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1.
Nat Med ; 25(12): 1839-1842, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768065

RESUMO

Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.


Assuntos
Quinase do Linfoma Anaplásico/genética , Histiocitose/genética , Proteínas Proto-Oncogênicas c-ret/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adolescente , Adulto , Aminopiridinas/farmacologia , Benzotiazóis/farmacologia , Criança , Pré-Escolar , Feminino , Genoma Humano , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Histiocitose/tratamento farmacológico , Histiocitose/patologia , Humanos , Lactente , Masculino , Mutação , Ácidos Picolínicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Receptores Proteína Tirosina Quinases/genética , Gêmeos Monozigóticos , Sequenciamento Completo do Exoma , Adulto Jovem
2.
BMC Med Genet ; 20(1): 147, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31464584

RESUMO

BACKGROUND: The SLC29A3 gene, encoding a nucleoside transporter protein, is found in intracellular membranes. Based on the literatures, mutations in this gene cause a wide range of clinical manifestations including H syndrome, pigmented hypertrichosis with insulin dependent diabetes, Faisalabad histiocytosis, and dysosteosclerosis. However, all these disorders with their different names and terminologies are actually the same entity termed H syndrome. CASE PRESENTATION: We report four GJB2 and GJB6 negative deaf patients from two Iranian related families who present the associated symptoms of SLC29A3-disorder. Whole Exome Sequencing (WES) using Next Generation Illumina Sequencing was used to enrich all exons of protein-coding genes as well as some other important genomic regions in one of studied patients. A novel homozygous frame-shift mutation c.307-308delTT (p.Phe103fs) in exon 3 of SLC29A3 gene was identified in a 35 years old man with profound hearing loss, camptodactyly, rheumatoid arthritis and delayed puberty without any skin changes, short stature and insulin dependent diabetes mellitus. The mutation found was also confirmed by Sanger sequencing in other studied patients and their healthy parents. In compared to proband, however the clinical manifestations of these patients were different, indicating variable expressivity of mutant SLC29A3 gene as well as possible involvement of other modifier genes. CONCLUSION: The present study uncovered a rare novel homozygous frame-shift mutation c.307-308delTT in SLC29A3 gene of four related patients with various manifestation of SLC29A3-disorder. Such studies can help to conduct genetic counseling and subsequently, prenatal diagnosis more accurately for individuals at the high risk of these types of genetic disorders.


Assuntos
Contratura/genética , Mutação da Fase de Leitura , Predisposição Genética para Doença/genética , Perda Auditiva Neurossensorial/genética , Histiocitose/genética , Homozigoto , Proteínas de Transporte de Nucleosídeos/genética , Adulto , Sequência de Bases , Conexina 30/genética , Conexinas/genética , Diabetes Mellitus Tipo 1/genética , Éxons , Feminino , Estudos de Associação Genética , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Linhagem
3.
Nature ; 567(7749): 521-524, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30867592

RESUMO

Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway1,2. For the 50% of patients with histiocytosis who have BRAFV600 mutations3-5, RAF inhibition is highly efficacious and has markedly altered the natural history of the disease6,7. However, no standard therapy exists for the remaining 50% of patients who lack BRAFV600 mutations. Although ERK dependence has been hypothesized to be a consistent feature across histiocytic neoplasms, this remains clinically unproven and many of the kinase mutations that are found in patients who lack BRAFV600 mutations have not previously been biologically characterized. Here we show ERK dependency in histiocytoses through a proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, in patients with histiocytoses. Patients were enrolled regardless of their tumour genotype. In parallel, MAPK alterations that were identified in treated patients were characterized for their ability to activate ERK. In the 18 patients that we treated, the overall response rate was 89% (90% confidence interval of 73-100). Responses were durable, with no acquired resistance to date. At one year, 100% of responses were ongoing and 94% of patients remained progression-free. Cobimetinib treatment was efficacious regardless of genotype, and responses were observed in patients with ARAF, BRAF, RAF1, NRAS, KRAS, MEK1 (also known as MAP2K1) and MEK2 (also known as MAP2K2) mutations. Consistent with the observed responses, the characterization of the mutations that we identified in these patients confirmed that the MAPK-pathway mutations were activating. Collectively, these data demonstrate that histiocytic neoplasms are characterized by a notable dependence on MAPK signalling-and that they are consequently responsive to MEK inhibition. These results extend the benefits of molecularly targeted therapy to the entire spectrum of patients with histiocytosis.


