RESUMO
Activated hepatic stellate cells (HSCs) are the main collagen-producing cells in liver fibrogenesis. With the purpose of analyzing their presence and relevance in predicting liver allograft fibrosis development, 162 liver biopsies of 54 pediatric liver transplantation (LT) recipients were assessed at 6 months, 3 years, and 7 years after LT. The proportion of activated HSCs, identified by α-smooth muscle actin (ASMA) immunostaining, and the amount of fibrosis, identified by picrosirius red (PSR%) staining, were determined by computer-based morphometric analysis. Fibrosis was also staged by using the semiquantitative liver allograft fibrosis score (LAFSc), specifically designed to score fibrosis in the pediatric LT population. Liver allograft fibrosis displayed progression over time by PSR% (P < 0.001) and by LAFSc (P < 0.001). The ASMA expression decreased in the long term, with inverse evolution with respect to fibrosis (P < 0.01). Patients with ASMA-positive HSCs area ≥ 8% at 6 months (n = 20) developed a higher fibrosis proportion compared to those with ASMA-positive HSCs area ≤ 8% (n = 34) at the same period of time and in the long term (P = 0.03 and P < 0.01, respectively), but not at 3 years (P = 0.8). ASMA expression ≥ 8% at 6 months was found to be an independent risk factor for 7-year fibrosis development by PSR% (r(2) = 0.5; P < 0.01) and by LAFSc (r(2) = 0.3; P = 0.03). Furthermore, ASMA expression ≥ 8% at 3 years showed an association with the development of fibrosis at 7 years (P = 0.02). In conclusion, there is a high proportion of activated HSCs in pediatric LT recipients. ASMA ≥ 8% at 6 months seems to be a risk factor for early and longterm fibrosis development. In addition, activated HSCs showed inverse evolution with respect to fibrosis in the long term. Liver Transplantation 22 822-829 2016 AASLD.
Assuntos
Actinas/metabolismo , Aloenxertos/patologia , Células Estreladas do Fígado/fisiologia , Cirrose Hepática/diagnóstico , Transplante de Fígado/efeitos adversos , Adolescente , Biópsia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Seguimentos , Células Estreladas do Fígado/metabolismo , Humanos , Lactente , Fígado/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Masculino , Fatores de Risco , Transplante Homólogo/efeitos adversosRESUMO
AIMS/HYPOTHESIS: Calcium plays an important role in the process of glucose-induced insulin release in pancreatic beta cells. These cells are equipped with a double system responsible for Ca(2+) extrusion--the Na/Ca exchanger (NCX) and the plasma membrane Ca(2+)-ATPase (PMCA). We have shown that heterozygous inactivation of NCX1 in mice increased glucose-induced insulin release and stimulated beta cell proliferation and mass. In the present study, we examined the effects of heterozygous inactivation of the PMCA on beta cell function. METHODS: Biological and morphological methods (Ca(2+) imaging, Ca(2+) uptake, glucose metabolism, insulin release and immunohistochemistry) were used to assess beta cell function and proliferation in Pmca2 (also known as Atp2b2) heterozygous mice and control littermates ex vivo. Blood glucose and insulin levels were also measured to assess glucose metabolism in vivo. RESULTS: Pmca (isoform 2) heterozygous inactivation increased intracellular Ca(2+) stores and glucose-induced insulin release. Moreover, increased beta cell proliferation, mass, viability and islet size were observed in Pmca2 heterozygous mice. However, no differences in beta cell glucose metabolism, proinsulin immunostaining and insulin content were observed. CONCLUSIONS/INTERPRETATION: The present data indicates that inhibition of Ca(2+) extrusion from the beta cell and its subsequent intracellular accumulation stimulates beta cell function, proliferation and mass. This is in agreement with our previous results observed in mice displaying heterozygous inactivation of NCX, and indicates that inhibition of Ca(2+) extrusion mechanisms by small molecules in beta cells may represent a new approach in the treatment of type 1 and type 2 diabetes.
