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1.
Nat Med ; 27(1): 165-173, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33442015

RESUMO

Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1fl/fl;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.


Assuntos
Anilidas/uso terapêutico , Neurofibroma Plexiforme/tratamento farmacológico , Neurofibromatose 1/tratamento farmacológico , Piridinas/uso terapêutico , Adolescente , Adulto , Anilidas/efeitos adversos , Anilidas/farmacocinética , Animais , Modelos Animais de Doenças , Feminino , Genes da Neurofibromatose 1 , Humanos , Masculino , Camundongos , Camundongos Mutantes , Neurofibroma Plexiforme/genética , Neurofibroma Plexiforme/patologia , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Medição da Dor , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/efeitos adversos , Piridinas/farmacocinética , Qualidade de Vida , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Pesquisa Médica Translacional , Adulto Jovem
2.
Anticancer Res ; 40(11): 6221-6228, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109559

RESUMO

BACKGROUND/AIM: Malignant peripheral nerve sheath tumor (MPNST) is a rare soft-tissue tumor, and its diagnosis is usually made histopathologically. The effectiveness of chemotherapy and radiotherapy has not been established. We elucidated prognostic factors, diagnostic markers, and therapeutic targets. MATERIALS AND METHODS: Cases of MPNST were studied using next-generation sequencing. A total of 24 tumor samples, 11 from von Recklinghausen's disease-associated MPNST (vRH-MPNST), 11 from sporadic non-vRH MPNST, and two neurofibroma (NF) cases were retrieved, on which next-generation sequencing and survival analysis were performed. RESULTS: We identified NF1 gene mutations, including three mutations in two NFs, and 10 mutations in eight MPNSTs (five vRH-MPNSTs and three sporadic MPNSTs). Meningioma 1 (MN1) gene alteration was detected in six cases of vRH-MPNST. It is considered that MN1 gene alteration is related to the tumorigenesis of vRH-MPNST. CONCLUSION: MN1 gene mutation was detected in more than half of our cases, it may have potential for use as a therapeutic target in vRH-MPNST.


Assuntos
Mutação/genética , Neoplasias da Bainha Neural/genética , Neoplasias da Bainha Neural/patologia , Transativadores/genética , Proteínas Supressoras de Tumor/genética , Apoptose/genética , Genes da Neurofibromatose 1 , Humanos , Neurofibroma/genética , Neurofibromatose 1/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Análise de Sobrevida
3.
Clin Dermatol ; 38(4): 421-431, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32972601

RESUMO

Café au lait spots are common birthmarks seen sporadically and in association with several genetic syndromes. Dermatologists are often asked to evaluate these birthmarks both by other physicians and by parents. In some cases, it is challenging to know when and how to pursue further evaluation. Diagnostic challenges may come in the form of the appearance of the individual lesions, areas and patterns of cutaneous involvement, and associated features (or lack thereof). In this review, we aim to clarify when and how to evaluate the child with multiple or patterned café au lait spots and to explain some emerging concepts in our understanding of the genetics of these lesions.


Assuntos
Manchas Café com Leite/congênito , Manchas Café com Leite/diagnóstico , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/genética , Pele/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Manchas Café com Leite/genética , Manchas Café com Leite/patologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Deleção de Genes , Estudos de Associação Genética , Mutação em Linhagem Germinativa , Humanos , Lactente , Recém-Nascido , Masculino , Neurofibromatose 1/patologia , Neurofibromina 1/genética , Dermatopatias Genéticas/patologia , Síndrome
4.
Clin Dermatol ; 38(4): 455-461, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32972603

RESUMO

RASopathies are a group of disorders characterized by mutations in the RAS-MAPK pathway. RAS-MAP signaling plays a critical role in cell differentiation, proliferation, and survival. Germline mutations can result in distinctive syndromes, including Noonan syndrome, Costello syndrome, and neurofibromatosis type 1. Mosaic RASopathies can present as localized cutaneous lesions like epidermal nevi and nevus sebaceous, or more extensive conditions such as encephalocraniocutaneous lipomatosis. We review the heterogenous presentation of RAS mutations, discuss new targeted therapies, and highlight areas of uncertainty, including carcinogenesis risk and appropriate screening.


