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2.
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
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.
Pediatr Dermatol ; 36(3): 411-413, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30907021

RESUMO

We report a pediatric case of extensive, progressive benign cephalic histiocytosis (BCH) involving the face, trunk, and extremities with response of facial lesions to treatment with topical 1% rapamycin. A split-face model was used to demonstrate improvement on the treated side versus the untreated side. After physician and parental perception of effectiveness, based in part on photodocumentation, subsequently both cheeks were treated with continued improvement.


Assuntos
Dermatoses Faciais/diagnóstico , Dermatoses Faciais/tratamento farmacológico , Histiocitose/diagnóstico , Histiocitose/tratamento farmacológico , Imunossupressores/uso terapêutico , Sirolimo/uso terapêutico , Administração Cutânea , Pré-Escolar , Humanos , Masculino , Pomadas
6.
Int J STD AIDS ; 29(13): 1354-1358, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30114998

RESUMO

We report a case of reactive hemophagocytic syndrome (RHS) in the setting of acute human immunodeficiency virus type 1 infection (AHI). In addition, we review 11 previously reported cases of RHS precipitated by AHI and discuss strategies in the diagnosis and management of these overlapping clinical entities.


Assuntos
Infecções por HIV/diagnóstico , HIV-1/imunologia , Histiocitose/diagnóstico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Corticosteroides/uso terapêutico , Adulto , Antirretrovirais/uso terapêutico , Etoposídeo/uso terapêutico , Exantema/etiologia , Infecções por HIV/tratamento farmacológico , Histiocitose/tratamento farmacológico , Humanos , Injeções Espinhais , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Masculino , Metotrexato/uso terapêutico , Resultado do Tratamento
7.
Childs Nerv Syst ; 34(11): 2321-2324, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29872899

RESUMO

Histiocytosis is a heterogeneous group of disease entities, comprised by two main categories, namely Langerhans and non-Langerhans cell histiocytoses. Central nervous system involvement in histiocytosis is considered very rare and is often secondary to affection of anatomically related bone structures and/or multi-organ disease. We present a never-before described case of rare childhood histiocytosis with hybrid features of Langerhans cell histiocytosis and juvenile xanthogranuloma confined to the central nervous system in a 2- and a half-year-old boy with distinct treatment response to clofarabine. The case also emphasizes the diagnostic significance of stereotactic brain biopsy.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/tratamento farmacológico , Clofarabina/uso terapêutico , Histiocitose/diagnóstico , Histiocitose/tratamento farmacológico , Biópsia , Encéfalo/patologia , Doenças do Sistema Nervoso Central/patologia , Pré-Escolar , Histiocitose/patologia , Humanos , Masculino , Técnicas Estereotáxicas
8.
Cutis ; 101(4): E1-E4, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29763489

RESUMO

Intralymphatic histiocytosis is a rare disorder associated with a variety of inflammatory conditions. We report the case of an 89-year-old woman with a history of a right knee replacement and a ruptured popliteal cyst who developed an erythematous indurated plaque over the surgical scar. Histopathology revealed fibrosis, chronic inflammation, and histiocytes within the lymphatics consistent with intralymphatic histiocytosis. The plaque flattened following intralesional injection of triamcinolone acetonide 10 mg/cc×1.6 cc once monthly for 2 consecutive months and application of a pressure bandage, with no recurrence after 4 months. This treatment may be useful for recalcitrant disease.