Assuntos
Membrana Celular/enzimologia , Glucose/farmacologia , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , ATPases Transportadoras de Cálcio da Membrana Plasmática/antagonistas & inibidores , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Teste de Tolerância a Glucose , Células Secretoras de Insulina/efeitos dos fármacos , Camundongos , Trocador de Sódio e Cálcio/genéticaRESUMO
Insulinomas are ß-cell tumors that cause hypoglycemia through inappropriate secretion of insulin. Characterization of the in vitro dynamics of insulin secretion by perifused fragments of 10 human insulinomas permitted their subdivision into three functional groups with similar insulin content. Group A (four patients with fasting and/or postprandial hypoglycemic episodes) showed qualitatively normal responses to glucose, leucine, diazoxide, tolbutamide, and extracellular CaCl2 omission or excess. The effect of glucose was concentration dependent, but, compared with normal islets, insulin secretion was excessive in both low- and high-glucose conditions. Group B (three patients with fasting hypoglycemic episodes) was mainly characterized by large insulin responses to 1 mmol/L glucose, resulting in very high basal secretion rates that were inhibited by diazoxide and restored by tolbutamide but were not further augmented by other agents except for high levels of CaCl2. Group C (three patients with fasting hypoglycemic episodes) displayed very low rates of insulin secretion and virtually no response to stimuli (including high CaCl2 concentration) and inhibitors (CaCl2 omission being paradoxically stimulatory). In group B, the presence of low-Km hexokinase-I in insulinoma ß-cells (not in adjacent islets) was revealed by immunohistochemistry. Human insulinomas thus show distinct, though not completely heterogeneous, defects in insulin secretion that are attributed to the undue expression of hexokinase-I in 3 of 10 patients.
Assuntos
Insulina/metabolismo , Insulinoma/metabolismo , Neoplasias Pancreáticas/metabolismo , Adulto , Idoso de 80 Anos ou mais , Cloreto de Cálcio/farmacologia , Diazóxido/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Glucose/farmacologia , Hexoquinase/genética , Hexoquinase/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Secreção de Insulina , Insulinoma/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Técnicas de Cultura de Tecidos , Tolbutamida/farmacologiaRESUMO
BACKGROUND: Encapsulated follicular tumours with equivocal papillary thyroid carcinoma (PTC) type nuclear features continue to remain a challenge despite the recent attempts to classify these borderline lesions. The term 'well differentiated tumour of uncertain malignant potential (WDT-UMP)' was introduced to classify these tumours. The present study aimed to evaluate the role of a cell cycle regulator like cyclin D1 in these tumours along with assessment of other well established PTC markers like galectin-3, HBME-1, CK19. METHODS: Thirteen cases of metastatic PTC, papillary microcarcinoma and follicular variant of PTC (FVPTC) were identified from a histological review of 510 cases. In addition, 13 cases of a subset of follicular adenomatoid nodules with focal areas showing nuclear features characteristic of PTC, identified as WDT-UMP, were also analyzed. Immunohistochemical analysis of galectin-3, HBME-1, CK19 and the proliferation markers Ki67 and cyclin D1 was performed. Lesions were analyzed for cyclin D1 gene amplification by fluorescent in-situ hybridization. RESULTS: All WDT-UMP lesions showed immunolabelling of cyclin D1, Ki67; 11/ 13 cases showed immunolabelling of CK19; 10/13 cases showed immunolabelling of HBME-1 and 4/13 cases showed immunolabelling of galectin-3. Surrounding benign adenomatoid areas showed no to faint focal staining in all thirteen cases of cyclin D1, HBME-1 and galectin-3. A low rate of cyclin D1 gene amplification was identified in a significant proportion of cells in the WDT-UMP lesions as compared to surrounding benign adenomatoid areas. CONCLUSIONS: Increased expression of cyclin D1 and amplification of its gene along with immunolabelling of HBME-1 in WDT-UMP lesions showing cytological features of papillary thyroid carcinoma within follicular adenomatoid nodules suggest that these areas could correspond to a precursor lesion of follicular variant of PTC. Overexpression of cyclin D1, associated with the amplification of the gene suggests that these WDT-UMP lesions are an intermediate between the benign and malignant groups making this group of lesions a reliable precursor of FVPTC. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1851820807142117.
