External quality assessment of BRAF molecular analysis in melanoma

The availability of BRAF inhibitors has given metastatic melanoma patients an effective new treatment choice and molecular testing to determine the presence or absence of a BRAF codon 600 mutation is pivotal in the clinical management of these patients. This molecular test must be performed accurately and appropriately to ensure that the patient receives the most suitable treatment in a timely manner. Laboratories have introduced such testing; however, some experience low sample throughput making it critical that an external quality assurance programme is available to help promote a high standard of testing, reporting and provide an educational aspect for BRAF molecular testing. Laboratories took part in three rounds of external quality assessment (EQA) during a 12-month period giving participants a measure of the accuracy of genotyping, clinical interpretation of the result and experience in testing a range of different samples. Formalin fixed paraffin embedded tissue sections from malignant melanoma patients were distributed to participants for BRAF molecular testing. The standard of testing was generally high but distribution of a mutation other than the most common, p.(Val600Glu), highlighted concerns with detection or reporting of the presence of rarer mutations. The main issues raised in the interpretation of the results were the importance of clear unambiguous interpretation of the result tailored to the patient and the understanding that the treatment is different from that given to other stratified medicine programmes. The variability in reporting and wide range of methodologies used indicate a continuing need for EQA in this field.

BRAF mutation testing algorithm for vemurafenib treatment in melanoma: recommendations from an expert panel.

The incidence of melanoma has increased rapidly over the past 30 years, and the disease is now the sixth most common cancer among men and women in the U.K. Many patients are diagnosed with or develop metastatic disease, and survival is substantially reduced in these patients. Mutations in the BRAF gene have been identified as key drivers of melanoma cells and are found in around 50% of cutaneous melanomas. Vemurafenib (Zelboraf(®) ; Roche Molecular Systems Inc., Pleasanton, CA, U.S.A.) is the first licensed inhibitor of mutated BRAF, and offers a new first-line option for patients with unresectable or metastatic melanoma who harbour BRAF mutations. Vemurafenib was developed in conjunction with a companion diagnostic, the cobas(®) 4800 BRAF V600 Mutation Test. The purpose of this paper is to make evidence-based recommendations to facilitate the implementation of BRAF mutation testing and targeted therapy in patients with metastatic melanoma in the U.K. The recommendations are the result of a meeting of an expert panel and have been reviewed by melanoma specialists and representatives of the National Cancer Research Network Clinical Study Group on behalf of the wider melanoma community. This article is intended to be a starting point for practical advice and recommendations, which will no doubt be updated as we gain further experience in personalizing therapy for patients with melanoma.

Boron uptake in normal melanocytes and melanoma cells and boron biodistribution study in mice bearing B16F10 melanoma for boron neutron capture therapy

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Brooke-Spiegler Syndrome - an underrecognized cause of multiple familial scalp tumors: report of a new germline mutation

BACKGROUND: Brooke-Spiegler syndrome (BSS) is probably an underdiagnosed genodermatosis that predisposes for the development of cylindromas, spiradenomas and trichoepitheliomas mainly of the head and neck. Wide phenotypic variability regarding the number and type of lesions can be observed within a family. Mutations of the CYLD gene are identified in the vast majority of cases and play a key role in BSS pathogenesis. MAIN OBSERVATIONS: Two first degree relatives with numerous erythematous telangiectatic nodules of the scalp present for decades, with recurring tendency regardless the multiple previous excisions. Histopathological review of the lesions revealed predominantly "spiradenocylindromas" in the proband and cylindromas in her sister. The suspicion of BSS was confirmed after detection of a new nonsense germline mutation of CYLD (c.1783C>T pGln 595*) in the proband. CONCLUSIONS: BSS diagnosis can be challenging and is based on clinical-pathological correlation, positive familial association and identification of CYLD mutations. CYLD exerts antineoplastic effects by downregulating intracellular NF-κB signalling pathways. The reported mutation affecting the ubiquitin-specific protease domain leads to a truncated and catalytically inactive enzyme. Despite the expanding list of CYLD mutations no firm genotype-phenotype correlation is known so far. Early recognition and treatment of BSS avoid disfiguring changes like "turban tumor".

