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1.
Ann Hematol ; 98(7): 1617-1626, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30923995

RESUMO

Langerhans cell histiocytosis (LCH) is a clonal histiocytic disorder with recurrent mutations of BRAF and MAP2K1, but data on the impact of genetic features on progression and long-term sequelae are sparse. Cases of pediatric LCH with long-term follow-up from our institution were analyzed for mutations in BRAFV600 and MAP2K1 exons 2 and 3 by immunostaining with mutation-specific VE1 antibody, as well as allele-specific PCR and sequencing, respectively. Clinical and follow-up data were obtained from our files and a questionnaire sent to all former patients. Sixteen of 37 (43%) evaluable cases showed BRAFV600E, one case a BRAFV600D and eleven (30%) a MAP2K1 mutation. Nine cases were unmutated for both genes. All cases with risk organ involvement showed either BRAFV600 or MAP2K1 mutation. Patients with BRAFV600 mutation excluding Hashimoto-Pritzker cases had a significantly higher risk for relapses (p = 0.02). Long-term sequelae were present in 19/46 (41%) patients (median follow-up 12.5 years, range 1.0 to 30.8) with a trend for higher rates in mutated cases (mutated = 9/17, 53% versus non-BRAFV600/MAP2K1 mutated = 2/7, 29%). In addition, 8/9 cases with skin involvement including all Hashimoto-Pritzker cases (n = 3) were positive for BRAFV600E. Infants below 2 years more frequently had BRAFV600 mutations (p = 0.013). Despite favorable prognosis, pediatric LCH shows a high frequency of relapses and long-term medical sequelae.


Assuntos
Histiocitose de Células de Langerhans/genética , MAP Quinase Quinase 1/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Histiocitose de Células de Langerhans/epidemiologia , Histiocitose de Células de Langerhans/patologia , Histiocitose de Células de Langerhans/terapia , Humanos , Lactente , Masculino , Estudos Retrospectivos , Fatores de Risco , Dermatopatias/epidemiologia , Dermatopatias/genética , Dermatopatias/patologia , Dermatopatias/terapia
2.
BMC Cancer ; 19(1): 170, 2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30795755

RESUMO

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare clonal disease, characterized by hyperproliferation of Langerhans cells. It may rarely involve the thyroid gland. Its association with papillary thyroid carcinoma (PTC) is extremely rare; with only few case reports available in the English literature. BRAF mutations are implicated in the development of papillary thyroid carcinoma, and have also been identified in Langerhans cell histiocytosis. CASE PRESENTATION: Here we present a rare case of a 36-year-old Indonesian female patient with dysphagia associated with neck mass which was complicated by skin sinus formation. The diagnosis of PTC was rendered on fine needle aspiration (FNA). Debulking thyroidectomy revealed co-existeence of PTC and LCH. On subsequent molecular testing, BRAF V600E and V600K mutations were detected in tissues macrodissected from both lesions, respectively. To the best of our knowledge, this case is the first case to report two different BRAF mutations in tissues of a Langerhans cell histiocytosis and a papillary thyroid carcinoma co-existing in the thyroid gland. The patient received chemotherapy of etoposide combined with prednisone. At the most recent follow-up, the patient is in a stable clinical condition. CONCLUSIONS: The coexistence of a PTC with LCH harboring BRAF mutation may suggest etiologic relation between the two conditions that involves the BRAF gene. Clinically, it may suggest an aggressive, locally advanced thyroid cancer, an impression that may reflect on the selected surgical management, chemotherapy and BRAF mutation-targeting therapy to these patients.


Assuntos
Histiocitose de Células de Langerhans/diagnóstico , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Câncer Papilífero da Tireoide/diagnóstico , Glândula Tireoide/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proliferação de Células , Procedimentos Cirúrgicos de Citorredução , Transtornos de Deglutição , Etoposídeo/uso terapêutico , Feminino , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/terapia , Humanos , Prednisona/uso terapêutico , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/terapia , Tireoidectomia
3.
J Dermatol ; 46(2): 161-165, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30536719

