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1.
Neuro Oncol ; 2019 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-31883020

RESUMO

BACKGROUND: Controversy exists as to what may be defined as standard of care (including markers for stratification) for patients with Atypical Teratoid Rhabdoid Tumors (ATRT). The European Rhabdoid Registry, EU-RHAB, recruits uniformly treated patients and offers standardized genetic and DNA methylation analyses. METHODS: Clinical, genetic and treatment data of 143 patients from 13 European countries were analyzed (2009 - 2017). Therapy consisted of surgery, anthracycline-based induction and either radiotherapy or high dose chemotherapy following a consensus among European experts. FISH, MLPA and sequencing were employed for assessment of somatic and germline mutations in SMARCB1. Molecular subgroups (ATRT-SHH, -TYR and -MYC) were determined using DNA-methylation arrays resulting in profiles of 84 tumors. RESULTS: Median age at diagnosis of 67 girls and 76 boys was 29.5 months. 5-year overall survival (OS) and event-free survival (EFS) were 34.7±4.5% and 30.5±4.2%. Tumors displayed allelic partial/whole gene deletions (66%; 122/186 alleles) or single nucleotide variants (34%; 64/186 alleles) of SMARCB1. Germline mutations were detected in 26% of ATRT (30/117). The patient cohort consisted of 47% ATRT-SHH (39/84), 33% ATRT-TYR (28/84), and 20% ATRT-MYC 17/84). Age <1 year, non-TYR signature (ATRT-SHH or -MYC), metastatic or synchronous tumors, germline mutation, incomplete remission and omission of radiotherapy were negative prognostic factors in univariate analyses (p<0.05). An adjusted multivariate model identified age <1 year and a non-TYR signature as independent negative predictors of OS: high risk (<1 year + non-TYR; 5-year OS = 0%), intermediate risk (<1 year + ATRT-TYR or ≥1 year + non-TYR; 5-year OS = 32.5±8.7%) and standard risk (≥1 year + ATRT-TYR, 5-year OS = 71.5±12.2%). CONCLUSIONS: Age and molecular subgroup status are independent risk factors for survival in children with ATRT. Our model warrants validation within future clinical trials.

2.
J Neurooncol ; 145(1): 177-184, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31522324

RESUMO

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a rare clinically, neuro-radiologically, and molecularly defined malignancy of the brainstem with a median overall survival of approximately 11 months. Our aim is to evaluate the current tendency for its treatment in Europe in order to develop (inter)national consensus guidelines. METHODS: Healthcare professionals specialized in DIPG were asked to fill in an online survey with questions regarding usual treatment strategies at diagnosis and at disease progression in their countries and/or their centers, respectively. RESULTS: Seventy-four healthcare professionals responded to the survey, of which 87.8% were pediatric oncologists. Only 13.5% of the respondents biopsy all of their patients, 41.9% biopsy their patients infrequently. More than half of the respondents (54.1%) treated their patients with radiotherapy only at diagnosis, whereas 44.6% preferred radiotherapy combined with chemotherapy. When the disease progresses, treatment strategies became even more diverse, and the tendency for no treatment increased from 1.4% at diagnosis to 77.0% after second progression. 36.5% of the healthcare professionals treat children younger than 3 years differently than older children at diagnosis. This percentage decreased, when the disease progresses. Most of the participants (51.4%) included less than 25% of their patients in clinical trials. CONCLUSION: This survey demonstrates a large heterogeneity of treatment regimens, especially at disease progression. We emphasize the need for international consensus guidelines for the treatment of DIPG, possible by more collaborative clinical trials.