Assuntos
Azetidinas/uso terapêutico , Transtornos Histiocíticos Malignos/tratamento farmacológico , Transtornos Histiocíticos Malignos/enzimologia , Histiocitose/tratamento farmacológico , Histiocitose/enzimologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Piperidinas/uso terapêutico , Azetidinas/farmacologia , Transtornos Histiocíticos Malignos/genética , Transtornos Histiocíticos Malignos/patologia , Histiocitose/genética , Histiocitose/patologia , Humanos , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mutação , Piperidinas/farmacologia , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/genética
4.
Horm Res Paediatr ; 91(5): 346-355, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30625464

RESUMO

BACKGROUND: The term "H syndrome" was coined to denote the major clinical findings, which include hyperpigmentation, hypertrichosis, hearing loss, hepatosplenomegaly, hyperglycaemia, hypogonadism, hallux flexion contractures, and short height. OBJECTIVE: To report the clinical, endocrinological, histochemical, and genetic findings of three siblings. METHODS: Skin and liver biopsies were taken to investigate the histochemical characteristics of hyperpigmented hypertrichotic skin lesions and massive hepatomegaly. The levels of basal serum thyroid hormones, oestradiol, total testosterone, follicle-stimulating hormone, luteinising hormone, and stimulated growth hormone (GH) were measured to investigate the endocrine aspects of the syndrome. Mutation analysis was carried out in all six exons and exon-intron boundaries of SLC29A3 by direct sequencing. RESULTS: Physical examination of the patients revealed common charac-teristic findings of H syndrome. Additional clinical findings were sectorial iris atrophy in the younger sister. Laboratory evaluation revealed microcytic anaemia, markedly increased erythrocyte sedimentation rate and C-reactive protein levels, and humoral immune deficiency in the younger siblings, who presented with recurrent fever and sinopulmonary infection. Two different GH stimulation tests revealed GH deficiency in the younger sister with short stature. Liver and skin biopsies revealed polyclonal lymphohistiocytic and plasma cell infiltration. Sequencing of SLC29A3 in the three siblings revealed a novel homozygous mutation in exon 6, which caused the transition of arginine to tryptophan. CONCLUSION: This study not only extended the clinical and mutation spectrum of SLC29A3 in H syndrome, but also showed that short children should be assessed according to the guidelines for short stature in children.


Assuntos
Contratura , Perda Auditiva Neurossensorial , Histiocitose , Hiperpigmentação , Hipertricose , Mutação , Proteínas de Transporte de Nucleosídeos , Irmãos , Adolescente , Adulto , Criança , Contratura/diagnóstico , Contratura/genética , Contratura/metabolismo , Contratura/patologia , Análise Mutacional de DNA , Éxons , Família , Feminino , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/metabolismo , Perda Auditiva Neurossensorial/patologia , Histiocitose/diagnóstico , Histiocitose/genética , Histiocitose/metabolismo , Histiocitose/patologia , Humanos , Hiperpigmentação/diagnóstico , Hiperpigmentação/genética , Hiperpigmentação/metabolismo , Hiperpigmentação/patologia , Hipertricose/diagnóstico , Hipertricose/genética , Hipertricose/metabolismo , Hipertricose/patologia , Masculino , Proteínas de Transporte de Nucleosídeos/genética , Proteínas de Transporte de Nucleosídeos/metabolismo , Síndrome , Turquia
6.
Am J Dermatopathol ; 41(2): 148-154, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30085957

