Can hair re-growth be considered an early clinical marker of treatment resistance to Hedgehog inhibitors in patients with advanced basal cell carcinoma? A report of two cases.

INTRODUCTION: Basal cell carcinomas (BCCs) are the most common skin cancers in the Caucasian population. BCCs are in the majority of cases adequately managed with surgical excision, however a small subset of these tumours exhibit resistance to conventional therapies and progress to become locally advanced or even metastatic. Although Hedgehog inhibitors have been successfully used during the last few years in the treatment of locally advanced or metastatic BCCs, resistance to treatment remains an issue. Until this point, no biomarkers or clinical markers of drug resistance for Hedgehog inhibitors have been identified. METHODS AND RESULTS: We report two patients, a female patient with Gorlin syndrome and a male patient with locally advanced BCC, which received treatment with the Hedgehog inhibitor Vismodegib. These patients responded adequately to treatment and they both developed Hedgehog inhibitor-induced alopecia as an adverse event. However, after 2.5 and 1.5 years of treatment, respectively, the patients exhibited progressive disease that was accompanied by reversal of the Hedgehog inhibitor-induced alopecia, although still under treatment with Vismodegib. CONCLUSION: Although alopecia is a well-known adverse event associated with the administration of Hh inhibitors, data associated with the appearance and/or clinical severity of alopecia and the treatment efficacy of Hedgehog inhibitors are limited. The Hedgehog pathway plays an important role in the normal cycling of the hair follicles in adults and, therefore, the pathomechanism of Hedgehog inhibitor-induced alopecia is considered unique for this drug class. Based on the fact that Hh inhibitor resistance is associated with partial reactivation of the Hh pathway, it would not be illogical to suggest that reversal of Hh inhibitor-induced alopecia in patients under treatment with Hh inhibitors could serve as a clinical marker of drug resistance. However, this observation, as reported in this paper, is only limited in two patients and therefore more information is needed in order to assess its actual clinical importance.

Demographic, behavioural and physician-related determinants of early melanoma detection in a low-incidence population.

BACKGROUND: Knowledge of the factors that influence early detection of melanoma is important in developing strategies to reduce associated mortality. OBJECTIVES: To identify sociodemographic, behavioural and medical care-related factors associated with melanoma thickness in a low-incidence population but with a high case fatality. PATIENTS AND METHODS: In a multicentre, retrospective, survey-based study of 202 patients with a recent diagnosis of invasive melanoma (< 1 year), we collected data on demographic and behavioural factors, attitudes towards prevention, access to medical care, frequency of skin self-examination (SSE) and physician skin examination (PSE) in relation to melanoma thickness. RESULTS: Thinner tumours (≤ 1 mm, 80 melanomas) were associated with female sex (P ≤ 0.049), nonnodular (superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanoma) histological subtypes (P < 0.001), absence of ulceration (P ≤ 0.001), and location other than lower extremity or trunk location (P ≤ 0.004). Patients married at the time of diagnosis or who performed SSE during the year prior to diagnosis were more likely to have thinner tumours than those who did not [odds ratio (OR) 3.45, 95% confidence interval (CI) 1.48-8.04 and OR 2.43, 95% CI 1.10-5.34, respectively]. Full-body skin examination by a physician was not significantly associated with thinner melanoma (OR 1.99, 95% CI 0.66-6.07). CONCLUSIONS: SSE was shown to be an important factor in the detection of thin melanoma, in contrast to partial or full-body PSE, which did not show any statistically significant effect on tumour thickness.

Comprehensive mutational analysis of CDKN2A and CDK4 in Greek patients with cutaneous melanoma.

BACKGROUND: The penetrance of CDKN2A mutations is subject to geographical and latitudinal variation and is presumably dictated by ultraviolet radiation exposure and possibly other co-inherited genetic factors. The frequency of mutations increases with the number of family members affected and the number of primary tumours, and also fluctuates with geography. To date, little is known about the prevalence of CDKN2A mutations in patients with melanoma from Greece. OBJECTIVE: To characterize the frequency of CDKN2A and CDK4 mutations in a hospital-based population of Greek patients with melanoma. METHODS: Three hundred and four consecutive single primary melanoma (SPM), nine familial melanoma (FM) and seven multiple primary melanoma cases (MPM) were assessed for sequence variants in exons 1α, 1ß and 2 of CDKN2A and exon 2 of CDK4. RESULTS: Germline CDKN2A mutations were detected in 10 of 304 SPM (3·3%), in four of seven MPM (57%) and in two of nine FM (22%) cases. The most common mutation was a Northern European allele (p16 p.R24P) detected in eight individuals. Five previously unreported CDKN2A variants were also identified: -34G>C, c.41_43delins20bp, c.301G>C (p.G101R), c.301G>A (p.G101E) and c.296_297insGACC. We also describe the first report of a CDK4 p.R24H substitution in a Greek family. CONCLUSIONS: The Greek population appears to harbour a higher prevalence of the CDKN2A mutation than other reported cohorts. This supports the notion that genetic susceptibility may play a stronger influence in a country with a relatively low incidence of melanoma. Furthermore, the identification of Northern European alleles suggests that gene migration may be responsible, in part, for the observed cases in Greece.