3.
PLoS One ; 14(7): e0219539, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31295288

RESUMO

OBJECTIVES: To analyse the internal consistency of an adaption of the methotrexate intolerance severity score (MISS); and to describe and compare the level of methotrexate intolerance evaluated by the MISS in Danish children with juvenile idiopathic arthritis (JIA) or acute lymphoblastic leukaemia (ALL), treated with low-dose methotrexate (MTX). METHODS: Cross-sectional study of children diagnosed with JIA or ALL, treated with low-dose MTX, aged 9 years or above, and cognitively intact. The patient's parents completed the MISS. MTX intolerance was defined as a total MISS score above 6. RESULTS: We enrolled 120 children with JIA and 23 children with ALL. The MISS had a good internal consistency in the JIA group. The median MISS score was higher in the JIA group than in the ALL group (JIA: 8; ALL: 1; p<0.0001); and the JIA group had a larger proportion of MTX intolerant children than the ALL group (JIA: 73/120; ALL: 4/23; p<0.001). Within both the JIA group and the ALL group, the MISS total score was not significantly correlated with age, MTX dose or the duration of low-dose MTX treatment. CONCLUSION: In the JIA group the level of MTX intolerance was higher and more attributed to anticipatory, associative and behavioural symptoms than in the ALL group. The MISS may help to uncover whether MTX intolerance is present and which aspects are affected in the individual patient, thus guiding intervention. The MISS may also be applicable within leukaemia care.

5.
J Nucl Med ; 60(8): 1053-1058, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30683767

RESUMO

Complete resection is the treatment of choice for most pediatric brain tumors, but early postoperative MRI for detection of residual tumor may be misleading because of MRI signal changes caused by the operation. PET imaging with amino acid tracers in adults increases the diagnostic accuracy for brain tumors, but the literature in pediatric neurooncology is limited. A hybrid PET/MRI system is highly beneficial in children, reducing the number of scanning procedures, and this is to our knowledge the first larger study using PET/MRI in pediatric neurooncology. We evaluated if additional postoperative 18F-fluoro-ethyl-tyrosine (18F-FET) PET in children and adolescents would improve diagnostic accuracy for the detection of residual tumor as compared with MRI alone and would assist clinical management. Methods: Twenty-two patients (7 male; mean age, 9.5 y; range, 0-19 y) were included prospectively and consecutively in the study and had 27 early postoperative 18F-FET PET exams performed preferentially in a hybrid PET/MRI system (NCT03402425). Results: Using follow-up (93%) or reoperation (7%) as the reference standard, PET combined with MRI discriminated tumor from treatment effects with a lesion-based sensitivity/specificity/accuracy (95% confidence intervals) of 0.73 (0.50-1.00)/1.00 (0.74-1.00)/0.87 (0.73-1.00) compared with MRI alone: 0.80 (0.57-1.00)/0.75 (0.53-0.94)/0.77 (0.65-0.90); that is, the specificity for PET/MRI was 1.00 as compared with 0.75 for MRI alone (P = 0.13). In 11 of 27 cases (41%), results from the 18F-FET PET scans added relevant clinical information, including one scan that directly influenced clinical management because an additional residual tumor site was identified. 18F-FET uptake in reactive changes was frequent (52%), but correct interpretation was possible in all cases. Conclusion: The high specificity for detecting residual tumor suggests that supplementary 18F-FET PET is relevant in cases where reoperation for residual tumor is considered.

6.
J Pediatr Hematol Oncol ; 41(1): e12-e17, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30550508

RESUMO

BACKGROUND: As more children survive acute myeloid leukemia (AML) it is increasingly important to assess possible late effects of the intensive treatment. Hearing loss has only sporadically been reported in survivors of childhood AML. We assessed hearing status in survivors of childhood AML treated with chemotherapy alone according to 3 consecutive NOPHO-AML trials. PROCEDURE: A population-based cohort of children treated according to the NOPHO-AML-84, NOPHO-AML-88, and NOPHO-AML-93 trials included 137 eligible survivors among whom 101 (74%) completed a questionnaire and 99 (72%) had otologic and audiologic examination performed including otoscopy (72%), pure tone audiometry (70%), and tympanometry (60%). Eighty-four of 93 (90%) eligible sibling controls completed a similar questionnaire. RESULTS: At a median of 11 years (range, 4 to 25) after diagnosis, hearing disorders were rare in survivors of childhood AML and in sibling controls, with no significant differences. None had severe or profound hearing loss diagnosed at audiometry. Audiometry detected a subclinical hearing loss ranging from slight to moderate in 19% of the survivors, 5% had low-frequency hearing loss, and 17% had high-frequency hearing loss. CONCLUSIONS: The frequency of hearing disorders was low, and hearing thresholds in survivors of childhood AML were similar to background populations of comparable age.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Transtornos da Audição , Audição/efeitos dos fármacos , Leucemia Mieloide Aguda , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Sobreviventes de Câncer , Criança , Pré-Escolar , Feminino , Seguimentos , Transtornos da Audição/induzido quimicamente , Transtornos da Audição/epidemiologia , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/epidemiologia , Masculino , Estudos Retrospectivos , Irmãos
7.
Lancet Oncol ; 19(8): e419-e428, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30102236