Assuntos
Adenocarcinoma Folicular/química , Adenoma/química , Biomarcadores Tumorais/análise , Carcinoma Papilar/química , Carcinoma/química , Diferenciação Celular , Ciclina D1/análise , Neoplasias da Glândula Tireoide/química , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/patologia , Adenoma/genética , Adenoma/patologia , Adolescente , Adulto , Biomarcadores Tumorais/genética , Biópsia , Proteínas Sanguíneas , Carcinoma/genética , Carcinoma/patologia , Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Ciclina D1/genética , Feminino , Galectina 3/análise , Galectinas , Amplificação de Genes , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Queratina-19/análise , Antígeno Ki-67/análise , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Regulação para CimaRESUMO
Congenital hyperinsulinism causes profound hypoglycemia, which may persist or resolve spontaneously. Among 13 children with congenital hyperinsulinism, elevated incretin hormone concentrations were detected in 2 with atypical, persistent disease. We suggest that incretin biomarkers may identify these patients, and that elevated hormone levels may contribute to their pathophysiology.
Assuntos
Biomarcadores/sangue , Hiperinsulinismo Congênito/sangue , Incretinas/sangue , Canais KATP/genética , Pré-Escolar , Hiperinsulinismo Congênito/genética , Humanos , Lactente , Recém-Nascido , Mutação , Reino UnidoRESUMO
OBJECTIVE: Congenital hyperinsulinism (CHI) requires rapid diagnosis and treatment to avoid irreversible neurological sequelae due to hypoglycaemia. Aetiological diagnosis is instrumental in directing the appropriate therapy. Current diagnostic algorithms provide a complete set of diagnostic tools including (i) biochemical assays, (ii) genetic facility and (iii) state-of-the-art imaging. They consider the response to a therapeutic diazoxide trial an early, crucial step before proceeding (or not) to specific genetic testing and eventually imaging, aimed at distinguishing diffuse vs focal CHI. However, interpretation of the diazoxide test is not trivial and can vary between research groups, which may lead to inappropriate decisions. Objective of this report is proposing a new algorithm in which early genetic screening, rather than diazoxide trial, dictates subsequent clinical decisions. PATIENTS, METHODS AND RESULTS: Two CHI patients weaned from parenteral glucose infusion and glucagon after starting diazoxide. No hypoglycaemia was registered during a 72-h continuous glucose monitoring (CGMS), or hypoglycaemic episodes were present for no longer than 3% of 72-h. Normoglycaemia was obtained by low-medium dose diazoxide combined with frequent carbohydrate feeds for several years. We identified monoallelic, paternally inherited mutations in KATP channel genes, and (18) F-DOPA PET-CT revealed a focal lesion that was surgically resected, resulting in complete remission of hypoglycaemia. CONCLUSIONS: Although rare, some patients with focal lesions may be responsive to diazoxide. As a consequence, we propose an algorithm that is not based on a 'formal' diazoxide response but on genetic testing, in which patients carrying paternally inherited ABCC8 or KCNJ11 mutations should always be subjected to (18) F-DOPA PET-CT.
Assuntos
Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/tratamento farmacológico , Diazóxido/uso terapêutico , Testes Genéticos , Algoritmos , Criança , Pré-Escolar , Hiperinsulinismo Congênito/dietoterapia , Hiperinsulinismo Congênito/genética , Árvores de Decisões , Feminino , Seguimentos , Humanos , Técnicas de Diagnóstico Molecular , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores de Sulfonilureias/genéticaRESUMO
OBJECTIVE: To describe the long-term metabolic outcome of children with congenital hyperinsulinism after near-total or partial elective pancreatectomy. RESEARCH DESIGN AND METHODS: Patients (n = 105: 58 diffuse and 47 focal congenital hyperinsulinism) received operations between 1984 and 2006. Follow-up consisted of periodic measurements of pre- and postprandial plasma glucose over 24 h, OGTT, and IVGTT. Cumulative incidence of hypo- or hyperglycemia/insulin treatment was estimated by Kaplan-Meier analysis. RESULTS: After near-total pancreatectomy, 59% of children with diffuse congenital hyperinsulinism still presented mild or asymptomatic hypoglycemia that responded to medical treatments and disappeared within 5 years. One-third of the patients had both preprandial hypoglycemia and postprandial hyperglycemia. Hyperglycemia was found in 53% of the patients immediately after surgery; its incidence increased regularly to 100% at 13 years. The cumulative incidence of insulin-treated patients was 42% at 8 years and reached 91% at 14 years, but the progression to insulin dependence was very variable among the patients. Plasma insulin responses to IVGTT and OGTT correlated well with glycemic alterations. In focal congenital hyperinsulinism, hypoglycemia or hyperglycemia were rare, mild, and transient. CONCLUSIONS: Patients with focal congenital hyperinsulinism are cured of hypoglycemia after limited surgery, while the outcome of diffuse congenital hyperinsulinism is very variable after near-total pancreatectomy. The incidence of insulin-dependent diabetes is very high in early adolescence.