Assuntos
Síndrome de Costello/genética , Oftalmopatias/genética , Mutação em Linhagem Germinativa , Lipomatose/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Síndromes Neurocutâneas/genética , Neurofibromatose 1/genética , Síndrome de Noonan/genética , Síndrome de Costello/diagnóstico , Síndrome de Costello/terapia , Oftalmopatias/diagnóstico por imagem , Oftalmopatias/terapia , Humanos , Lipomatose/diagnóstico por imagem , Lipomatose/terapia , Terapia de Alvo Molecular , Mutação , Síndromes Neurocutâneas/diagnóstico por imagem , Síndromes Neurocutâneas/terapia , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/terapia , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/terapia , Risco
5.
Clin Dermatol ; 38(4): 462-466, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32972604

RESUMO

The human genome project yielded a compendium of genetic material that has allowed rapid advancement both in the technique of whole exome sequencing and also in the ability to identify single gene defects. The next generation of genetics has investigated how these genes interact in the development of disease, identifying pathways of illness and end organ tissue abnormal development. From the knowledge of single genes and pathways of genodermatosis development arises the opportunity to produce genetic therapies. This contribution reviews some of the exciting, emerging genetic therapies in genodermatoses.


Assuntos
Dermatopatias Genéticas/terapia , Administração Tópica , Anticolesterolemiantes/administração & dosagem , Displasia Ectodérmica Anidrótica Tipo 1/diagnóstico , Displasia Ectodérmica Anidrótica Tipo 1/genética , Displasia Ectodérmica Anidrótica Tipo 1/terapia , Epidermólise Bolhosa/diagnóstico , Epidermólise Bolhosa/genética , Epidermólise Bolhosa/terapia , Edição de Genes , Humanos , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Neurofibromatose 1/terapia , Transdução de Sinais/genética , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/genética , Ustekinumab/uso terapêutico , Sequenciamento Completo do Exoma
6.
PLoS One ; 15(8): e0237097, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32810864

RESUMO

Neurofibromatosis type 1 (NF1) is a genetic disorder that affects a range of tissue systems, however the associated muscle weakness and fatigability can have a profound impact on quality of life. Prior studies using the limb-specific Nf1 knockout mouse (Nf1Prx1-/-) revealed an accumulation of intramyocellular lipid (IMCL) that could be rescued by a diet supplemented with L-carnitine and enriched for medium-chain fatty acids (MCFAs). In this study we used the Nf1Prx1-/- mouse to model a range of dietary interventions designed to reduce IMCL accumulation, and analyze using other modalities including in situ muscle physiology and lipid mass spectrometry. Histological IMCL accumulation was significantly reduced by a range of treatments including L-carnitine and high MCFAs alone. A low-fat diet did not affect IMCL, but did provide improvements to muscle strength. Supplementation yielded rapid improvements in IMCL within 4 weeks, but were lost once treatment was discontinued. In situ muscle measurements were highly variable in Nf1Prx1-/- mice, attributable to the severe phenotype present in this model, with fusion of the hips and an overall small hind limb muscle size. Lipidome analysis enabled segregation of the normal and modified chow diets, and fatty acid data suggested increased muscle lipolysis with the intervention. Acylcarnitines were also affected, suggestive of a mitochondrial fatty acid oxidation disorder. These data support the theory that NF1 is a lipid storage disease that can be treated by dietary intervention, and encourages future human trials.