RESUMO

Paediatric CNS tumours are the most common cause of childhood cancer-related morbidity and mortality, and improvements in their diagnosis and treatment are needed. New genetic and epigenetic information about paediatric CNS tumours is transforming the field dramatically. For most paediatric CNS tumour entities, subgroups with distinct biological characteristics have been identified, and these characteristics are increasingly used to facilitate accurate diagnoses and therapeutic recommendations. Future treatments will be further tailored to specific molecular subtypes of disease, specific tumour predisposition syndromes, and other biological criteria. Successful biomaterial collection is a key requirement for the application of contemporary methodologies for the validation of candidate prognostic factors, the discovery of new biomarkers, the establishment of appropriate preclinical research models for targeted agents, a quicker clinical implementation of precision medicine, and for other therapeutic uses (eg, for immunotherapies). However, deficits in organisational structures and interdisciplinary cooperation are impeding the collection of high-quality biomaterial from CNS tumours in most centres. Practical, legal, and ethical guidelines for consent, storage, material transfer, biobanking, data sharing, and funding should be established by research consortia and local institutions to allow optimal collection of primary and subsequent tumour tissue, body fluids, and normal tissue. Procedures for the collection and storage of biomaterials and related data should be implemented according to the individual and organisational structures of the local institutions.


Assuntos
Bancos de Espécimes Biológicos/normas , Biomarcadores Tumorais , Neoplasias do Sistema Nervoso Central , Oncologia/normas , Pesquisa Médica Translacional/métodos , Bancos de Espécimes Biológicos/ética , Bancos de Espécimes Biológicos/organização & administração , Criança , Feminino , Humanos , Masculino , Oncologia/organização & administração , Oncologia/tendências , Pesquisa Médica Translacional/organização & administração , Pesquisa Médica Translacional/normas
8.
Radiother Oncol ; 128(2): 209-213, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29859753

RESUMO

BACKGROUND AND PURPOSE: The purpose of this study was to investigate whether treatment information from medical records can be used to estimate radiation doses to heart and lungs retrospectively in pediatric patients receiving spinal irradiation with conventional posterior fields. MATERIAL AND METHODS: An algorithm for retrospective dosimetry in children treated with spinal irradiation was developed in a cohort of 21 pediatric patients with available CT-scans and treatment plans. We developed a multivariable linear regression model with explanatory variables identifiable in case note review for retrospective estimation of minimum, maximum, mean and V10%-V80% doses to the heart and lungs. Doses were estimated for both linear accelerator (Linac) and 60Co radiation therapy modalities. RESULTS: Age and spinal field width were identified as statistically significant predictors of heart and lung doses in multivariable analyses (p < 0.01 in all models). Models showed excellent predictive performance with R2 = 0.70 for mean heart dose and 0.79 for mean lung dose, for Linac plans. In leave-one-out cross-validation analysis the average difference between predicted and actual mean heart dose was 6.7% and 7.6% of the prescription dose for Linac and 60Co plans, respectively, and 5.2% and 4.9% for mean lung dose. Due to the small sample size and large inter-patient variation in heart and lung dose, prospective studies validating these findings are highly warranted. CONCLUSIONS: The models presented here provide retrospective estimates of heart and lung doses for historical cohorts of pediatric patients, thus facilitating studies of long-term adverse effects of radiation.


