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1.
Front Immunol ; 10: 1913, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507588

RESUMO

The generation of high-affinity antibodies depends on somatic hypermutation (SHM). SHM is initiated by the activation-induced cytidine deaminase (AID), which generates uracil (U) lesions in the B-cell receptor (BCR) encoding genes. Error-prone processing of U lesions creates a typical spectrum of point mutations during SHM. The aim of this study was to determine the molecular mechanism of SHM in humans; currently available knowledge is limited by the number of mutations analyzed per patient. We collected a unique cohort of 10 well-defined patients with bi-allelic mutations in genes involved in base excision repair (BER) (UNG) or mismatch repair (MMR) (MSH2, MSH6, or PMS2) and are the first to present next-generation sequencing (NGS) data of the BCR, allowing us to study SHM extensively in humans. Analysis using ARGalaxy revealed selective skewing of SHM mutation patterns specific for each genetic defect, which are in line with the five-pathway model of SHM that was recently proposed based on mice data. However, trans-species comparison revealed differences in the role of PMS2 and MSH2 in strand targeting between mice and man. In conclusion, our results indicate a role for UNG, MSH2, MSH6, and PMS2 in the generation of SHM in humans comparable to their function in mice. However, we observed differences in strand targeting between humans and mice, emphasizing the importance of studying molecular mechanisms in a human setting. The here developed method combining NGS and ARGalaxy analysis of BCR mutation data forms the basis for efficient SHM analyses of other immune deficiencies.

2.
Eur J Pediatr ; 178(6): 837-850, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30900075

RESUMO

Situation awareness (SA) is an important human factor and necessary for effective teamwork and patient safety. Human patient simulation (HPS) with video feedback allows for a safe environment where health care professionals can develop both technical and teamwork skills. It is, however, very difficult to observe and measure SA directly. The Situation Global Assessment Technique (SAGAT) was developed by Endsley to measure SA during real-time simulation. Our objective was to measure SA among team members during simulation of acute pediatric care scenarios on the medical ward and its relationship with team effectiveness. Twenty-four pediatric teams, consisting of two nurses, one resident, and one consultant, participated in three acute care scenarios, using high-fidelity simulation. Individual SAGAT scores contained shared and complimentary knowledge questions on different levels of SA. Within each scenario, two "freezes" were incorporated to assess SA of each team members' clinical assessment and decision-making. SA overlap within the team (team SA) was computed and compared to indicators of team effectiveness (time to goal achievement, consensus on primary problem, diagnosis, task prioritization, leadership, and teamwork satisfaction). In 13 scenarios (18%), the team failed to reach the primary goals within the prescribed time of 1200 s. There was no significant difference in failure of goal completion between the scripted scenarios; however, there was a significant difference between scenario 3 and the other scenarios in time to goal completion. In all three scenarios, SA overlap level 2 (consensus on primary problem during the first freeze and consensus on diagnosis during the second freeze) leads to significantly faster achievement of the predefined goals. There was a strong relationship between team SA on the primary problem and diagnosis and team SA on task prioritization. Consensus on leadership within the team was low. Teamwork satisfaction was more influenced by knowledge about the importance of the assigned task than outcome of the scenario.Conclusion: The use of SAGAT enables us to measure SA of team members during real-time simulation of acute care scenarios. Although there is no direct connection between team SA and goal achievement, SAGAT provides insight in differences in SA among team members, and the process of shared mental model formation. By measuring SA, issues that may improve team effectiveness (prioritizing tasks, enhancing shared mental models, and providing leadership) can be trained and assessed during medical team simulation, enhancing teamwork in health care settings. What is known? • Teamwork skills such as communication, leadership, and situational awareness have become increasingly recognized as essential for good performance in pediatric resuscitation. However, the assessment of pediatric team performance in these clinical situations has been traditionally difficult. • The Situation Awareness Global Assessment Technique (SAGAT) is a method of objectively and directly measuring SA during a team simulation using "freezes" at predetermined points in time with participants reporting on "what is going on" from their perspective on the situation. What is new? • We assessed SA, and its relationship with team effectiveness, in multidisciplinary pediatric teams performing simulated critical events in critically ill children on the medical ward using the SAGAT model, outside the emergency room setting. • In all three scenarios, consensus on the primary problem (shared mental model) leads to faster achievement of predefined goals. Consensus on leadership was overall low, without a significant impact on goal achievement.