RESUMO

Peripheral T-cell lymphoma (PTCL), not otherwise specified (NOS) is a diagnosis of exclusion, showing extreme cytological and phenotypic heterogeneity. Skin involvement of PTCL may be primary or secondary. Diagnosis of histiocytosis may be difficult, requiring clinical-pathological correlation. We describe a laryngeal atypical histiocytic lesion (AHL) and a nasal PTCL, NOS with cutaneous involvement in the same patient presenting with peculiar histopathologic and immunophenotypic features. The laryngeal neoplasm showed morphological and immunophenotypic evidence of histiocytic differentiation and does not fit any other category of the WHO classification nor the revised classification of histiocytosis. The nasal and cutaneous lesions presented features close to natural killer/T-cell lymphoma and gamma-delta T-cell lymphoma but did not meet accurately the WHO criteria. A somatic activating Q61K mutation was found on exon 3 of the NRAS gene in both AHL and PTCL, NOS. The mutation on NRAS gene in both AHL and PTCL, NOS may suggest a common origin from a precursor cell.


Assuntos
Histiocitose/patologia , Doenças da Laringe/patologia , Linfoma de Células T Periférico/patologia , Neoplasias Nasais/patologia , Neoplasias Cutâneas/patologia , Idoso de 80 Anos ou mais , Feminino , GTP Fosfo-Hidrolases/genética , Histiocitose/genética , Humanos , Doenças da Laringe/genética , Linfoma de Células T Periférico/genética , Proteínas de Membrana/genética , Mutação , Neoplasias Nasais/genética , Neoplasias Cutâneas/genética
7.
Ann Hematol ; 97(11): 2117-2128, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30084011

RESUMO

The bone marrow is a preferential site for both reactive and neoplastic histiocytic proliferations. The differential diagnosis ranges from reactive histiocyte hyperplasia in systemic infections, vaccinations, storage diseases, post myeloablative therapy, due to increased cell turnover, and in hemophagocytic lymphohistiocytosis, through extranodal Rosai-Dorfman disease to neoplasms derived from histiocytes, including histiocytic sarcomas (HS), Langerhans cell histiocytoses (LCH), Erdheim-Chester disease (ECD), and disseminated juvenile xanthogranuloma (JXG). One of the most important recent developments in understanding the biology of histiocytic neoplasms and in contributing to diagnosis was the detection of recurrent mutations of genes of the Ras/Raf/MEK/ERK signaling pathway, in particular the BRAFV600E mutation, in LCH and ECD. Here, we summarize clinical and pathological findings of 17 histiocytic neoplasms that were presented during the bone marrow symposium and workshop of the 18th European Association for Haematopathology (EAHP) meeting held in Basel, Switzerland, in 2016. A substantial proportion of these histiocytic neoplasms was combined with clonally related lymphoid (n = 2) or myeloid diseases (n = 5, all ECD). Based on the latter observation, we suggest excluding co-existent myeloid neoplasms at initial staging of elderly ECD patients. The recurrent nature of Ras/Raf/MEK/ERK signaling pathway mutations in histiocytic neoplasms was confirmed in 6 of the 17 workshop cases, illustrating their diagnostic significance and suggesting apotential target for tailored treatments.


Assuntos
Neoplasias da Medula Óssea , Hematologia , Histiocitose , Sociedades Médicas , Substituição de Aminoácidos , Neoplasias da Medula Óssea/genética , Neoplasias da Medula Óssea/metabolismo , Neoplasias da Medula Óssea/patologia , Neoplasias da Medula Óssea/terapia , Congressos como Assunto , Europa (Continente) , Histiocitose/genética , Histiocitose/metabolismo , Histiocitose/patologia , Histiocitose/terapia , Humanos , Sistema de Sinalização das MAP Quinases/genética , Mutação de Sentido Incorreto , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo
8.
J Dermatol ; 45(8): 978-985, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29808591

RESUMO

H syndrome is a rare autosomal recessive disorder with characteristic dermatological findings consisting of hyperpigmentation and hypertrichosis patches mainly located on the inner thighs and multisystemic involvement including hepatosplenomegaly, hearing loss, heart abnormalities and hypogonadism. The aim of this study was to conduct a clinical and genetic investigation in five unrelated Tunisian patients with suspected H syndrome. Hence, genetic analysis of the SLC29A3 gene was performed for four patients with a clinical diagnosis of H syndrome. We identified a novel frame-shift mutation in the SLC29A3 gene in a female patient with a severe clinical presentation. Furthermore, we report two mutations previously described, the p.R363Q mutation in a male patient and the p.P324L mutation in two patients of different age and sex. This paper extends the mutation spectrum of H syndrome by reporting a novel frame-shift mutation, the p.S15Pfs*86 in exon 2 of SLC29A3 gene and emphasizes the relevance of genetic testing for its considerable implications in early diagnosis and clinical management.