RESUMO

Histiocytoses, including Langerhans cell histiocytosis (LCH), juvenile or adult xanthogranuloma (AXG) and Rosai-Dorfman disease (RDD), are rare disorders characterized by the proliferation of cells derived from monocyte/macrophage lineages. A few cases of LCH coexisting with xanthogranuloma or RDD have been reported. The etiology of these diseases remains unclear. However, oncogenic BRAFV 600E mutations have been identified in LCH. Here, we report the case of a 26-year-old Japanese man with a 3-month history of a solitary occipital nodule. No abnormality was detected in his other organs, and a total resection of the nodule was performed. Histopathological examination revealed the coexistence of LCH and AXG with prominent emperipolesis characteristic of RDD. Immunohistochemistry showed that most of the large histiocytes were positive for CD68, weakly positive or negative for S100, and negative for CD207 and CD1a, supporting the diagnosis of AXG. The tumor cells with emperipolesis did not show S100-positive findings characteristic of RDD. The focally aggregated oval histiocytic cells were positive for CD1a, CD207, CD68 and S100, and were compatible with the immunophenotype of LCH cells. In addition, these cells were positive for BRAFV 600E mutation. The tumor cells in our patient exhibited a cellular morphology characteristic of multiple histiocytoses in a solitary cutaneous nodule, which may imply an etiological association among LCH, AXG and RDD. To our knowledge, this is the first report of a BRAFV 600E mutation-positive case of LCH coexisting with AXG. Because patients with BRAFV 600E mutation have higher risks of multisystemic LCH and recurrence, we should carefully follow up the patient.


Assuntos
Histiocitose de Células de Langerhans/diagnóstico , Células de Langerhans/patologia , Xantogranuloma Necrobiótico/diagnóstico , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Histiocitose de Células de Langerhans/complicações , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/patologia , Humanos , Masculino , Xantogranuloma Necrobiótico/complicações , Xantogranuloma Necrobiótico/genética , Xantogranuloma Necrobiótico/patologia
4.
Int J Cancer ; 144(1): 117-124, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30098202

RESUMO

Langerhans cell histiocytosis (LCH) is the most common histiocytosis with constitutive activation of the RAS-RAF-MEK-ERK (MAPKinase) cell signaling pathway. We analyzed 89 cases of BRAF and MAP2K1 mutations by Sanger sequencing, of which 18 cases showed that these two gene mutations are negative. Whole genome sequencing of suitable specimens in these negative cases revealed a translocation from the 3 intron of PLEKHA6 to the 13 intron of NTRK3 in one case. We identified that this translocation could cause a novel fusion mutation, PLEKHA6-NTRK3. Overexpression of the PLEKHA6-NTRK3 mutant in NIH 3T3 cells enhanced MAPKinase pathway activation, promote cell growth. Our result suggested that a new mutation need be included in LCH molecular screening panel to better define its prevalence in LCH.


Assuntos
Histiocitose de Células de Langerhans/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Receptor trkC/genética , Proteínas Recombinantes de Fusão/genética , Adolescente , Animais , Proliferação de Células/genética , Criança , Pré-Escolar , Feminino , Histiocitose de Células de Langerhans/patologia , Humanos , Lactente , Masculino , Camundongos , Mutação , Células NIH 3T3
6.
Zhongguo Dang Dai Er Ke Za Zhi ; 20(4): 290-294, 2018 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-29658453

RESUMO

OBJECTIVE: To investigate the clinical significance of BRAF-V600E mutation in children with Langerhans cell histiocytosis (LCH). METHODS: Real-time fluorescence quantitative PCR was used to detect BRAF-V600E mutation in paraffin-embedded tissue samples from 26 children with LCH. A retrospective analysis was performed for the association of BRAF-V600E mutation with clinical features and prognosis of children with LCH. RESULTS: Of the 26 children, 25 received standard chemotherapy, with a 2-year overall survival (OS) rate of 100% and a 2-year event-free survival (EFS) rate of 88%. Of the 26 pathological samples, 18 (70%) came from bone tissue, and the positive rate of BRAF-V600E mutation reached 50% (13/26). The positive rate of BRAF-V600E gene mutation was not associated with age, sex, affected organ, clinical classification, early treatment response, recurrence, and 2-year OS and EFS rates of the children with LCH (P>0.05), but it was associated with clinical grouping of LCH (P<0.05). CONCLUSIONS: Children with LCH tend to have a high OS rate and a high incidence rate of BRAF-V600E mutation. BRAF-V600E mutation is associated with clinical grouping of LCH.


