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      MEK inhibition appears to improve symptom control in primary NRAS-driven CNS melanoma in children

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          Abstract

          Background:

          Primary melanoma of the CNS in children is extremely rare, and usually linked to congenital melanocytic naevus syndrome, caused by mosaicism for oncogenic NRAS mutations. Outcome is fatal in all cases. Data from murine and in vitro studies suggest that MEK inhibition is a possible therapeutic option.

          Methods:

          Four children with NRAS-mutated CNS melanoma were treated with Trametinib on a compassionate basis.

          Results:

          All four had an improvement in symptoms and objectively in signs. These varied from mild improvement for 1 month, to a sustained symptom-free period of 9 months in one case. In all cases there was eventual disease progression through treatment, followed by rapid death after discontinuation. There were no clinically-significant side effects.

          Conclusions:

          Trametinib is the first therapy to show any objective or measurable effect in NRAS-mutated primary CNS melanoma, with few side effects in this small series. The role of this therapy should be explored further in this rare paediatric tumour.

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          Most cited references16

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          Classifying melanocytic tumors based on DNA copy number changes.

          Melanoma and benign melanocytic nevi can overlap significantly in their histopathological presentation and misdiagnoses are common. To determine whether genetic criteria can be of diagnostic help we determined DNA copy number changes in 186 melanocytic tumors (132 melanomas and 54 benign nevi) using comparative genomic hybridization. We found highly significant differences between melanomas and nevi. Whereas 127 (96.2%) of the melanomas had some form of chromosomal aberration, only 7 (13.0%) of the benign nevi cases had aberrations. All seven cases with aberrations were Spitz nevi, in six of which the aberration was an isolated gain involving the entire short arm of chromosome 11. This aberration was not observed in any of the 132 melanomas. We also analyzed the 132 melanomas for genetic differences depending on anatomical site, Clark's histogenetic type, and sun-exposure pattern. We show that melanomas on acral sites have significantly more aberrations involving chromosomes 5p, 11q, 12q, and 15, as well as focused gene amplifications. Melanomas classified as lentigo maligna melanomas or as occurring on severely sun-damaged skin showed markedly more frequent losses of chromosomes 17p and 13q. This study shows a pattern of chromosomal aberration in melanoma that is distinct from melanocytic nevi and should be further evaluated as a diagnostic test for melanocytic lesions that are now ambiguous. In addition, we show marked differences in the genetic make-up of melanomas that depend on anatomical location and sun-exposure pattern indicating that potential therapeutic targets might vary among melanoma types.
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            Multiple Congenital Melanocytic Nevi and Neurocutaneous Melanosis Are Caused by Postzygotic Mutations in Codon 61 of NRAS

            Congenital melanocytic nevi (CMN) can be associated with neurological abnormalities and an increased risk of melanoma. Mutations in NRAS, BRAF, and Tp53 have been described in individual CMN samples; however, their role in the pathogenesis of multiple CMN within the same subject and development of associated features has not been clear. We hypothesized that a single postzygotic mutation in NRAS could be responsible for multiple CMN in the same individual, as well as for melanocytic and nonmelanocytic central nervous system (CNS) lesions. From 15 patients, 55 samples with multiple CMN were sequenced after site-directed mutagenesis and enzymatic digestion of the wild-type allele. Oncogenic missense mutations in codon 61 of NRAS were found in affected neurological and cutaneous tissues of 12 out of 15 patients, but were absent from unaffected tissues and blood, consistent with NRAS mutation mosaicism. In 10 patients, the mutation was consistently c.181C>A, p.Q61K, and in 2 patients c.182A>G, p.Q61R. All 11 non-melanocytic and melanocytic CNS samples from 5 patients were mutation positive, despite NRAS rarely being reported as mutated in CNS tumors. Loss of heterozygosity was associated with the onset of melanoma in two cases, implying a multistep progression to malignancy. These results suggest that single postzygotic NRAS mutations are responsible for multiple CMN and associated neurological lesions in the majority of cases.
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              New recommendations for the categorization of cutaneous features of congenital melanocytic nevi.

              The diameter of congenital melanocytic nevi (CMN) has served as the lone criterion for determining risks of adverse outcomes such as melanoma. A standardized description of additional morphologic features is needed. We sought to develop a consensus-based standardized categorization of cutaneous features of CMN and to test agreement among experts on the proposed scheme. An interdisciplinary group of experts in the field of CMN was surveyed using a detailed questionnaire. Applicability of the expert consensus-based scheme was tested for interobserver agreement. The principal variable of the consensus-based categorization is CMN size, based on maximal diameter the CMN is projected to attain by adulthood. CMN size categories include: small ( 10-20 cm); large (L1: >20-30 cm, L2: >30-40 cm); and giant (G1: >40-60 cm, G2: >60 cm). In addition, number of satellite nevi in the first year of life is categorized into none, 1 to 20, more than 20 to 50, and more than 50 satellites. Additional descriptors of CMN include anatomic localization, color heterogeneity, surface rugousity and presence of hypertrichosis (described as none, moderate, marked), and presence of dermal or subcutaneous nodules (none, scattered, extensive). Assessment of consistency among 3 experts showed moderate to excellent interobserver agreement for categorization of the clinical descriptors (kappa values 0.54-0.93). Applicability of the proposed scheme was tested in a virtual setting and only among experts. The proposed categorization scheme for CMN was agreed upon by experts and showed good interobserver agreement. Such standardized reporting of patients with CMN facilitates the development of an international clinical database for the study of large and giant CMN. Copyright © 2012 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.
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                Author and article information

                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                11 April 2017
                02 March 2017
                11 April 2017
                : 116
                : 8
                : 990-993
                Affiliations
                [1 ]Paediatric Dermatology, Great Ormond Street Hospital for Children NHS Foundation Trust , London WC1N 3JH, UK
                [2 ]Genetics and Genomic Medicine, UCL Institute of Child Health , 30 Guilford Street, London WC1N 1EH, UK
                [3 ]Paediatric Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust , London WC1N 3JH, UK
                [4 ]Paediatric Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust , London WC1N 3JH, UK
                [5 ]Developmental Biology and Cancer Programme, UCL Institute of Child Health , 30 Guilford Street, London WC1N 1EH, UK
                Author notes
                Article
                bjc201749
                10.1038/bjc.2017.49
                5396107
                28253523
                093ddfe3-a362-4fba-a66d-1c78acbc7a34
                Copyright © 2017 The Author(s)

                This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 12 October 2016
                : 11 December 2016
                : 20 January 2017
                Categories
                Clinical Study

                Oncology & Radiotherapy
                melanoma,cns,nras,trametinib,mek inhibitor,paediatric,congenital melanocytic naevus

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