Assuntos
Neoplasias Cerebelares/radioterapia , Radiação Cranioespinal/efeitos adversos , Coração/efeitos da radiação , Pulmão/efeitos da radiação , Meduloblastoma/radioterapia , Adolescente , Algoritmos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Radiometria , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Adulto Jovem
9.
Front Pediatr ; 6: 114, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29732366

RESUMO

Purpose: Pediatric cancers are often difficult to classify and can be complex to treat. To ensure precise diagnostics and identify relevant treatment targets, we implemented comprehensive molecular profiling of consecutive pediatric patients with cancer relapse. We evaluated the clinical impact of extensive molecular profiling by assessing the frequency of identified biological onco-drivers, altered diagnosis, and/or identification of new relevant targeted therapies. Patients and Methods: Forty-six tumor samples (44 fresh-frozen; two formalin-fixed paraffin embedded), two bone marrow aspirates, three cerebrospinal fluid samples, and one archived DNA were obtained from 48 children (0-17 years; median 9.5) with relapsed or refractory cancer, where the disease was rapidly progressing in spite of their current treatment or they had exhausted all treatment options. The samples were analyzed by whole-exome sequencing (WES), RNA sequencing (RNAseq), transcriptome arrays, and SNP arrays. Final reports were available within 3-4 weeks after patient inclusion and included mutation status, a description of copy number alterations, differentially expressed genes, and gene fusions, as well as suggestions for targeted treatment. Results: Of the 48 patients, 33 had actionable findings. The most efficient method for the identification of actionable findings was WES (39%), followed by SNP array (37%). Of note, gene fusions were identified by RNAseq in 21% of the samples. Eleven findings led to clinical intervention, i.e., oncogenetic counseling, targeted treatment, and treatment based on changed diagnosis. Four patients received compassionate use targeted therapy. Six patients experienced direct benefits in the form of stable disease or response. Conclusion: The application of comprehensive genetic diagnostics in children with recurrent cancers allowed for discovery and implementation of effective targeted therapies and hereby improvement of outcome in some patients.

10.
Eur J Cancer ; 86: 358-363, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29100190

RESUMO

BACKGROUND: Ipilimumab is approved for the treatment of advanced melanoma in adults; however, little information on the efficacy and safety of ipilimumab in younger patients is available. METHODS: Patients aged 12 to <18 years with previously treated or untreated, unresectable stage III or IV malignant melanoma received ipilimumab 3 or 10 mg/kg every 3 weeks. Primary end-points were 1-year overall survival and safety. RESULTS: Over a period of 3.5 years, 12 patients received ipilimumab at either 3 mg/kg (n = 4) or 10 mg/kg (n = 8). The median number of ipilimumab doses was four for 3 mg/kg and three for 10 mg/kg. At 1 year, three of four patients on 3 mg/kg and five of eight patients on 10 mg/kg were alive. Two patients on 10 mg/kg had partial response, and one on 3 mg/kg had stable disease. One patient had durable partial response at 3 years without further treatment, at time of this report. There was one grade 3/4 immune-mediated adverse reaction with 3 mg/kg and five with 10 mg/kg. There were no treatment-related deaths. The study was stopped due to slow accrual. CONCLUSIONS: At >1 year follow-up, ipilimumab demonstrated activity in melanoma patients aged 12 to <18 years, with a similar safety profile as that seen in adults. Our trial highlights the difficulties of enrolling younger patients with rare diseases in clinical trials for treatments that are approved in adults, suggesting adolescents with cancer types occurring predominantly in adults should be considered for inclusion in adult trials of promising new drugs. CLINICAL TRIAL REGISTRATION: NCT01696045.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Ipilimumab/administração & dosagem , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adolescente , Fatores Etários , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Criança , Progressão da Doença , Intervalo Livre de Doença , Esquema de Medicação , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Ipilimumab/efeitos adversos , Ipilimumab/farmacocinética , Estimativa de Kaplan-Meier , Masculino , Melanoma/mortalidade , Melanoma/patologia , Estadiamento de Neoplasias , Seleção de Pacientes , Tamanho da Amostra , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Fatores de Tempo , Resultado do Tratamento
11.
Ugeskr Laeger ; 179(42)2017 Oct 16.
Artigo em Dinamarquês | MEDLINE | ID: mdl-29053095

RESUMO

The Danish parliament has decided to establish a four-year pilot scheme for medical treatment with cannabis. We increasingly experience requests from parents for medical treatment with cannabis of children and have the impression that a growing number of parents treat their children with illegally acquired cannabis products for various conditions. We summarize the sparse evidence regarding effects, side effects and long-term effects of medical treatment with cannabis in children and adolescents. At present, cannabis should very rarely be considered as part of medical treatment for children and adolescents.