3.
Eur J Hum Genet ; 26(10): 1417-1423, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29904176

RESUMO

Constitutional MisMatch Repair Deficiency (CMMRD) is caused by homozygous or compound heterozygous germline variants in one of the mismatch repair (MMR) genes (MSH2, MSH6, PMS2, MLH1). This syndrome results in early onset colorectal cancer, leukemia and lymphoma, brain tumors and other malignancies. Children with CMMRD are at high risk of developing multiple cancers and cancer surveillance does not guarantee detection of cancer at a curable stage. The development of a preventive treatment strategy would be a major step forward. Long-term daily use of acetylsalicylic acid (ASA) has been shown to reduce cancer risk in individuals with Lynch syndrome (LS). LS is caused by heterozygous germline variants of MSH2, MSH6, PMS2 and MLH1 and characterized by an increased risk of developing colorectal and endometrial cancer at adult age. Here we discuss the potential use of ASA for cancer prevention in patients with CMMRD.

4.
Clin Cancer Res ; 24(7): 1594-1603, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29351919

RESUMO

Purpose: In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole-exome sequencing on a selected cohort of children with cancer.Experimental Design: To identify mutations in known and novel cancer-predisposing genes, we performed trio-based whole-exome sequencing on germline DNA of 40 selected children and their parents. These children were diagnosed with cancer and had at least one of the following features: (1) intellectual disability and/or congenital anomalies, (2) multiple malignancies, (3) family history of cancer, or (4) an adult type of cancer. We first analyzed the sequence data for germline mutations in 146 known cancer-predisposing genes. If no causative mutation was found, the analysis was extended to the whole exome.Results: Four patients carried causative mutations in a known cancer-predisposing gene: TP53 and DICER1 (n = 3). In another 4 patients, exome sequencing revealed mutations causing syndromes that might have contributed to the malignancy (EP300-based Rubinstein-Taybi syndrome, ARID1A-based Coffin-Siris syndrome, ACTB-based Baraitser-Winter syndrome, and EZH2-based Weaver syndrome). In addition, we identified two genes, KDM3B and TYK2, which are possibly involved in genetic cancer predisposition.Conclusions: In our selected cohort of patients, pathogenic germline mutations causative or likely causative of the cancer phenotype were found in 8 patients, and two possible novel cancer-predisposing genes were identified. Therewith, our study shows the added value of sequencing beyond a cancer gene panel in selected patients, to recognize childhood cancer predisposition. Clin Cancer Res; 24(7); 1594-603. ©2018 AACR.

5.
Front Immunol ; 9: 2912, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619276

RESUMO

Patients with inborn errors of immunity or DNA repair defects are at significant risk of developing malignancy and this complication of their underlying condition represents a substantial cause of morbidity and mortality. Whilst this risk is increasingly well-recognized, our understanding of the causative mechanisms remains incomplete. Diagnosing cancer is challenging in the presence of underlying co-morbidities and frequently other inflammatory and lymphoproliferative processes. We lack a structured approach to management despite recognizing the competing challenges of poor response to therapy and increased risk of toxicity. Finally, clinicians need guidance on how to screen for malignancy in many of these predisposing immunodeficiencies. In order to begin to address these challenges, we brought together representatives of European Immunology and Pediatric Haemato-Oncology to define the current state of our knowledge and identify priorities for clinical and research development. We propose key developmental priorities which our two communities will need to work together to address, collaborating with colleagues around the world.


Assuntos
Distúrbios no Reparo do DNA/complicações , Síndromes de Imunodeficiência/complicações , Neoplasias/diagnóstico , Neoplasias/terapia , Pesquisa , Alergia e Imunologia/tendências , Criança , Humanos , Comunicação Interdisciplinar , Oncologia/métodos , Oncologia/tendências , Neoplasias/complicações , Pediatria/métodos , Pediatria/tendências
6.
Dev Med Child Neurol ; 59(7): 680-689, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28318010

RESUMO

Ataxia-telangiectasia is a rare, neurodegenerative, and multisystem disease, characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure, and an increased risk of malignancies. It demands specialized care tailored to the individual patient's needs. Besides the classic ataxia-telangiectasia phenotype, a variant phenotype exists with partly overlapping but some distinctive disease characteristics. This guideline summarizes frequently encountered medical problems in the disease course of patients with classic and variant ataxia-telangiectasia, in the domains of neurology, immunology and infectious diseases, pulmonology, anaesthetic and perioperative risk, oncology, endocrinology, and nutrition. Furthermore, it provides a practical guide with evidence- and expert-based recommendations for the follow-up and treatment of all these different clinical topics.


