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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.
Am J Case Rep ; 22: e927761, 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33452231

RESUMO

BACKGROUND Neurofibromatosis type 1 (NF1) is a multi-tumor syndrome in which affected patients develop malignancies that are rare in the overall population, such as tumors of neural or endocrine origin. CASE REPORT A 67-year-old woman with a clinical diagnosis of NF1 presented with abdominal pain and pneumoperitoneum. She underwent small-bowel resections for a perforated jejunal lesion and a second lesion in the ileum; pathology showed a neurofibroma at the site of the perforation and a 1-cm low-grade GIST, respectively. Additional staging with cross-sectional imaging identified a 3.7-cm pancreatic head mass and a 1.7-cm left adrenal mass; biochemical studies revealed elevated serum gastrin and urinary free metanephrines and catecholamines consistent with pheochromocytoma. Initial surgical management was a left posterior retroperitoneoscopic adrenalectomy. Postoperatively, gallium-68-DOTATOC PET/CT showed uptake in the pancreatic head and a 28-mm left thyroid nodule. Months later, she had an open pancreaticoduodenectomy. Pathology showed pheochromocytoma and a low-grade (G1) gastrinoma involving 2/8 peripancreatic lymph nodes (pT3pN1M0), respectively. Fine-needle aspiration biopsy of the thyroid nodule showed features consistent with a Hürthle cell neoplasm. Genetic testing identified a pathogenic mutation in NF1 and no mutations in BRCA1/2, CDC72, MEN1, or PALB2. The patient continues surveillance, with no evidence of recurrent disease. CONCLUSIONS We report the fifth case of gastrinoma associated with NF1 and the first to arise from the pancreas. This case of a pancreatic neuroendocrine tumor was associated with multiple additional neoplasms. Neuroendocrine tumors found in NF1 should raise suspicion of other malignancies.


Assuntos
Adenoma Oxífilo/patologia , Neoplasias das Glândulas Endócrinas/patologia , Gastrinoma/patologia , Tumores do Estroma Gastrointestinal/patologia , Neurofibromatose 1/patologia , Feocromocitoma/patologia , Adenoma Oxífilo/terapia , Idoso , Neoplasias das Glândulas Endócrinas/terapia , Feminino , Gastrinoma/terapia , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/terapia , Tumores do Estroma Gastrointestinal/terapia , Humanos , Neurofibromatose 1/complicações , Neurofibromatose 1/terapia , Feocromocitoma/terapia
4.
Clin Ter ; 171(5): e371-e377, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32901776

RESUMO

OBJECTIVE: To better understand the real prevalence of cutaneous manifestations, in Neurofibromatosis type 1. MATERIALS AND METHODS: We reviewed all clinical charts of 1102 NF1 patients followed by February 1983 to February 2020 at the "Sapienza" University of Rome, Italy. NF1 patients are seen usually every year by a dermatologist. RESULT: Café-au-lait macules were shown in 1063 patients (96.5%), axillary and inguinal freckling in 991 (90%) and neurofibromas in 861 (78.1%). Other skin manifestations included: lipoma (6.2%), nevus anemicus (3.9%), psoriasis (3.4%), spilus nevus (3.2%), juvenile xanthogranuloma (3.2%), vitiligo (2.3%), Becker's nevus (1.9%), melanoma (0.7%) and poliosis (0.5%). CONCLUSION: Neurofibromatosis type 1 is a multisystem disorder primarily involving the skin and nervous system. The clinical manifestations are extremely variable even within a family. This study was performed to delineate the prevalence of cutaneous manifestations in NF1.


Assuntos
Neurofibromatose 1/complicações , Dermatopatias/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Neurofibromatose 1/patologia , Prevalência , Dermatopatias/epidemiologia , Dermatopatias/patologia , Adulto Jovem
6.
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
7.
Ann Thorac Cardiovasc Surg ; 26(5): 294-297, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-32741884

RESUMO

The Montgomery T-tube is widely used to stent airway stenotic diseases. Conventional insertion methods can sometimes fail in the case of long-distance subglottic stenosis due to the flexibility of a T-tube made of silicon, which kinks when forced against resistance. Therefore, an alternative approach can assist in the insertion of an extra-long T-tube, especially when using a long proximal limb. We report herein the case of a patient with a large mediastinal tumor caused by neurofibromatosis type 1 in which airway obstruction was avoided through the use of a novel extra-long T-tube placement technique.