Assuntos
Contratura/genética , Perda Auditiva Neurossensorial/genética , Histiocitose/genética , Proteínas de Transporte de Nucleosídeos/genética , Doenças Raras/genética , Adulto , Pré-Escolar , Contratura/diagnóstico , Contratura/patologia , Éxons/genética , Feminino , Mutação da Fase de Leitura , Testes Genéticos , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Histiocitose/diagnóstico , Histiocitose/patologia , Humanos , Masculino , Linhagem , Doenças Raras/diagnóstico , Doenças Raras/patologia , Pele/patologia , Tunísia , Adulto Jovem
9.
BMJ Case Rep ; 20172017 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-29070620

RESUMO

Indeterminate cell histiocytosis is a rare variant of histiocytosis. The diagnosis is currently based on presence and absence of immunohistochemical markers. The current case described an indeterminate cell histiocytosis with ETV3-NCOA2 translocation.


Assuntos
Histiocitose/genética , Histiocitose/patologia , Coativador 2 de Receptor Nuclear/genética , Terapia Ultravioleta/métodos , Idoso , Diagnóstico Diferencial , Histiocitose/radioterapia , Humanos , Masculino , Proteínas Proto-Oncogênicas c-ets/genética , Doenças Raras , Translocação Genética , Resultado do Tratamento
10.
Pediatrics ; 140(5)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29079714

RESUMO

Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) is associated with recessive mutations in SLC29A3, encoding the equilibrative nucleoside transporter hENT3 expressed in mitochondria, causing PHID and H syndromes, familial Rosai-Dorfman disease, and histiocytosis-lymphadenopathy-plus syndrome. Autoinflammation is increasingly recognized in these syndromes. We previously reported a 16-year-old girl with PHID syndrome associated with severe autoinflammation that was recalcitrant to interleukin-1 and tumor necrosis factor-α blockade. Tocilizumab is a humanized, monoclonal, anti-human interleukin-6 receptor antibody routinely used to treat arthritis in children and adults. Herein we report the first case of successful treatment of PHID syndrome using tocilizumab. Before commencing tocilizumab, there was evidence of significant systemic inflammation, and progressive sclerodermatous changes (physician global assessment [PGA] 7/10). Twelve weeks after starting tocilizumab (8 mg/kg every 2 weeks, intravenously) systemic inflammatory symptoms improved, and acute phase response markers normalized; serum amyloid A reduced from 178 to 8.4 mg/L. After a dose increase to 12 mg/kg every 2 weeks her energy levels, appetite, fevers, and night sweats further improved. Less skin tightness (PGA 5/10) was documented 12 months later. This excellent clinical and serological response was sustained over 48 months, and cutaneous sclerosis had improved further (PGA 3/10). Her height remained well below the 0.4th centile, and tocilizumab also had no impact on her diabetes or exocrine pancreatic insufficiency. Although the mechanism of autoinflammation of PHID remains uncertain, we suggest that tocilizumab should be the first choice when considering treatment of the autoinflammatory or cutaneous manifestations of this genetic disease.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Contratura/tratamento farmacológico , Contratura/genética , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/genética , Histiocitose/tratamento farmacológico , Histiocitose/genética , Mutação/genética , Proteínas de Transporte de Nucleosídeos/genética , Adolescente , Contratura/diagnóstico , Feminino , Perda Auditiva Neurossensorial/diagnóstico , Histiocitose/diagnóstico , Humanos , Síndrome , Resultado do Tratamento
11.
Nature ; 549(7672): 389-393, 2017 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-28854169