Assuntos
Histiocitose de Células de Langerhans/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Criança , Pré-Escolar , Feminino , Histiocitose de Células de Langerhans/classificação , Histiocitose de Células de Langerhans/mortalidade , Humanos , Lactente , Masculino , Estudos Retrospectivos
8.
J Am Acad Dermatol ; 78(3): 579-590.e4, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29107340

RESUMO

Langerhans cell histiocytosis (LCH) is a disorder of myeloid neoplasia of dendritic cells that affects 1 in 200,000 children <15 years of age and even fewer adults. LCH presents with a spectrum of clinical manifestations. High-risk stratification is reserved for infiltration of blood, spleen, liver, and lungs. After decades of debate on the disease pathogenesis, a neoplastic mechanism is now favored on the basis of LCH cell clonality, rare cases of familial clustering, and recent evidence of mutations involving the Ras/Raf/MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinase) pathway in lesional biopsy specimens. Somatic mutations are most often found in BRAF (BRAFV600E in 47.1% of reported patients) and MAP2K1 (21.7%) and uncommonly found in MAP3K1 or ARAF. Increased levels of phospho-ERK in lesional tissue, activation of Ras/Raf/MEK/ERK signaling with these mutations in vitro, and the mutual exclusivity of these mutations in a given patient suggest a central role for activation of the Ras/Raf/MEK/ERK oncogenic pathway in LCH. Immunohistochemical assessment of lesional tissue using the VE1 BRAFV600E mutation-specific antibody can serve as a screening tool for BRAFV600E-positive LCH. Case reports suggest that BRAFV600E-positive LCH unresponsive to standard therapy might respond to B-Raf-MEK pathway inhibition, but rigorous randomized clinical trials have yet to be performed.


Assuntos
Carcinogênese/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , Histiocitose de Células de Langerhans/genética , Proteínas Proto-Oncogênicas B-raf/genética , Transdução de Sinais/genética , Histiocitose de Células de Langerhans/tratamento farmacológico , Humanos , MAP Quinase Quinase 1/genética , MAP Quinase Quinase Quinase 1/genética , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas A-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas ras/genética
9.
Virchows Arch ; 472(2): 247-258, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28711990

RESUMO

The neoplastic nature of pulmonary Langerhans cell histiocytosis (PLCH) is still debated. As the detection of BRAF V600E and MAP2K1 mutations in patients with PCLH is now considered for such assessment, the aim of our study was to evaluate digital droplet polymerase chain reaction (ddPCR) in PCLH diagnosis. We retrospectively analyzed BRAFV600E detection in a cohort of 42 PCLH tissues and 18 bronchoalveolar lavages (BALs) by ddPCR, immunohistochemistry, high-resolution melting PCR (HRM), and next-generation sequencing (NGS). The presence of BRAFV600E mutation was assessed by at least two concordant techniques to further evaluate specificity and sensitivity of each method. The BRAF V600E mutation prevalence was detected in 18 out of 41 cases by ddPCR, 10 out of 36 cases by HRM PCR, and 16 out of 31 cases by NGS. BRAFV600E immunohistochemistry sensitivity was 94%, and specificity was 79%. HRM PCR sensitivity was only 59%, and specificity was 100%. NGS sensitivity and specificity were 100% for interpretable cases (n = 31), but in 11 cases, this technique was non-contributive. The analysis of BAL samples by ddPCR revealed a BRAFV600E mutation both in tissue and in BAL samples in one patient, a wild-type status both in tissue and in BAL samples in two patients, and a wild-type BRAF status in BAL and a BRAFV600E mutation in tissue samples in four patients. The study supports the usefulness of ddPCR for BRAF status assessment in either tissue or BAL samples to increase the accuracy of PLCH diagnosis.


Assuntos
Líquido da Lavagem Broncoalveolar/química , Lavagem Broncoalveolar , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/genética , Pulmão/patologia , Reação em Cadeia da Polimerase/métodos , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Biópsia , Análise Mutacional de DNA/métodos , Feminino , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Histiocitose de Células de Langerhans/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , Sensibilidade e Especificidade
10.
Pediatr Blood Cancer ; 65(1)2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28748614

RESUMO

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm characterized by constitutive activation of extracellular signal-regulated kinase (ERK). Genomic characterization has identified activating point mutations including mutually exclusive BRAFV600E and activating MAP2K1 mutations to be responsible for ERK activation in a majority of pediatric LCH patients. Here, we report the discovery of a novel BRAF kinase fusion, PACSIN2-BRAF, in a child with multisystem LCH. This is the second reported case of an activating BRAF kinase fusion and indicates a recurrent pathologic mechanism. Genomic evaluation for activating kinase fusions should be strongly considered in pediatric LCH patients lacking more common mutations.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , MAP Quinases Reguladas por Sinal Extracelular , Histiocitose de Células de Langerhans/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas B-raf/genética , Criança , Ativação Enzimática/genética , Humanos , Masculino
12.
Adv Respir Med ; 85(6): 297-300, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29288477