Assuntos
Glicemia/metabolismo , Hiperinsulinismo Congênito/sangue , Hiperinsulinismo Congênito/cirurgia , Pancreatectomia , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Insulina/sangue , Estimativa de Kaplan-Meier , Masculino , Resultado do TratamentoRESUMO
Congenital hyperinsulinism (CHI) is the major cause of persistent neonatal hypoglycemia. CHI most often occurs due to mutations in the ABCC8 (which encodes sulfonylurea receptor 1) or KCNJ11 (which encodes the potassium channel Kir6.2) gene, which result in a lack of functional KATP channels in pancreatic ß cells. Diffuse forms of CHI (DiCHI), in which all ß cells are abnormal, often require subtotal pancreatectomy, whereas focal forms (FoCHI), which are characterized by localized hyperplasia of abnormal ß cells, can be cured by resection of the lesion. Here, we characterized the in vitro kinetics of insulin secretion by pancreatic fragments from 6 DiCHI patients and by focal lesion and normal adjacent pancreas from 18 FoCHI patients. Responses of normal pancreas were similar to those reported for islets from adult organ donors. Compared with normal pancreas, basal insulin secretion was elevated in both FoCHI and DiCHI tissue. Affected tissues were heterogeneous in their secretory responses, with increased glucose levels often producing a rapid increase in insulin secretion that could be followed by a paradoxical decrease below prestimulatory levels. The KATP channel blocker tolbutamide was consistently ineffective in stimulating insulin secretion; conversely, the KATP channel activator diazoxide often caused an unanticipated increase in insulin secretion. These observed alterations in secretory behavior were similar in focal lesion and DiCHI tissue, and independent of the specific mutation in ABCC8 or KCNJ11. They cannot be explained by classic models of ß cell function. Our results provide insight into the excessive and sometimes paradoxical changes in insulin secretion observed in CHI patients with inactivating mutations of KATP channels.
Assuntos
Hiperinsulinismo Congênito/tratamento farmacológico , Hiperinsulinismo Congênito/fisiopatologia , Diazóxido/farmacologia , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/patologia , Inibidor de Quinase Dependente de Ciclina p57/genética , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Resistência a Medicamentos , Humanos , Técnicas In Vitro , Lactente , Secreção de Insulina , Modelos Biológicos , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/agonistas , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores de Droga/genética , Receptores de Sulfonilureias , Tolbutamida/farmacologiaRESUMO
BACKGROUND: Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia. Histologically, there are two subgroups, diffuse and focal. Focal CHI is a consequence of two independent events, inheritance of a paternal mutation in ABCC8/KCNJ11 and paternal uniparental isodisomy of chromosome 11p15 within the embryonic pancreas, leading to an imbalance in the expression of imprinted genes. The probability of both events occurring within siblings is rare. AIM: We describe the first familial form of focal CHI in two siblings. PATIENTS AND METHODS: The proband presented with medically unresponsive CHI. He underwent pancreatic venous sampling and Fluorine-18-L-dihydroxyphenylalanine positron emission tomography scan, which localized a 5-mm focal lesion in the isthmus of the pancreas. The sibling presented 8 yr later also with medically unresponsive CHI. An Fluorine-18-L-dihydroxyphenylalanine positron emission-computerised tomography scan showed a 7-mm focal lesion in the posterior section of the head of the pancreas. Both siblings were found to be heterozygous for two paternally inherited ABCC8 mutations, A355T and R1494W. Surgical removal of the focal lesions in both siblings cured the Hyperinsulinaemic hypoglycaemia. CONCLUSION: This is the first report of focal CHI occurring in siblings. Genetic counseling for families of patients with focal CHI should be recommended, despite the rare risk of recurrence of this disease.
