RESUMO
The aim of our study was to assess the relationship between colorectal tumor responsiveness to irinotecan and microsatellite instability (MSI), a feature of colorectal tumors with DNA mismatch repair defect. Seventy-two patients with metastatic colorectal cancer were included in our retrospective study. A complete response to irinotecan was observed in 1 patient and a partial response in 10 patients, whereas 61 patients did not respond to this treatment. We analyzed the protein expression of hMLH1, hMSH2, and BAX by immunohistochemistry, determined the MSI phenotype, and looked for mutations in the coding repeats located in the transforming growth factor beta-RII, BAX, hMSH3, and hMSH6 genes. All 44 tumors analyzed expressed detectable levels of hMLH1; 1 tumor lacked hMSH2 staining, whereas 4 tumors showed a marked decrease in BAX expression. A better response to irinotecan was observed in the patients whose tumors have lost BAX expression (P < 0.001). Among the 7 tumors that displayed a MSI-H phenotype, 4 responded to irinotecan, whereas only 7 of the 65 MSI-L/ microsatellite stable tumors did (P = 0.009). Seven of the 72 tumors had inactivating mutations in the coding repeats of the target genes. Three tumors displayed a mutation in the poly-A10 tract of the transforming growth factor beta-RII gene, associated with a 1-bp deletion in the poly-A8 tract of hMSH3 in one tumor and with a 1-bp deletion in the poly-G8 tract of BAX in another. Four tumors displayed mutations in the poly-G8 repeat of BAX, whereas 2 mutations in hMSH6 and hMSH3 were characterized. Among the 7 tumors with mutations in these target genes, 5 responded to irinotecan, whereas only 6 of the other 65 tumors did (P < 0.001), indicating that MSI-driven inactivation of target genes modifies tumor chemosensitivity. Our observations allowed us to define the first useful predictive criteria for irinotecan response in patients with colorectal cancer.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Enzimas Reparadoras do DNA , Instabilidade Genômica , Proteínas Proto-Oncogênicas c-bcl-2 , Proteínas Adaptadoras de Transdução de Sinal , Adenosina Trifosfatases/biossíntese , Adenosina Trifosfatases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Pareamento Incorreto de Bases/genética , Proteínas de Transporte , Neoplasias Colorretais/metabolismo , Reparo do DNA/genética , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Éxons , Feminino , Deleção de Genes , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas Nucleares , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , Proteína X Associada a bcl-2RESUMO
UNLABELLED: The ability of endogenous IL-10 to modulate inflammatory response and to limit hepatotoxicity has been shown in several models of liver injury. AIMS: The objectives of this study were to evaluate the relationship between liver disease and the balance between pro and anti-inflammatory cytokines in acute alcoholic hepatitis. METHODS: Twenty-five patients with pure steatosis, 17 with cirrhosis and mild acute alcoholic hepatitis (discriminant function value<32) and 41 patients with cirrhosis and severe acute alcoholic hepatitis (discriminant function value >=32) were studied. Plasma levels of interleukin 10 (IL-10) and soluble TNF receptors (TNFsRp75 and 55) were analyzed using ELISA assays. Hepatocyte proliferative activity was assessed with proliferating cell nuclear antigen labeling index (PCNA-LI) on formalin-fixed paraffin embedded liver biopsy specimens. RESULTS: In patients with steatosis, cirrhosis with mild and severe acute alcoholic hepatitis, the plasma levels of IL-10 were higher (P<0.05) than in healthy controls. Between day 1 and day 8, the TNFsRp55/IL-10 ratio increased by 137 +/- 47 in the 10 patients with severe acute alcoholic hepatitis treated with prednisolone who died within 2 months and by 9.3 +/- 14 in the 19 patients still alive at 2 months (P=0.031). In patients with severe acute alcoholic hepatitis, PCNA-LI on liver biopsy was negatively correlated with the TNFsRp55/IL-10 ratio increase from day 1 to day 8 (r=- 0.42, P=0.11). PCNA-LI was positively correlated with TNFsRp75/TNFsRp 55 ratio increase from day 1 to day 15 (r=0.52; p<0.05). CONCLUSION: Our data suggest the anti-inflammatory system is up-regulated in patients with alcoholic liver disease. Nevertheless, in patients with severe acute alcoholic hepatitis, IL-10 production seems insufficient to modulate TNF-alpha cytotoxicity mediated by TNFRp55.
