Abbreviations: TI, time interval between onset of sorafenib treatment and first skin neoplasms; KA, keratoacanthoma; SCC, squamous cell carcinoma. Fig 1. Clinical and histologic aspects of classical keratoacanthoma (patient 4).

Purpose: The emergence of skin tumors in patients treated with sorafenib or with more recent BRAF inhibitors is an intriguing and potentially serious event. We carried out a clinical, pathologic, and molecular study of skin lesions occurring in patients receiving sorafenib.Experimental Design: Thirty-one skin lesions from patients receiving sorafenib were characterized clinically and pathologically. DNA extracted from the lesions was screened for mutation hot spots of HRAS, NRAS, KiRAS, TP53, EGFR, BRAF, AKT1, PI3KCA, TGFBR1, and PTEN. Biological effect of sorafenib was studied in vivo in normal skin specimen and in vitro on cultured keratinocytes.Results: We observed a continuous spectrum of lesions: from benign to more inflammatory and proliferative lesions, all seemingly initiated in the hair follicles. Eight oncogenic HRAS, TGFBR1, and TP53 mutations were found in 2 benign lesions, 3 keratoacanthomas (KA) and 3 KA-like squamous cell carcinoma (SCC). Six of them correspond to the typical UV signature. Treatment with sorafenib led to an increased keratinocyte proliferation and a tendency toward increased mitogen-activated protein kinase (MAPK) pathway activation in normal skin.Sorafenib induced BRAF-CRAF dimerization in cultured keratinocytes and activated CRAF with a dosedependent effect on MAP-kinase pathway activation and on keratinocyte proliferation.Conclusion: Sorafenib induces keratinocyte proliferation in vivo and a time-and dose-dependent activation of the MAP kinase pathway in vitro. It is associated with a spectrum of lesions ranging from benign follicular cystic lesions to KA-like SCC. Additional and potentially preexisting somatic genetic events, like UV-induced mutations, might influence the evolution of benign lesions to more proliferative and malignant tumors.

RESEARCH LETTERSA New Spectrum of Skin Toxic Effects Associated With the Multikinase Inhibitor Vandetanib S kin manifestations are among the most frequent adverse effects of targeted therapies. 1 Hyperkeratosis and hand-foot skin reaction are observed with most raf and vascular endothelial growth factor (VEGF) inhibitors, whereas folliculitis is a hallmark of epidermal growth factor receptor (EGFR) blocking agents. 1 Vandetanib (Zactima, ZD6474; AstraZeneca) is a multikinase inhibitor that targets EGFR, VEGF receptors 1, 2, and 3 and the RET (rearranged during transfection) receptor. 2 Methods. Between November 2005 and October 2009, patients with metastatic thyroid cancer received vandetanib at a dose of 300 mg/d in 3 clinical trials: a phase 2 open-label study (NCT00098345) 3 and 2 randomized phase 3 studies comparing vandetanib with a placebo (NCT00537095 and NCT00410761). Clinical examination of all patients exhibiting any skin manifestation was performed. Skin toxic effects were assessed using version 3 of the National Cancer Institute Common Terminology Criteria (http://ctep.cancer.gov/protocolDevelopment /electronic_applications/ctc.htm), and additional drug intake was recorded. All patients participating in this study provided a written informed consent for the clinical trials.This study was conducted according to the Declaration of Helsinki Good Clinical Practice guidelines and in accordance with applicable local laws and regulations.

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Venous thrombosis (VT) is a frequent complication in venous malformations (VM) in relation with blood stasis and localized intravascular coagulopathy (LIC). Our aim was to describe the clinical characteristics and the treatment of patients with facial and non facial VM with VT. We implemented an observational retrospective study of patients with VM followed between 2002 and 2017. We compared features of facial and non facial VM. Descriptive and bivariate statistics were computed and the P value was set at 0.05. Fifty patients were included between 2002 and 2017. 24 of them were women (44%). The median age of the patients at diagnosis was 16,5 [8-31] years. The median follow up was 2 [2; 4] years. In non facial VM venous thrombosis occurred in 12 cases. In facial VM, 3 patients had thrombotic complication (15%). We demonstrate no difference of VT between facial VM and other localization. No patients had clinical risk factors for VT at diagnosis. Our study showed that VT is a frequent complication of VM and its proportion is not different between facial and non facial VM. Studies are needed to confirm the role of LIC in VT in VM, particularly in facial VM.

PURPOSE Mitogen-activating protein kinase inhibitors (MAPKis) are largely used in V600E/K BRAF–mutated metastatic melanomas, but data regarding effectiveness of targeted therapy in patients with rare BRAF mutations and molecular description of these infrequent mutations are scarce. PATIENTS AND METHODS A multicenter study was conducted on patients with metastatic melanoma harboring a well-identified mutation of BRAF and enrolled from March 2013 to June 2021 in the French nationwide prospective cohort MelBase. The molecular BRAF mutation pattern, response to MAPKis when applicable, and survival data were analyzed. RESULTS Of 856 selected patients, 51 (6%) harbored a non-V600E/K BRAF mutation involving codons V600 (24 of 51, 47%; V600G 27.4%, V600R 15.6%), K601 (6 of 51, 11.7%), and L597 (4 of 51, 7.8%). An objective response to MAPKis either BRAF inhibitor (BRAFi) alone or combined with MEK inhibitor was achieved in 56% (353 of 631) of V600E/K, 58% (11 of 19) of non-E/K V600, and 22% (2 of 9) of non-V600 BRAF-mutated patients, with a median progression-free survival of 7.7, 7.8, and 2.8 months, respectively. Overall, objective response rate was higher with BRAFi + MEK inhibitor combination than with BRAFi in monotherapy for each subset. CONCLUSION Rare BRAF mutations are not anecdotal in the metastatic melanoma population. Although data interpretation must remain careful owing to the limited size of some subsets of patients, non-E/K V600 BRAF mutations seem to confer a high sensitivity to targeted therapy, whereas MAPKis seem less effective in patients with non-V600 BRAF mutations. However, this strategy may be used as an alternative option in the case of immunotherapy failure in the latter population.

This retrospective observational study aimed to determine the effectiveness, safety and patterns of the use of nivolumab in patients with advanced melanoma in real‐world clinical practice in France using data from a Temporary Authorization for Use Program (ATU). Data were collected from patients with unresectable or metastatic melanoma enrolled in a French national database (Réseau pour la Recherche et l'Investigation Clinique sur le Mélanome: Ric‐Mel) and treated with nivolumab during the ATU program (12 September 2014 to 31 August 2015). The primary objectives of the study were to evaluate the effect of patient characteristics on clinical response and overall survival (OS). Among 400 included patients (median age 66 years), the majority (83%) received nivolumab as second‐ or subsequent‐line therapy. The median durations of progression‐free survival and OS were 3.3 and 14.1 months, respectively, and 31.6% of patients achieved an objective response with a median duration of 20.1 months (range: 0‐34.7). The safety profile of nivolumab was manageable and consistent with those of previous clinical trials, with an incidence of grade 3‐5 adverse events of 13.8%. The safety and effectiveness of nivolumab in patients with advanced melanoma in real‐world clinical practice in France were in line with the data reported in the Phase 3 trials CheckMate 066 and 037 of nivolumab in this patient population.

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