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We thank Raimondi et al. for their alternative interpretation of our results on the prognostic value of 25-hydroxyvitamin D3 (25[OH]D3) serum level in melanoma patients. With the observation that standardized value of 25(OH)D3 at diagnosis was not a prognostic factor, our major finding was that a change of 25(OH)D3 serum level upon time in both directions was associated with worse disease-free and overall survivals, with U-shaped curves. We postulated that this latter result was unlikely to be a direct consequence of vitamin D biological actions but rather reflected a global instability in patients’ metabolisms, which finally impact 25(OH)D3 serum level by any

GLI2-Mediated Melanoma Invasion and Metastasis

Background The transforming growth factor-β (TGF-β) pathway, which has both tumor suppressor and pro-oncogenic activities, is often constitutively active in melanoma and is a marker of poor prognosis. Recently, we identified GLI2, a mediator of the hedgehog pathway, as a transcriptional target of TGF-β signaling. Methods We used real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blotting to determine GLI2 expression in human melanoma cell lines and subsequently classified them as GLI2high or as GLI2low according to their relative GLI2 mRNA and protein expression levels. GLI2 expression was reduced in a GLI2high cell line with lentiviral expression of short hairpin RNA targeting GLI2. We assessed the role of GLI2 in melanoma cell invasiveness in Matrigel assays. We measured secretion of matrix metalloproteinase (MMP)-2 and MMP-9 by gelatin zymography and expression of E-cadherin by western blotting and RT-PCR. The role of GLI2 in development of bone metastases was determined following intracardiac injection of melanoma cells in immunocompromised mice (n = 5-13). Human melanoma samples (n = 79) at various stages of disease progression were analyzed for GLI2 and E-cadherin expression by immunohistochemistry, in situ hybridization, or RT-PCR. All statistical tests were two-sided. Results Among melanoma cell lines, increased GLI2 expression was associated with loss of E-cadherin expression and with increased capacity to invade Matrigel and to form bone metastases in mice (mean osteolytic tumor area: GLI2high vs GLI2low, 2.81 vs 0.93 mm2, difference = 1.88 mm2, 95% confidence interval [CI] = 1.16 to 2.60, P < .001). Reduction of GLI2 expression in melanoma cells that had expressed high levels of GLI2 substantially inhibited both basal and TGF-β-induced cell migration, invasion (mean number of Matrigel invading cells: shGLI2 vs shCtrl (control), 52.6 vs 100, difference = 47.4, 95% CI = 37.0 to 57.8, P = .024; for shGLI2 + TGF-β vs shCtrl + TGF-β, 31.0 vs 161.9, difference = −130.9, 95% CI = −96.2 to −165.5, P = .002), and MMP secretion in vitro and the development of experimental bone metastases in mice. Within human melanoma lesions, GLI2 expression was heterogeneous, associated with tumor regions in which E-cadherin was lost and increased in the most aggressive tumors. Conclusion GLI2 was directly involved in driving melanoma invasion and metastasis in this preclinical stud

Effect of time to sentinel-node biopsy on the prognosis of cutaneous melanoma

Introduction: In patients with primary cutaneous melanoma, there is generally a delay between excisional biopsy of the primary tumour and sentinel-node biopsy. The objective of this study is to analyse the prognostic implications of this delay. Patients and method: This was an observational, retrospective, cohort study in four tertiary referral hospitals. A total of 1963 patients were included. The factor of interest was the interval between the date of the excisional biopsy of the primary melanoma and the date of the sentinel-node biopsy (delay time) in the prognosis. The primary outcome was melanoma-specific survival and disease-free survival. Results: A delay time of 40 days or less (hazard ratio (HR), 1.7; confidence interval (CI), 1.2-2.5) increased Breslow thickness (Breslow ⩾2 mm, HR, >3.7; CI, 1.4-10.7), ulceration (HR, 1.6; CI, 1.1-2.3), sentinel-node metastasis (HR, 2.9; CI, 1.9-4.2), and primary melanoma localised in the head or neck were independently associated with worse melanoma-specific survival (all P < 0.03). The stratified analysis showed that the effect of delay time was at the expense of the patients with a negative sentinel-node biopsy and without regression. Conclusion: Early sentinel-node biopsy is associated with worse survival in patients with cutaneous melanoma

