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1.
Acta Neuropathol Commun ; 8(1): 182, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33153497

RESUMO

Recent discoveries have provided valuable insight into the genomic landscape of pediatric low-grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs' genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and/or targeted sequencing were performed on paired tumor samples from primary diagnostic and subsequent surgeries. Ninety-four tumor samples from 45 patients (41 with two specimens, four with three specimens) from three institutions underwent testing. Conservation of BRAF fusion, BRAFV600E mutation, and FGFR1 rearrangement status was observed in 100%, 98%, and 96% of paired specimens, respectively. No loss or gain of IDH1 mutations or NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. Changes in CDKN2A deletion status at recurrence occurred in 11 patients (42%), with acquisition of hemizygous CDKN2A deletion in seven and loss in four. Shorter time to progression and shorter time to subsequent surgery were observed among patients with acquired CDKN2A deletions compared to patients without acquisition of this alteration [median time to progression: 5.5 versus 16.0 months (p = 0.048); median time to next surgery: 17.0 months versus 29.0 months (p = 0.031)]. Most targetable genetic aberrations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or irradiation. However, changes in CDKN2A deletion status over time were demonstrated. Acquisition of CDKN2A deletion may define a higher risk subgroup of pediatric LGGs with a poorer prognosis. Given the potential for targeted therapies for tumors harboring CDKN2A deletions, biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Recidiva Local de Neoplasia/genética , Adolescente , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , Inibidor p16 de Quinase Dependente de Ciclina/genética , Progressão da Doença , Feminino , Deleção de Genes , Genoma , Genômica , Glioma/patologia , Glioma/terapia , Humanos , Lactente , Isocitrato Desidrogenase/genética , Masculino , Glicoproteínas de Membrana/genética , Gradação de Tumores , Recidiva Local de Neoplasia/terapia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-myb/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor trkB/genética , Transativadores/genética
2.
J Pediatr Hematol Oncol ; 37(4): e258-63, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25757023

RESUMO

Chemotherapy is an essential component of therapy for infants and children with hepatoblastoma. Vincristine has been a mainstay of chemotherapeutic regimens used by North American cooperative groups, based on indirect evidence of benefit and an assumption of minimal added toxicity. European cooperative group trials have reported comparable survival rates using regimens that omit vincristine. Further examination of the risk and benefit profile of vincristine relevant to hepatoblastoma clinical care paradigms is thus warranted. We evaluated the incidence of vincristine-related sensorimotor peripheral, autonomic, and cranial nerve neurological morbidities in 45 consecutive hepatoblastoma patients treated at our institution. Data suggest an increased risk of vincristine-associated neuropathic grade 2 and 3 events (neuropathic pain and gross motor impairment) in children ages 24 months old or younger, and particularly in children born prematurely. Formal prospective investigation of the relative risks and benefits of vincristine in hepatoblastoma treatment is warranted to assess the value of continued use of vincristine in this patient population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Hepatoblastoma/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Vincristina/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Morbidade
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