Antioxidant effect of endothelin-1 receptor antagonist protects the rat kidney against chronic injury induced by hypertension and hyperglycemia / Efeito antioxidante de antagonista dos receptores de endotelina-1 protege ratos contra lesão renal crônica induzida por hipertensão e hiperglicemia

ABSTRACT Hypertension and Diabetes mellitus are the two main causes of chronic kidney disease that culminate in the final stage of kidney disease. Since these two risk factors are common and can overlap, new approaches to prevent or treat them are needed. Macitentan (MAC) is a new non-selective antagonist of the endothelin-1 (ET-1) receptor. This study aimed to evaluate the effect of chronic blockade of ET-1 receptor with MAC on the alteration of renal function observed in hypertensive and hyperglycemic animals. Genetically hypertensive rats were divided into control hypertensive (HT-CTL) group, hypertensive and hyperglycemic (HT+DIAB) group, and hypertensive and hyperglycemic group that received 25 mg/kg macitentan (HT-DIAB+MAC25) via gavage for 60 days. Kidney function and parameters associated with oxidative and nitrosative stress were evaluated. Immunohistochemistry for neutrophil gelatinase-associated lipocalin (NGAL), ET-1, and catalase in the renal cortex was performed. The HT+DIAB group showed a decrease in kidney function and an increase in NGAL expression in the renal cortex, as well as an increase in oxidative stress. MAC treatment was associated with attenuated ET-1 and NGAL production and increases in antioxidant defense (catalase expression) and nitric oxide production. In addition, MAC prevented an increase in oxidant injury (as measured by urinary hydroperoxide and lipid peroxidation), thus improving renal function. Our results suggest that the antioxidant effect of the ET-1 receptor antagonist MAC is involved in the improvement of kidney function observed in hypertensive and hyperglycemic rats.

RESUMO Hipertensão e Diabetes Mellitus figuram como as duas principais causas de doença renal crônica que culmina em doença renal terminal. Uma vez que os dois fatores de risco são comuns e podem se sobrepor, novas abordagens preventivas e terapêuticas se fazem necessárias. O macitentan (MAC) é um novo antagonista não-seletivo dos receptores da endotelina-1 (ET-1). O presente estudo teve como objetivo avaliar os efeitos do bloqueio crônico dos receptores da ET-1 com MAC sobre a alteração da função renal em animais hipertensos e hiperglicêmicos. Ratos geneticamente hipertensos foram divididos em grupos com animais hipertensos de controle (HT-CTL), hipertensos e hiperglicêmicos (HT+DIAB) e hipertensos e hiperglicêmicos tratados com 25 mg/kg de macitentan (HT-DIAB+MAC25) via gavagem por 60 dias. Foram avaliados função renal e parâmetros associados ao estresse oxidativo e nitrosativo. Exames de imunoistoquímica foram realizados para lipocalina associada à gelatinase neutrofílica (NGAL), ET-1 e catalase no córtex renal. O grupo HT+DIAB exibiu diminuição da função renal e aumento na expressão de NGAL no córtex renal, bem como estresse oxidativo aumentado. O tratamento com MAC foi associado a atenuação da produção de ET-1 e NGAL e maior ativação das defesas antioxidantes (expressão de catalase) e elevação da produção de óxido nítrico. Além disso, o MAC evitou exacerbação da lesão oxidante (medida por hidroperóxidos urinários e peroxidação lipídica), melhorando assim a função renal. Nossos resultados sugerem que o efeito antioxidante do antagonista dos receptores da ET-1 MAC esteja imbricado no aprimoramento da função renal observada em ratos hipertensos e hiperglicêmicos.