Assuntos
Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/cirurgia , Pâncreas/cirurgia , Hiperinsulinismo Congênito/patologia , Feminino , Humanos , Recém-Nascido , Perda de Heterozigosidade , Masculino , Pâncreas/patologia , Reação em Cadeia da Polimerase , Irmãos , Resultado do TratamentoRESUMO
Congenital hyperinsulinism is clinically characterized by an inappropriate insulin secretion resulting in recurrent severe hypoglycemia. Nesidioblastosis, the proliferation of islet cells budding off from ducts, has been considered for years as the histologic lesion responsible for the syndrome. In our morphologic studies, we demonstrate that nesidioblastosis is not specific of the disease, which is actually not a single entity. Indeed, we recognize the existence of 2 different forms-a diffuse form and a focal form-and demonstrate that they can be differentiated by morphologic criteria, even on frozen sections during surgery. This histologic distinction directs the therapeutic approach because the patients experiencing the focal form of the syndrome can be completely cured by a very limited pancreatectomy. Molecular findings confirmed the reliability of this histologic distinction, showing a specific background for each form.
Assuntos
Hiperinsulinismo Congênito/patologia , Ilhotas Pancreáticas/patologia , Nesidioblastose/patologia , Hiperinsulinismo Congênito/etiologia , Hiperinsulinismo Congênito/cirurgia , Humanos , Imuno-Histoquímica , Lactente , Recém-Nascido , Células Secretoras de Insulina/metabolismo , PancreatectomiaRESUMO
Beyond the 2 classical forms of congenital hyperinsulinism, focal and diffuse, we report our experience on the surgical treatment of atypical forms. We define 2 subtypes among these atypical forms of hyperinsulinism: in case of a giant focal form the surgical strategy is the same as in focal forms. In case of hyperinsulinism caused by a mosaic, our experience suggests the benefit of a limited resection from the tail to the body of the pancreas.
Assuntos
Hiperinsulinismo Congênito/cirurgia , Pancreatectomia/métodos , Hiperinsulinismo Congênito/patologia , Humanos , Lactente , Paris , Estudos RetrospectivosRESUMO
Congenital hyperinsulinism (CHI or HI) is a condition leading to recurrent hypoglycemia due to an inappropriate insulin secretion by the pancreatic islet beta cells. HI has two main characteristics: a high glucose requirement to correct hypoglycemia and a responsiveness of hypoglycemia to exogenous glucagon. HI is usually isolated but may be rarely part of a genetic syndrome (e.g. Beckwith-Wiedemann syndrome, Sotos syndrome etc.). The severity of HI is evaluated by the glucose administration rate required to maintain normal glycemia and the responsiveness to medical treatment. Neonatal onset HI is usually severe while late onset and syndromic HI are generally responsive to a medical treatment. Glycemia must be maintained within normal ranges to avoid brain damages, initially with glucose administration and glucagon infusion then, once the diagnosis is set, with specific HI treatment. Oral diazoxide is a first line treatment. In case of unresponsiveness to this treatment, somatostatin analogues and calcium antagonists may be added, and further investigations are required for the putative histological diagnosis: pancreatic (18)F-fluoro-L-DOPA PET-CT and molecular analysis. Indeed, focal forms consist of a focal adenomatous hyperplasia of islet cells, and will be cured after a partial pancreatectomy. Diffuse HI involves all the pancreatic beta cells of the whole pancreas. Diffuse HI resistant to medical treatment (octreotide, diazoxide, calcium antagonists and continuous feeding) may require subtotal pancreatectomy which post-operative outcome is unpredictable. The genetics of focal islet-cells hyperplasia associates a paternally inherited mutation of the ABCC8 or the KCNJ11 genes, with a loss of the maternal allele specifically in the hyperplasic islet cells. The genetics of diffuse isolated HI is heterogeneous and may be recessively inherited (ABCC8 and KCNJ11) or dominantly inherited (ABCC8, KCNJ11, GCK, GLUD1, SLC16A1, HNF4A and HADH). Syndromic HI are always diffuse form and the genetics depend on the syndrome. Except for HI due to potassium channel defect (ABCC8 and KCNJ11), most of these HI are sensitive to diazoxide. The main points sum up the management of HI: i) prevention of brain damages by normalizing glycemia and ii) screening for focal HI as they may be definitively cured after a limited pancreatectomy.