RESUMO

The pathophysiology of neurodegenerative diseases is poorly understood and there are few therapeutic options. Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss, and chronic glial activation. Whether microglial activation, which is generally viewed as a secondary process, is harmful or protective in neurodegeneration remains unclear. Late-onset neurodegenerative disease observed in patients with histiocytoses, which are clonal myeloid diseases associated with somatic mutations in the RAS-MEK-ERK pathway such as BRAF(V600E), suggests a possible role of somatic mutations in myeloid cells in neurodegeneration. Yet the expression of BRAF(V600E) in the haematopoietic stem cell lineage causes leukaemic and tumoural diseases but not neurodegenerative disease. Microglia belong to a lineage of adult tissue-resident myeloid cells that develop during organogenesis from yolk-sac erythro-myeloid progenitors (EMPs) distinct from haematopoietic stem cells. We therefore hypothesized that a somatic BRAF(V600E) mutation in the EMP lineage may cause neurodegeneration. Here we show that mosaic expression of BRAF(V600E) in mouse EMPs results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioural signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. These results identify the fetal precursors of tissue-resident macrophages as a potential cell-of-origin for histiocytoses and demonstrate that a somatic mutation in the EMP lineage in mice can drive late-onset neurodegeneration. Moreover, these data identify activation of the MAP kinase pathway in microglia as a cause of neurodegeneration and this offers opportunities for therapeutic intervention aimed at the prevention of neuronal death in neurodegenerative diseases.


Assuntos
Células Precursoras Eritroides/patologia , Sistema de Sinalização das MAP Quinases , Mutação , Células Progenitoras Mieloides/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Células Clonais/enzimologia , Células Clonais/metabolismo , Células Clonais/patologia , Modelos Animais de Doenças , Células Precursoras Eritroides/enzimologia , Células Precursoras Eritroides/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Histiocitose/enzimologia , Histiocitose/genética , Histiocitose/metabolismo , Histiocitose/patologia , Humanos , Macrófagos/enzimologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Microglia/enzimologia , Microglia/metabolismo , Microglia/patologia , Mosaicismo , Células Progenitoras Mieloides/enzimologia , Células Progenitoras Mieloides/metabolismo , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/metabolismo , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo
12.
Actas Dermosifiliogr ; 108(7): 620-629, 2017 Sep.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-28438265

RESUMO

The discovery of new autoinflammatory syndromes and novel mutations has advanced at breakneck speed in recent years. Part 2 of this review focuses on vasculitis syndromes and the group of histiocytic and macrophage activation syndromes. We also include a table showing the mutations associated with these autoinflammatory syndromes and treatment alternatives.


Assuntos
Doenças Hereditárias Autoinflamatórias , Dermatopatias Genéticas , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/imunologia , Criança , Gerenciamento Clínico , Doenças Hereditárias Autoinflamatórias/classificação , Doenças Hereditárias Autoinflamatórias/imunologia , Histiocitose/genética , Histiocitose/imunologia , Humanos , Interferon-alfa/fisiologia , Ativação de Macrófagos , Dermatopatias Genéticas/classificação , Dermatopatias Genéticas/imunologia , Vasculite/genética , Vasculite/imunologia
13.
Hum Pathol ; 65: 180-186, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28232159

RESUMO

Crystal-storing histiocytosis (CSH) is an uncommon finding in lymphoplasmacytic disorders that presents histiocytes with abnormal intralysosomal accumulations of immunoglobulin light chains as crystals of unknown etiology. A 38-year-old woman with antiphospholipid syndrome had a surgical lung biopsy because of multiple lung mass lesions. In a right middle lobe lesion, lymphoplasmacytic cells had a monocytoid appearance, destructive lymphoepithelial lesions, and positive immunoglobulin heavy chain (IGH) gene rearrangements. A right upper lobe lesion manifested proliferating rounded histiocytes with abundant, deeply eosinophilic cytoplasm and negative IGH gene rearrangements. Electron microscopy and mass spectrometry revealed a case of pulmonary CSH: abnormal proliferation of the immunoglobulin κ chain of a variable region that may be crystallized within plasma cells and histiocytes. We report a rare case of localized pulmonary CSH complicating pulmonary mucosa-associated lymphoid tissue lymphoma with multiple mass lesions. We demonstrate advances in the understanding of the pathogenesis of CSH by various analyses of these lesions.


