Sorafenib in advanced melanoma: a critical role for pharmacokinetics?

BACKGROUND: Inter-patient pharmacokinetic variability can lead to suboptimal drug exposure, and therefore might impact the efficacy of sorafenib. This study reports long-term pharmacokinetic monitoring of patients treated with sorafenib and a retrospective pharmacodynamic/pharmacokinetic analysis in melanoma patients. PATIENTS AND METHODS: Heavily pretreated patients with stage IV melanoma were started on sorafenib 400 mg twice daily (bid). In the absence of limiting toxicity, dose escalation of 200 mg bid levels was done every 2 weeks. Plasma sorafenib measurement was performed at each visit, allowing a retrospective pharmacodynamic/pharmacokinetic analysis for safety and efficacy. RESULTS: In all, 19 of 30 patients underwent dose escalation over 400 mg bid, and 28 were evaluable for response. The overall disease control rate was 61% (95% confidence interval (CI): 42.6-78.8), including three confirmed responses (12%). Disease control rate and progression-free survival (PFS) were improved in patients with high vs low exposure (80% vs 32%, P=0.02, and 5.25 vs 2.5 months, P=0.005, hazard ratio (HR)=0.28 (95% CI: 0.11-0.73)). In contrast, drug dosing had no effect on PFS. In multivariate analysis, drug exposure was the only factor associated with PFS (HR=0.36 (95% CI: 0.13-0.99)). Diarrhoea and anorexia were correlated with drug dosing, while hypertension and hand-foot skin reaction were correlated with drug exposure. CONCLUSIONS: Although sorafenib had modest efficacy in melanoma, these results suggest a correlation between exposure and efficacy of sorafenib. Therefore, dose optimisation in patients with low exposure at standard doses should be evaluated in validated indications.

[The anatomy and the MRI anatomy of the interhemispheric cerebral commissures]. / Anatomie et anatomie IRM des commissures inter-hémisphériques cérébrales.

Correlation of myelin-stained or cryotomic sections of human brain with inversion-recovery MR images can display the cerebral commissures as white-matter tracts (in hypersignal on MRI), crossing the mid-line. MRI shows routinely in three orthogonal planes a) the corpus callosum stretched above the supra-tentorial ventricles, it's four portions (rostrum, genu, body and splenium) and connections with the Deep Grey Nuclei b) the fornix, intralimbic commissure joining anteriorly the mammillary bodies (through it's columns) to the alveus posteriorly and inferiorly (via it's two crura), arcing around the thalamus and lying over the hippocampus and the dentate gyrus as shown on the frontal sections c) the anterior commissure, white-matter tract connecting the two temporal lobes. In axial view, the anterior commissure has the shape of bicycle handlebars, coursing posteriorly, inferiorly and laterally behind the head of the caudate nucleus and passes into the lateral nucleus of the globus pallidus into the inferior and middle temporal gyri. Because the anterior commissure is easily recognisable in all planes, it's appears to be a important landmark for identification of the lateral and medial nuclei of the globus pallidus on axial and sagittal planes d) at least, the posterior commissure, anterior margin of the pineal region, closely related to the superior colliculi, acquire a major importance in the AC-PC line delineation becoming a reference landmark for stereotatical procedures.