Combined nivolumab and ipilimumab in non-resectable Merkel cell carcinoma

International audienc

Valeur pronostique des mutations BRAF dans les mélanomes de stade III après résection des métastases ganglionnaires

Les mutations BRAF V600 sont fréquentes dans le mélanome ; les thérapies anti-BRAF ont une efficacité démontrée, mais souvent transitoire, chez les patients au stade IV métastatique. Le pronostic des mélanomes de stade III est hétérogène. Notre but était de déterminer la survie globale des patients au stade III avec un glanglion métastatique mesurant >= 2mm, en fonction du statut mutationnel BRAF V600, et en fonction des critères pronostiques connus. Cette étude rétrospective a inclus 105 patients avec un mélanome cutané stade III. Les mutations BRAF 600 ont été détectées par séquençage et pyroséquençage d'échantillons d'ADN contenant au minimum 60% de cellules de mélanome. Les mutations BRAF (V600E et V600K : 83 et 14% des cas) ont été dtectées chez 40% des patients. Pour les patients avec et sans la mutation BRAF, le décès est survenu dans 83.3 et 60.3% des cas, avec une médiane de survie globale de 1.4 et 2.8 ans. L'âge des patients, l'ulcération du mélanome primitif, le nombre de ganglions envahis, le stade AJCC au moment de l'entrée dans l'étude et le statut BRAF étaients associés à la survie globale dans l'anlyse univariée. Les caractéristiques associées avec la survie globale dans l'analyse multivariée étaient le nombre de ganglions envahis (p=0.005, HR 2.2, 95% CI 1.3-3.9) et le statut BRAF (p=0.005, HR 1.9, 95% CI 1.2-3.1). Le statut mutationnel BRAF V600 pourrait être utilisé pour stadifier les mélanomes avec métastases ganglionnaires. Nos résultats pourraient aider à planifier des essais cliniques chez ces patients, chez qui la charge tumorale moins importante qu'au stade métastatique pourrait permettre une efficacité plus longue des thérapies ciblées anti-BRAFBRAF (V600) mutations are frequent in melanomas, and BRAF (V600)-targeted therapy have dramatic, but often transitory, efficacy in stage IV patients. Prognosis of patients with America Joint Comittee on Cancer (AJCC) stage III melanoma is heterogeneous. We aimed to determine the overall survival (OS) of stage III patients with a nodal deposit of >= 2 mm according to BRAF (V600) mutations and other previously reported prognostic criteria. This retrospective study included 105 consecutive patients with stage III cutaneous melanomas. Most patients underwent a prospective follow-up. BRAF (V600) mutations were detected by sequencing and pyrosequencing of DNA in samples containing > 60% melanoma cells. BRAF mutations (p. V600E and p. V600K in 83 and 14% of cases, respectively) were detected in 40% of the patients. For patients with and without BRAF mutations, death occurred in 83.3 and 60.3% with a median OS of 1.4 and 2.8 years, respectively. Patient age, primary melanoma ulceration, number of invaded lymph nodes, AJCC staging at study entry, and BRAF status were linked to OS in the univariate analysis. The only characteristics associated with OS in multivariate analysis were number of invaded lymph nodes (P=0.005, hazard ratio 2.2, 95% confidence interval 1.3-3.9) and BRAF status (P + 0.005? HAZARD RATIO 1.9% confidence interval 1.2-3.1). BRAF (V600) status could be used to stage melanoma patients with nodal deposits. Our results may also help to plan adjuvant trials in these patients, for whom the low tumor load may induce longer efficacy of BRAF-targeted therapiesST QUENTIN EN YVELINES-BU (782972101) / SudocSudocFranceF

Changement climatique et risques du rayonnement UV

International audienc