Assuntos
Biomarcadores Tumorais/análise , Histiócitos/imunologia , Histiocitose/imunologia , Cadeias kappa de Imunoglobulina/análise , Neoplasias Pulmonares/imunologia , Linfoma de Zona Marginal Tipo Células B/imunologia , Adulto , Biomarcadores Tumorais/genética , Cromatografia Líquida , Cristalização , Feminino , Rearranjo Gênico , Genes de Cadeia Pesada de Imunoglobulina , Histiócitos/ultraestrutura , Histiocitose/genética , Histiocitose/patologia , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/ultraestrutura , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/ultraestrutura , Microscopia Eletrônica , Reação em Cadeia da Polimerase , Tomografia por Emissão de Pósitrons , Espectrometria de Massas em Tandem , Tomografia Computadorizada por Raios X
14.
JCI Insight ; 2(3): e89473, 2017 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-28194436

RESUMO

Many patients with histiocytic disorders such as Langerhans cell histiocytosis (LCH) or Erdheim-Chester disease (ECD) have treatment-refractory disease or suffer recurrences. Recent findings of gene mutations in histiocytoses have generated options for targeted therapies. We sought to determine the utility of prospective sequencing of select genes to further characterize mutations and identify targeted therapies for patients with histiocytoses. Biopsies of 72 patients with a variety of histiocytoses underwent comprehensive genomic profiling with targeted DNA and RNA sequencing. Fifteen patients (21%) carried the known BRAF V600E mutation, and 11 patients (15%) carried various mutations in MAP2K1, which we confirm induce constitutive activation of extracellular signal-regulated kinase (ERK) and were sensitive to inhibitors of mitogen-activated protein kinase kinase (MEK, the product of MAP2K1). We also identified recurring ALK rearrangements, and 4 LCH patients with an uncommon in-frame deletion in BRAF (N486_P490del or N486_T491>K), resulting in constitutive activation of ERK with resistance to V600E-specific inhibitors. We subsequently describe clinical cases where patients with aggressive multisystem LCH experience dramatic and sustained responses to monotherapy with either dabrafenib or trametinib. These findings support our conclusion that comprehensive genomic profiling should be regularly applied to these disorders at diagnosis, and can positively impact clinical care.


Assuntos
Quinase do Linfoma Anaplásico/genética , Histiocitose/tratamento farmacológico , MAP Quinase Quinase 1/genética , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Análise de Sequência de DNA/métodos , Análise de Sequência de RNA/métodos , Células 3T3 , Adulto , Animais , Resistencia a Medicamentos Antineoplásicos , Feminino , Histiocitose/genética , Histiocitose/patologia , Humanos , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Lactente , Masculino , Camundongos , Mutação , Oximas/administração & dosagem , Oximas/uso terapêutico , Estudos Prospectivos , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Pirimidinonas/administração & dosagem , Pirimidinonas/uso terapêutico , Resultado do Tratamento , Adulto Jovem
15.
Presse Med ; 46(1): 46-54, 2017 Jan.
Artigo em Francês | MEDLINE | ID: mdl-26952138

RESUMO

Histiocytoses are rare and heterogeneous disease sharing histology, characterized by accumulation of histiocytes. They may be inherited or sporadic, and related to the accumulation of endo- or exogenous material in macrophages or to macrophage activation. Recent discoveries have shown that some histiocytoses, such as Langerhans cell histiocytosis or Erdheim-Chester disease, previously considered as idiopathic or inflammatory were clonal myeloid proliferations. This review presents the general classification of histiocytoses, and describes diagnostic and molecular criteria of idiopathic histiocytoses and histiocytic neoplasms.