Assuntos
Hiperinsulinismo Congênito/terapia , Hiperinsulinismo Congênito/complicações , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/etiologia , Procedimentos Cirúrgicos Endócrinos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/terapia , Humanos , Hipoglicemia/complicações , Hipoglicemia/diagnóstico , Hipoglicemia/terapia , Recém-Nascido , Tomografia por Emissão de Pósitrons/métodos , PrognósticoRESUMO
BACKGROUND: Minimal immunosuppression (IS) is desirable in organ transplantation to reduce side effects and to promote the process of tolerance induction. MATERIAL AND METHODS: Between February 2000 and September 2004, 156 adults (>15 years old) receiving a primary liver graft were enrolled in a prospective, randomized, double-blind, placebo-controlled, investigator-driven single-center study comparing tacrolimus (TAC)-placebo (PL) and TAC-low-dose, short-term (64 days) steroid (ST) IS. There were no exclusion criteria at moment of randomization. All patients had a 12-month follow-up (range, 12-84). RESULTS: Three- and 12-month patient survival rates were 93.6% and 87.2% in the TAC-PL group and 98.7% and 94.7% in TAC-ST group (P = 0.096 and P = 0.093, respectively). Three- and 12-month graft survival rates were 92.3% and 85.9% versus 97.4% and 92.3% (P = 0.14 and 0.13, respectively). By 3 and 12 months, rejection treatment had been given in 20.5% (16 pts) and 23% (18 pts) of TAC-PL patients and in 12.7% (10 pts) and 20.5% (16 pts) of TAC-ST patients (P = 0.20 and 0.54). Corticosteroid-resistant rejection (CRR) at 3 and 12 months was recorded in 12.8% (10 pts) of TAC-PL patients and 3.8% (3 pts) of TAC-ST patients (P = 0.04). When considering the 145 patients transplanted without artificial organ support (n = 145), CRR at 3 and 12 months was recorded in 8.8% (6/68 pts) of TAC-PL patients and in 3.9% (3/77 pts) of TAC-ST patients (P = 0.22). Vanishing bile duct syndrome was diagnosed in 1 (1.2%) TAC-PL patient and 4 (5.1%) TAC-ST patients (P = 0.17). By 1 year, 78.2% (61/78) of TAC-PL patients and 82% (64/78) of TAC-ST patients were on TAC monotherapy (P = 0.54). When considering 67 TAC-PL and 74 TAC-ST survivors, rates of monotherapy were 91% (61 pts) and 86.5% (64 pts) (P = 0.39). At 1 year, 62.5% (42 pts) of TAC-PL survivors and 64.9% (48 pts) of TAC-ST survivors were on low-dosage (<6 ng/mL) TAC monotherapy (P 0.79). CONCLUSION: TAC monotherapy can be achieved safely without compromising graft nor patient survival in a primary, even unselected, adult liver transplant population. The higher incidence of early CRR in the TAC-PL group related to the significantly higher number of patients transplanted while being on artificial organ support. In such condition, this monodrug immunosuppressive strategy needs to be adapted. TAC monotherapy strategy should lay the basis for further large scale minimization studies in liver transplantation.
