Epidemiology of Merkel cell carcinoma. A population-based study from 1985 to 2013, in northeastern of France.

Merkel Cell Carcinoma (MCC) is an aggressive skin cancer with an increasing incidence. Population-based epidemiologic data about MCC in France are rare. Our study aims to describe the epidemiology of MCC in Bas-Rhin, Northeastern of France, between 1985 and 2013. Data were collected from the Bas-Rhin Cancer Registry. We measured age-adjusted incidence rates (per 100,000 person-years) and effect of age, sex and period of diagnosis on survival. The world age-standardized incidence rate was 0.17 and it quadrupled between 1985 and 2013. Cases (n = 111) occurred mostly in women (60%) and in persons ≥70 years of age (74%). Incidence rates was close for men (0.18) and women (0.16) and was 25-time higher in people ≥70 years of age but incidence rate similarly increased between 1985 and 2013 in persons older and younger than 70 years. Net 5-year survival was 48.5%; female sex and younger age were positive predictors of survival. Given the low number of cases, incidence and survival data should be interpreted with caution. Incidence of MCC in Bas-Rhin quadrupled between 1985 and 2013. The highest incidence rate was observed in people ≥70 years. Better survival was associated with female sex and younger age. We hypothesize that MCC will still increase and be diagnosed in increasingly younger patients in next generations.

[Large bowel ganglioneuromatosis associated with neurofibromatosis type 1]. / Ganglioneuromatose du tube digestif dans le cadre d'une neurofibromatose de type 1.

Gastrointestinal tract ganglioneuromatosis is a rare condition, which is isolated or included in a syndromique disease. Multiple endocrine neoplasia type 2 is the most frequently associated syndrome. Association with type 1 neurofibromatosis has also been established, but much rarely. We report the case of large bowel ganglioneuromatosis found incidentally in a patient with type 1 neurofibromatosis.

Impact of Mogamulizumab in Real-Life Advanced Cutaneous T-Cell Lymphomas: A Multicentric Retrospective Cohort Study.

BACKGROUND: Advanced mycosis fungoides (MF) and Sézary syndrome (SS) are rare, aggressive cutaneous T-cell lymphomas that may be difficult to treat. Mogamulizumab is a recent monoclonal antibody targeting the CCR4 receptor expressed on the surface of Sézary cells. It can be prescribed in MF/SS stages III to IV in the second line after systemic therapy or in stages IB-II after two unsuccessful systemic therapies. We lack data on long-term efficiency and potential side effects in real-life conditions. Our study aims to determine efficacy considering the median PFS of advanced CTCL with mogamulizumab. Secondary objectives were to consider tolerance and estimate delay until side effects appeared. METHODS: Data on patients with advanced cutaneous T-cell lymphomas were collected since French Authorization, in six French university hospitals. Patients were followed until they stopped mogamulizumab because of relapse or toxicity. For those still treated by mogamulizumab, the end point was 1 September 2021. We excluded 3 patients as they had already been included in the MAVORIC study and data was not available. RESULTS: The median time of follow-up was 11.6 months. Of the 21 patients included, we reported four full-response patients, eight in partial response, one in stability, three in progression, and five were deceased. One patient had visceral progression, and seven had new lymphadenopathy. Progression-free survival was estimated at 22 months. Twenty patients presented adverse events, of which 10 were severe, i.e., grade III-IV. The median time between the introduction of mogamulizumab and the first adverse event was 21 days. CONCLUSIONS: Our study suggests that mogamulizumab can give patients with advanced refractory CTCL a consequent PFS, estimated at 22 months. The long-term safety of mogamulizumab was determined to be acceptable since we reported few grade III-IV AEs, comparable with other studies. No other study using real-life data has been performed to investigate the AEs of mogamulizumab.

Dynamic Evolution of Clonal Composition and Neoantigen Landscape in Recurrent Metastatic Melanoma with a Rare Combination of Driver Mutations.

In melanoma, initiating oncogenic mutations in BRAF or NRAS are detected in premalignant lesions that accumulate additional mutations and genomic instability as the tumor evolves to the metastatic state. Here we investigate evolution of clonal composition and neoantigen landscape in an atypical melanoma displaying recurrent cutaneous lesions over a 6-year period without development of extracutaneous metastases. Whole exome sequencing of four cutaneous lesions taken during the 6-year period identified a collection of single nucleotide variants and small insertions and deletions shared among all tumors, along with progressive selection of subclones displaying fewer single nucleotide variants. Later tumors also displayed lower neoantigen burden compared to early tumors, suggesting that clonal evolution was driven, at least in part, by counter selection of subclones with high neoantigen burdens. Among the selected mutations are a missense mutation in MAP2K1 (F53Y) and an inversion on chromosome 7 generating a AKAP9-BRAF fusion. The mutant proteins cooperatively activate the MAPK signaling pathway confirming they are potential driver mutations of this tumor. We therefore describe the long-term genetic evolution of cutaneous metastatic melanoma characterized by an unexpected phenotypic stability and neoantigen-driven clonal selection.

MITF-High and MITF-Low Cells and a Novel Subpopulation Expressing Genes of Both Cell States Contribute to Intra- and Intertumoral Heterogeneity of Primary Melanoma.

Purpose: Understanding tumor heterogeneity is an important challenge in current cancer research. Transcription and epigenetic profiling of cultured melanoma cells have defined at least two distinct cell phenotypes characterized by distinctive gene expression signatures associated with high or low/absent expression of microphthalmia-associated transcription factor (MITF). Nevertheless, heterogeneity of cell populations and gene expression in primary human tumors is much less well characterized.Experimental Design: We performed single-cell gene expression analyses on 472 cells isolated from needle biopsies of 5 primary human melanomas, 4 superficial spreading, and one acral melanoma. The expression of MITF-high and MITF-low signature genes was assessed and compared to investigate intra- and intertumoral heterogeneity and correlated gene expression profiles.Results: Single-cell gene expression analyses revealed varying degrees of intra- and intertumor heterogeneity conferred by the variable expression of distinct sets of genes in different tumors. Expression of MITF partially correlated with that of its known target genes, while SOX10 expression correlated best with PAX3 and ZEB2 Nevertheless, cells simultaneously expressing MITF-high and MITF-low signature genes were observed both by single-cell analyses and RNAscope.Conclusions: Single-cell analyses can be performed on limiting numbers of cells from primary human melanomas revealing their heterogeneity. Although tumors comprised variable proportions of cells with the MITF-high and MITF-low gene expression signatures characteristic of melanoma cultures, primary tumors also comprised cells expressing markers of both signatures defining a novel cell state in tumors in vivoClin Cancer Res; 23(22); 7097-107. ©2017 AACR.