Assuntos
Histiócitos/patologia , Histiocitose/classificação , Histiocitose/patologia , Diagnóstico Diferencial , Histiocitose/genética , Humanos , Mutação , Terminologia como Assunto
19.
N Engl J Med ; 373(8): 726-36, 2015 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-26287849

RESUMO

BACKGROUND: BRAF V600 mutations occur in various nonmelanoma cancers. We undertook a histology-independent phase 2 "basket" study of vemurafenib in BRAF V600 mutation-positive nonmelanoma cancers. METHODS: We enrolled patients in six prespecified cancer cohorts; patients with all other tumor types were enrolled in a seventh cohort. A total of 122 patients with BRAF V600 mutation-positive cancer were treated, including 27 patients with colorectal cancer who received vemurafenib and cetuximab. The primary end point was the response rate; secondary end points included progression-free and overall survival. RESULTS: In the cohort with non-small-cell lung cancer, the response rate was 42% (95% confidence interval [CI], 20 to 67) and median progression-free survival was 7.3 months (95% CI, 3.5 to 10.8). In the cohort with Erdheim-Chester disease or Langerhans'-cell histiocytosis, the response rate was 43% (95% CI, 18 to 71); the median treatment duration was 5.9 months (range, 0.6 to 18.6), and no patients had disease progression during therapy. There were anecdotal responses among patients with pleomorphic xanthoastrocytoma, anaplastic thyroid cancer, cholangiocarcinoma, salivary-duct cancer, ovarian cancer, and clear-cell sarcoma and among patients with colorectal cancer who received vemurafenib and cetuximab. Safety was similar to that in prior studies of vemurafenib for melanoma. CONCLUSIONS: BRAF V600 appears to be a targetable oncogene in some, but not all, nonmelanoma cancers. Preliminary vemurafenib activity was observed in non-small-cell lung cancer and in Erdheim-Chester disease and Langerhans'-cell histiocytosis. The histologic context is an important determinant of response in BRAF V600-mutated cancers. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT01524978.).


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Histiocitose/tratamento farmacológico , Indóis/uso terapêutico , Mutação , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Intervalo Livre de Doença , Feminino , Histiocitose/genética , Humanos , Indóis/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Sulfonamidas/efeitos adversos , Vemurafenib
20.
J Dermatol ; 42(12): 1169-71, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26074390

RESUMO

We describe a case of H syndrome with massive skin involvement, retroperitoneal fibrosis and Raynaud's phenomenon. A 48-year-old man with parents of a consanguineous marriage, first appeared with decreased urine output, skin sclerosis on his inner thighs and short stature (142 cm, 47 kg). The patient had suffered from hearing loss since the age of 1 year, and his secondary sexual characteristics had not developed. Computed tomography showed periaortic fibrosis, bilateral ureteral stenosis, hydronephrosis and sclerosis of the germinal cords. A biopsy from the retroperitoneal mass revealed remarkable fibrosis with chronic inflammatory cells. Biopsies from the skin lesion showed thick collagen bundles through the dermis and lymphohistiocytic infiltration with numerous plasma cells. Serum inflammatory markers, such as C-reactive protein, vascular endothelial factor, transforming growth factor-ß and soluble interleukin-2 receptor, were elevated. Prednisolone was effective in treating skin lesions and in lowering serum inflammatory markers. After a long period of follow up, genomic DNA of the patient was obtained, and we identified a homozygous mutation in exon 5, c.625G>A, which caused transition of glycine to arginine, p.Gly208Arg, in the patient, but not in DNA samples from another 50 healthy individuals. This is the first case of H syndrome with Raynaud's phenomenon and retroperitoneal fibrosis, and the first Japanese case of H syndrome reported in the English published work with a novel mutation in the SLC29A3 gene.


Assuntos
Contratura/genética , Perda Auditiva Neurossensorial/genética , Histiocitose/genética , Proteínas de Transporte de Nucleosídeos/genética , Doença de Raynaud/genética , Fibrose Retroperitoneal/genética , Dermatopatias Genéticas/genética , Contratura/patologia , Perda Auditiva Neurossensorial/patologia , Histiocitose/patologia , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Dermatopatias Genéticas/patologia , Síndrome
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