Assuntos
Ataxia Telangiectasia/terapia , Ataxia Telangiectasia/diagnóstico , Humanos
7.
BMJ Open ; 7(1): e013237, 2017 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-28110285

RESUMO

INTRODUCTION: Recognising a tumour predisposition syndrome (TPS) in patients with childhood cancer is of significant clinical relevance, as it affects treatment, prognosis and facilitates genetic counselling. Previous studies revealed that only half of the known TPSs are recognised during standard paediatric cancer care. In current medical practice it is impossible to refer every patient with childhood cancer to a clinical geneticist, due to limited capacity for routine genetic consultation. Therefore, we have developed a screening instrument to identify patients with childhood cancer with a high probability of having a TPS. The aim of this study is to validate the clinical screening instrument for TPS in patients with childhood cancer. METHODS AND ANALYSIS: This study is a prospective nationwide cohort study including all newly diagnosed patients with childhood cancer in the Netherlands. The screening instrument consists of a checklist, two- and three-dimensional photographic series of the patient. 2 independent clinical geneticists will assess the content of the screening instrument. If a TPS is suspected based on the instrument data and thus further evaluation is indicated, the patient will be invited for full genetic consultation. A negative control group consists of 20% of the patients in whom a TPS is not suspected based on the instrument; they will be randomly invited for full genetic consultation. Primary outcome measurement will be sensitivity of the instrument. ETHICS AND DISSEMINATION: The Medical Ethical Committee of the Academic Medical Centre stated that the Medical Research Involving Human Subjects Act does not apply to this study and that official approval of this study by the Committee was not required. The results will be offered for publication in peer-reviewed journals and presented at International Conferences on Oncology and Clinical Genetics. The clinical data gathered in this study will be available for all participating centres. TRIAL REGISTRATION NUMBER: NTR5605.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Programas de Rastreamento/métodos , Neoplasias/genética , Adolescente , Lista de Checagem , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias/etiologia , Países Baixos , Fotografação , Estudos Prospectivos , Projetos de Pesquisa , Síndrome
8.
Haematologica ; 101(12): 1581-1591, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27515251

RESUMO

Children and adolescents with pre-existing conditions such as DNA repair defects or other primary immunodeficiencies have an increased risk of non-Hodgkin lymphoma. However, large-scale data on patients with non-Hodgkin lymphoma and their entire spectrum of pre-existing conditions are scarce. A retrospective multinational study was conducted by means of questionnaires sent out to the national study groups or centers, by the two largest consortia in childhood non-Hodgkin lymphoma, the European Intergroup for Childhood non-Hodgkin Lymphoma, and the international Berlin-Frankfurt-Münster Study Group. The study identified 213 patients with non-Hodgkin lymphoma and a pre-existing condition. Four subcategories were established: a) cancer predisposition syndromes (n=124, 58%); b) primary immunodeficiencies not further specified (n=27, 13%); c) genetic diseases with no increased cancer risk (n=40, 19%); and d) non-classifiable conditions (n=22, 10%). Seventy-nine of 124 (64%) cancer predispositions were reported in groups with more than 20 patients: ataxia telangiectasia (n=32), Nijmegen breakage syndrome (n=26), constitutional mismatch repair deficiency (n=21). For the 151 patients with a known cancer risk, 5-year event-free survival and overall survival rates were 40%±4% and 51%±4%, respectively. Five-year cumulative incidences of progression/relapse and treatment-related death as a first event were 22%±4% and 24%±4%, respectively. Ten-year incidence of second malignancy was 24%±5% and 7-year overall survival of the 21 patients with a second malignancy was 41%±11%. Patients with non-Hodgkin lymphoma and pre-existing conditions have an inferior survival rate with a large proportion of therapy-related deaths compared to patients with non-Hodgkin lymphoma and no pre-existing conditions. They may require special vigilance when receiving standard or modified/reduced-intensity chemotherapy or when undergoing allogeneic stem cell transplantation.