Retrospective analysis of efficacy, safety, and prognostic factors in a cohort of Chinese hepatocellular carcinoma patients treated with drug-eluting bead transarterial chemoembolization

The aim of our study was to assess the efficacy, safety, and prognostic factors of drug-eluting bead transarterial chemoembolization (DEB-TACE) in Chinese hepatocellular carcinoma (HCC) patients. Patients (n=102) diagnosed as primary HCC were consecutively enrolled in this retrospective cohort study. Treatment responses were assessed following the modified Response Evaluation Criteria in Solid Tumors. Progression-free survival (PFS) and overall survival (OS) were evaluated, and adverse events (AEs) as well as liver function-related laboratory indexes of all DEB-TACE records (N=131) were assessed. Complete response (CR) rate, objective response rate, and disease control rate were 51.0, 87.3, and 95.1%, respectively, at 1-3 months post DEB-TACE. The mean PFS and OS were 227 (95%CI: 200-255) days and 343 (95%CI: 309-377) days, respectively. Multivariate logistic regression revealed that portal vein invasion and abnormal total protein (TP) were independent predictive factors for worse CR, and multivariate Cox's regression analysis showed that multifocal disease independently correlated with shorter PFS. Most of the liver function-related laboratory indexes worsened at 1 week but recovered at 1-3 months post-treatment, only the percentage of patients with abnormal ALP increased at 1-3 months. In addition, 112 (85.5%), 84 (64.1%), 53 (40.5%), 40 (30.5%), and 16 (12.2%) patients had pain, fever, nausea, vomiting, and other AEs, respectively. DEB-TACE is efficient and safe in Chinese HCC patients, and portal vein invasion, abnormal TP level as well as multifocal disease could be used as unfavorable prognostic factors to DEB-TACE treatment.

Uso de mitomicina C em neoplasia intra-epitelial córneo-conjuntival: modalidades de abordagem - relato de casos / Use of mitomycin C for corneal-conjunctival intraepithelial neoplasia: management options - case reports

São relatados três casos de neoplasia intra-epitelial córneo-conjuntival nos quais a mitomicina C foi utilizada em abordagens distintas de acordo com a situação clínica encontrada. Os pacientes selecionados foram atendidos no Departamento de Oftalmologia da Casa de Saúde Santo Inácio, com diagnóstico clínico e/ou histopatológico de neoplasia intra-epitelial córneo-conjuntival. Com base na apresentação clínica das lesões, utilizou-se a mitomicina C a 0,04 por cento em três abordagens terapêuticas distintas: 1) quimioablação pós-operatória; 2) quimiorredução pré-operatória; e 3) quimioablação isolada. Obteve-se regressão da lesão tumoral nos três casos, sem recorrência em tempo de seguimento variando de 18-29 meses. Hiperemia conjuntival em um dos casos foi a única complicação observada. A mitomicina C mostrou-se eficaz e segura para tratamento de neoplasia intra-epitelial córneo-conjuntival, possibilitando várias abordagens terapêuticas de acordo com as características das lesões.

17-year follow-up of a randomized prospective controlled trial of adjuvant intravesical doxorubicin in the treatment of superficial bladder cancer

PURPOSE: To evaluate the efficacy of adjuvant intravesical doxorubicin in superficial transitional cell carcinoma of the urinary bladder on long-term follow-up. MATERIALS AND METHODS: Between July 1986 and November 1991, all patients harboring superficial bladder cancers (Ta or T1) with one or more of these criteria (stage > a, grade > 1, size > 1 cm, multiple or recurrent tumors) were randomized to receive either 50 mg doxorubicin or no adjuvant therapy. Patients with recurrences were allowed to receive doxorubicin or other intravesical agents. Recurrence, progression and survival were analyzed. RESULTS: There were 82 patients included (64 males and 18 females). The mean age was 64 years. Forty-six patients were randomized to the doxorubicin group and 36 to the control group. Final analysis was made at median follow-up of 45, 128 and 131.5 months for recurrence, progression and survival, respectively. Recurrence free, progression free and disease specific survival did not differ significantly between groups. The 10-year Kaplan-Meier estimates for recurrence free, progression free and disease specific survival were 67 percent, 84 percent and 92 percent, respectively for the doxorubicin group, and were 50 percent, 89 percent and 97 percent, respectively for the control group. Tumor size predicted recurrence (p = 0.013) and grade predicted progression (p = 0.004) with multivariate analysis. CONCLUSIONS: Adjuvant intravesical doxorubicin could not be shown to improve recurrence, progression and survival of superficial bladder cancer, compared with control on long-term follow-up. Tumor size and grade were shown to be prognostic factors for recurrence and progression, respectively.