Assuntos
Maconha Medicinal/uso terapêutico , Adolescente , Canabinoides/efeitos adversos , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Criança , Dinamarca , Epilepsia/tratamento farmacológico , Humanos , Maconha Medicinal/efeitos adversos , Maconha Medicinal/farmacologia , Neoplasias/tratamento farmacológico , Dor/tratamento farmacológico
12.
BMC Cancer ; 17(1): 439, 2017 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-28637445

RESUMO

BACKGROUND: Central nervous system tumours constitute 25% of all childhood cancers; more than half are located in the posterior fossa and surgery is usually part of therapy. One of the most disabling late effects of posterior fossa tumour surgery is the cerebellar mutism syndrome (CMS) which has been reported in up to 39% of the patients but the exact incidence is uncertain since milder cases may be unrecognized. Recovery is usually incomplete. Reported risk factors are tumour type, midline location and brainstem involvement, but the exact aetiology, surgical and other risk factors, the clinical course and strategies for prevention and treatment are yet to be determined. METHODS: This observational, prospective, multicentre study will include 500 children with posterior fossa tumours. It opened late 2014 with participation from 20 Nordic and Baltic centres. From 2016, five British centres and four Dutch centres will join with a total annual accrual of 130 patients. Three other major European centres are invited to join from 2016/17. Follow-up will run for 12 months after inclusion of the last patient. All patients are treated according to local practice. Clinical data are collected through standardized online registration at pre-determined time points pre- and postoperatively. Neurological status and speech functions are examined pre-operatively and postoperatively at 1-4 weeks, 2 and 12 months. Pre- and postoperative speech samples are recorded and analysed. Imaging will be reviewed centrally. Pathology is classified according to the 2007 WHO system. Germline DNA will be collected from all patients for associations between CMS characteristics and host genome variants including pathway profiles. DISCUSSION: Through prospective and detailed collection of information on 1) differences in incidence and clinical course of CMS for different patient and tumour characteristics, 2) standardized surgical data and their association with CMS, 3) diversities and results of other therapeutic interventions, and 4) the role of host genome variants, we aim to achieve a better understanding of risk factors for and the clinical course of CMS - with the ultimate goal of defining strategies for prevention and treatment of this severely disabling condition. TRIAL REGISTRATION: Clinicaltrials.gov : NCT02300766 , date of registration: November 21, 2014.


Assuntos
Neoplasias Cerebelares/cirurgia , Neoplasias Infratentoriais/cirurgia , Mutismo/fisiopatologia , Complicações Pós-Operatórias/fisiopatologia , Adolescente , Neoplasias Cerebelares/complicações , Neoplasias Cerebelares/epidemiologia , Neoplasias Cerebelares/fisiopatologia , Cerebelo/fisiopatologia , Cerebelo/cirurgia , Criança , Pré-Escolar , Dinamarca/epidemiologia , Feminino , Humanos , Lactente , Neoplasias Infratentoriais/complicações , Neoplasias Infratentoriais/epidemiologia , Neoplasias Infratentoriais/fisiopatologia , Masculino , Mutismo/epidemiologia , Mutismo/etiologia , Procedimentos Neurocirúrgicos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Fatores de Risco
13.
Cancer Genet ; 212-213: 32-37, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28449809

RESUMO

Meningiomas are rare in children. They are highly complex, harboring unique clinical and pathological characteristics, and many occur in patients with neurofibromatosis type 2. Hereby, we present a case of a two-year-old boy presented with a diagnostically challenging intraventricular tumor. It was incompletely resected 6 times over 14 months but kept progressing and was ultimately deemed unresectable. Histologically, the tumor was initially classified as schwannoma, but extensive international review concluded it was most likely an atypical meningioma, WHO grade II. Comprehensive genomic profiling revealed a TFG-ROS1 fusion, suggesting that ROS1-signaling pathway alterations were driving the tumor growth. In light of this new information, the possibility of a diagnosis of inflammatory myofibroblastic tumor was considered; however the histopathological results were not conclusive. This specific molecular finding allowed the potential use of precision medicine and the patient was enrolled in the AcSé phase 2 trial with crizotinib (NCT02034981), leading to a prolonged partial tumor response which is persisting since 14 months. This case highlights the value of precision cancer medicine in children.


