A Phase I Trial of Trametinib in Combination with Sorafenib in Patients with Advanced Hepatocellular Cancer

Lessons Learned

• The combination of trametinib and sorafenib has an acceptable safety profile, albeit at doses lower than approved for monotherapy.
• Maximum tolerated dose is trametinib 1.5 mg daily and sorafenib 200 mg twice daily.
• The limited anticancer activity observed in this unselected patient population does not support further exploration of trametinib plus sorafenib in patients with hepatocellular carcinoma.

BackgroundThe RAS/RAF/MEK/ERK signaling pathway is associated with proliferation and progression of hepatocellular carcinoma (HCC). Preclinical data suggest that paradoxical activation of the MAPK pathway may be one of the resistance mechanisms of sorafenib; therefore, we evaluated trametinib plus sorafenib in HCC.MethodsThis was a phase I study with a 3+3 design in patients with treatment‐naïve advanced HCC. The primary objective was safety and tolerability. The secondary objective was clinical efficacy.ResultsA total of 17 patients were treated with three different doses of trametinib and sorafenib. Two patients experienced dose‐limiting toxicity, including grade 4 hypertension and grade 3 elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/bilirubin over 7 days. Maximum tolerated dose was trametinib 1.5 mg daily and sorafenib 200 mg twice a day. The most common grade 3/4 treatment‐related adverse events were elevated AST (37%) and hypertension (24%). Among 11 evaluable patients, 7 (63.6%) had stable disease with no objective response. The median progression‐free survival (PFS) and overall survival (OS) were 3.7 and 7.8 months, respectively. Phosphorylated‐ERK was evaluated as a pharmacodynamic marker, and sorafenib plus trametinib inhibited phosphorylated‐ERK up to 98.1% (median: 81.2%) in peripheral blood mononuclear cells.ConclusionTrametinib and sorafenib can be safely administered up to trametinib 1.5 mg daily and sorafenib 200 mg twice a day with limited anticancer activity in advanced HCC.     

Dorsal suspension for Morton’s neuroma: A comparison with neurectomy

BackgroundThe purpose of this study was to investigate and compare the clinical outcomes of dorsal suspension with those of neurectomy for the treatment of Morton’s neuroma.MethodsWe conducted a retrospective study of dorsal suspension and neurectomy group. The dorsal suspension was performed by dorsal transposition of neuroma over the dorsal transverse ligament after neurolysis. The visual analog scale (VAS), the Foot and Ankle Ability Measure (FAAM), postoperative satisfaction, and complications were evaluated.ResultsBoth groups reported significant pain relief, and there were no significant differences between the groups with respect to postoperative pain. The postoperative FAAM outcomes showed no significant between-group differences. Satisfaction analysis showed ‘excellent’ and ‘good’ results in the dorsal suspension and neurectomy groups (95% and 77.7%, respectively). Complications of numbness and paresthesia reported in the dorsal suspension group (5% and 5%, respectively) were significantly fewer than those of neurectomy group (61.1% and 33.3%, respectively) (both, p < .05).ConclusionsWith its favorable results, dorsal suspension can be another operative option for the treatment of Morton’s neuroma.Level of Evidence: Level III, retrospective comparative case series.     

Application of a pigment measuring device – Mexameter®– for the differential diagnosis of vitiligo and nevus depigmentosus

Background/purpose: Vitiligo and nevus depigmentosus (ND) present similar hypopigmented macules with significantly different prognoses. Although the distinction between the two diseases is important, differential diagnosis relies on medical history and physical examination, which is far from decisive in some cases. The Mexameter^® is an objective skin color-measuring device, and has been reported to provide a reproducible and sensitive means of quantifying small skin color differences. In this study, we investigated the usefulness of a Mexameter^® for discriminating these diseases.
Methods: A selection of 202 hypopigmented skin lesions (182 from vitiligo and 20 from ND) were the objects of this study. Using a Mexameter, MIs were obtained from lesions and symmetrically located control skin. RMIs, ratios of the MIs of lesional skins to control skins, were calculated.
Results: The mean MIs and RMIs were significantly different for vitiligo and ND. The mean RMI of ND lesions was 74±13, which was significantly higher than that of vitiligo lesions (50±24). No ND lesion had an RMI of <50%.
Conclusion: This study shows that the Mexameter^®, an objective pigment-measuring device, can be used to achieve a more accurate diagnosis of hypopigmentary disorders, and that the relative melanin index (RMI), which represents the relative pigment levels, might be a more effective parameter than the melanin index (MI) itself for comparing pigmentation differences.