Assuntos
Metabolismo dos Lipídeos , Força Muscular , Músculo Esquelético/metabolismo , Neurofibromatose 1/dietoterapia , Animais , Carnitina/administração & dosagem , Carnitina/uso terapêutico , Suplementos Nutricionais , Ácidos Graxos/administração & dosagem , Ácidos Graxos/uso terapêutico , Feminino , Camundongos , Músculo Esquelético/fisiopatologia , Neurofibromatose 1/genética , Neurofibromina 1/genética
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(9): 976-979, 2020 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-32820511

RESUMO

OBJECTIVE: To provide appropriate treatment strategy and precise genetic counseling through studying the phenotype and genotype of a patient featuring learning difficulty and abnormal gait. METHODS: Detailed history taking, physical examination and auxiliary examination (including neuropsychological evaluation, brain imaging and skeletal system X ray) were conducted. The patient was also analyzed by whole exome sequencing, G banding karyotyping and array-based comparative genomic hybridization (aCGH). Multiples ligation-dependent probe amplification (MLPA) was applied to his parents to determine the origin of genomic variation. RESULTS: In addition to obvious dermatological manifestation (Cafe-au-Lait spots), the patient also had facial abnormalities, ocular disorders, skeletal malformations, neurological manifestations, psychiatric and behavioral abnormalities. Whole exome sequencing and G banding karyotyping were both negative. aCGH has identified a microdeletion at 17q11.2, which encompassed the NF1 and neighboring genes. Neither parents has carried the same microdeletion by MLPA analysis. CONCLUSION: The patient had a de novo 17q11.2 microdeletion, which probably accounted for his neurofibromatosis type 1-microdeletion syndrome phenotype.


Assuntos
Deleção Cromossômica , Neurofibromatose 1 , Bandeamento Cromossômico , Cromossomos Humanos Par 17 , Hibridização Genômica Comparativa , Humanos , Cariotipagem , Neurofibromatose 1/genética , Sequenciamento Completo do Exoma
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(8): 851-854, 2020 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-32761593

RESUMO

OBJECTIVE: To explore the genetic basis for a child with global developmental delay and neurofibromatosis type 1 (NF1). METHODS: The patient underwent clinical examination. Whole exome sequencing (WES) was carried out to detect pathogenic genetic variants. RESULTS: The child had cafe au lait spots all over her body, pigmentation in the back, and global developmental delay as assessed by Gese II. Cranial MRI revealed globular abnormal density in the lower hemisphere of left posterior cranial fossa. WES detected a novel variant of the NF1 gene, c.6513-6515del (p.Tyr2171), which was strongly correlated with her clinical phenotype. The same variant was not found in either parent and was unreported previously. CONCLUSION: The c.3842T>G variant of the NF1 gene probably underlay the NF1 and global developmental delay in this child, for whom prompt symptomatic treatment and regular follow-up were recommended.


Assuntos
Deficiências do Desenvolvimento , Genes da Neurofibromatose 1 , Testes Genéticos , Neurofibromatose 1 , Manchas Café com Leite/diagnóstico , Manchas Café com Leite/genética , Criança , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Fenótipo
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(8): 871-874, 2020 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-32761598

RESUMO

OBJECTIVE: To explore the genetic basis for a sporadic case with neurofibromatosis type 1 (NF1). METHODS: Peripheral blood samples were collected from the patient, his unaffected parents and 100 healthy controls. The NF1 gene was detected by PCR and direct sequencing. RESULTS: The patient was found to carry a novel nonsense variant c.4339C>T (p.Q1447X) in exon 33 of the NF1 gene. The same variant was not found in his unaffected parents and the 100 healthy controls. CONCLUSION: The c.4339C>T (p.Q1447X) variant probably underlies the pathogenesis of NF1 in this patient.


Assuntos
Genes da Neurofibromatose 1 , Neurofibromatose 1 , Neurofibromina 1/genética , Códon sem Sentido , Éxons/genética , Humanos , Masculino , Neurofibromatose 1/genética , Reação em Cadeia da Polimerase
10.
PLoS Genet ; 16(7): e1008920, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32697780

RESUMO

Neurofibromatosis type 1 is a monogenetic disorder that predisposes individuals to tumor formation and cognitive and behavioral symptoms. The neuronal circuitry and developmental events underlying these neurological symptoms are unknown. To better understand how mutations of the underlying gene (NF1) drive behavioral alterations, we have examined grooming in the Drosophila neurofibromatosis 1 model. Mutations of the fly NF1 ortholog drive excessive grooming, and increased grooming was observed in adults when Nf1 was knocked down during development. Furthermore, intact Nf1 Ras GAP-related domain signaling was required to maintain normal grooming. The requirement for Nf1 was distributed across neuronal circuits, which were additive when targeted in parallel, rather than mapping to discrete microcircuits. Overall, these data suggest that broadly-distributed alterations in neuronal function during development, requiring intact Ras signaling, drive key Nf1-mediated behavioral alterations. Thus, global developmental alterations in brain circuits/systems function may contribute to behavioral phenotypes in neurofibromatosis type 1.


