RESUMO
Aim: To define the optimal cutoff point for determining methylation status of O6-methylguanine-DNA methyltransferase (MGMT) by pyrosequencing in glioblastoma. Patients & methods: A retrospective study of 109 glioblastoma patients was performed to determine the optimal cutoff point for MGMT methylation status. Results: Receiver operating characteristic (ROC) analysis revealed 21% as the optimal cutoff (sensitivity: 68%; specificity: 59%) for MGMT methylation corresponding with the highest likelihood ratio of 1.66 and accuracy of 0.65. Methylation status (hazard ratio: 0.453; 95% CI: 0.279-0.735; p = 0.001) was associated with better overall survival. The crude model indicated linearity between methylation percent and survival rate; an increase of 10% of methylation resulted in a reduction of risk of death by 20% (p = 0.004). Conclusion: ROC analysis determined 21% as the optimal cutoff point for MGMT methylation status by pyrosequencing.
Lay abstract Glioblastoma is a highly aggressive cancer with less than 6% of patients surviving at 2 years from diagnosis. Patients with hypermethylation of the MGMT gene promoter have improved survival compared with those with unmethylated MGMT. There is considerable debate regarding the ideal cutoff value for calling MGMT promoter hypermethylated or not. The authors performed a retrospective study of 109 patients diagnosed with glioblastoma from 2000 to 2018 to determine the optimal cutoff point. Using receiver operating characteristic (ROC) analysis, the researchers determined that 21% is the optimal cutoff for MGMT methylation. Methylation status and total surgical resection were associated with better survival. Further, the crude model indicates linearity between methylation percent and survival rate; an increase of 10% methylation resulted in a reduction of risk of death by 20% (p = 0.004).
Assuntos
Neoplasias Encefálicas , Glioblastoma , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Metilação de DNA/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Humanos , Estudos Retrospectivos , Proteínas Supressoras de Tumor/genéticaRESUMO
INTRODUCTION: We have completed in vivo safety and efficacy studies of the use of a novel drug delivery system, a gel matrix-temozolomide formulation that is injected intracranially into the post-resection cavity, as a candidate for glioma therapy. METHODS: A rat intracranial resection model of C6-GFP intracranial glioma was used for safety and toxicity studies. Biodistribution studies were performed using gel matrix-gallocyanine formulations and were evaluated at various time intervals using real-time analysis of dye distribution. Additionally, the resection model was used to determine the efficacy of gel matrix-temozolomide as compared to blank gel matrix. A subcutaneous human xenograft glioma model was used to further assess the efficacy of gel matrix-temozolomide in reducing the overall tumor load. RESULTS: Gel matrix-temozolomide exhibited minimal cytotoxicity toward normal brain tissue while displaying high levels of oncolytic activity toward glioma cells. In the intracranial glioma resection and subcutaneous glioma model, administration of gel matrix-temozolomide directly to the tumor bed was well tolerated and effective at reducing the tumor load. A significant reduction of tumor load was observed (P < 0.0001) in the 30% temozolomide group (approximately 95%) as compared to blank control. There was little morbidity and no mortality associated with gel matrix treatment. CONCLUSIONS: Gel matrix-temozolomide appears to be safe and effective when used in vivo to treat intracranial glioma and warrants further development as a potential adjuvant therapy.