Cystic craniopharyngioma: intratumoral chemotherapy with alpha interferon / Craniofaringioma cístico: quimioterapia intratumoral com interferon alfa

OBJECTIVE: To assess whether the cystic craniopharyngiomas can be controlled with the use of intratumoral applications of interferon alpha. METHOD: Nineteen patients with the diagnosis of cystic craniopharyngioma were treated with intratumoral chemotherapy with interferon alpha from January 2002 to April 2006. All patients underwent placement of an intracystic catheter connected to an Ommaya reservoir. Through this reservoir were made applications during chemotherapy cycles. Each cycle corresponded to application of 3,000,000 units of interferon alpha three times per week on alternate days totalizing 36,000,000 units. Response to treatment was evaluated by calculating the tumor volume on MRI control after one, three and six months after the end of each cycle. Patients who developed worsening of symptoms or who had insignificant reduction in tumor volume during follow-up underwent repeat cycle chemotherapy. RESULTS: Four patients received four cycles of chemotherapy, three patients received three cycles, six patients received two cycles and six patients received one. The lower percentage of reduction in tumor volume was 60 percent and the bigger reduction was 98.37 percent. Eleven patients had a reduction greater than 90 percent. Five patients had a tumor reduction between 75 and 90 percent and in three patients the tumors were reduced by less than 75 percent. No deaths occurred during treatment and side effects of interferon alpha were well tolerated. No treatment was discontinued. Follow-up after the last application ranged from one year and five months to three years and nine months. CONCLUSION: The intratumoral chemotherapy with interferon alpha decreases the volume of cystic craniopharyngiomas and so far can be considered a new therapeutic alternative.

OBJETIVO: Avaliar se os craniofaringiomas císticos podem ser controlados com aplicações intratumorais de interferon alfa. MÉTODO: De janeiro de 2002 a abril de 2006, 19 pacientes foram submetidos à colocação de um cateter intracístico conectado a reservatório de Ommaya para aplicações intratumorais de ciclos de 36.000.000 de unidades de interferon alfa. A resposta ao tratamento foi avaliada pelo cálculo do volume tumoral na ressonância magnética de controle ao término de cada ciclo. RESULTADOS: Os pacientes receberam de um a quatro ciclos de quimioterapia. Onze pacientes apresentaram uma redução do volume tumoral maior que 90 por cento; cinco pacientes apresentaram uma redução entre 75 por cento e 90 por cento e três pacientes uma redução menor de 75 por cento. Não houve óbitos durante o tratamento e os efeitos colaterais do inferferon alfa foram bem tolerados. Nenhum tratamento foi interrompido. CONCLUSÃO: A quimioterapia intratumoral com interferon alfa diminui o volume dos craniofaringeomas císticos e pode ser considerada uma nova alternativa terapêutica.

Caracterização do padrão de expressão e metilação dos genes ADAM 12 e 33 em tumores de mama e sua correlação com dados clínico-patológicos / Characterization of the expression pattern and methylation status of the ADAMs 12 and 33 genes in breast tumors and the correlation with clinical pathological data

As proteínas que fazem parte da Família ADAM são glicoproteínas transmembrânicas formadas por multidomínios... Para melhor entender o papel dos diferentes membros da família ADAM na tumorigenese, este trabalho avaliou o padrão de expressão dos genes ADAM 8, 10, 12, 15, 17, 19, 22, 23 e 33 em tecido normal e linhagens tumorais de mama. Após a análises computacionais, verificou-se a presença de ilhas de CpG na região promotora destes genes sugerindo que a metilação poderia estar envolvida na regulação da expressão desses genes. A análise do padrão de expressão destes genes através de RT-PCR revelou uma redução significativa nos níveis de expressão dos genes ADAM 12 e 33 nas linhagens tumorais em relação ao tecido normal. Utilizando a metodologia de tratamento com bissulfito de sódio seguido de sequenciamento, foi possível verificar a existência de uma correlação direta para a maioria das linhagens tumorais analisadas entre a diminuição dos níveis de expressão dos genes ADAM12 e 33 e a presença de metilação na região promotora desses genes... A correlação entre o padrão de metilação e os dados clínico-patológicos das pacientes revelou uma associação estatisticamente significativa entre a presença de metilação na região promotora das ADAM12 e 33 com o estádio do tumor. Também foi observada uma associação positiva entre a metilação no gene ADAM 12, o tamanho do tumor e o status do linfonodo. No entanto, a hipermetilação da região promotora destes genes não mostrou estar estatisticamente correlacionada com a sobrevida global e com a sobrevida livre de doença...(AU)

The ADAMs (A Desintegrin And Metalloprotease domain) comprise a family of multidomain membrane-anchored cell surface proteins with a common structural organization. They are unique among cell surface proteins in possessing both a desintegrin domain, with adhesion properties, and a metalloprotease domain, with a protease activity. Members of this family play am important role in shedding of cell surface proteins (adhesion molecules, cytokines, growth factors and their receptors) and in process of cell-cell and cell-matrix interactions. The availability of growth factors and their receptors as well as the cell-cell and cell-matrix interactions are important in the process of cell proliferation, adhesion and migration. These processes are crucial in progression of tumor and metastasis. As a further contribution to investigate the role of ADAM family members in the tumorigenesis process, we have evaluated the expression pattern of the ADAMs 8, 10, 12, 15, 17, 19, 22 and 33. After a computational analysis using the CpG plot program, these members were shown to have a characteristic CpG island in their promoter region, suggesting that the regulation of these ADAMs could be controlled by methylation. Analysis of the expression pattern by RT-PCR, followed by Southern blot and densitometry showed a significant reduction of the ADAMs 12 and 33 in the breast cell lines relative to the normal tissue. By bisulfite treatment followed by DNA sequencing it was possible to verify a direct correlation between downregulation of the ADAMs 12 and 33 in the cell lines and the hypermethylation of the promoter regions of these genes in almost all cell lines analysed. Expression of these two genes was also activated through treatment of two different cell lines with the demetilating agent 5´-aza-2´-deoxicytidine. This fact confirmed the involvement of methylation in regulation of the expression of the ADAMs 12 and 33. As further contribution to elucidate the role of ADAMs 12 and 33 in breast tumorigenesis, we evaluated the methylation status of the corresponding promoter region of these genes by bissulfite treatment followed by Methylation Specific PCR (MSP) in 108 breast ductal invasive primary tumors. We have detected ADAM12 promoter hypermethylation in 49.1% of the cases and ADAM33 promoter hypermethylation in 55.6% of the cases. The statistical analyses of the methylation pattern of the promoter regions of the ADAMs 12 and 33 and the clinical-pathological data of the patients revealed a significant association between both promoter regions hypermetylation with tumor stage (p=0.005 and p=0.017 respectively). We also observed a significant association between the hypermethylation of ADAM12 promoter region with tumor size (p=0.028) and number of positive lymph nodes (p=0.038). However, the hypermethylation of the both promoter regions were not significantly associated with overall and disease-free survival (AU)