet alpha and beta cells, with reduced expression in T2D islets, and show that DPP-4 inhibition has beneficial effects on human ND and T2D beta cells. This suggests that DPP-4, besides playing a role in incretin effects, directly affects beta cell function and survival.
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Diabetes Mellitus Tipo 2/enzimología , Diabetes Mellitus Tipo 2/patología , Dipeptidil Peptidasa 4/metabolismo , Células Secretoras de Insulina/enzimología , Anciano , Apoptosis/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citocinas/toxicidad , Citoprotección/efectos de los fármacos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Regulación hacia Abajo/efectos de los fármacos , Femenino , Humanos , Secreción de Insulina/efectos de los fármacos , Células Secretoras de Insulina/ultraestructura , Masculino , Persona de Mediana EdadRESUMEN
AIMS/HYPOTHESIS: Pancreatic islet beta cell failure causes type 2 diabetes in humans. To identify transcriptomic changes in type 2 diabetic islets, the Innovative Medicines Initiative for Diabetes: Improving beta-cell function and identification of diagnostic biomarkers for treatment monitoring in Diabetes (IMIDIA) consortium ( www.imidia.org ) established a comprehensive, unique multicentre biobank of human islets and pancreas tissues from organ donors and metabolically phenotyped pancreatectomised patients (PPP). METHODS: Affymetrix microarrays were used to assess the islet transcriptome of islets isolated either by enzymatic digestion from 103 organ donors (OD), including 84 non-diabetic and 19 type 2 diabetic individuals, or by laser capture microdissection (LCM) from surgical specimens of 103 PPP, including 32 non-diabetic, 36 with type 2 diabetes, 15 with impaired glucose tolerance (IGT) and 20 with recent-onset diabetes (<1 year), conceivably secondary to the pancreatic disorder leading to surgery (type 3c diabetes). Bioinformatics tools were used to (1) compare the islet transcriptome of type 2 diabetic vs non-diabetic OD and PPP as well as vs IGT and type 3c diabetes within the PPP group; and (2) identify transcription factors driving gene co-expression modules correlated with insulin secretion ex vivo and glucose tolerance in vivo. Selected genes of interest were validated for their expression and function in beta cells. RESULTS: Comparative transcriptomic analysis identified 19 genes differentially expressed (false discovery rate ≤0.05, fold change ≥1.5) in type 2 diabetic vs non-diabetic islets from OD and PPP. Nine out of these 19 dysregulated genes were not previously reported to be dysregulated in type 2 diabetic islets. Signature genes included TMEM37, which inhibited Ca2+-influx and insulin secretion in beta cells, and ARG2 and PPP1R1A, which promoted insulin secretion. Systems biology approaches identified HNF1A, PDX1 and REST as drivers of gene co-expression modules correlated with impaired insulin secretion or glucose tolerance, and 14 out of 19 differentially expressed type 2 diabetic islet signature genes were enriched in these modules. None of these signature genes was significantly dysregulated in islets of PPP with impaired glucose tolerance or type 3c diabetes. CONCLUSIONS/INTERPRETATION: These studies enabled the stringent definition of a novel transcriptomic signature of type 2 diabetic islets, regardless of islet source and isolation procedure. Lack of this signature in islets from PPP with IGT or type 3c diabetes indicates differences possibly due to peculiarities of these hyperglycaemic conditions and/or a role for duration and severity of hyperglycaemia. Alternatively, these transcriptomic changes capture, but may not precede, beta cell failure.