Assuntos
Comorbidade , Suscetibilidade a Doenças , Linfoma não Hodgkin/epidemiologia , Vigilância em Saúde Pública , Adolescente , Criança , Pré-Escolar , Terapia Combinada , Progressão da Doença , Feminino , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/terapia , Masculino , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Recidiva , Resultado do Tratamento
9.
Pediatr Rheumatol Online J ; 14(1): 18, 2016 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-27012661

RESUMO

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibro-inflammatory condition with an unclear pathophysiological mechanism affecting different parts of the body. If untreated, the disease can lead to fibrosis and irreversible organ damage. IgG4-RD mostly has been described in adults, hence it is generally unknown among pediatricians. This systematic search of the literature provides an overview of all reports published on IgG4-RD in children in order to create awareness of IgG4-RD in pediatrics and to emphasize the broad clinical presentation of this disease. METHODS: A systematic literature search of Embase, Medline, Web-of-Science, PubMed publisher, Cochrane and Google Scholar was performed for case reports on IgG4-RD in children. RESULTS: Of total 740 articles identified by the search, 22 case reports including 25 cases of IgG4-RD in children were found. The median age of the children was 13 years, of which 64 % were girls. IgG4-related orbital disease (44 %) and autoimmune pancreatitis type 1/IgG4-related pancreatitis (12 %) predominantly occurred. Less frequently, other manifestations as pulmonary manifestation, cholangitis and lymphadenopathy were also found. Almost all cases were histologically proven. Prednisone was the first choice of treatment leading to favorable clinical response in 83 % of the cases. Maintenance therapy with steroid sparing agents was required in 43 % of the cases needing therapy. Rituximab was successful in all 4 cases, whereas, the disease modifying rheumatic drugs (DMARDs) mycophenolate mofetil, azathioprine and methotrexate were effective in almost 50 % of the cases. CONCLUSION: IgG4-RD in children is a generally unknown disease among pediatricians, but several pediatric cases have been described. Prednisone is the first choice of treatment leading to disease remission in the majority of the cases. DMARDs and rituximab are alternative effective steroid sparing agents with more positive evidence for the latter.


Assuntos
Anticorpos Anti-Idiotípicos/imunologia , Doenças Autoimunes/imunologia , Autoimunidade , Imunoglobulina G/imunologia , Inflamação/imunologia , Adolescente , Criança , Humanos
10.
Eur J Med Genet ; 59(3): 116-25, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26825391

RESUMO

Genetic predisposition for childhood cancer is under diagnosed. Identifying these patients may lead to therapy adjustments in case of syndrome-related increased toxicity or resistant disease and syndrome-specific screening programs may lead to early detection of a further independent malignancy. Cancer surveillance might also be warranted for affected relatives and detection of a genetic mutation can allow for reproductive counseling. Here we present an easy-to-use selection tool, based on a systematic review of pediatric cancer predisposing syndromes, to identify patients who may benefit from genetic counseling. The selection tool involves five questions concerning family history, the type of malignancy, multiple primary malignancies, specific features and excessive toxicity, which results in the selection of those patients that may benefit from referral to a clinical geneticist.


Assuntos
Predisposição Genética para Doença , Neoplasias/epidemiologia , Neoplasias/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/genética , Fatores Etários , Criança , Pré-Escolar , Estudos de Associação Genética , Humanos , Neoplasias/diagnóstico , Fenótipo , Vigilância da População/métodos , Risco , Síndrome
11.
Cancer ; 122(4): 642-50, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26588808