Assuntos
Fusão Gênica , Neoplasias Meníngeas/diagnóstico , Meningioma/diagnóstico , Fatores de Crescimento Transformadores/genética , Pré-Escolar , Crizotinibe , Diagnóstico Diferencial , Humanos , Masculino , Neoplasias Meníngeas/tratamento farmacológico , Neoplasias Meníngeas/genética , Meningioma/tratamento farmacológico , Meningioma/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Pirazóis/uso terapêutico , Piridinas/uso terapêutico
14.
J Neurooncol ; 132(2): 255-266, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28110411

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is a rare and deadly childhood malignancy. After 40 years of mostly single-center, often non-randomized trials with variable patient inclusions, there has been no improvement in survival. It is therefore time for international collaboration in DIPG research, to provide new hope for children, parents and medical professionals fighting DIPG. In a first step towards collaboration, in 2011, a network of biologists and clinicians working in the field of DIPG was established within the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group: the SIOPE DIPG Network. By bringing together biomedical professionals and parents as patient representatives, several collaborative DIPG-related projects have been realized. With help from experts in the fields of information technology, and legal advisors, an international, web-based comprehensive database was developed, The SIOPE DIPG Registry and Imaging Repository, to centrally collect data of DIPG patients. As for April 2016, clinical data as well as MR-scans of 694 patients have been entered into the SIOPE DIPG Registry/Imaging Repository. The median progression free survival is 6.0 months (95% Confidence Interval (CI) 5.6-6.4 months) and the median overall survival is 11.0 months (95% CI 10.5-11.5 months). At two and five years post-diagnosis, 10 and 2% of patients are alive, respectively. The establishment of the SIOPE DIPG Network and SIOPE DIPG Registry means a paradigm shift towards collaborative research into DIPG. This is seen as an essential first step towards understanding the disease, improving care and (ultimately) cure for children with DIPG.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Glioma/diagnóstico por imagem , Serviços de Informação , Cooperação Internacional , Imagem por Ressonância Magnética , Sistema de Registros , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Ponte/diagnóstico por imagem , Adulto Jovem
15.
Cancer Genet ; 209(10): 440-444, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27810072

RESUMO

Pilocytic astrocytoma (PA) is one of the most common brain cancers among children and activation of the Mitogen-Activated Protein Kinase (MAPK) pathway is considered the hallmark. In the majority of cases, oncogenic BRAF fusions or BRAF V600E mutations are observed, while RAF1 or NF1 alterations are more rarely found. However, in some cases, no apparent cancer driver events can be identified. Here, we describe a novel fusion between the transcription factor nuclear factor 1A (NFIA) and Raf-1 proto-oncogene (RAF1) in a 5-year old boy with PA. The novel fusion was identified as part of a comprehensive genomic tumor profiling. We show that the NFIA:RAF1 fusion results in constitutive Raf1 kinase activity, leading to activation of downstream MEK1/2 cascade and increased proliferation of cancer cells. The NFIA:RAF1 fusion displayed distinct subcellular localization towards the plasma membrane indicative of Raf-1 activation, in contrast to both wild type NFIA and Raf-1, which were localized in the nucleus and cytoplasm, respectively. In conclusion, our data support the existence of rare oncogenic RAF1 fusions with constitutive Raf-1 activity. This highlights the need for broad genetic testing in order to refine diagnostics of PA and to unravel potential treatment options, e.g. with MEK inhibitors.