Familial amyloid polyneuropathy: TTR sequencing and "in silico" analysis

Familial amyloid polyneuropathy (FAP) or paramiloidosis is an autosomal dominant neurodegenerative disease with onset on adult age that is characterized by mutated protein deposition in the form of amyloid substance. FAP is due to a point alteration in the transthyretin (TTR) gene and until now more than 100 amyloidogenic mutations have been described in TTR gene. FAP shows a wide variation in age-at-onset (AO) (19-82 years, in Portuguese cases) and the V30M mutation often runs through several generation of asymptomatic carriers, before expressing in a proband, but the protective effect disappear in a single generation, with offspring of late-onset cases having early onset. V30M mutation does not explain alone the symptoms and AO variability of the disease observed in the same family. Our aim in this study was to identify genetic factors associated with AO variability and reduced penetrance which can have important clinical implications. To accomplish this we genotyped 230 individuals, using a directautomated sequencing approach in order to identify possible genetic modifiers within the TTR locus. After genotyping, we assessed a putative association of the SNPs found with AO and an intensive in silico analysis was performed in order to understand a possible regulation of gene expression. Although we did not find any significant association between SNPs and AO, we found very interesting and unreported results in the in silico analysis since we observed some alterations in the mechanism of splicing, transcription factors binding and miRNAs binding. All of these mechanisms when altered can lead to dysregulation of gene expression, which can have an impact in AO and phenotypic variability. These putative mechanisms of regulation of gene expression within the TTR gene could be used in the future as potential therapeutical targets, and could improve genetic counselling and follow-up of mutation carriers.

What Drives Parental Concerns about their 18-Month-Olds at Familial Risk for Autism Spectrum Disorder?

Thesis (Master's)--University of Washington, 2016-08

Les répercussions du cadre familial actuel sur les enfants de l'école primaire

Depuis les deux dernières décennies, l'enfant est au coeur des changements rapides de la famille et des bouleversements de la société. Des changements sociaux et économiques ont modifié considérablement les relations enfant, éducateur, parents. Si la notion de famille a évolué rapidement, est-ce que le rôle des parents, des instituteurs, des écoles, s'est adapté de pair à ces changements? Si nos enfants sont appelés à devenir les membres de notre future société, il est temps de s'interroger si ceux-ci possèdent tout le bagage et les outils nécessaires pour devenir de vrais citoyens et des adultes à l’image d'une société que nous anticipons. À tous ceux qui consulteront ce document. J'espère que cet essai vous aidera à devenir de "VRAIS BATISSEURS" auprès des jeunes et à développer le goût d’investir auprès d'eux; sachant que les répercussions du décrochage scolaire auront un impact encore plus grand dans notre société.

Analyse exploratoire du phénomène de l’apprentissage précoce de la lecture en milieu familial dans une perspective heuristique

Les expériences des dernières années, dans le domaine de l'apprentissage précoce de la lecture, ont entraîné la remise en question de positions longtemps considérées comme définitives en rapport notamment avec l'âge optimal pour débuter la scolarisation et la pertinence de même que l'intérêt d'aborder à la maison des apprentissages normalement laissés à la compétence des professionnels de l'enseignement. Intéressée par ce phénomène de la rencontre précoce avec l'écrit, nous avons profité de notre double condition d'orthopédagogue et de mère de deux enfants, pour tenter d'entreprendre un processus d'apprentissage précoce de la lecture tout en conservant le recul nécessaire pour jeter un regard critique sur notre démarche. Le présent travail vise à faire le point sur ces années d'exploration en en dégageant les observations les plus significatives. Le premier chapitre contient un exposé théorique en trois volets destiné à faire ressortir les données disponibles de même que les interrogations qui demeurent en rapport avec l’apprentissage précoce de la lecture: on y retrouve un survol historique de l'évolution des positions face au développement du potentiel cognitif, une présentation des méthodes conventionnelles d'apprentissage de la lecture ainsi que des adaptations élaborées en fonction de l'apprentissage précoce, et un relevé des sources de controverses issues des premières explorations. Il se termine par la constatation que de nombreuses questions demeurent ouvertes tant sur le plan de l'approche à privilégier que sur celui des conséquences à court et à long termes. Le second chapitre comporte une présentation des sujets en cause, des éléments méthodologiques retenus et de la démarche d'objectivation des acquisitions. Le troisième chapitre est consacré à une présentation heuristique du processus d'apprentissage de la lecture; il comprend quelques précisions sur l'approche heuristique et une description détaillée du cheminement ayant conduit à la finalisation de l'apprentissage, incluant les réflexions, interrogations et modifications qui l'ont ponctuée. Le quatrième chapitre donne accès aux résultats obtenus au terme du processus d'apprentissage, leur présentation étant suivie d'une discussion générale où sont reprises les interrogations en rapport avec le potentiel d'apprentissage de l'enfant, la méthode ou plutôt, dans notre cas, l'approche la plus susceptible de permettre une intégration harmonieuse de l'écrit, la compétence des parents et les effets de l'apprentissage précoce de la lecture sur les plans cognitif et affectif. La conclusion propose certaines réflexions sur le sens et la contribution de notre démarche au-delà des aménagements techniques suggérés.

