RESUMO
BACKGROUND: The pathomechanism and location of idiopathic sudden sensorineural hearing loss (ISSHL) is unclear. In a previous case-control study, we found elevated fibrinogen concentrations and a higher prevalence of T allele carriers of the glycoprotein (Gp) Ia C807T polymorphism in ISSHL patients. METHODOLOGY: 127 patients with ISSHL (mean age 53.3 years, 48.8% females), who underwent a standard therapy with high dose steroids, pentoxifyllin and sterofundine over 8 days were included. We examined the influence of GpIa genotype and fibrinogen (BclI-, A312-, HaeIII-) genotype and fibrinogen plasma levels on hearing recovery after 8 weeks (change from baseline: 0 dB â=â no recovery, >0 to 10 dBâ=âmoderate recovery, >10 dBâ=âgood recovery). In a subsample of 59 patients with ISSHL, we further studied the association of platelet glycoprotein GpIa, Ib and IIIa densities on hearing recovery as well as the possible effect-modification of platelet glycoproteins on hearing recovery by plasma fibrinogen. RESULTS: In univariate analysis, neither the GpIa genotype nor fibrinogen genotype (all p>0.1) but lower fibrinogen levels (pâ=â0.029), less vertigo (pâ=â0.002) and lower GpIIIa receptor density (pâ=â0.037, nâ=â59) were associated with hearing recovery. In multivariate analysis, fibrinogen significantly modified the effect of GPIa receptor density on good hearing recovery (effect-modification on multiplicative scale ORâ=â0.45 (95% confidence interval (0.21-0.94)), pâ=â0.03). GPIb receptor density below the mean was associated with a 2-fold increase in good hearing recovery both in patients with fibrinogen levels above (pâ=â0.04) as well as in patients with fibrinogen levels below the mean (pâ=â0.06). There was no indication for an effect-modification (pâ=â0.97). CONCLUSIONS: The findings suggest a vascular/rheological origin of ISSHL with unique features of thrombosis in the inner ear artery that may include complex interrelationships among platelet glycoproteins and plasma fibrinogen.
Assuntos
Anti-Inflamatórios/uso terapêutico , Biomarcadores/sangue , Fibrinogênio/metabolismo , Perda Auditiva Súbita/tratamento farmacológico , Perda Auditiva Súbita/genética , Integrina alfa2/genética , Polimorfismo Genético/genética , Estudos de Casos e Controles , Feminino , Fibrinogênio/genética , Citometria de Fluxo , Genótipo , Perda Auditiva Súbita/sangue , Humanos , Integrina alfa2/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da PolimeraseRESUMO
High-dose chemotherapy of solid tumors aims at eliminating residual or metastatic tumor cells, which remained after conventional treatment. Thus, anticancer drugs used for high-dose chemotherapy should display significant cytotoxicity against the respective tumors. As little data are available about the in-vitro toxicity of busulfan and treosulfan especially on pediatric tumor cell lines, we compared the cytotoxicity of treosulfan and busulfan on four Ewing tumor, four neuroblastoma, two osteosarcoma and two leukemia cell lines in vitro. Growth inhibition of tumor cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide test after 24, 48, 72 and 96 h. Treosulfan and busulfan reduced the growth of all tumor cell lines in a time-dependent and dose-dependent manner. In vitro treosulfan was consistently more cytotoxic than busulfan. Fifty percent growth inhibitions of 608-0.73 micromol/l were determined for treosulfan and of above 5,000-2.81 micromol/l for busulfan. Both drugs exhibited similar cytotoxicity profiles. Busulfan-sensitive/resistant cell lines were also sensitive/resistant to treosulfan. Overall, the leukemia cell lines were most sensitive to busulfan and treosulfan. The Ewing tumor cell lines were the second most sensitive followed by the neuroblastoma cell lines. The osteosarcoma cell lines were the most resistant cell lines. Although the in-vitro stability of both drugs makes direct comparison of their in-vitro toxicity difficult and does not allow any estimation of dosages needed clinically, the in-vitro results indicate substantial cytotoxicity of both drugs on leukemias, Ewing tumors and neuroblastomas. These data suggest further evaluation of treosulfan for high-dose chemotherapy of advanced Ewing tumors, neuroblastomas and high-risk leukemias.