RESUMO
PURPOSE: Patients with recurrent glioblastoma (rGBM) have a poor prognosis, with survival ranging from 25 to 40 weeks. Antiangiogenic agents are widely used, showing a variable response. In this study, we explored the efficacy of carmustine plus bevacizumab (BCNU/Bev) for treating rGBM. METHODS/PATIENTS: In this study, we assessed 59 adult patients with histologically confirmed rGBM who were treated with BCNU/Bev as second-line regimen. The response rate (RR), progression-free survival (PFS) and overall survival (OS) were evaluated according to their molecular expression profile, including CD133 mRNA expression, MGMT methylation (pMGMT), PDGFR amplification, YKL40 mRNA expression, IDH1/2 condition, p53 and EGFRvIII mutation status. RESULTS: Median follow-up was 18.6 months, overall RR to the combination was 56.3%, and median PFS was 9.0 months (95% CI 8.0-9.9). OS from time of diagnosis was 21.0 months (95% CI 13.2-28.7) and from starting BCNU/Bev it was 10.7 months (95% CI 9.5-11.8). IDH1/2 mutations were found in 30.5% of the patients, pMGMT in 55.9% and high CD133 mRNA expression in 57.6%. Factors which positively affected PFS included performance status (p = 0.015), IDH+ (p = 0.05), CD133 mRNA expression (p = 0.009) and pMGMT+ (p = 0.007). OS was positively affected by pMGMT+ (p = 0.05). Meanwhile, YKL40 negatively affected PFS (p = 0.01) and OS (p = 0.0001). Grade ≥ 3 toxicities included hypertension (22%) and fatigue (12%). CONCLUSIONS: BCNU/Bev is a safe and tolerable treatment for rGBM. Patients with MGMT+/IDH+ derive the greatest benefit from the treatment combination in the second-line setting. Nonetheless, high YKL40 expression discourages the use of antiangiogenic therapy.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Carmustina/uso terapêutico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Antígeno AC133/genética , Antígeno AC133/metabolismo , Adulto , Idoso , Inibidores da Angiogênese/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Bevacizumab/efeitos adversos , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Carmustina/efeitos adversos , Proteína 1 Semelhante à Quitinase-3/genética , Colômbia , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Esquema de Medicação , Feminino , Genes erbB-1 , Genes p53 , Glioblastoma/irrigação sanguínea , Glioblastoma/genética , Glioblastoma/mortalidade , Humanos , Isocitrato Desidrogenase/genética , Masculino , Metilação , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/irrigação sanguínea , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Intervalo Livre de Progressão , RNA Mensageiro/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/genética , Análise de Sobrevida , Proteínas Supressoras de Tumor/metabolismo , Adulto JovemRESUMO
OBJECTIVES: To assess neurobehavioural effects of low exposure to lead, 43 workers from a lead smelter and 45 workers from a glass factory were evaluated with the World Health Organisation neurobehavioural core test battery (NCTB) in a cross sectional study. METHODS: The NCTB comprises a questionnaire and seven tests that measure simple reaction time, short-term memory (digit span, Benton), mood (profile of mood states), eye-hand coordination (Santa Ana pegboard, pursuit aiming II), and perceptual speed (digit-symbol). RESULTS: Smelter workers were employed on average for four years, and had a mean blood lead concentration of 2.0 mumol/l (42 micrograms/dl). Glass factory workers had a mean of 0.72 mumol/l (15 micrograms/dl). Historical blood lead concentrations were used to classify exposure based on current, peak, and time weighted average. Although the exposed workers performed less well than the non-exposed in 10 of 14 response variables, only profile of mood states tension-anxiety, hostility, and depression mood scales showed a significantly poorer dose-response relation with blood lead concentration in multiple linear regression models that included age, education, and alcohol intake as covariates. The frequency of symptoms of anger, depression, fatigue, and joint pain were also significantly increased in the exposed group. CONCLUSION: This study is consistent with the larger body of neurobehavioural research of low occupational exposure to lead. The small effects found in this study occurred at blood lead concentrations slightly lower than those reported in several previous studies.
Assuntos
Chumbo/efeitos adversos , Metalurgia , Transtornos do Humor/induzido quimicamente , Doenças do Sistema Nervoso/induzido quimicamente , Doenças Profissionais/induzido quimicamente , Adulto , Idoso , Estudos Transversais , Relação Dose-Resposta a Droga , Humanos , Chumbo/sangue , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/sangue , Doenças do Sistema Nervoso/sangue , Doenças Profissionais/sangue , Exposição Ocupacional , VenezuelaRESUMO
To assess the applicability of the World Health Organization (WHO) Neurobehavioral Core Test Battery (NCTB), we evaluated 53 male and 29 female Venezuelan workers exposed to mixtures of organic solvents in an adhesive factory, and 56 male and 11 female workers unexposed to any type of neurotoxic chemical. The average age of unexposed workers was 30 years and 33 years for those exposed, average schooling for both groups was 8 years, and the mean duration of exposure was 7 years. The NCTB, which assesses central nervous system functions, is composed of seven tests that measure simple motor function, short-term memory, eye-hand coordination, affective behavior, and psychomotor perception and speed. The battery includes: profile of mood states (POMS); Simple Reaction Time for attention and response speed; Digit Span for auditory memory; Santa Ana manual dexterity; Digit-Symbol for perceptual motor speed; the Benton visual retention for visual perception and memory; and Pursuit Aiming II for motor steadiness. In each of 13 subtests, the exposed group had a poorer performance than the nonexposed group. The range of differences in mean performance was between 5% and 89%, particularly in POMS (tension-anxiety, anger-hostility, depression-rejection, fatigue-inertia, confusion-bewilderment), Simple Reaction Time, Digit-Symbol, and Santa Ana Pegboard (p < .05). In multivariate regression analyses, controlling for the effects of age, sex, and education, significantly poorer performance in the exposed was found for tension-anxiety, hostility, depression, and confusion moods in the POMS, and in digit-symbol and simple reaction time (p < .05). These alterations were also dose-related using years of exposure in analyses of covariance. Compared to the nonexposed, the exposed subjects demonstrated an increased frequency of subjective symptoms of fatigue, difficulties with memory, confusion, paresthesias in upper and lower extremities, and sleep disturbances. We conclude that the methodology is applicable to the population studied. The tests of the NCTB were accepted by the subjects and were administered satisfactorily, except for occasional difficulties in verbal comprehension in subtests of POMS, which is the only test that requires more demanding verbal skills. The magnitude of the behavioral deficits is consistent with the probable high level of exposure and with the range of deficits previously reported in workers with long-term solvent exposures.