RESUMO
Reports on pediatric low-grade diffuse glioma WHO-grade II (DG2) suggest an impaired survival rate, but lack conclusive results for genetically defined DG2-entities. We analyzed the natural history, treatment and prognosis of DG2 and investigated which genetically defined sub-entities proved unfavorable for survival. Within the prospectively registered, population-based German/Swiss SIOP-LGG 2004 cohort 100 patients (age 0.8-17.8 years, 4% neurofibromatosis [NF1]) were diagnosed with a DG2. Following biopsy (41%) or variable extent of resection (59%), 65 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemotherapy (n = 18) or radiotherapy (n = 17). Multiple lines of salvage treatment were necessary for 19/35 patients. Five years event-free survival dropped to 0.44, while 5 years overall survival was 0.90 (median observation time 8.3 years). Extensive genetic profiling of 65/100 DG2 identified Histone3-K27M-mutation in 4, IDH1-mutation in 11, BRAF-V600-mutation in 12, KIAA1549-BRAF-fusions in 6 patients, while the remaining 32 tumor tissues did not show alterations of these genes. Progression to malignant glioma occurred in 12 cases of all genetically defined subgroups within a range of 0.5 to 10.8 years, except for tumors carrying KIAA1549-BRAF-fusions. Histone3-K27M-mutant tumors proved uniformly fatal within 0.6 to 2.4 years. The current LGG treatment strategy seems appropriate for all DG2-entities, with the exemption of Histone3-K27M-mutant tumors that require a HGG-related treatment strategy. Our data confirm the importance to genetically define pediatric low-grade diffuse gliomas for proper treatment decisions and risk assessment.
Assuntos
Neoplasias Encefálicas/patologia , Glioma/patologia , Adolescente , Neoplasias Encefálicas/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Alemanha , Glioma/genética , Humanos , Lactente , Masculino , Mutação/genética , Gradação de Tumores/métodos , Prognóstico , Intervalo Livre de Progressão , Estudos Prospectivos , Terapia de Salvação/métodos , Suíça , Organização Mundial da SaúdeRESUMO
BACKGROUND: Children diagnosed with LGG at an age <1 year are reported to have an impaired prognosis in comparison to older patients. Analysis of this subgroup could reveal the necessity to develop risk-adapted treatment approaches. PROCEDURE: Children <1 year at diagnosis (n = 66, median age 7.3 months, 33 female, none NFI) from the HIT-LGG 1996 cohort were analyzed for risk factors for EFS, PFS and OS. Several children suffered from diencephalic syndrome (DS, n = 22) and primary dissemination (DLGG, n = 9), 50 had a supratentorial midline (SML) location. Extent of resection was complete/subtotal in 12, partial in 15, biopsy in 27. Tumors were pilocytic astrocytoma WHO grade I (n = 33), other WHO grade I (n = 14), pilomyxoid astrocytomas WHO grade II (n = 3), and neuroepithelial tumors WHO grade II (n = 4). RESULTS: One-year EFS was 34.8%. SML-localisation, minor extent of surgery, pilocytic astrocytoma, DLGG and DS were unfavorable predictive factors. No additional non-surgical therapy was applied in 24, 36 were treated with VCR/carboplatin chemotherapy, 6 with radiotherapy (5/6 brachytherapy). Ten-year-PFS-rate following non-surgical therapy was 16.7%; DS and DLGG were unfavorable factors. Ten-year-OS-rate was 72.8%, lower for children <6 months at diagnosis, with DS, or with DLGG. At last follow up in August 2011, vision in 31 living children was often severely impaired. CONCLUSIONS: Children <1 year at diagnosis have a conspicuously impaired survival with current treatment approaches. Age <6 months, diencephalic syndrome and dissemination constitute risk factors for even lower PFS and OS. Treatment adaptations are needed to improve outcome and molecular genetics may explain tumor aggressiveness.