Assuntos
Manuseio das Vias Aéreas/instrumentação , Neoplasias do Mediastino/complicações , Neurofibromatose 1/complicações , Estenose Traqueal/terapia , Adolescente , Feminino , Humanos , Neoplasias do Mediastino/diagnóstico por imagem , Neoplasias do Mediastino/patologia , Neurofibromatose 1/diagnóstico por imagem , Neurofibromatose 1/patologia , Estenose Traqueal/diagnóstico por imagem , Estenose Traqueal/etiologia , Resultado do Tratamento , Carga Tumoral
8.
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
9.
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
10.
Paediatr Drugs ; 22(4): 417-423, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32533336

RESUMO

BACKGROUND: Plexiform neurofibromas (PN) are congenital tumors that affect up to 50% of individuals with neurofibromatosis type 1. Despite their benign nature, they can grow rapidly and cause severe morbidities. Selumetinib, an inhibitor of mitogen-activated protein kinase (MEK) 1 and 2, was reported to induce a clinical response in pediatric subjects with inoperable PN. OBJECTIVE: The aim of this paper is to describe a prospective case series of patients treated with selumetinib with emphasis on drug adverse events. PATIENTS AND METHODS: All the subjects who received selumetinib at the Pediatric Department of Scientific Research Institute and Hospital "Burlo Garofolo", from November 2017 to January 2020, were progressively included. We monitored the patients with a follow-up visit every 3 months. MRI or CT scans to monitor the growth of the tumor were performed after 3 months of treatment, and then every 6-9 months. RESULTS: Selumetinib was prescribed to nine children, with a total of 17 inoperable PN. The mean follow-up period was 12 months. During the follow-up, one patient experienced an ischemic stroke, unrelated to the treatment. Only minor adverse events were observed: six individuals developed gastrointestinal side effects, seven patients presented a mild form of acne, six had paronychia, four developed irritability, and two showed a mild increase in creatine kinase. None of the patients stopped the treatment. Tumor reduction > 20% was recorded in 16 out of 17 PN (94%). One PN remained stable. No tumor growth was recorded during the treatment. CONCLUSIONS: In this case series, selumetinib appears to be effective and safe for the pediatric population.


Assuntos
Benzimidazóis/administração & dosagem , Neurofibroma Plexiforme/tratamento farmacológico , Neurofibromatose 1/tratamento farmacológico , Adolescente , Benzimidazóis/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , MAP Quinase Quinase 1/antagonistas & inibidores , Imagem por Ressonância Magnética , Masculino , Neurofibroma Plexiforme/patologia , Neurofibromatose 1/patologia , Estudos Prospectivos
11.
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
12.
J Clin Neurosci ; 77: 98-105, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32417129

RESUMO

Neurofibromatosis type 1 (NF1) manifests itself in many ways in the spine. This study aims to report the types of spinal lesions, clinical and demographic data in a large cohort from a complex NF1 centre. The characteristics of those with spinal neurofibromatosis, where neurofibromas are present on every spinal nerve root, were sought for comparison with the wider group of NF1 patients. This is a retrospective review of MDT minutes of 303 patients from a UK NF1 centre and the largest reported series of NF1 patients based on radiological data. Prevalence of each symptom and lesion was calculated and statistically significant associations were established. The most reported findings were cutaneous lesions (44.9%) and neurological deficit (27.4%). 28.4% had dural ectasia, 52.5% had some form of spinal deformity. 57.8% had spinal nerve root tumours, the most common of which were at C2. The most progressive lesions were spinal nerve root tumours (29.1%). The only statistically significant association found was between dural ectasia and spinal deformity (P < 0.003), where dural ectasia is associated with a 32.6% increase in spinal deformity incidence. This is the largest descriptive study of spinal lesions in NF1. Spinal tumours and spinal deformity are prevalent in NF1. The predilection of spinal tumours for flexible spinal regions suggests that repetitive movement might be an important factor in pathogenesis. Physicians and patients should be alert to the observation that although many spinal neurofibromatosis patients display no neurological deficit, they often have significant lesions which require monitoring and sometimes surgery.


Assuntos
Neurofibromatose 1/etiologia , Neurofibromatose 1/patologia , Raízes Nervosas Espinhais/patologia , Coluna Vertebral/patologia , Adulto , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neurofibroma/patologia , Neurofibromatoses , Neurofibromatose 1/complicações , Neurofibromatose 1/epidemiologia , Estudos Retrospectivos , Neoplasias da Medula Espinal/patologia , Curvaturas da Coluna Vertebral , Reino Unido/epidemiologia
13.
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
14.
Neurology ; 95(8): e1052-e1059, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32300062

