RESUMO
We present a complex case of a splanchnic arterioportal vein fistula in a patient who presented with weight loss, abdominal pain, diarrhea, and pancreatitis. We report successful use of the Guglielmi Detachable Coil (GDC) and N-butyl cyanoacrylate glue for the therapeutic embolization of the fistula between the superior mesenteric artery, the common hepatic artery, and the portal vein. On the day following the procedure, the patient reported total remission of the abdominal pain and diarrhea. These results were maintained at 3 months follow-up.
Assuntos
Fístula Arteriovenosa/terapia , Cianoacrilatos/administração & dosagem , Embolização Terapêutica , Artéria Hepática , Artéria Mesentérica Superior , Veia Porta , Adesivos Teciduais/administração & dosagem , Ferimentos por Arma de Fogo/complicações , Adulto , Fístula Arteriovenosa/diagnóstico por imagem , Fístula Arteriovenosa/etiologia , Fístula Arteriovenosa/fisiopatologia , Embucrilato , Artéria Hepática/diagnóstico por imagem , Artéria Hepática/fisiopatologia , Humanos , Masculino , Artéria Mesentérica Superior/diagnóstico por imagem , Artéria Mesentérica Superior/fisiopatologia , Veia Porta/diagnóstico por imagem , Veia Porta/fisiopatologia , Radiografia Intervencionista , Circulação Esplâncnica , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Optimal reexpression of most genes silenced through promoter methylation requires the sequential application of DNA methyltransferase inhibitors followed by histone deacetylase inhibitors in tumor cell cultures. Patients with myelodysplastic syndrome or acute myeloid leukemia (AML) were treated with the methyltransferase inhibitor 5-azacitidine (aza-CR) followed by the histone deacetylase inhibitor sodium phenylbutyrate. Major responses associated with cytogenetic complete response developed in patients receiving prolonged dosing schedules of aza-CR. Bisulfite sequencing of the p15 promoter in marrow DNA during the first cycle of treatment showed heterogeneous allelic demethylation in three responding patients, suggesting ongoing demethylation within the tumor clone, but no demethylation in two nonresponders. Six of six responding patients with pretreatment methylation of p15 or CDH-1 promoters reversed methylation during the first cycle of therapy (methylation-specific PCR), whereas none of six nonresponders showed any demethylation. Gene demethylation correlated with the area under the aza-CR plasma concentration-time curve. Administration of both drugs was associated with induction of acetylation of histones H3 and H4. This study provides the first demonstration that molecular mechanisms responsible for responses to DNA methyltransferase/histone deacetylase inhibitor combinations may include reversal of aberrant epigenetic gene silencing. The promising percentage of major hematologic responses justifies the testing of such combinations in prospective randomized trials.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Inibidores de Histona Desacetilases , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/enzimologia , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/enzimologia , Acetilação/efeitos dos fármacos , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/farmacocinética , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Estudos de Viabilidade , Feminino , Histona Desacetilases/genética , Histonas/metabolismo , Humanos , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Fenilbutiratos/administração & dosagem , Fenilbutiratos/efeitos adversos , Fenilbutiratos/farmacocinética , Regiões Promotoras Genéticas , Resultado do TratamentoAssuntos
Fluordesoxiglucose F18 , Melanoma/diagnóstico por imagem , Melanoma/secundário , Tomografia por Emissão de Pósitrons/métodos , Técnica de Subtração , Neoplasias Testiculares/diagnóstico por imagem , Neoplasias Testiculares/secundário , Tomografia Computadorizada por Raios X/métodos , Idoso , Idoso de 80 Anos ou mais , Humanos , Aumento da Imagem/métodos , Masculino , Melanoma/patologia , Estadiamento de Neoplasias/métodos , Compostos Radiofarmacêuticos , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/patologia , Neoplasias Testiculares/patologiaAssuntos
Adenocarcinoma/secundário , Neoplasias das Glândulas Suprarrenais/secundário , Neoplasias do Colo/patologia , Tomografia Computadorizada de Emissão , Tomografia Computadorizada por Raios X , Neoplasias das Glândulas Suprarrenais/diagnóstico , Fluordesoxiglucose F18 , Humanos , Compostos RadiofarmacêuticosRESUMO
The aromatic fatty acid sodium phenylbutyrate (PB) promotes cytostasis and differentiation in a wide variety of tumor types; among several molecular activities, inhibition of histone deacetylase (HDAC) may account for many of its pharmacodynamic effects. A Phase I study demonstrated promising preliminary evidence of clinical activity in acute myeloid leukemia and myelodysplastic syndrome; however, plasma concentrations achieved at the maximum tolerated dose were less than those targeted based on in vitro studies. Because prolonged exposure to suboptimal concentrations of PB in vitro led to pharmacodynamic changes similar to a more brief exposure to higher concentrations, a study of the feasibility of prolonged administration of sodium PB was performed. Selected patients with acute myeloid leukemia and myelodysplastic syndrome were treated with sodium PB as a continuous i.v. infusion via ambulatory infusion pump. Sequential cohorts were treated for 7 consecutive days out of 14 or with 21 consecutive days out of 28. Prolonged infusions were well tolerated; dose-limiting central nervous system toxicity developed in 1 of 23 patients treated. End-of-infusion plasma concentrations were maintained within a range sufficient to inhibit HDAC. Two patients on the 21/28 schedule developed hematological improvement. Prolonged infusions of PB are well tolerated making this an attractive platform for the clinical investigation of HDAC inhibition.