Assuntos
Proteínas de Drosophila/genética , Desenvolvimento Embrionário/genética , Proteínas do Tecido Nervoso/genética , Neurofibromatose 1/genética , Neurônios/metabolismo , Proteínas Ativadoras de ras GTPase/genética , Animais , Cognição/fisiologia , Modelos Animais de Doenças , Drosophila melanogaster/genética , Embrião não Mamífero , Técnicas de Silenciamento de Genes , Asseio Animal/fisiologia , Humanos , Mutação/genética , Neurofibromatose 1/patologia , Neurônios/patologia
11.
Ann Afr Med ; 19(2): 150-152, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32499474

RESUMO

Neurofibromatosis type 1 is the most common inherited nervous system disorder affecting 1 in 3500 live births. Cutaneous neurofibromas, the most characteristic feature of the disease, begin to appear in adolescence and continue throughout adulthood. Although neurofibromas have been noted to increase in size or number during pregnancy, there have been very few reports of eruption of a large number of lesions during this period. We report a case of a 24-year-old Nigerian woman of 32-week gestation who presented with a history of sudden eruption of neurofibromas during the current pregnancy and the previous one 3 years earlier. We discuss how hormones and growth factors contribute to the increase in numbers of neurofibromas during pregnancy, which is occasionally severe, as in our case, and the complications which may arise in the mother and fetus.


Assuntos
Neurofibroma/patologia , Neurofibromatose 1/patologia , Complicações Neoplásicas na Gravidez/patologia , Neoplasias Cutâneas/patologia , Feminino , Humanos , Neurofibroma/genética , Neurofibromatose 1/genética , Gravidez , Pele/patologia , Neoplasias Cutâneas/genética , Adulto Jovem
12.
Anticancer Res ; 40(6): 3423-3427, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487640

RESUMO

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary disease with complete penetrance and a very variable phenotype. Recent research has shown that postzygotic NF1 gene mutations occur to a far greater extent than previously thought. The phenotype of affected individuals reflects the time of somatic mutation and the phenotype is correspondingly diverse. This report describes histological and genetic findings in a case of mosaic NF1, the clinical control of which documents almost stationary skin findings over a period of 9 years. CASE REPORT: The 55-year-old female first presented for advice on a strip of nodular skin tumours of the calf skin. She had no hallmarks of NF1. It was only 9 years later that she had the skin tumours removed, all of which were partially diffuse and partially plexiform neurofibroma. The genetic examination showed an atypical large deletion of the NF1 gene in the skin tumours, but not in overlying skin or blood. CONCLUSION: Segmental NF1 is a distinct type of mosaic/somatic NF1 mutation. The phenotype of diffuse and plexiform skin neurofibromas can resemble cutaneous neurofibroma. Surgical therapy for segmental neurofibromatosis does not differ from the concepts for treating nerve sheath tumours in NF1 patients with a germline NF1 mutation.


Assuntos
Mosaicismo , Neurofibroma Plexiforme/diagnóstico , Neurofibroma Plexiforme/genética , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Biópsia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Humanos , Perna (Membro)/patologia , Pessoa de Meia-Idade
13.
APMIS ; 128(9): 515-522, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32580246