Assuntos
Astrocitoma/genética , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/metabolismo , Fatores de Transcrição NFI/genética , Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-raf/genética , Astrocitoma/metabolismo , Astrocitoma/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Pré-Escolar , Humanos , Masculino , Mutação , Fosforilação , Prognóstico
16.
Eur J Haematol ; 97(1): 55-62, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26383901

RESUMO

OBJECTIVES: We report cardiac function of patients treated for Childhood acute myeloid leukemia with chemotherapy only according to three consecutive Nordic protocols. METHODS: Ninety-eight of 138 eligible patients accepted examination with standardized echocardiography. Results were compared with age- and sex-matched controls. RESULTS: The median age was 3 yr at diagnosis (range 0-15), and the median time from diagnosis to study was 11 yr (4-25). All but one patient had received doxorubicin and 90% had received mitoxantrone. The median cumulative dose of daunorubicin equivalents was 300 mg/m(2) (210-525). Left ventricular fractional shortening (LVFS) and ejection fraction (LVEF) were lower in patients than in controls (32.6% (SD 4.0) vs. 35.2% (SD 3.4), P = 0.002 and 59.9% (SD 5.5) vs. 64.2% (SD 4.4), P = 0.001). The myocardial performance index (MPI) was higher in patients than in controls (0.32 (SD 0.081) vs. 0.26 (SD 0.074), P < 0.0001). Cumulative dose of doxorubicin but not mitoxantrone was related to lower LVFS (P = 0.037) and LVEF (P = 0.016). Longer follow-up was associated with lower LVFS (P = 0.034). Higher MPI was associated with young age at diagnosis (P = 0.04) and longer follow-up (P = 0.031). CONCLUSIONS: In this study, most patients had cardiac function within normal limits and reported very few cardiac symptoms. However, compared with healthy controls, they had significantly reduced left ventricular function.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cardiopatias/etiologia , Cardiopatias/fisiopatologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Ecocardiografia , Feminino , Cardiopatias/diagnóstico , Cardiopatias/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Autorrelato , Função Ventricular Esquerda
17.
Ugeskr Laeger ; 177(51): V06150498, 2015 Dec 14.
Artigo em Dinamarquês | MEDLINE | ID: mdl-26692033

RESUMO

Two children are presented with autosomal recessive hyper IgE syndrome caused by a mutation in the dedicator of cytokinesis 8 gene (DOCK8). The manifestations are typically severe atopic dermatitis, food allergies, elevated serum IgE concentration, viral skin infections and risk of malignancies. DOCK8 deficiency was first reported in 2009, following the death of the oldest sibling. The youngest sibling was cured after allogenic stem cell transplantation. This case report illustrates the need of awareness of primary immunodeficiency in children with atypical manifestation of atopic dermatitis in combination with recurrent infections.


Assuntos
Dermatite Atópica/imunologia , Fatores de Troca do Nucleotídeo Guanina , Síndrome de Job , Dermatite Atópica/patologia , Evolução Fatal , Feminino , Fatores de Troca do Nucleotídeo Guanina/deficiência , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Lactente , Síndrome de Job/diagnóstico , Síndrome de Job/genética , Síndrome de Job/patologia , Síndrome de Job/terapia , Masculino , Doenças Raras
18.
Childs Nerv Syst ; 31(11): 2173-7, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26070965

RESUMO

PURPOSE: Medulloblastoma is the most common malignant brain tumor in childhood. Radical surgery in the non-metastatic stage is an important factor with respect to overall survival. In this case, 5-aminolevulinic acid (5-ALA) was used at second-look surgery in order to improve surgical results. METHODS: The child was pretreated with 3 × 4 mg dexamethasone for 4 days prior to the second surgery. At 5 a.m. on the day of surgery, a freshly prepared solution of 5-ALA (20 mg/kg body weight; Medac, Germany) was given orally. RESULTS: At surgery, through the original opening, the vague red fluorescence of the tumor was clearly distinctive from the cerebellum with no tumor infiltration. All fluorescent tissue was removed. Postoperative MRI gave suspicion of yet at small tumor residue, but this structure is less than 1.5 ml in calculated volume, and consequently the recommended adjuvant therapy of the child changed from the high-risk medulloblastoma regimen to the standard-risk regimen. CONCLUSIONS: In this particular difficult case of non-contrast-enhancing tumor, 5-ALA was of vital importance to improve rate of resection and change the aggressiveness needed in postsurgery radiation therapy.