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Bancos de Muestras Biológicas , Diabetes Mellitus Tipo 2/metabolismo , Biología de Sistemas/métodos , Donantes de Tejidos , Transcriptoma/genética , Anciano , Anciano de 80 o más Años , Biología Computacional , Femenino , Humanos , Masculino , PancreatectomíaRESUMEN
OBJECTIVE: To evaluate the use of elderly donors in liver transplantation (LT) and identify risk factors associated with a worse outcome. SUMMARY BACKGROUND DATA: Use of livers from very old donors could expand the donor pool but is not universally implemented. METHODS: This is a retrospective, single-center medical record review. From January 2001 to December 2014, 1354 LTs were performed. After exclusion of donors <18 years, ABO-incompatible LT, re-LT and UNOS 1 status patients, LT recipients were stratified into 2 groups based on donor age: 18-69 (n=692) vs. ≥70 years (n=515) then matched using a propensity score approach. Two groups were finally matched (young group = 448 cases; old group = 515 cases). RESULTS: The median (interquartile range [IQR]) follow-up was 5.0 (2.0-8.4) years. Comparing the 2 identified groups, no differences were observed regarding early retransplants (1.8 vs. 2.9; P = 0.3), HCV-related death (7.6 vs. 8.7%; P = 0.6), vascular (5.8 vs. 5.0%; P = 0.7), and biliary complications (16.5 vs. 18.6%; P = 0.4). On multivariate analysis, independent risk factors for graft loss were: HCV-positive recipient (HR = 2.1; 95% CI = 1.6-2.7; P < 0.001), donor age (HR = 1.0; 95% CI = 1.0-1.0; P < 0.001), cold ischemia time (HR = 1.0; 95% CI = 1.0-1.0; P = 0.042), and donor history of diabetes mellitus (HR = 1.48; 95% CI = 1.03-2.13; P = 0.036). CONCLUSIONS: Use of elderly donors is not associated per se with an increased risk of vascular and biliary complications. In the presence of cold ischemia time and diabetes mellitus, appropriate donor-to-recipient matching is warranted.
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Enfermedad Hepática en Estado Terminal/cirugía , Trasplante de Hígado/métodos , Adolescente , Adulto , Factores de Edad , Anciano , Femenino , Estudios de Seguimiento , Supervivencia de Injerto , Humanos , Masculino , Análisis por Apareamiento , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Puntaje de Propensión , Estudios Retrospectivos , Factores de Riesgo , Donantes de Tejidos , Resultado del Tratamiento , Adulto JovenRESUMEN
Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers, is the second leading cause of cancer-related deaths and the leading cause of death in patients with cirrhosis. Liver transplantation (LT) represents the ideal treatment for selected patients as it removes both the tumor and the underlying cirrhotic liver with 5-year survival rates higher than 70%. Unfortunately, due to tumor characteristics, patient co-morbidities or shortage of organs available for transplant, only 20% of patients can undergo curative treatment. Ex situ machine perfusion (MP) is a technology recently introduced that might potentially improve organ preservation, allow graft assessment and increase the pool of available organs. The purpose of this review is to provide an update on the current role of ex situ liver MP in liver transplantation for HCC patients.
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Recently osteopontin (OPN), a protein of the extracellular matrix, has generated in hepatocellular carcinoma (HCC) a significant interest as a prognostic factor. Aim of this study was to confirm, in liver tissues of subjects with HCV-positive HCC undergoing liver transplantation (RL, n=10) and of donors (DL, n=14), the increase of OPN plasma and tissue concentration, the OPN splicing isoforms expression profiling together with those of thrombin, and to evaluate a possible association between OPN measurements. Their association with Notch-1, IV-Collagen-7s domain, IL-6 and TNF-α were also evaluated. Real-Time PCR experiments and immunometric assay were performed. mRNA expression resulted higher in RL than in DL for all analyzed genes and several correlations were found between them. The more relevant association were between OPN-a and OPN-b (p<0.0001), between thrombin and OPN-a (p=0.007), between 7s-collagen and OPN isoforms (p<0.05) and between Notch-1 with OPN-c (p=0.004). Both OPN plasma and liver tissue extract concentrations were assessed confirming the trend observed at the mRNA level. An important association was found between OPN plasma and protein (p<0.0001, r=0.96) even splitting patients in DL (p<0.0001, r=0.93) and RL (p<0.0001, r=0.96). A reduction of OPN plasma levels was found at 6months after transplantation. Considering MELD score as liver disease severity, the mRNA expression of our markers as well as of OPN plasma and tissue concentrations resulted increased as a function of clinical severity. Our results might be considered a useful starting point to validate OPN as a prognostic and diagnostic marker of HCC.