RESUMO

Peripheral nerve sheath tumors may occur sporadically or related to neurofibromatosis (NF). Unless the mechanisms of tumorigenesis in NF related malignant peripheral nerve sheath tumors (MPNST) are better understood, it remained unclear in sporadic cases. We aimed to investigate the genetic route for malignancy in both individuals with NF-1 and sporadic ones to open a way for targeted therapies in the future. We investigated the role of HER2 with Dual ISH DNA Probe Cocktail test, BRAF mutation (exon 15) and TERT promoter mutation frequency with Sanger sequencing method in respectively 25 sporadic neurofibromas, 25 NF-1 related neurofibromas and 25 MPNST cases from two institutes. Categorical data were analyzed and summarized as frequency and percentage. Statistical analysis was done with SPSS v.22 statistical package, and the statistical significance level was considered as 0.05. We identified TERT promoter mutation only in one sporadic MPNST (4%) and no BRAF mutation in any case. HER2 amplification is found in 10/25 (40%) MPNST cases. No mutations or gene amplification detected in neurofibromas (p < 0.001). MPNSTs are sarcomas with poor prognosis and limited treatment options. TERT promoter mutations and HER2 amplification may play a putative role in therapeutic purposes.


Assuntos
Neurofibromatose 1/genética , Neurofibrossarcoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Receptor ErbB-2/genética , Telomerase/genética , Adolescente , Adulto , Idoso , Criança , Feminino , Amplificação de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neurofibroma/genética , Regiões Promotoras Genéticas , Adulto Jovem
14.
Sci Data ; 7(1): 184, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32561749

RESUMO

Nerve sheath tumors occur as a heterogeneous group of neoplasms in patients with neurofibromatosis type 1 (NF1). The malignant form represents the most common cause of death in people with NF1, and even when benign, these tumors can result in significant disfigurement, neurologic dysfunction, and a range of profound symptoms. Lack of human tissue across the peripheral nerve tumors common in NF1 has been a major limitation in the development of new therapies. To address this unmet need, we have created an annotated collection of patient tumor samples, patient-derived cell lines, and patient-derived xenografts, and carried out high-throughput genomic and transcriptomic characterization to serve as a resource for further biologic and preclinical therapeutic studies. In this work, we release genomic and transcriptomic datasets comprised of 55 tumor samples derived from 23 individuals, complete with clinical annotation. All data are publicly available through the NF Data Portal and at http://synapse.org/jhubiobank.


Assuntos
Neoplasias da Bainha Neural/genética , Neoplasias da Bainha Neural/patologia , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Linhagem Celular Tumoral , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Transcriptoma
16.
Nat Commun ; 11(1): 2177, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358581

RESUMO

Brain tumors (gliomas) are heterogeneous cellular ecosystems, where non-neoplastic monocytic cells have emerged as key regulators of tumor maintenance and progression. However, relative to macrophages/microglia, comparatively less is known about the roles of neurons and T cells in glioma pathobiology. Herein, we leverage genetically engineered mouse models and human biospecimens to define the axis in which neurons, T cells, and microglia interact to govern Neurofibromatosis-1 (NF1) low-grade glioma (LGG) growth. NF1-mutant human and mouse brain neurons elaborate midkine to activate naïve CD8+ T cells to produce Ccl4, which induces microglia to produce a key LGG growth factor (Ccl5) critical for LGG stem cell survival. Importantly, increased CCL5 expression is associated with reduced survival in patients with LGG. The elucidation of the critical intercellular dependencies that constitute the LGG neuroimmune axis provides insights into the role of neurons and immune cells in controlling glioma growth, relevant to future therapeutic targeting.


Assuntos
Astrocitoma/imunologia , Neoplasias Encefálicas/imunologia , Linfócitos T CD8-Positivos/imunologia , Microglia/imunologia , Midkina/metabolismo , Neurofibromatose 1/metabolismo , Neurônios/metabolismo , Glioma do Nervo Óptico/imunologia , Animais , Apoptose/imunologia , Astrocitoma/mortalidade , Astrocitoma/patologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Quimiocina CCL4/metabolismo , Quimiocina CCL5/metabolismo , Criança , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Neurofibromatose 1/genética , Glioma do Nervo Óptico/mortalidade , Glioma do Nervo Óptico/patologia , Microambiente Tumoral/imunologia
17.
Nat Commun ; 11(1): 2660, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32461556