Assuntos
Neoplasias Encefálicas/terapia , Glioma/terapia , Fatores Etários , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Feminino , Glioma/mortalidade , Glioma/patologia , Humanos , Lactente , Masculino , Gradação de Tumores , Fatores de Tempo , Resultado do TratamentoRESUMO
A genome-wide association study identified interferon-related development regulator-1 (IFRD1), a protein expressed by neutrophils, as a key modifier gene in cystic fibrosis (CF) lung disease. Here, we investigated the expression and regulation of IFRD1 in CF neutrophils. IFRD1 expression was quantified in peripheral blood and airway neutrophils from patients with CF, patients with non-CF lung disease, and healthy control subjects. The regulation of IFRD1 expression was analyzed using isolated neutrophils and ex vivo stimulation assays with CF airway fluids. IFRD1 single-nucleotide polymorphisms (SNPs) were analyzed in a CF cohort (n = 572) and correlated with longitudinal lung function and IFRD1 expression. Patients with CF expressed higher protein levels of IFRD1 in peripheral blood neutrophils compared with healthy or non-CF disease control subjects. Within patients with CF, IFRD1 protein expression levels in neutrophils were lower in airway fluids compared with peripheral blood. High IFRD1 expression was positively associated with the production of reactive oxygen species (ROS) in CF neutrophils. In vitro regulation studies showed that CF airway fluid and the CF-characteristic chemokines CXCL8 and CXCL2 down-regulated IFRD1 expression in neutrophils, an effect that was mediated through CXCR2. Genetic analyses showed that three IFRD1 SNPs were associated with longitudinal declines in lung function, and modulated IFRD1 expression. These studies demonstrate that IFRD1 expression is systemically up-regulated in human CF neutrophils, is linked to the production of ROS, and is modulated by chemokines in CF airway fluids, depending on the IFRD1 genotype. Understanding the regulation of IFRD1 may pave the way for novel therapeutic approaches to target neutrophilic inflammation in CF.
Assuntos
Fibrose Cística/genética , Fibrose Cística/fisiopatologia , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , Estudos de Casos e Controles , Quimiocina CXCL2/metabolismo , Estudos de Coortes , Fibrose Cística/imunologia , Humanos , Imunidade Inata , Interleucina-8/metabolismo , Pulmão/imunologia , Pulmão/fisiopatologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Polimorfismo de Nucleotídeo Único , Espécies Reativas de Oxigênio/metabolismoRESUMO
INTRODUCTION: The current SIOP (International Society for Paediatric Oncology)-LGG (low grade glioma) study protocol allows chiasmatic tumours identified as LGG on the basis of neuroradiological characteristics to be treated without histological verification. As some tumours do not respond well to treatment, the search for molecular tissue markers will gain importance for future studies. Anecdotal observations of infarctions after surgery for chiasmatic tumours during central reviewing initiated this study. MATERIALS AND METHODS: In 84 patients, histology was obtained during 102 interventions in the years 1992-2009 by 33 biopsies, 67 partial/subtotal and 2 total resections. Median age at the time of operation was 5 years (mean 5 years 11 months). We could identify 17 infarctions following partial resection of chiasmatic LGG. Biopsies were not complicated by infarction. Children developing infarction were considerably younger (median 3 years; mean 4 years 5 months) than the patients without infarction (median 5 years 4 months; mean 6 years 2 months). A total of 51 patients with cerebellar LGG (median 7 years; mean 7 years 4 months) served as a control group, with 65 surgical procedures (2 biopsies, 22 partial/subtotal resections and 41 total resections) performed in the years 2004-2009. Only one total resection (1.5%) in this group was followed by infarction. CONCLUSION: Partial/subtotal resections of chiasmatic LGG in our study population bear a considerable risk for infarction especially in young children. As there is currently no evidence for a better outcome after tumour resection, we suggest that the sampling of tumour tissue should be performed via biopsies whenever possible.
Assuntos
Infarto Encefálico/etiologia , Glioma do Nervo Óptico/cirurgia , Complicações Pós-Operatórias , Infarto Encefálico/diagnóstico , Neoplasias Cerebelares/cirurgia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Estudos RetrospectivosRESUMO
Activation of the MAPK signaling pathway has been shown to be a unifying molecular feature in pilocytic astrocytoma (PA). Genetically, tandem duplications at chromosome 7q34 resulting in KIAA1549-BRAF fusion genes constitute the most common mechanism identified to date. To elucidate alternative mechanisms of aberrant MAPK activation in PA, we screened 125 primary tumors for RAF fusion genes and mutations in KRAS, NRAS, HRAS, PTPN11, BRAF and RAF1. Using microarray-based comparative genomic hybridization (aCGH), we identified in three cases an interstitial deletion of ~2.5 Mb as a novel recurrent mechanism forming BRAF gene fusions with FAM131B, a currently uncharacterized gene on chromosome 7q34. This deletion removes the BRAF N-terminal inhibitory domains, giving a constitutively active BRAF kinase. Functional characterization of the novel FAM131B-BRAF fusion demonstrated constitutive MEK phosphorylation potential and transforming activity in vitro. In addition, our study confirmed previously reported BRAF and RAF1 fusion variants in 72% (90/125) of PA. Mutations in BRAF (8/125), KRAS (2/125) and NF1 (4/125) and the rare RAF1 gene fusions (2/125) were mutually exclusive with BRAF rearrangements, with the exception of two cases in our series that concomitantly harbored more than one hit in the MAPK pathway. In summary, our findings further underline the fundamental role of RAF kinase fusion products as a tumor-specific marker and an ideally suited drug target for PA.
Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Sistema de Sinalização das MAP Quinases/genética , Mutação/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Pré-Escolar , Cromossomos Humanos Par 7/genética , Hibridização Genômica Comparativa , Feminino , Seguimentos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Lactente , Masculino , Camundongos , Células NIH 3T3 , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação/genética , Deleção de Sequência , Estatísticas não Paramétricas , Transfecção/métodosRESUMO
The purpose of this study was to analyze thermal effects during laser-assisted periodontal treatment. An in vitro model for temperature measurements was developed to investigate different laser settings regarding pulp safety. Additionally, the influence of transmission on pulp temperature elevation was evaluated. Longitudinal root sections were irradiated with a 940-nm diode laser with 1.0 and 1.5 W in continuous wave mode. According to wall thicknesses, irradiation times were adjusted to 20 s for upper and 10 s for lower incisors, respectively. Transmission was relatively low in both upper (4.8% to 8.3% of incident power) and lower incisors (10.2% to 15.0%). Samples were embedded in a polyurethane model and six thermocouples were affixed. Regardless of dentine thickness, the middle third of the root was identified to be the area with the most heat load, where a temperature rise of 7.5°C (1.0 W) and 10.5°C (1.5 W) was registered in upper incisors. A difference of 1.5°C to 3°C was detected in lower incisors compared with uppers. All settings were safe except for 1.5 W, 20 s. Transmission affected heat generation remarkably. The proposed model provides advantages regarding heat transfer and enables for spatially resolved temperature measurements.
Assuntos
Lasers , Desbridamento Periodontal/instrumentação , Desbridamento Periodontal/métodos , Raiz Dentária/efeitos da radiação , Polpa Dentária/fisiologia , Temperatura Alta , Humanos , Incisivo/efeitos da radiação , Bolsa PeriodontalRESUMO
The Hirntumorstudien (HIT)-LGG-1996 protocol offered a comprehensive treatment strategy for pediatric patients with low-grade glioma (LGG), ie, observation, surgery, adjuvant radiotherapy, and chemotherapy to defer the start of irradiation in young children. In this current study, we sought to determine clinical factors for progression and survival. Between October 1, 1996 and March 31, 2004, 1031 patients were prospectively recruited into an observation arm (n = 668) and a nonsurgical arm stratifying 12 months of vincristine-carboplatin chemotherapy (n = 216) and conventional radiotherapy/brachytherapy (n = 147) in an age-dependent manner. Median patient age was 6.9 years; 28 patients had diencephalic syndrome, 44 had dissemination, and 108 had neurofibromatosis type 1(NF-1). Main tumor location was the supratentorial midline (40.4%), and the main histology was pilocytic astrocytoma (67.9%). Following a median observation of 9.3 years, 10-year overall survival (OS) was 0.94 and 10-year event-free survival (EFS) was 0.47. Ten-year progression-free survival was 0.62 following radiotherapy and 0.44 following chemotherapy. Sixty-one of 216 chemotherapy patients received radiotherapy 0.3-8.7 years after initial diagnosis. By multivariate analysis, diencephalic syndrome and incomplete resection were found to be unfavorable factors for OS and EFS, age ≥11 years for OS, and supratentorial midline location for EFS. Dissemination, age <1 year, and nonpilocytic histology were unfavorable factors for progression following radiotherapy (138 patients); and diencephalic syndrome, dissemination, and age ≥11 years were unfavorable factors following chemotherapy (210 patients). NF-1 patients and boys experienced prolonged tumor stabilization with chemotherapy. A nationwide multimodal treatment strategy is feasible for pediatric LGG. Extended follow-up yielded results comparable to single-institution series for the treatment groups. Three-quarters of surviving chemotherapy patients have not yet received radiation therapy. Infants with or without diencephalic syndrome and dissemination bear the highest risk for death and progression following diagnosis or treatment.