Assuntos
Glucocorticoides/administração & dosagem , Histiocitose/terapia , Doenças Linfáticas/terapia , Triancinolona Acetonida/administração & dosagem , Idoso de 80 Anos ou mais , Bandagens Compressivas , Feminino , Histiocitose/tratamento farmacológico , Humanos , Injeções Intralesionais , Doenças Linfáticas/tratamento farmacológico
10.
Actas Dermosifiliogr ; 109(1): e1-e5, 2018.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-28256202

RESUMO

Intralymphatic histiocytosis is a benign condition characterized by poorly defined erythematous plaques (sometimes forming a reticular pattern) as well as the presence of nodules and vesicles. Its etiology and pathogenesis appear to be related to chronic inflammation in the affected area, prior surgery, or systemic disease, particularly rheumatoid arthritis. We report on 2 new cases, both associated with joint surgery in the affected area and osteoarticular disease (primary synovial osteochondromatosis and rheumatoid arthritis). This is a chronic disease and there is no specific treatment. Different treatment options were chosen in the 2 cases described. A spectacular response to treatment with oral pentoxifylline and topical tacrolimus was observed in 1 of the patients.


Assuntos
Artrite Reumatoide/complicações , Condromatose Sinovial/complicações , Histiocitose/etiologia , Doenças Linfáticas/etiologia , Idoso , Antígenos CD/análise , Condromatose Sinovial/diagnóstico por imagem , Feminino , Histiócitos/química , Histiocitose/tratamento farmacológico , Humanos , Doenças Linfáticas/tratamento farmacológico , Imagem por Ressonância Magnética , Pentoxifilina/uso terapêutico , Manguito Rotador/cirurgia , Ombro , Tacrolimo/uso terapêutico
12.
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
13.
Pediatr Rheumatol Online J ; 15(1): 76, 2017 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-29041934

RESUMO

BACKGROUND: H Syndrome is an autosomal recessive disorder characterized by cutaneous hyperpigmentation, hypertrichosis, and induration with numerous systemic manifestations. The syndrome is caused by mutations in SLC29A3, a gene located on chromosome 10q23, which encodes the human equilibrative transporter 3 (hENT3). Less than 100 patients with H syndrome have been described in the literature, with the majority being of Arab descent, and only a few from North America. CASE PRESENTATION: Here we report five pediatric patients from three medical centers in the United States who were identified to have H syndrome by whole exome sequencing. These five patients, all of whom presented to pediatric rheumatologists prior to diagnosis, include two of Northern European descent, bringing the total number of Caucasian patients described to three. The patients share many of the characteristics previously reported with H syndrome, including hyperpigmentation, hypertrichosis, short stature, insulin-dependent diabetes, arthritis and systemic inflammation, as well as some novel features, including selective IgG subclass deficiency and autoimmune hepatitis. They share genetic mutations previously described in patients of the same ethnic background, as well as a novel mutation. In two patients, treatment with prednisone improved inflammation, however both patients flared once prednisone was tapered. In one of these patients, treatment with tocilizumab alone resulted in marked improvement in systemic inflammation and growth. The other had partial response to prednisone, azathioprine, and TNF inhibition; thus, his anti-TNF biologic was recently switched to tocilizumab due to persistent polyarthritis. Another patient improved on Methotrexate, with further improvement after the addition of tocilizumab. CONCLUSION: H syndrome is a rare autoinflammatory syndrome with pleiotropic manifestations that affect multiple organ systems and is often mistaken for other conditions. Rheumatologists should be aware of this syndrome and its association with arthritis. It should be considered in patients with short stature and systemic inflammation, particularly with cutaneous findings. Some patients respond to treatment with biologics alone or in combination with other immune suppressants; in particular, treatment of systemic inflammation with IL-6 blockade appears to be promising. Overall, better identification and understanding of the pathophysiology may help devise earlier diagnosis and better treatment strategies.


Assuntos
Contratura/tratamento farmacológico , Perda Auditiva Neurossensorial/tratamento farmacológico , Histiocitose/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Azatioprina/uso terapêutico , Criança , Pré-Escolar , Contratura/diagnóstico , Diagnóstico Diferencial , Feminino , Glucocorticoides/uso terapêutico , Perda Auditiva Neurossensorial/diagnóstico , Histiocitose/diagnóstico , Humanos , Lactente , Masculino , Metotrexato/uso terapêutico , Proteínas de Transporte de Nucleosídeos/genética , Prednisona/uso terapêutico , Resultado do Tratamento , Estados Unidos
15.
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
17.
BMJ Case Rep ; 20172017 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-28073874