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Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Osteopontina/metabolismo , Empalme Alternativo/genética , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Colágeno/metabolismo , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Osteopontina/sangre , Isoformas de Proteínas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Trombina/genética , Trombina/metabolismo , Factores de Tiempo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND AND OBJECTIVES: Electrochemotherapy is a novel ablation technique combining chemotherapeutic agents with reversible cell membrane electroporation. Previous experiences have shown its efficacy for cutaneous tumors. Its application for deep-seated malignancies is under investigation. We performed a prospective, pilot study to evaluate the feasibility, safety, and efficacy of intraoperative electrochemotherapy for otherwise unresectable colorectal liver metastases. METHODS: Electrochemotherapy with bleomycin was combined with open liver resection and performed with linear or hexagonal needle electrodes according to an individualized pretreatment plan. The primary endpoints were: feasibility, as ratio of completed to planned treatments; safety, and efficacy, as per response assessed at 30 days with MRI and according to RECIST. The secondary endpoint was overall and progression-free survival at month 6. RESULTS: A total of 9 colorectal liver metastases were treated in 5 patients with 20 electrode applications. No intraoperative complications were observed. At day 30, complete response was 55.5% and stable disease 45.5%. All (5) patients reached a 6 months overall survival, and 4 out of 5 patients had 6 months progression free survival. CONCLUSIONS: Electrochemotherapy is a feasible and safe adjunct to open surgery for treatment of unresectable colorectal liver metastases. Larger studies and longer follow-ups are favored to better define its role in the treatment of secondary liver malignancies.
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Antineoplásicos/uso terapéutico , Bleomicina/uso terapéutico , Neoplasias Colorrectales/patología , Electroquimioterapia , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Adulto , Anciano , Neoplasias del Colon/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/terapia , Supervivencia sin Enfermedad , Estudios de Factibilidad , Femenino , Hepatectomía , Humanos , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios ProspectivosRESUMEN
Management of complications post-liver transplantation (LT) includes immunosuppressive manipulations with the aim to reduce the overall burden of immunologic suppression and compensate for renal, cardiovascular, metabolic toxicities, and for the increased oncologic risk. Two approaches can be implemented to reduce immunosuppression-related adverse events: upfront schedules tailored to the pretransplant individual patient's risk profile versus downstream modifications in the event of immunosuppression-related complications. Upfront strategies are supported by evidence originating from prospective randomized trials and consist of triple/quadruple schedules whereby calcineurin inhibitors (CNI)-exposure is reduced with combination of anti-CD25 monoclonal antibodies, antimetabolites and corticosteroids. Quadruple regimens allow for staggering of CNI introduction and higher renal function in the early term, but their superiority in the long term has not yet been established. A more recent upfront schedule contemplates early (4 weeks) introduction of mammalian target of rapamycin inhibitor (mTORi) everolimus and allows for reduction of CNI up to 4 years posttransplantation. Incorporation of mTORi has the potential to prolong time to recurrence for patients with hepatocellular carcinoma. However, as suggested by the available evidence, downstream immunosuppressive manipulations are more frequently adopted in clinical practice. These encompass CNI replacement and immunosuppression withdrawal. Switching CNI to mTORi monotherapy is the option most commonly adopted to relieve renal function and compensate for posttransplant malignancies. Its impact is dependent on interval from transplantation and underlying severity of renal impairment. Introduction of mTORi is associated with longer overall survival for patients with extrahepatic posttransplant malignancies, but results are awaited for recurrences of hepatocellular carcinoma. Immunosuppression withdrawal seems feasible (70%) in very long term survivors (>10 years), but is not associated with reversal of immunosuppression-related complications. Awaiting novel immunosuppressive drug categories, integration of upfront strategies with the aim to reduce CNI-exposure and a low threshold for adjustment in the posttransplant course are both advisable to improve long-term outcomes of LT.