RESUMO

High-grade serous ovarian cancer (HG-SOC)-often referred to as a "silent killer"-is the most lethal gynecological malignancy. The fallopian tube (murine oviduct) and ovarian surface epithelium (OSE) are considered the main candidate tissues of origin of this cancer. However, the relative contribution of each tissue to HG-SOC is not yet clear. Here, we establish organoid-based tumor progression models of HG-SOC from murine oviductal and OSE tissues. We use CRISPR-Cas9 genome editing to introduce mutations into genes commonly found mutated in HG-SOC, such as Trp53, Brca1, Nf1 and Pten. Our results support the dual origin hypothesis of HG-SOC, as we demonstrate that both epithelia can give rise to ovarian tumors with high-grade pathology. However, the mutated oviductal organoids expand much faster in vitro and more readily form malignant tumors upon transplantation. Furthermore, in vitro drug testing reveals distinct lineage-dependent sensitivities to the common drugs used to treat HG-SOC in patients.


Assuntos
Sistemas CRISPR-Cas/genética , Organoides , Neoplasias Ovarianas/etiologia , Animais , Antineoplásicos/farmacologia , Proteína BRCA1/genética , Proteína 9 Associada à CRISPR , Epitélio/patologia , Tubas Uterinas/patologia , Feminino , Edição de Genes/métodos , Camundongos , Mutação , Neurofibromatose 1/genética , Técnicas de Cultura de Órgãos/métodos , Organoides/efeitos dos fármacos , Organoides/fisiopatologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Ovário/patologia , PTEN Fosfo-Hidrolase/genética , Proteína Supressora de Tumor p53/genética
18.
Am J Respir Crit Care Med ; 202(6): 843-852, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32437637

RESUMO

Rationale: Pulmonary hypertension (PH) associated with neurofibromatosis type 1 (NF1) is a rare and largely unknown complication of NF1.Objectives: To describe characteristics and outcomes of PH-NF1.Methods: We reported the clinical, functional, radiologic, histologic, and hemodynamic characteristics, response to pulmonary arterial hypertension (PAH)-approved drugs, and transplant-free survival of patients with PH-NF1 from the French PH registry.Measurements and Main Results: We identified 49 PH-NF1 cases, characterized by a female/male ratio of 3.9 and a median (minimum-maximum) age at diagnosis of 62 (18-82) years. At diagnosis, 92% were in New York Heart Association functional class III or IV. The 6-minute-walk distance was 211 (0-460) m. Pulmonary function tests showed low DlCO (30% [12-79%]) and severe hypoxemia (PaO2 56 [38-99] mm Hg). Right heart catheterization showed severe precapillary PH with a mean pulmonary artery pressure of 45 (10) mm Hg and a pulmonary vascular resistance of 10.7 (4.2) Wood units. High-resolution computed tomography images revealed cysts (76%), ground-glass opacities (73%), emphysema (49%), and reticulations (39%). Forty patients received PAH-approved drugs with a significant improvement in functional class and hemodynamic parameters. Transplant-free survival at 1, 3, and 5 years was 87%, 54%, and 42%, respectively, and four patients were transplanted. Pathologic assessment showed nonspecific interstitial pneumonia and major pulmonary vascular remodeling.Conclusions: PH-NF1 is characterized by a female predominance, a low DlCO, and severe functional and hemodynamic impairment. Despite a potential benefit of PAH treatment, prognosis remains poor, and double-lung transplantation is an option for eligible patients.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/cirurgia , Neoplasias Pulmonares/fisiopatologia , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Neurofibromina 1/genética , Adolescente , Adulto , Feminino , França , Humanos , Hipertensão Pulmonar/etiologia , Transplante de Pulmão/métodos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Adulto Jovem
19.
Pediatr Blood Cancer ; 67(8): e28372, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32459399