RESUMO

INTRODUCTION: The alpha-1 antitrypsin deficiency (A1ATD) is one of the three most common genetic disorders in Caucasians. It considerably increases the risk of progressive obstructive lung diseases, mostly chronic obstructive pulmonary disease. There is no data regarding prevalence of main, clinically most important A1ATD alleles PI*Z and PI*S in patients with pulmonary Langerhans cell histiocytosis (PLCH). PLCH is not only strongly linked to the cigarette smoking, but is also characterised by polycystic lung lesions. The goal of the study was to assess the incidence of A1ATD alleles in patients with PLCH. MATERIAL AND METHODS: Blood samples were collected from 34 adult patients (14 women and 20 men), with histologically confirmed PLCH. AAT serum concentration was assessed by nephelometry and PI-phenotype, identified by isoelectrofocusing. The PI*S and PI*Z alleles were confirmed by genotyping usisng real-time PCR. RESULTS: Deficiency alleles PI*Z and PI*S were detected in 3 patients (one woman and 2 men), respectively in 5.88% and 2.94%. The estimated incidence of deficiency alleles was 29.4/1000 (95% CI; 10-69.5) for PI*Z and 14.7/1000(95%CI; 13.9-43.3) for PI*S. According to our previous reports, the expected prevalence of PI*Z and PI*S alleles in general Polish population was 13.7/1000 (95% CI 5.8-21.5), and 7,6/1000 (95% CI 1.7-13.5) respectively. CONCLUSIONS: The incidence of main A1AT deficiency alleles in patients with PLCH seems higher than in general Polish population. The study is on-going.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Histiocitose de Células de Langerhans/genética , Deficiência de alfa 1-Antitripsina/genética , alfa 1-Antitripsina/genética , Adulto , Feminino , Frequência do Gene , Testes Genéticos , Histiocitose de Células de Langerhans/sangue , Histiocitose de Células de Langerhans/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Polônia/epidemiologia , alfa 1-Antitripsina/sangue , Deficiência de alfa 1-Antitripsina/sangue
14.
Eur Respir Rev ; 26(145)2017 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-28877978

RESUMO

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare sporadic cystic lung disease of unknown aetiology that is characterised by the infiltration and destruction of the wall of distal bronchioles by CD1a+ Langerhans-like cells. In adults, PLCH is frequently isolated and affects young smokers of both sexes. Recent multicentre studies have led to the more standardised management of patients in clinical practice. Smoking cessation is essential and is occasionally the only suitable intervention. Serial lung function testing is important because a significant proportion of patients may experience an early decline in forced expiratory volume in 1 s and develop airflow obstruction. Cladribine was reported to dramatically improve progressive PLCH in some patients. Its efficacy and tolerance are currently being evaluated. Patients who complain of unexplained dyspnoea with decreased diffusing capacity of the lung for carbon monoxide should be screened for pulmonary hypertension by Doppler echocardiography, which must be confirmed by right heart catheterisation. Lung transplantation is a therapeutic option for patients with advanced PLCH.The identification of the BRAFV600E mutation in approximately half of Langerhans cell histiocytosis lesions, including PLCH, and other mutations of the mitogen-activated protein kinase (MAPK) pathway in a subset of lesions has led to targeted treatments (BRAF and MEK (MAPK kinase) inhibitors). These treatments need to be rigorously evaluated because of their potentially severe side-effects.


Assuntos
Cladribina/uso terapêutico , Histiocitose de Células de Langerhans/terapia , Imunossupressores/uso terapêutico , Pneumopatias/terapia , Transplante de Pulmão , Pulmão/efeitos dos fármacos , Adulto , Cladribina/efeitos adversos , Feminino , Predisposição Genética para Doença , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/fisiopatologia , Humanos , Imunossupressores/efeitos adversos , Pulmão/fisiopatologia , Pneumopatias/diagnóstico , Pneumopatias/genética , Pneumopatias/fisiopatologia , Transplante de Pulmão/efeitos adversos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Fenótipo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Testes de Função Respiratória , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto Jovem
15.
Eur Respir Rev ; 26(145)2017 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-28954765

RESUMO

Lymphangioleiomyomatosis (LAM) and pulmonary Langerhans cell histiocytosis (PLCH) are rare diseases that lead to progressive cystic destruction of the lungs. Despite their distinctive characteristics, these diseases share several features. Patients affected by LAM or PLCH have similar radiological cystic patterns, a similar age of onset, and the possibility of extrapulmonary involvement. In this review, the recent advances in the understanding of the molecular pathogenesis, as well as the current and most promising biomarkers and therapeutic approaches, are described.