RESUMO

Chronic histiocytic intervillositis (CHI) is a rare placental lesion associated with adverse obstetric outcomes and high recurrence rate. We report a case of six consecutive pregnancies in one woman, where CHI was detected following an intrauterine death in the fifth pregnancy, after being missed in four earlier losses. The successful sixth pregnancy was treated with a combination of immunosuppressive and antithrombotic agents. While low-molecular-weight heparin (LMWH) and aspirin had been shown to improve pregnancy outcome in recurrent pregnancy loss, there was limited evidence of improved outcome in CHI. It has been suggested that CHI may result from a maternal immunological process and there have been a few reports of the use of corticosteroids because of this possibility, though without convincing evidence of efficacy. We too tried a corticosteroid, in combination with LMWH and aspirin. Comparative histopathological analysis of the placentae supported post-treatment effectiveness of our intervention strategy.


Assuntos
Corioamnionite/tratamento farmacológico , Vilosidades Coriônicas , Histiocitose/tratamento farmacológico , Aborto Habitual/prevenção & controle , Adulto , Doença Crônica , Feminino , Humanos , Gravidez , Resultado da Gravidez , Cuidado Pré-Natal , Recidiva
18.
Mol Med Rep ; 14(1): 209-17, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27175854

RESUMO

Multicentric reticulohistiocytosis (MRH) is a rare and debilitating systemic disorder characterized by cutaneous nodules and destructive polyarthritis. Due to its unknown etiology, the treatment of MRH varies with different rates of success, which causes treatment options to be rather independent and empirical. In the present study, a case of a 48­year­old woman with a 12­month history of polyarthralgia and skin nodules was reported. Biopsy samples, which were obtained from her skin eruption exhibited dermal infiltration with histiocytes and multinucleated giant cells. Immunohistochemical staining indicated positivity for CD68. The patient was diagnosed with MRH and treated with a combination therapy of infliximab, prednisolone and methotrexate. Her symptoms improved markedly within 2 weeks. Following the results of this case study, a systematic review of 17 cases of MRH treated with tumor necrosis factor (TNF) antagonists was performed, and the efficacy of anti­TNF treatment in MRH was analyzed.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Histiocitose/tratamento farmacológico , Histiocitose/metabolismo , Artrite/diagnóstico , Artrite/tratamento farmacológico , Artrite/etiologia , Artrite/metabolismo , Biomarcadores , Feminino , Histiocitose/diagnóstico , Histiocitose/etiologia , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Dermatopatias/diagnóstico , Dermatopatias/tratamento farmacológico , Dermatopatias/etiologia , Dermatopatias/metabolismo , Resultado do Tratamento
19.
Clin Rheumatol ; 35(2): 527-34, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24733253

RESUMO

Multicentric reticulohistiocytosis (MRH) is a rare systemic and devastating disease with main involvement of skin and joints, frequently related with malignancies. Macrophages and TNFα are the main targets of multiple treatment options with variable results. Although MRH has the tendency of self-resolve in an average of 8 years, treatment must be started early to avoid sequelae, mainly in joints with severe deformities and daily life activity impairment. We describe a 50-year-old man with skin and joint involvement, with a non-previously described muscle affectation, that failed to different drugs and achieved skin improvement with infliximab. We review for the first time in medical literature the available therapeutic options of MRH and its outcomes and propose possible future targets.


Assuntos
Antirreumáticos/uso terapêutico , Histiocitose/tratamento farmacológico , Infliximab/uso terapêutico , Mãos/patologia , Histiocitose/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Falha de Tratamento
20.
Cancer Discov ; 5(11): 1117, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26385779

RESUMO

In a phase II basket trial, vemurafenib, an enzyme inhibitor prescribed for certain BRAF V600-mutant melanomas, proved effective in some nonmelanoma cancers that also carried a BRAF V600 mutation.


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 , Feminino , Humanos , Masculino
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