RESUMO

BACKGROUND: Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by plexiform neurofibromas (pNF), which are thought to be congenital tumors that arise in utero and enlarge throughout life. Genetic studies in murine models delineated an indispensable role for the stem cell factor (SCF)/c-kit pathway in pNF initiation and progression. A subsequent phase 2 clinical trial using imatinib mesylate to inhibit SCF/c-kit demonstrated tumor shrinkage in a subset of preexisting pNF; however, imatinib's role on preventing pNF development has yet to be explored. PROCEDURE: We evaluated the effect of imatinib dosed at 10-100 mg/kg/day for 12 weeks to one-month-old Nf1flox/flox ;PostnCre(+) mice, prior to onset of pNF formation. To determine durability of response, we then monitored for pNF growth at later time points, comparing imatinib- with vehicle-treated mice. We assessed gross and histopathological analysis of tumor burden. RESULTS: Imatinib administered preventatively led to a significant decrease in pNF number, even at doses as low as 10 mg/kg/day. Tumor development continued to be significantly inhibited after cessation of imatinib dosed at 50 and 100 mg/kg/day. In the cohort of treated mice that underwent prolonged follow-up, the size of residual tumors was significantly reduced as compared with age-matched littermates that received vehicle control. CONCLUSIONS: Early administration of imatinib inhibits pNF genesis in vivo, and effects are sustained after discontinuation of therapy. These findings may guide clinical use of imatinib in young NF1 patients prior to the substantial development of pNF.


Assuntos
Mesilato de Imatinib/administração & dosagem , Neoplasias Experimentais/prevenção & controle , Neurofibroma Plexiforme/prevenção & controle , Neurofibromatose 1/prevenção & controle , Animais , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neurofibroma Plexiforme/genética , Neurofibroma Plexiforme/metabolismo , Neurofibroma Plexiforme/patologia , Neurofibromatose 1/genética , Neurofibromatose 1/metabolismo , Neurofibromatose 1/patologia
20.
Neurology ; 94(24): e2521-e2531, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32345730

RESUMO

OBJECTIVE: To investigate the genotype-phenotype correlation between neurofibromatosis 1 (NF1) germline mutations and imaging features of neurofibromas on whole-body MRI (WBMRI) by using radiomics image analysis techniques. MATERIALS AND METHODS: Twenty-nine patients with NF1 who had known germline mutations determined by targeted next-generation sequencing were selected from a previous WBMRI study using coronal short tau inversion recovery sequence. Each tumor was segmented in WBMRI and a set of 59 imaging features was calculated using our in-house volumetric image analysis platform, 3DQI. A radiomics heatmap of 59 imaging features was analyzed to investigate the per-tumor and per-patient associations between the imaging features and mutation domains and mutation types. Linear mixed-effect models and one-way analysis of variance tests were performed to assess the similarity of tumor imaging features within mutation groups, between mutation groups, and between randomly selected groups. RESULTS: A total of 218 neurofibromas (97 discrete neurofibromas and 121 plexiform neurofibromas) were identified in 19 of the 29 patients. The unsupervised hierarchical clustering in heatmap analysis revealed 6 major image feature patterns that were significantly correlated with gene mutation domains and types with strong to very strong associations of genotype-phenotype correlations in both per-tumor and per-patient studies (p < 0.05, Cramer V > 0.5), whereas tumor size and locations showed no correlations with imaging features (p = 0.79 and p = 0.42, respectively). The statistical analyses revealed that the number of significantly different features (SDFs) within mutation groups were significantly lower than those between mutation groups (mutation domains: 10.9 ± 9.5% vs 31.9 ± 23.8% and mutation types: 31.8 ± 30.7% vs 52.6 ± 29.3%). The first and second quartile p values of within-patient groups were more than 2 times higher than those between-patient groups. However, the numbers of SDFs between randomly selected groups were much lower (approximately 5.2%). CONCLUSION: This preliminary study identified the NF1 radiogenomics linkage between NF1 causative mutations and MRI radiomic features, i.e., the correlation between NF1 genotype and imaging phenotype on WBMRI.


Assuntos
Imagem por Ressonância Magnética , Neurofibromatose 1/diagnóstico por imagem , Neurofibromatose 1/genética , Adulto , Feminino , Estudos de Associação Genética , Genótipo , Mutação em Linhagem Germinativa/genética , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Neurofibroma/diagnóstico por imagem , Fenótipo , Imagem Corporal Total
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