RESUMO

OBJECTIVE: To define the radiologic features and natural history of nonoptic pathway tumors (non-OPTs) in children with neurofibromatosis type 1 (NF1). METHODS: We performed a retrospective cross-sectional analysis of 64 children with NF1 harboring 100 probable non-OPTs. Age at diagnosis, sex, tumor location, number of tumors, symptomology, concurrent OPT, radiographic progression (defined as qualitative and quantitative increases in size), and treatment were assessed. Tumor volumes were measured from initial presentation until treatment or end of disease progression. RESULTS: Sixty-three percent of probable non-OPTs progressed over time, where radiographic progression was concomitantly associated with clinical progression. Fifty-two percent of patients had incidentally identified probable non-OPTs. Twenty-five percent of patients were symptomatic at initial diagnosis, all of whom harbored tumors that grew on subsequent scans and required tumor-directed therapy. There were no clinical differences between probable non-OPTs localized to the brainstem vs other locations with respect to age, sex, concurrent optic pathway glioma, symptomology, and treatment. The average time from diagnosis to stabilization or decrease in tumor size was 2.34 years (SD, 2.15 years). Nineteen biopsied lesions were all histopathologically confirmed as tumor. Six children (9%) had deep extensive tumors, who presented earlier (mean age at diagnosis, 3.88 years), required multiple treatments, and had a shorter mean progression-free survival (48 months). CONCLUSIONS: Over half of children with NF1 in this study developed probable non-OPTs, the majority of which were clinically and radiographically progressive. While brainstem and nonbrainstem gliomas share similar clinical features and natural history, deep extensive tumors comprise a distinct aggressive group of tumors that warrant close attention.


Assuntos
Neoplasias Encefálicas/patologia , Neurofibromatose 1/patologia , Adolescente , Neoplasias Encefálicas/diagnóstico por imagem , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética/métodos , Masculino , Neurofibromatose 1/diagnóstico por imagem , Estudos Retrospectivos
15.
Anticancer Res ; 40(4): 1817-1831, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234870

RESUMO

Almost all individuals with neurofibromatosis type 1 (NF1) develop peripheral nerve sheath tumors (PNSTs), mainly benign neurofibromas, however about 10% of PNSTs will undergo transformation to malignant peripheral nerve sheath tumors (MPNSTs). Surgical treatment of PNSTs has traditionally been regarded as a standard approach. The availability of new agents that target specific molecular pathways involved in the pathogenesis of PNST has led to a number of clinical trials, which resulted in increased chances for better survival and quality of life. This review presents the latest evidence and clinical implications for new therapies of PNSTs in patients with NF1 emphasizing the potential benefit from the use of Ras/MAPK pathway inhibitors, immunotherapy, chemotherapy or radiation therapy. We present evaluation of current knowledge on available treatment modalities.


Assuntos
Neoplasias/tratamento farmacológico , Neoplasias da Bainha Neural/tratamento farmacológico , Neurofibromatose 1/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Neoplasias/complicações , Neoplasias/genética , Neoplasias/patologia , Neoplasias da Bainha Neural/complicações , Neoplasias da Bainha Neural/genética , Neoplasias da Bainha Neural/patologia , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Transdução de Sinais/efeitos dos fármacos , Tomografia Computadorizada por Raios X , Proteínas ras/antagonistas & inibidores , Proteínas ras/genética
16.
N Engl J Med ; 382(15): 1430-1442, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32187457

RESUMO

BACKGROUND: No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1. METHODS: We conducted an open-label, phase 2 trial of selumetinib to determine the objective response rate among patients with plexiform neurofibromas and to assess clinical benefit. Children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable). RESULTS: A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia. CONCLUSIONS: In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib. (Funded by the Intramural Research Program of the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.).


Assuntos
Benzimidazóis/uso terapêutico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Neurofibroma Plexiforme/tratamento farmacológico , Neurofibromatose 1/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Benzimidazóis/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Náusea/induzido quimicamente , Neurofibroma Plexiforme/complicações , Neurofibroma Plexiforme/patologia , Neurofibromatose 1/complicações , Neurofibromatose 1/patologia , Dor/etiologia , Medidas de Resultados Relatados pelo Paciente , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Carga Tumoral/efeitos dos fármacos
17.
Proc Natl Acad Sci U S A ; 117(11): 6189-6195, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123116

RESUMO

Neurofibromatosis 1 (NF1) is caused by mutations in the NF1 gene, which encodes the protein, neurofibromin, an inhibitor of Ras activity. Cortical GABAergic interneurons (CINs) are implicated in NF1 pathology, but the cellular and molecular changes to CINs are unknown. We deleted mouse Nf1 from the medial ganglionic eminence, which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin. Nf1 loss led to a persistence of immature oligodendrocytes that prevented later-generated oligodendrocytes from occupying the cortex. Moreover, molecular and cellular properties of parvalbumin (PV)-positive CINs were altered by the loss of Nf1, without changes in somatostatin (SST)-positive CINs. We discovered that loss of Nf1 results in a dose-dependent decrease in Lhx6 expression, the transcription factor necessary to establish SST+ and PV+ CINs, which was rescued by the MEK inhibitor SL327, revealing a mechanism whereby a neurofibromin/Ras/MEK pathway regulates a critical CIN developmental milestone.


