[Melanoma update]. / Actualités dans le mélanome cutané.

Incidence of malignant melanoma has been increasing since the 1980s. For loco-regional stages, surgery is still the best treatment. Melanoma has a high distant metastatic potential and prognosis of advanced stages was until recently very poor. Since 2011 however, a real revolution has taken place in the treatment of metastatic melanoma. This is based upon considerably improved knowledge of the molecular mechanisms of melanoma and cancer immunology. Thus, two new classes of systemic therapeutic agents are now available: immunotherapies (immunological checkpoint inhibitors), which increase the antitumor immune response, and targeted therapies (BRAF and MEK inhibitors) for patients with BRAF V600-mutant melanoma. Overall survival is now 2 years or above, with hope for a cure in some cases. Unfortunately, the efficacy of these treatments is incomplete and many studies are underway to try to identify predictive biomarkers, and multiple combinations are being evaluated to increase response rates. The efficacy of these treatments has also been shown in the adjuvant setting in high-risk melanoma, they should be available shortly.

Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumour response and tolerance.

BACKGROUND: Vemurafenib improves survival in advanced BRAFV600(mut) melanoma patients, but tolerance is often poor and resistance frequently occurs, without predictive factor. Our aim was to investigate for the first time a relationship between plasma vemurafenib concentration (PVC) and efficacy or tolerance. METHODS: Plasma samples from unresectable metastatic BRAFV600(mut) melanoma patients treated with vemurafenib monotherapy were prospectively collected at each tumour response evaluation (RECIST 1.1) or when adverse event occurred (CTCAE 4.0). PVC was measured with liquid chromatography-tandem mass spectrometry. Herein, we report on PVC at steady state (≥14 days after vemurafenib introduction or dose modification). Samples collected after first melanoma progression were excluded from the response analysis. All samples were analysed in the tolerance analysis. We kept the closest collected sample from the onset of each adverse effect or the one with the highest PVC in the absence of this adverse effect. Comparisons of means (Student's t-tests and Wilcoxon rank sum tests) and of frequencies (χ(2) tests) were carried out. A logistic regression analysis identified predictors of progression. RESULTS: We included 105 plasma samples in 23 patients (10M/13F). Initial vemurafenib dose was 960 mg b.i.d., reduced by 25% (8 patients) or 50% (2 patients) for intolerance in 10 patients (44%). PVC displayed high inter-individual variability (13.0-109.8 µg/ml, median 54.0). Mean PVC was lower at time of first progression (38.8 ± 19.7 µg/ml) than mean PVC found when tumour was stable or in partial or complete response (56.4 ± 21.0 µg/ml, P = 0.013, 21 patients). Logistic regression revealed that having a low PVC (P = 0.01) or brain metastasis (P = 0.01) were both significantly and independently associated with tumour progression. High PVC was not statistically significantly associated with the occurrence of adverse effects. CONCLUSION: PVC at steady state is highly variable and low PVC was associated with tumour progression, suggesting a new path to melanoma resistance to vemurafenib.

[In-transit metastasis in melanoma: Efficacy of topical imiquimod combined with carbon dioxide laser or with electrocautery]. / Métastases en transit du mélanome : efficacité de l'imiquimod topique combiné au laser CO2 ou à l'électrocoagulation.

BACKGROUND: In-transit metastases in cutaneous melanoma are common and difficult to manage. Therapy is mainly palliative. Use of topical imiquimod has been assessed for surface metastases. PATIENTS AND METHODS: We report on four patients with cutaneous melanoma metastases treated with topical imiquimod associated with carbon dioxide laser in the first two patients and with electrocoagulation in the two others. For two patients, we noted complete regression of the lesions after 15 and 18 months. For the two others, treatment was stopped after 9 to 10 months because of progression of subcutaneous metastasis and distant metastasis. DISCUSSION: Topical imiquimod is an alternative treatment used in superficial in-transit metastasis of melanoma. Its use as a monotherapy is sometimes ineffective. We elected to use combined pre-treatment with carbon dioxide laser or electrocoagulation in order to potentiate the action of imiquimod. This simple and inexpensive therapeutic strategy constitutes a palliative treatment that can allow prolonged local control of cutaneous metastasis.