Assuntos
Histiocitose de Células de Langerhans , Pulmão , Linfangioleiomiomatose , Animais , Diagnóstico Diferencial , Marcadores Genéticos , Predisposição Genética para Doença , Histiocitose de Células de Langerhans/diagnóstico por imagem , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/patologia , Humanos , Pulmão/diagnóstico por imagem , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Linfangioleiomiomatose/diagnóstico por imagem , Linfangioleiomiomatose/tratamento farmacológico , Linfangioleiomiomatose/genética , Linfangioleiomiomatose/patologia , Terapia de Alvo Molecular , Fenótipo , Valor Preditivo dos Testes , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Testes de Função Respiratória , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Tomografia Computadorizada por Raios X
17.
Arkh Patol ; 79(4): 33-39, 2017.
Artigo em Russo | MEDLINE | ID: mdl-28791997

RESUMO

The paper describes a case of eosinophilic granuloma of the parietal bone in a 32-year-old man. Histological examination revealed a large number of bean-shaped Langerhans cell histiocytes with lobed nuclei and nuclear grooves. The histiocytes alternated with the foci of obvious eosinophilic infiltration and with eosinophilic microabscesses. There were osteoclast-like multinucleated giant cells, bone resorption, and numerous bone rods covered with osteoblast chains. The histiocytes expressed CD1α, langerin, CD68, S100, and p53 (in 90.0% of the tumor cells). The Ki-67 proliferation index was 18.0%. A molecular genetic study identified BRAFV600E mutation (nucleotide substitution s.1799 T>A (p.V600E) in the heterozygous state). Clinical and morphological data and the results of molecular genetic studies led to the conclusion that there was eosinophilic granuloma of the right parietal bone (the unifocal form of Langerhans cell histiocytosis (LCH), type I, group A1, with the monoossal nature of lesion and with BRAFV600E mutation). In adults, this disease is extremely rare (2-5 cases of LCH per million people, bone loss in the fourth decade of life in 2.5% of the patients).


Assuntos
Granuloma Eosinófilo/patologia , Histiocitose de Células de Langerhans/patologia , Osso Parietal/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Granuloma Eosinófilo/diagnóstico , Granuloma Eosinófilo/diagnóstico por imagem , Granuloma Eosinófilo/genética , Histiócitos , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/diagnóstico por imagem , Histiocitose de Células de Langerhans/genética , Humanos , Imuno-Histoquímica , Masculino , Mutação , Osso Parietal/diagnóstico por imagem
18.
Thorax ; 72(10): 937-945, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28689173

RESUMO

Pulmonary Langerhans cell histiocytosis (PLCH) is a diffuse lung disease that usually affects young adult smokers. PLCH affects different lung compartments; bronchiolar, interstitial and pulmonary vascular dysfunction may coexist to varying extents, resulting in diverse phenotypes. Analyses of PLCH tissues have identified activating mutations of specific mitogen-activated protein kinases (BRAFV600E and others). The current consensus is that PLCH represents a myeloid neoplasm with inflammatory properties: the myeloid tumour cells exhibit surface CD1a expression and up to 50% of the cells harbour activating BRAF or other MAPK mutations. PLCH may be associated with multisystem disease. The detection of disease outside of the thorax is facilitated by whole body positron emission tomography. The natural history of PLCH is unpredictable. In some patients, disease may remit or stabilise following smoking cessation. Others develop progressive lung disease, often associated with evidence of airflow limitation and pulmonary vascular dysfunction. Due to the inability to accurately predict the natural history, it is important that all patients undergo longitudinal follow-up at least twice a year for the first few years following diagnosis. The treatment of PLCH is challenging and should be individualised. While there is no general consensus regarding the role of immunosuppression or chemotherapy in management, selected patients may experience improvement in lung function with therapy. Determination of BRAFV600E or other mutations may assist with the development of an individualised approach to therapy. Patients with progressive disease should be referred to specialised centres and considered for a trial of pharmacotherapy or evaluated for transplantation.


