Monitoring Serum Levels of Sorafenib and Its N-Oxide Is Essential for Long-Term Sorafenib Treatment of Patients with Hepatocellular Carcinoma.

Sorafenib, an oral multi-kinase inhibitor, is the final therapy prior to palliative care for advanced hepatocellular carcinoma (HCC). However, due to its adverse effects, 20% of patients must discontinue sorafenib within 1 month after first administration. To identify ways to predict the adverse effects and administer the drug for longer periods, we explored the relationship between the duration of sorafenib treatment and the pharmacokinetics of sorafenib and its major metabolite, sorafenib N-oxide. Twenty-five subjects enrolled in the study were divided into two groups: patients with dosage reduced or withdrawn due to adverse effects (n = 8), and patients with dosage maintained for 1 month after initial administration (n = 17). We evaluated early sorafenib accumulation as the area under the curve of sorafenib and sorafenib N-oxide concentrations during days 1-7 (AUC(sorafenib) and AUC(N-oxide), respectively). Inter-group comparison revealed that AUC(N-oxide) and AUC ratio (AUC(N-oxide)/AUC(sorafenib)) were significantly higher in the dosage reduction/withdrawal group (P = 0.031 and P = 0.0022, respectively). Receiver operating characteristic analysis indicated that AUC(N-oxide) and AUC ratio were reliable predictors of adverse effects. When patients were classified by cut-off points (AUC(N-oxide:) 2.0 µg ∙ day/mL, AUC ratio: 0.13), progression-free survival was significantly longer in patients with AUC(N-oxide) ≤ 2.0 µg ∙ day/mL (P = 0.0048, log-rank test). In conclusion, we recommend to simultaneously monitor serum levels of sorafenib and its N-oxide during the early stage after the first administration, which enables us to provide safe and long-term therapy for each HCC patient with sorafenib.

Diagnostic significance of membrane attack complex and vitronectin in childhood dermatomyositis.

In the current study, whether particular histologic distributions of membrane attack complex and vitronectin are correlated to clinical characteristics of patients with childhood dermatomyositis was investigated. The specimens from 11 patients with childhood dermatomyositis were examined immunocytochemically and compared with those taken from 6 adult dermatomyositis and 5 childhood polymyositis patients. Four out of five membrane attack complex-positive specimens were derived from patients who were within 1 to 3 months from the onset of childhood dermatomyositis and were not treated with prednisone. There were two patients at early stages of childhood dermatomyositis without pathologic characteristics of the disease. However, marked deposits of membrane attack complex on capillaries were seen in one of them. The immunoreactivity of vitronectin was detected at locations similar to those of membrane attack complex. Our results suggest that the detection of membrane attack complex and vitronectin in muscle capillaries will help us diagnose childhood dermatomyositis at an early stage.