A systematic review on external ear melanoma

Background External ear melanoma accounts for only 1% of all cutaneous melanomas, and data on its optimal management and prognosis are limited. Aim We aim to review the literature on external ear melanoma to guide surgeons in the treatment of this uncommon and peculiar pathology. Materials and methods A systematic review of English language studies on ear melanoma published from 1993 to 2013 was performed using the PubMed electronic database. Data on epidemiology, oncological treatment (tumor resection and regional lymph nodes management), and reconstruction were extrapolated from selected papers. Results The total number of patients was 858 (30 studies). The helix was the most common location (57%); superficial spreading melanoma was the most common histopathological subtype (41%). The mean Breslow thickness was 2.01 mm, with 88% of stage I-II patients. Sentinel lymph node biopsy was performed in 45% of patients, with 8% of positive nodes. Available data on its prognosis are fragmentary and contrasting, but the Breslow thickness appears to be the main prognostic factor. There is a tendency towards reduced resection margins and preservation of the underlying perichondrium and cartilage. Local flaps are the most popular reconstructive option. Conclusion To the best of our knowledge, this systematic review presents the largest data series on external ear melanoma. There is no general agreement on its surgical management, but a favorable prognosis seems to justify the tendency towards conservative treatments

Destabilizers of the thymidylate synthase homodimer accelerate its proteasomal degradation and inhibit cancer growth

Drugs that target human thymidylate synthase (hTS), a dimeric enzyme, are widely used in anticancer therapy. However, treatment with classical substrate-site-directed TS inhibitors induces over-expression of this protein and development of drug resistance. We thus pursued an alternative strategy that led us to the discovery of TS-dimer destabilizers. These compounds bind at the monomer-monomer interface and shift the dimerization equilibrium of both the recombinant and the intracellular protein toward the inactive monomers. A structural, spectroscopic, and kinetic investigation has provided evidence and quantitative information on the effects of the interaction of these small molecules with hTS. Focusing on the best among them, E7, we have shown that it inhibits hTS in cancer cells and accelerates its proteasomal degradation, thus causing a decrease in the enzyme intracellular level. E7 also showed a superior anticancer profile to fluorouracil in a mouse model of human pancreatic and ovarian cancer. Thus, over sixty years after the discovery of the first TS prodrug inhibitor, fluorouracil, E7 breaks the link between TS inhibition and enhanced expression in response, providing a strategy to fight drug-resistant cancers