Assuntos
Córtex Cerebral/patologia , Neurônios GABAérgicos/patologia , Interneurônios/patologia , Proteínas com Homeodomínio LIM/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurofibromatose 1/patologia , Neurofibromina 1/genética , Fatores de Transcrição/metabolismo , Aminoacetonitrila/administração & dosagem , Aminoacetonitrila/análogos & derivados , Animais , Células Cultivadas , Córtex Cerebral/citologia , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Neurônios GABAérgicos/metabolismo , Humanos , Interneurônios/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Eminência Mediana/citologia , Camundongos , Camundongos Knockout , Neurofibromatose 1/genética , Neurofibromina 1/metabolismo , Neuroglia/citologia , Parvalbuminas/metabolismo , Cultura Primária de Células , Somatostatina/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo
18.
Anticancer Res ; 40(3): 1619-1624, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132065

RESUMO

BACKGROUND: Prognosis of metastatic malignant peripheral nerve sheath tumor (MPNST) is poor and the role of chemotherapy is controversial. There has been no report of metastatic MPNST with a good prognosis without surgery for metastases. CASE REPORT: A 40-year-old man with neurofibromatosis type 1 (NF1)-related MPNST on his shoulder with multiple lung metastases visited our hospital. After two cycles of chemotherapy with ifosfamide, carboplatin and etoposide (ICE), the primary lesion and lung metastases had shrunk. The primary lesion was resected with negative margins. Subsequently, 'gradual subtraction' ICE was administered, wherein the dose was reduced and the treatment interval was increased. After 14 courses of ICE over a period of 2 years, the lung metastases disappeared; there has been no recurrence for over 12 years. CONCLUSION: ICE can be an excellent, inexpensive treatment for NF1-related MPNST. 'Gradual subtraction' chemotherapy allowed us to maintain long-term efficacy, induce tumor dormancy, and reduce side-effects.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Etoposídeo/uso terapêutico , Ifosfamida/uso terapêutico , Neoplasias da Bainha Neural/tratamento farmacológico , Neurofibromatose 1/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carboplatina/farmacologia , Etoposídeo/farmacologia , Humanos , Ifosfamida/farmacologia , Masculino , Metástase Neoplásica , Neoplasias da Bainha Neural/patologia , Prognóstico
19.
Rev. argent. dermatol ; 101(1): 81-91, mar. 2020. graf
Artigo em Espanhol | LILACS | ID: biblio-1125809

RESUMO

RESUMEN Presentamos un caso de neurofibromatosis segmentaria, en un paciente de sexo masculino de 60 años de edad. Los neurofibromas se localizaban en región cervical, los mismos eran asintomáticos, de 8 años de evolución.


ABSTRACT A case of segmental neurofibromatosis in a 60 years old male patient is presented along with a brief review of the literature. The patient had 8 years old neurofibromas, located in the cervical region; they were asymptomatic. No other alteration of type 1 neurofibromatosis was found.


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/patologia , Neurofibromatose 1/terapia , Neurofibroma/epidemiologia
20.
Indian J Pathol Microbiol ; 63(1): 112-115, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32031137

RESUMO

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease, is a type of genodermatoses having an autosomal dominant inheritance pattern and is recently considered as a RASopathy. Such patients are very much prone to develop mesenchymal tumors. However, carcinomas are quite rare in NF1 patients. This case study is the first case of oral squamous cell carcinoma (SCC) in tongue of an NF1 patient. A 35-year-old male reported to the Department of Oral Pathology in a tertiary care center with a chief complain of a painful ulcer on tongue for last 1 month. For confirmation of diagnosis of NF1, the "Diagnostic Criteria for Neurofibromatosis Type 1" was followed. Biopsied specimen of the tongue lesion was examined under microscope and histopathological features were suggestive of infiltrating SCC. Immunohistochemistry with Pan CK and beta-catenin was positive. RASopathy, WNT-beta-catenin pathway alteration, heat shock factor 1 production, and miRNA activity are investigated to explain the pathogenesis of malignancies in NF1 patients. In this first case of tongue SCC, we have found out the altered WNT-beta-catenin pathway.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/patologia , Neoplasias da Língua/diagnóstico , Adulto , Biópsia , Técnicas Histológicas , Humanos , Imuno-Histoquímica , Masculino , Transdução de Sinais , Língua/patologia , Via de Sinalização Wnt
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