Portrait de la planification de l’implantation du cadre de référence des ressources intermédiaires et de type familial au sein du réseau des établissements de santé et services sociaux du Québec

Suivant l’entrée en vigueur de la Loi sur la représentation des ressources (LRR), le nouveau cadre de référence ressources intermédiaires (RI) et de type familial (RTF) élaboré par le ministère de la Santé et des Services sociaux encadre les changements de pratiques professionnelles. Sachant qu’un tel changement peut entraîner certaines résistances et même un échec, une revue des facteurs favorisant une implantation a été développée, l’objectif étant de dresser un portrait de la situation quant à la planification réalisée dans chacun des établissements. Ainsi, un questionnaire a été envoyé à tous les gestionnaires responsables de l’application du nouveau cadre de référence RI-RTF. Les résultats montrent notamment des lacunes quant à la prévision des incitatifs motivationnels, au développement des objectifs et des indicateurs nécessaires pour suivre l’implantation et favoriser la motivation. Il en ressort aussi que le cadre RI-RTF s’intègre bien à la culture et aux valeurs des établissements.

Brooke-Spiegler Syndrome - an underrecognized cause of multiple familial scalp tumors: report of a new germline mutation

BACKGROUND: Brooke-Spiegler syndrome (BSS) is probably an underdiagnosed genodermatosis that predisposes for the development of cylindromas, spiradenomas and trichoepitheliomas mainly of the head and neck. Wide phenotypic variability regarding the number and type of lesions can be observed within a family. Mutations of the CYLD gene are identified in the vast majority of cases and play a key role in BSS pathogenesis. MAIN OBSERVATIONS: Two first degree relatives with numerous erythematous telangiectatic nodules of the scalp present for decades, with recurring tendency regardless the multiple previous excisions. Histopathological review of the lesions revealed predominantly "spiradenocylindromas" in the proband and cylindromas in her sister. The suspicion of BSS was confirmed after detection of a new nonsense germline mutation of CYLD (c.1783C>T pGln 595*) in the proband. CONCLUSIONS: BSS diagnosis can be challenging and is based on clinical-pathological correlation, positive familial association and identification of CYLD mutations. CYLD exerts antineoplastic effects by downregulating intracellular NF-κB signalling pathways. The reported mutation affecting the ubiquitin-specific protease domain leads to a truncated and catalytically inactive enzyme. Despite the expanding list of CYLD mutations no firm genotype-phenotype correlation is known so far. Early recognition and treatment of BSS avoid disfiguring changes like "turban tumor".

Melanoma maligno da mucosa da cabeça e pescoço: casuística do IPO de Lisboa

Introdução: O melanoma maligno da mucosa (MMM) é uma doença rara com mau prognóstico. Material e Métodos: Estudo retrospetivo de 32 doentes do Instituto Português de Oncologia Francisco Gentil de Lisboa com MMM da cabeça e pescoço, no período de 1998 a 2012. Resultados: Dos 32 casos analisados a idade média foi de 70 anos. O tumor primário localizou-se na cavidade nasal e seios peri-nasais em 24 doentes e na cavidade oral em 8 casos. A maioria dos doentes (23) foi submetida a tratamento cirúrgico. Destes, 16 foram propostos para terapêutica complementar com Radioterapia. O tempo de seguimento variou de 26 dias a 10 anos. A sobrevida aos 5 anos foi de 18%. Conclusões: A maioria dos doentes apresentou um estadio avançado na altura do diagnóstico e, apesar dos tratamentos instituídos, verificou-se uma elevada mortalidade. O tratamento de escolha é a cirurgia. O papel da radioterapia continua a ser controverso.