RESUMO
Genotyping of putative determinants of temozolomide (TMZ)-induced life-threatening bone marrow suppression was performed in two patients with glioma treated with adjuvant TMZ and radiation therapy. DNA was extracted from the patients' mononuclear cells and genotyping of O-methylguanine-DNA-methyltransferase (MGMT), multidrug resistance (MDR1; also known as ABCB1), NQO1, and GSTP1 genes and analysis for the epigenetic silencing of specific MGMT gene promoters were carried out to evaluate the possible genetic determinants of increased risk of severe TMZ-induced myelosuppression. Although both patients were heterozygous for all ABCB1 single nucleotide polymorphisms and for rs12917 and rs1803965 in the MGMT gene, patient 1 was heterozygous for rs1695 in GSTP1 and rs2308327 in the MGMT gene. This patient also exhibited GG genotype for the MGMT single nucleotide polymorphisms, rs2308321, which is noteworthy for its 0.7% frequency globally. Epigenetic silencing of MGMT gene was not detected in either patient. Two single nucleotide polymorphisms identified in patient 1 (missense I143V and K178R polymorphisms; rs2308321 and rs2308327, respectively) have recently been shown to correlate with an increased risk of severe TMZ-induced myelosuppression. The polymorphisms identified in patient 2 have not been associated with an increased risk of severe TMZ-induced myelosuppression. Genotyping analyses of larger patient populations administered TMZ are required to validate the genetic determinants of severe TMZ-induced myelosuppression.
Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Dacarbazina/análogos & derivados , Glioma/tratamento farmacológico , Transtornos Mieloproliferativos/induzido quimicamente , Transtornos Mieloproliferativos/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Adulto , Antineoplásicos Alquilantes/farmacologia , Dacarbazina/efeitos adversos , Dacarbazina/uso terapêutico , Feminino , Glioma/enzimologia , Glioma/genética , Glutationa S-Transferase pi/genética , Humanos , Masculino , Pessoa de Meia-Idade , NAD(P)H Desidrogenase (Quinona)/genética , Neoplasias Neuroepiteliomatosas/complicações , Neoplasias Neuroepiteliomatosas/terapia , O(6)-Metilguanina-DNA Metiltransferase/genética , Pacientes , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , TemozolomidaRESUMO
BACKGROUND: The objective of ECOG 1503 was to determine the response rate of this combination in the second-line treatment of advanced NSCLC. METHODS: Triapine 105 mg/m(2) IV on days 1, 8, and 15, and gemcitabine 1,000 mg/m(2) on days 1, 8, and 15, of a 28 day cycle. RESULTS: Eighteen patients enrolled. Three patients were not eligible due to protocol violations. No objective antitumor responses were seen. Three patients (20%) experienced stable disease (90% CI 5.7-44%). Median overall survival: 5.4 months (95% CI 4.2-11.6 months); median time to progression: 1.8 months (95% CI 1.7-3.5 months). Five patients developed acute infusion reactions to Triapine related to elevated methemoglobinemia. Patients with MDR1 variant genotypes of C3435T experienced superior overall survival compared to non-variants (13.3 vs. 4.3 months, respectively, p = 0.023). CONCLUSION: This regimen did not demonstrate activity in relapsed NSCLC. Prolonged survival seen with MDR1 variant genotypes is hypothesis-generating.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Comportamento Cooperativo , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Oncologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Feminino , Genótipo , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Análise de Sobrevida , Tiossemicarbazonas/efeitos adversos , Tiossemicarbazonas/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , GencitabinaRESUMO
We describe 4 patients with West Nile virus encephalitis who all displayed previously unreported plasma cell pleocytosis of the cerebrospinal fluid (CSF). Three patients recovered but had varying degrees of mild neurologic disability on discharge from the hospital, and 1 patient died. The finding of significant numbers of plasma cells in CSF may serve as a useful early diagnostic clue for West Nile virus encephalitis.