[Penile dermatological lesions: how to identify premalignant lesions?]. / Le point sur les lésions dermatologiques du pénis: comment repérer les lésions précancéreuses du pénis?

Penile squamous cell carcinoma is a highly evolving tumor. Thus an early diagnosis is a major matter in order to avoid tumoral spread and mutilating surgery. Intra-epithelial neoplasia is a carcinoma in situ involving a disorganized cytological structure and intraepithelial architecture without any change on the derma. It has a bimodal pathogenesis: it can be induced by papilloma virus HPV infection and thus Bowen's disease or Bowenoïd papulosis, or by a lichen sclerosus. Bowen's disease concerns mainly men after 50 years old. There are not any spontaneous remission and it transforms slowly in 20-30% of the cases into a squamous cell carcinoma. Its treatment is surgical removal of the lesion. The Bowenoïd papulosis concerns mainly young men. These lesions are rarely invasive and are likely to regress spontaneously. It can be treated conservatively. The lichen sclerosis is an inflammatory chronic disease which etiology is still unknown. It is localized on the glans and the prepuce. Its treatment is essentially circumcision. After treatment, patients must be followed-up and biopsies must be performed for any sign of degeneration.

Human papillomavirus 16-specific T cell responses in classic HPV-related vulvar intra-epithelial neoplasia. Determination of strongly immunogenic regions from E6 and E7 proteins.

Cell-mediated immunity directed against human papillomavirus 16 (HPV-16) antigens was studied in 16 patients affected with classic vulvar intra-epithelial neoplasia (VIN), also known as bowenoid papulosis (BP). Ten patients had blood lymphocyte proliferative T cell responses directed against E6/2 (14-34) and/or E6/4 (45-68) peptides, which were identified in the present study as immunodominant among HPV-16 E6 and E7 large peptides. Ex vivo enzyme-linked immunospot-interferon (IFN)-gamma assay was positive in three patients who had proliferative responses. Twelve months later, proliferative T cell responses remained detectable in only six women and the immunodominant antigens remained the E6/2 (14-34) and E6/4 (45-68) peptides. The latter large fragments of peptides contained many epitopes able to bind to at least seven human leucocyte antigen (HLA) class I molecules and were strong binders to seven HLA-DR class II molecules. In order to build a therapeutic anti-HPV-16 vaccine, E6/2 (14-34) and E6/4 (45-68) fragments thus appear to be good candidates to increase HPV-specific effector T lymphocyte responses and clear classic VIN (BP) disease lesions.

[Notoriety of the French dermatology: analysis through dermatological publications]. / Rayonnement de la dermatologie française: analyse à travers ses publications.

INTRODUCTION: The aim of this study was to evaluate the publications of French dermatologists in medical journals. METHODS: All papers published in 1998 and indexed in PubMed were searched under the names of all dermatologists listed in a French registry of hospital dermatologists and analyzed. A sample of 8 departments of dermatology in University hospitals was selected at random and the publications from these departments were compared to those from the departments of rheumatology in the same hospitals. In addition the publications of French, German and Italian dermatologists were compared for the years 1989, 1994 and 1999. RESULTS AND CONCLUSION: In 1998, 452 papers were published by French dermatologists. This was more than for rheumatologists in the selected sample (133 vs 82). The impact factor was rather low (1.8 +/- 3), in part because many papers (43 p. 100) were written in French. In addition original studies and research papers accounted for only 20 p. 100 of all papers. The numbers of papers devoted to clinical research had increased in the last 10 years and compared favorably with German and Italian dermatology. In contrast, the number of research papers had decreased in the last 10 years in strong contrast with the dramatic increase of research papers originating from Germany.