Assuntos
Ácido Aminolevulínico/uso terapêutico , Neoplasias Cerebelares/tratamento farmacológico , Meduloblastoma/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias Cerebelares/cirurgia , Criança , Terapia Combinada , Seguimentos , Humanos , Imagem por Ressonância Magnética , Masculino , Meduloblastoma/cirurgia , Procedimentos Neurocirúrgicos/métodos
19.
J Nucl Med ; 56(1): 88-92, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25525183

RESUMO

UNLABELLED: Experience regarding O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET in children and adolescents with brain tumors is limited. METHODS: Sixty-nine (18)F-FET PET scans of 48 children and adolescents (median age, 13 y; range, 1-18 y) were analyzed retrospectively. Twenty-six scans to assess newly diagnosed cerebral lesions, 24 scans for diagnosing tumor progression or recurrence, 8 scans for monitoring of chemotherapy effects, and 11 scans for the detection of residual tumor after resection were obtained. Maximum and mean tumor-to-brain ratios (TBRs) were determined at 20-40 min after injection, and time-activity curves of (18)F-FET uptake were assigned to 3 different patterns: constant increase; peak at greater than 20-40 min after injection, followed by a plateau; and early peak (≤ 20 min), followed by a constant descent. The diagnostic accuracy of (18)F-FET PET was assessed by receiver-operating-characteristic curve analyses using histology or clinical course as a reference. RESULTS: In patients with newly diagnosed cerebral lesions, the highest accuracy (77%) to detect neoplastic tissue (19/26 patients) was obtained when the maximum TBR was 1.7 or greater (area under the curve, 0.80 ± 0.09; sensitivity, 79%; specificity, 71%; positive predictive value, 88%; P = 0.02). For diagnosing tumor progression or recurrence, the highest accuracy (82%) was obtained when curve patterns 2 or 3 were present (area under the curve, 0.80 ± 0.11; sensitivity, 75%; specificity, 90%; positive predictive value, 90%; P = 0.02). During chemotherapy, a decrease of TBRs was associated with a stable clinical course, and in 2 patients PET detected residual tumor after presumably complete tumor resection. CONCLUSION: Our findings suggest that (18)F-FET PET can add valuable information for clinical decision making in pediatric brain tumor patients.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Tirosina/análogos & derivados , Adolescente , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Lactente , Masculino , Neoplasia Residual , Recidiva , Sensibilidade e Especificidade
20.
Pediatr Blood Cancer ; 61(9): 1638-43, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24760750

RESUMO

BACKGROUND: We investigated the spectrum, frequency, and risk factors for renal, gastrointestinal, and hepatic late adverse effects in survivors of childhood acute myeloid leukemia (AML) without relapse treated with chemotherapy alone according to three consecutive AML trials by the Nordic Society of Pediatric Hematology and Oncology (NOPHO). METHODS: A population-based cohort of children treated for AML according to the NOPHO-AML-84, -88, and -93 trials included 138 eligible survivors of whom 102 (74%) completed a questionnaire and 104 (75%) had a clinical examination and blood sampling performed. Eighty-five of 94 (90%) eligible sibling controls completed a similar questionnaire. Siblings had no clinical examination or blood sampling performed. RESULTS: At a median of 11 years (range 4-25) after diagnosis, renal, gastrointestinal, and hepatic disorders were rare both in survivors of childhood AML and in sibling controls, with no significant differences. Ferritin was elevated in 21 (21%) AML survivors but none had biochemical signs of liver damage. Viral hepatitis was present in three and cholelithiasis in two AML survivors. One adult survivor had hypertension, two had slightly elevated systolic blood pressure, and eight survivors had slightly elevated diastolic blood pressure. These persons all had normal creatinine and cystatin C levels. Marginal abnormalities in potassium, magnesium, calcium, or bicarbonate levels were found in 34 survivors. CONCLUSION: Survivors of childhood AML treated with chemotherapy only experienced few renal, gastrointestinal, and hepatic late effects.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Gastroenteropatias/induzido quimicamente , Nefropatias/induzido quimicamente , Leucemia Mieloide Aguda/tratamento farmacológico , Hepatopatias/etiologia , Sobreviventes/estatística & dados numéricos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Gastroenteropatias/diagnóstico , Gastroenteropatias/mortalidade , Humanos , Lactente , Recém-Nascido , Nefropatias/diagnóstico , Nefropatias/mortalidade , Hepatopatias/diagnóstico , Hepatopatias/mortalidade , Masculino , Prognóstico , Taxa de Sobrevida , Adulto Jovem
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