Assuntos
Imunossupressores/uso terapêutico , Transplante de Fígado , Tacrolimo/uso terapêutico , Adulto , Idoso , Colestase Intra-Hepática/cirurgia , Método Duplo-Cego , Feminino , Humanos , Cirrose Hepática/cirurgia , Testes de Função Hepática , Transplante de Fígado/imunologia , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND & AIMS: The purpose of our study was to prospectively compare the success rate and diagnostic accuracy of magnetic resonance elastography, ultrasound elastography, and aspartate aminotransferase to platelets ratio index (APRI) measurements for the noninvasive staging of fibrosis in patients with chronic liver disease. METHODS: We performed a prospective blind comparison of magnetic resonance elastography, ultrasound elastography, and APRI in a consecutive series of patients who underwent liver biopsy for chronic liver disease in a university-based hospital. Histopathologic staging of liver fibrosis according to the METAVIR scoring system served as the reference. RESULTS: A total of 141 patients were assessed. The technical success rate of magnetic resonance elastography was higher than that of ultrasound elastography (133/141 [94%] vs 118/141 [84%]; P = .016). Magnetic and ultrasound elastography, APRI measurements, and histopathologic analysis of liver biopsy specimens were technically successful in 96 patients. The areas under the receiver operating characteristic curves of magnetic resonance elasticity (0.994 for F >or= 2; 0.985 for F >or= 3; 0.998 for F = 4) were larger (P < .05) than those of ultrasound elasticity, APRI, and the combination of ultrasound elasticity and APRI (0.837, 0.709, and 0.849 for F >or= 2; 0.906, 0.816, and 0.936 for F >or= 3; 0.930, 0.820, and 0.944 for F = 4, respectively). CONCLUSIONS: Magnetic resonance elastography has a higher technical success rate than ultrasound elastography and a better diagnostic accuracy than ultrasound elastography and APRI for staging liver fibrosis.
Assuntos
Técnicas de Imagem por Elasticidade/normas , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Imageamento por Ressonância Magnética/normas , Ultrassonografia/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Aspartato Aminotransferases/sangue , Biópsia , Técnicas de Imagem por Elasticidade/métodos , Feminino , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Índice de Gravidade de DoençaRESUMO
BACKGROUND/AIMS: Surgical resection is a standard treatment of hepatocellular carcinoma, but liver cirrhosis is known to be associated to a high tumor recurrence rate. METHODOLOGY: A retrospective study of 55 consecutive patients (37 males, 18 females) suffering from hepatocellular carcinoma having undergone surgical resection. Hepatocellular carcinoma developed in 29 patients with normal liver (group A) and in 26 patients with chronic liver disease (CLD) (group B). Patients were significantly older and at high-risk in Group B. RESULTS: Radical liver resection was achieved in 98% (100% in group A; 96% in group B). Overall 2-month mortality was 2% (0% in group A; 4% in group B). The 5-year overall and disease-free survival was respectively 55% and 35%. However, the 5-year overall and disease-free survival was significantly better in Group A (71% and 59%) compared to Group B (37% and 6%) (p < 0.001), respectively. Multivariate statistical analysis demonstrated that age > 50 years, poor tumor differentiation and presence of satellite nodules were significant independent adverse predictive factors of overall and disease-free survival. CONCLUSIONS: Resection of HCC is safe and effective with satisfactory overall and disease-free survival rates, except when underlying chronic liver disease and poor tumor differentiation are present.
Assuntos
Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Adolescente , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Hepatectomia , Humanos , Fígado/cirurgia , Cirrose Hepática/patologia , Cirrose Hepática/cirurgia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias/patologia , Recidiva , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: the purpose of this study was to report a single academic institution's experience with radiofrequency ablation (RFA) of liver malignancies METHODS: Sixty-five patients underwent RFA technique through a percutaneous (Group I: 33 patients) or a surgical approach (Group II: 32 patients). The two groups were different according to type of disease selection (more hepatocellular carcinoma in Group I and liver metastases in Group II) and tumour features (smaller size but greater number of lesions in Group II). In Group II, RFA was associated to liver resection in 23 patients (72%). RESULTS: The 2-month postoperative mortality and complication rates were low in both groups. The postoperative hospital stay was longer in Group II. During a median follow-up of 24 months in Group I and 21 months in Group II, the local "in-situ" recurrence rate was 41.4% and 9.1%, respectively. For RFA-treated tumours < 30 mm in size, the local "in-situ" recurrence rate was 40.5% in Group I and 0% in Group II. Multivariate statistical analysis demonstrated that larger tumour and a percutaneous approach for RFA were independent predictive factors of local "in-situ" liver tumour recurrence. CONCLUSIONS: RFA appears to be a safe technique for treating liver malignancies by both approaches. Tumour size and type of RFA approach are predictive factors of in-situ liver tumour recurrence.