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Inhibidores de la Calcineurina/efectos adversos , Terapia de Inmunosupresión/métodos , Inmunosupresores/efectos adversos , Trasplante de Hígado/efectos adversos , Inhibidores de la Calcineurina/farmacología , Humanos , Inmunosupresores/uso terapéutico , Estudios Prospectivos , Factores de RiesgoRESUMEN
To search for clues suggesting that beta cells may generate by transdifferentiation in humans, we assessed the presence of cells double positive for exocrine (amylase, carboxypeptidase A) and endocrine (insulin) markers in the pancreas of non-diabetic individuals (ND) and patients with type 2 diabetes (T2D). Samples from twelve ND and twelve matched T2D multiorgan donors were studied by electron microscopy, including amylase and insulin immunogold labeling; carboxypeptidase A immunofluorescence light microscopy assessment was also performed. In the pancreas from four T2D donors, cells containing both zymogen-like and insulin-like granules were observed, scattered in the exocrine compartment. Nature of granules was confirmed by immunogold labeling for amylase and insulin. Double positive cells ranged from 0.82 to 1.74 per mm2, corresponding to 0.26±0.045% of the counted exocrine cells. Intriguingly, cells of the innate immune systems (mast cells and/or macrophages) were adjacent to 33.3±13.6% of these hybrid cells. No cells showing co-localization of amylase and insulin were found in ND samples by electron microscopy. Similarly, cells containing both carboxypeptidase A and insulin were more frequently observed in the diabetic pancreata. These results demonstrate more abundant presence of cells containing both acinar markers and insulin in the pancreas of T2D subjects, which suggests possible conversion from one cellular type to the other and specific association with the diseased condition.
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Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Páncreas Exocrino/metabolismo , Anciano , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Páncreas Exocrino/ultraestructuraAsunto(s)
Trasplante de Hígado/métodos , Donantes de Tejidos , Neoplasias Urogenitales/diagnóstico , Carcinoma de Células Renales/diagnóstico , Femenino , Humanos , Hallazgos Incidentales , Neoplasias Renales/diagnóstico , Trasplante de Hígado/efectos adversos , Masculino , Neoplasias de la Próstata/diagnóstico , Factores de Riesgo , Obtención de Tejidos y ÓrganosRESUMEN
BACKGROUND: Both types of diabetes are characterized by beta-cell failure and death, leading to insulin insufficiency. Very limited information is currently available about the ultrastructural alterations of beta cells in human diabetes. Our aim was to provide a comprehensive ultrastructural analysis of human pancreatic islets in type 1 (T1D) and type 2 (T2D) diabetic patients. METHODS: We performed a morphometric electron microscopy evaluation of beta cells obtained from the pancreas of 8 nondiabetic (ND), 5 T1D, and 8 T2D organ donors. RESULTS: A lower amount of beta cells was found in both T1D and T2D than in ND islets, whereas alpha cells were increased only in T2D. An increased number of bi-hormonal cells (showing both insulin and glucagon granules in their cytoplasm) were found in T1D. Insulin granules were less represented in T2D than in ND beta cells, whereas no significant changes were found in T1D. Volume density of the endoplasmic reticulum was increased in T2D and unchanged in T1D; mitochondria number and volume were significantly higher in T2D than in ND beta cells, whereas no significant differences were found in T1D. In both T1D and T2D, more beta cells showed signs of apoptosis than in ND. CONCLUSIONS: Our results show that in each type of diabetes, beta cells exhibit specific ultrastructural alterations, whose better understanding might improve therapeutic strategies.
Asunto(s)
Diabetes Mellitus/patología , Células Secretoras de Insulina/patología , Células Secretoras de Insulina/ultraestructura , Islotes Pancreáticos/patología , Islotes Pancreáticos/ultraestructura , Adulto , Anciano , Autopsia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Use of grafts from very old donors for liver transplantation is controversial. AIM: To compare the perioperative course of patients receiving liver grafts from young ideal vs octogenarian donors. METHODS: Analysis of the perioperative course of patients receiving liver grafts from young, ideal (18-39 years) vs octogenarian (≥80years) deceased donors between 2001 and 2014. RESULTS: 346 patients were studied: 179 (51.7%) received grafts aged 18-39 years whereas 167 (48.3%) received a graft from a donor aged ≥80years. Intra-operative cardiovascular (p=0.2), coagulopathy (p=0.5) and respiratory (p=1.0) complications and incidence of reperfusion syndrome (p=0.3) were similar. Patients receiving a young graft required more fresh frozen plasma units (p≤0.03) but did not differ for the need of packed red cells (p=0.2) and platelet (p=0.3) transfusions. Median ICU stay was identical (p=0.4). Patients receiving octogenarian vs young grafts did not differ in terms of death or re-transplant (p=1.0) during the ICU stay. Similar cardiovascular, respiratory, renal, infectious and neurological postoperative complication rates were observed in the two groups. CONCLUSIONS: Octogenarian donors in liver transplantation grant an equivalent perioperative course to ideal young donors.