Assuntos
Interleucina-10/sangue , Hepatopatias Alcoólicas/imunologia , Receptores do Fator de Necrose Tumoral/sangue , Doença Aguda , Biópsia , Estudos de Casos e Controles , Fígado Gorduroso/sangue , Fígado Gorduroso/imunologia , Feminino , Glucocorticoides/uso terapêutico , Humanos , Fígado/patologia , Hepatopatias Alcoólicas/sangue , Hepatopatias Alcoólicas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Antígeno Nuclear de Célula em Proliferação/análise , Estudos Prospectivos , Regulação para CimaRESUMO
We report the first description of portal and mesenteric vein thrombosis associated with suppurative mesenteric adenitis in a 71-year-old woman. The bacterium detected in mesenteric lymph nodes was Fusobacterium nucleatum, an anaerobic Gram-negative bacillus. Our patient had a clinical syndrome of pharyngitis and fever preceding portal vein thrombosis. Abdominal symptoms improved with antibiotics and anticoagulant therapy. This location of F. nucleatum in mesenteric lymph nodes provides an interesting insight into the occurrence of septic thrombosis in the portal vein following pharyngo-tonsillar infection.
Assuntos
Infecções por Fusobacterium/complicações , Fusobacterium nucleatum , Linfadenite Mesentérica/microbiologia , Oclusão Vascular Mesentérica/microbiologia , Veia Porta , Trombose/microbiologia , Idoso , Feminino , Infecções por Fusobacterium/diagnóstico por imagem , Fusobacterium nucleatum/isolamento & purificação , Humanos , Linfonodos/microbiologia , Linfadenite Mesentérica/diagnóstico por imagem , Oclusão Vascular Mesentérica/diagnóstico por imagem , Trombose/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
UNLABELLED: An adolescent was hospitalized for recurring abdominal pains, which had previously led to appendicectomy. Laboratory data finally led to the diagnosis of hereditary angioneurotic oedema, after several hypotheses had been raised and ruled out. CONCLUSIONS: Angioneurotic oedema is a rare condition, which should be suspected in children with recurring abdominal pains, especially when there is liquid within the peritoneal cavity.
Assuntos
Dor Abdominal/diagnóstico , Angioedema/diagnóstico , Angioedema/tratamento farmacológico , Danazol/administração & dosagem , Doença Aguda , Adolescente , Angioedema/genética , Diagnóstico Diferencial , Relação Dose-Resposta a Droga , Esquema de Medicação , Serviço Hospitalar de Emergência , Seguimentos , Humanos , Masculino , Medição da Dor , Recidiva , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
In patients with nonalcoholic steatohepatitis (NASH), age, obesity, and diabetes mellitus are independent predictors of the degree of fibrosis. The relative risk for fibrosis adjusted for sex was also associated with increasing grade of Perls stain. The aim of this study was to determine whether the risk factors for fibrosis described in NASH are also risk factors in alcohol-induced liver disease. A total of 268 alcoholic patients with negative hepatitis B virus and hepatitis C virus serology underwent liver biopsy. Fibrosis was assessed semiquantitatively by a score fluctuating between 0 to 8. Liver iron overload was assessed by Perls staining and graded in 4 classes. We have used multivariate regression with partial correlation analysis to assess the variability of fibrosis score according to the value of 7 variables: sex, age, body mass index (BMI) in the past year before the hospitalization when the patient was asymptomatic, daily alcohol intake over the past 5 years, total duration of alcohol abuse, Perls grade, and blood glucose level. In the multivariate regression, fibrosis score was positively correlated with age (P =.001), BMI (P =.002), female sex (P <.05), Perls grade (P <.05), and blood glucose level (P <.05). Twenty percent of the variability of fibrosis score was explained by the 7 variables. In conclusion, after adjustment for daily alcohol intake and total duration of alcohol abuse, BMI, Perls grade, and blood glucose are also independent risk factors for fibrosis in alcohol-induced liver disease, raising therapeutic implications for the management of these patients.