Assuntos
Ablação por Cateter/métodos , Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bélgica/epidemiologia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Estadiamento de Neoplasias , Prevalência , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
AIMS: This report describes three patients suffering from nodular regenerative hyperplasia (NRH). METHODS: These patients have received six, 16 and 20 cycles of neoadjuvant 5-fluorouracil and oxaliplatin-based chemotherapy before planned extended hepatectomy. Two patients underwent uneventful portal vein embolization to hypertrophy the future remnant liver. RESULTS: At the end of chemotherapy, liver function tests deteriorated and portal hypertension appeared in two patients, including ascites, splenomegaly and oesophageal varices. Liver biopsy was performed through a percutaneous (two patients) or a transjugular approach (one patient) and allowed the diagnosis of NRH, which was considered to be a contraindication for major liver resection in all three patients, associated with extrahepatic disease progression in one patient. All patients died from neoplastic disease progression despite further chemotherapy at 6, 17 and 31 months following the diagnosis of NRH. One patient developed liver failure and ascites at the time of death. CONCLUSIONS: Physicians should be aware of the potential occurrence and therapeutic impact of NRH in patients suffering from CRLM and treated by neoadjuvant 5FU-oxaliplatin-based chemotherapy before major liver surgery.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Regeneração Hepática/efeitos dos fármacos , Fígado/efeitos dos fármacos , Idoso , Quimioterapia Adjuvante/efeitos adversos , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Contraindicações , Progressão da Doença , Feminino , Fluoruracila/administração & dosagem , Hepatectomia , Humanos , Hiperplasia , Fígado/patologia , Fígado/cirurgia , Hepatopatias/diagnóstico , Hepatopatias/mortalidade , Hepatopatias/patologia , Hepatopatias/terapia , Testes de Função Hepática , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Fatores de Tempo , Resultado do TratamentoRESUMO
Solid pseudopapillary tumors (SPT) of the pancreas are rare neoplasms that occur mostly in young women. Despite of a low malignant potential, 10% to 15% of the cases have aggressive behavior with metastatic dissemination possibly leading to death. To date, no pathological factor can reliably predict the outcome of these tumours. Galectin-3, a major actor in the carcinogenesis of pancreatic ductal adenocarcinoma, has not been investigated in SPT. The presence of progesterone receptors is frequently reported in SPT, whereas that of estrogen receptor (ER) is unclear. We studied 5 cases of SPT consisting of 4 pancreatic tumors and 1 metastatic case. The morphological distinctive feature of metastatic nodules was the presence of polygonal or spindle cells with pleiomorphic nuclei and high mitotic count exhibiting a diffuse, infiltrative growth pattern. We found a strong expression of galectin-3 in all SPTs, whereas, interestingly, it was lower in metastatic nodules. Conversely, no galectin-3 expression was found in normal pancreatic endocrine cells or in neuroendocrine tumors. We suggest therefore that galectin-3 is a useful marker to distinguish SPT from neuroendocrine tumor, and also indicator of behavior because its low expression is associated with metastatic spreading. Moreover, the presence of galectin-3 in both SPT and pancreatic ducts rises the hypothesis of a posible ductal origin of these tumors. Specific antibodies for anti-ERalpha and anti-ERbeta demonstrated a strong expression of ERbeta whereas ERalpha was not detected. In conclusion, the present study brings the first evidence of the involvement of galectin-3 in SPT but also brought up clues which allowed to reconcile previously conflicting results on the presence of ER.