Long-term efficacy of antifungals in toenail onychomycosis: a critical review

BACKGROUND: Modern antifungal drugs achieve high mycological and clinical cure rates in onychomycosis of the toes, but little is known about the long-term evolution of the treated patients. OBJECTIVES: The aim of this review was to analyse the therapeutic results recorded more than 1 year after initiation of therapy. METHODS: We used two endpoints for the analysis: EP1 (the number of patients with negative mycology after follow-up, divided by the number of patients included at day 0, including all patients lost to follow-up), and EP2 (the number of patients with negative mycology after follow-up divided by the number of patients with negative mycology at week 48). Clinical cure rate (EPclin) was the number of patients clinically cured or with minimal residual lesions divided by the number of patients included at day 0. RESULTS: From a Medline search we identified 17 studies providing results beyond 48 weeks. Ketoconazole 200 mg d(-1) up to 1 year resulted in EP1 of 11% at 18 months, and EP2 of 43%. Griseofulvin 1 g d(-1) for 1 year allowed an EP1 of 43% at 18 months, and EP2 of 71%. The mean EP1 after fluconazole once weekly up to 1 year was 49% at 18 months, and EP2 was 91%. With itraconazole 200 mg d(-1) or 400 mg d(-1) for 1 week each month for 3-4 months, EP1 was 37% at 18 months, and 53% at 2 years; EP2 was 76% at 4 years. Terbinafine 250 mg d(-1) for 12-16 weeks achieved an EP1 of 62% at 18 months, 72% at 2 years, and 60% at 4 years; EP2 was 80% at 18 months, 81% at 2 years, and 71% at 4 years. In the only study planned to compare the long-term efficacy of terbinafine and itraconazole, EP1 at 18 months was significantly higher with continuous terbinafine than with intermittent itraconazole (66% vs. 37%, P < 0.001). The clinical cure rates were 21% at 60 weeks and 37% at 72 weeks with fluconazole. EPclin was 27% at 18 months and 35% at 2 years with itraconazole. EPclin was 48% at 18 months, 69% at 2 years and 50% at 4 years with terbinafine. CONCLUSIONS: Considering the stringency of the criteria we used, this critical review suggests that the long-term efficacy achieved with terbinafine is superior to that obtained with griseofulvin, ketoconazole, fluconazole or itraconazole.     

Expression of stromelysin 3 in basal cell carcinomas.

Stromelysin 3 is a member of the metalloproteinase family, which is expressed in various remodelling processes. The prognosis of breast cancers and squamous cell carcinomas is correlated to the level of expression of this protein. The purpose of the present work was to evaluate the expression of stromelysin 3 in the major types of basal cell carcinomas. We selected cases of primary tumours that were fully excised, without previous biopsy: 40 Pinkus tumors, 40 superficial, 40 nodular, 38 morpheiform basal cell carcinomas and 10 cases showing deep subcutaneous or muscular invasion. Immunohistochemistry was carried out using monoclonal anti-ST3 antibodies (MC Rio, IGBMC Strasbourg), and evaluated on a semi-quantitative scale from 0 to 3. Positively stained cells were restricted to the periphery of the epithelial cells, which, by contrast, never expressed stromelysin 3. The global rate of expression was 27% in Pinkus tumors, 65% in superficial, 72.5% in nodular, 87% in morpheiform and 100% in deeply invasive carcinomas. The rates of tumours showing the highest number of positively stained cells (class 2 or 3) were respectively 7.5%, 20%, 45%, 63% and 100%. This systematic study of stromelysin3 expression in basal cell carcinomas confirms that it is a marker of poor prognosis, because the rate of positive tumours was much higher in aggressive carcinomas. Moreover, the majority of tumours showing an intense expression (i.e. the highest number of positively stained cells in their stroma) were of the morpheiform and deeply invasive types, which are of poor prognosis. Altogether, the studies performed on cutaneous tumours are consistent with the theory of stromelysin 3 playing an active role in tumour progression.     

On the regulation of hair keratin expression: lessons from studies in pilomatricomas

Human hair follicles exhibit a complex pattern of sequential hair keratin expression in the hair matrix, cuticle, and cortex. In pilomatricomas, that is, benign skin tumors thought to arise from germinative matrix cells of the hair follicle and retaining morphological signs of cortical differentiation, this differential hair keratin pattern has been shown to be faithfully preserved in the lower and upper transitional cell compartments of the tumors. Here we show that also the co-expression of hair keratin hHa5 with its regulatory nuclear homeoprotein HOXC13 in matrix cells of the hair follicle is maintained in lower transitional cells of pilomatricomas. In contrast, the nuclear co-expression of LEF1 and beta-catenin, which in the hair follicle has been postulated to initiate cortex cell differentiation through the induction of hair keratin hHa1 expression (Merill et al, Genes Dev 15:1688-1705, 2001), is not preserved in upper transitional cells of pilomatricomas. Although these cells correctly express hHa1, they are completely devoid of LEF1 and nuclear LEF1/beta-catenin co-expression is shifted to a subpopulation of hair keratin-free basaloid cells of the tumors. These data imply that unlike the normal hair follicle, cortical differentiation in pilomatricomas is not under the control of the canonical Wnt signaling pathway.