Assuntos
Histiocitose de Células de Langerhans/terapia , Pneumopatias/terapia , Progressão da Doença , Histiocitose de Células de Langerhans/etiologia , Histiocitose de Células de Langerhans/genética , Humanos , Pneumopatias/etiologia , Pneumopatias/genética , Fenótipo , Fumar/efeitos adversos
19.
Mol Cancer ; 16(1): 115, 2017 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-28679432

RESUMO

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with constitutive activation of the MAPKinase RAS-RAF-MEK-ERK cell signaling pathway. We analyzed 9 LCH cases without BRAF V600 and MAP2K1 mutations by whole exome sequencing. We identified a new somatic BRAF splicing mutation in 2 cases. Both cases were childhood single system (SS) LCH cases, with self-healing outcome of the bone lesions. This mutant consisted in a 9 base pair duplication (c.1511_1517 + 2 duplication), encoding for a predicted mutant protein with insertion of 3 amino acids (p.Arg506_Lys507insLeuLeuArg) in the N-terminal lobe of the kinase domain of BRAF. Transient expression of the c.1511_1517 + 2dup BRAF mutant in HEK293 cells enhanced MAPKinase pathway activation, and was not inhibited by vemurafenib but was inhibited by PLX8394, a second-generation BRAF inhibitor able to inhibit signaling of BRAF monomers and dimers. Future LCH molecular screening panel should include this new mutation to better define its prevalence in LCH and its restriction to autoregressive bone SS LCH.


Assuntos
Histiocitose de Células de Langerhans/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Processamento de RNA/genética , Adolescente , Sequência de Bases , Criança , Pré-Escolar , Éxons/genética , Feminino , Duplicação Gênica , Histiocitose de Células de Langerhans/tratamento farmacológico , Humanos , Lactente , Masculino , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico
20.
Cytokine ; 97: 73-79, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28582647

RESUMO

OBJECTIVE: Langerhans cell histiocytosis (LCH) is characterized by immature dendritic cell proliferation, infiltration of LCH lesions by various inflammatory cells, and a lesional cytokine storm. It is classified into three groups on the basis of disease extent, namely, multisystem with risk-organ involvement (MS+), multisystem without risk-organ involvement (MS-), and single-system (SS) disease. We comprehensively analyzed whether serum levels of cytokines/chemokines reflect the disease extent. METHODS: Serum samples from 52 children with LCH (eight, 25, and 19 with MS+, MS-, and SS, respectively) and 34 control children were analyzed quantitatively for 48 humoral factors. DNA samples extracted from biopsied LCH lesions from 12 patients were tested for BRAF V600E status. RESULTS: The LCH patients had significantly higher serum levels of IL-1Ra, IL-3, IL-6, IL-8, IL-9, IL-10, IL12, IL-13, IL-15, IL-17, IL-18, TNF-α, G-CSF, M-CSF, MIF, HGF, VEGF, CCL2, CCL3, CCL7, CXCL1, and CXCL9 than the controls by univariate analysis. Of these IL-9, IL-15 and MIF were significant by multivariate analysis; but not differed between MS and SS diseases. MS disease associated with significantly higher IL-2R, IL-3, IL-8, IL-18, M-CSF, HGF, CCL2, CXCL1, and CXCL9 levels than SS disease by univariate analysis. Of these, CCL2 and M-CSF were significant by multivariate analysis. IL-18 levels were significantly higher in MS+ disease than MS- disease. The LCH patients with BRAF V600E mutation had higher serum levels of CCL7. CONCLUSION: Numerous inflammatory cytokines and chemokines play a role in LCH. Of those, more specific ones reflect the disease extent (MS vs. SS and MS+ vs. MS-) or the BRAF V600E mutation status. It is thought that the most responsible cytokines and chemokines involved in the poor outcome may become future candidate therapeutic targets in LCH.


Assuntos
Quimiocinas/sangue , Citocinas/sangue , Histiocitose de Células de Langerhans/imunologia , Adolescente , Quimiocinas/imunologia , Criança , Pré-Escolar , Citocinas/imunologia , Feminino , Histiocitose de Células de Langerhans/sangue , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/genética , Humanos , Lactente , Proteína Antagonista do Receptor de Interleucina 1/sangue , Interleucina-10/sangue , Interleucina-15/sangue , Interleucina-17/sangue , Interleucina-18 , Interleucina-6/sangue , Masculino , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Fator de Necrose Tumoral alfa/sangue
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