RESUMO

BACKGROUND: Current treatment strategies in pediatric oncology are intensive and lead to high survival rates but also to treatment-related complications. Therefore, supportive care plays an increasingly important role. This study was designed to evaluate variations in supportive care practice in children with cancer in the Netherlands and adherence to selected existing international guidelines through an in-depth review of local guidelines and protocols at all 6 Dutch pediatric cancer centers. METHODS: Based on shared expert opinion, a questionnaire regarding current supportive care practice was compiled. For each center, the required information was extracted from local supportive care guidelines, and the list was sent to a pediatric oncologist of that center to verify its correspondence with local daily practice. Subsequently, it was determined whether clinical practice was concordant (same in ≥ 5 of 6 centers), partly concordant (highly overlapping in ≥ 5 of 6 centers), or discordant (same in < 5 of 6 centers). Local practices were compared with strong recommendations from high-quality, evidence-based guidelines. RESULTS: The questionnaire comprised 67 questions regarding supportive care practice. Concordance was observed for 11 of 67 practice items (16%), partial concordance was observed for 6 of 67 practice items (9%), and discordance was observed for 50 of 67 practice items (75%). Adherence to strong recommendations of 4 high-quality, evidence-based guidelines varied but was generally low. CONCLUSIONS: Large variations exist in pediatric oncology supportive care practice, and this could negatively influence care. Adherence to existing evidence-based guidelines and the development and implementation of new clinical practice guidelines have the potential of standardizing supportive care practice and thereby improving outcomes for children with cancer.


Assuntos
Antineoplásicos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Oncologia , Neoplasias/terapia , Manejo da Dor/métodos , Cuidados Paliativos/métodos , Padrões de Prática Médica , Lesões por Radiação/prevenção & controle , Radioterapia/efeitos adversos , Criança , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Medicina Baseada em Evidências , Humanos , Países Baixos , Guias de Prática Clínica como Assunto , Lesões por Radiação/diagnóstico , Lesões por Radiação/terapia , Inquéritos e Questionários
12.
Ned Tijdschr Geneeskd ; 159: A8602, 2015.
Artigo em Holandês | MEDLINE | ID: mdl-26200421

RESUMO

BACKGROUND: Constitutional mismatch repair deficiency (CMMR-D) syndrome is characterised by a significantly increased risk for developing cancer in childhood. It arises when both parents have a mutation in the same mismatch repair gene and pass it on to their child. CASE DESCRIPTION: An 8-year-old girl was diagnosed with CMMR-D syndrome after she developed a brain tumour at the age of 4 and a T-cell non-Hodgkin lymphoma at the age of 6. She had multiple hyperpigmented skin lesions and died of myelodysplastic syndrome at the age of 11. CONCLUSION: In children with cancer CMMR-D syndrome can be recognized particularly if there are multiple primary malignancies and skin hyperpigmentations and hypopigmentations. The parents of these children are at high risk for colorectal and endometrial cancer (Lynch syndrome), amongst others.


Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Colorretais/diagnóstico , Linfoma não Hodgkin/diagnóstico , Síndromes Neoplásicas Hereditárias/diagnóstico , Neoplasias Encefálicas/genética , Criança , Neoplasias Colorretais/genética , Proteínas de Ligação a DNA/genética , Evolução Fatal , Feminino , Humanos , Linfoma não Hodgkin/genética , Mutação , Neoplasias Primárias Múltiplas , Síndromes Neoplásicas Hereditárias/genética
13.
Adv Med Educ Pract ; 6: 19-26, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25610010

RESUMO

PURPOSE: Leadership has been identified as a key variable for the functioning of teams and as one of the main reasons for success or failure of team-based work systems. Pediatricians often function as team leaders in the resuscitation of a critically ill child. However, pediatric residents often report having little opportunity to perform in the role of team leader during residency. In order to gain more insight into leadership skills and behaviors, we classified leadership styles of pediatric residents during simulated emergencies. METHODS: We conducted a prospective quantitative study to investigate leadership styles used by pediatric residents during simulated emergencies with clinical deterioration of a child at a pediatric ward. Using videotaped scenarios of 48 simulated critical events among 12 residents, we were able to classify verbal and nonverbal communication into different leadership styles according to the situational leadership theory. RESULTS: The coaching style (mean 54.5%, SD 7.8) is the most frequently applied by residents, followed by the directing style (mean 35.6%, SD 4.1). This pattern conforms to the task- and role-related requirements in our scenarios and it also conforms to the concept of situational leadership. We did not find any significant differences in leadership style according to the postgraduate year or scenario content. CONCLUSION: The model used in this pilot study helps us to gain a better understanding of the development of effective leadership behavior and supports the applicability of situational leadership theory in training leadership skills during residency.

14.
Eur J Pediatr ; 174(1): 15-21, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24942238

RESUMO

UNLABELLED: Timely recognition of deterioration of hospitalised children is important to improve mortality. We developed a modified Paediatric Early Warning Score (PEWS) and studied the effects by performing three different cohort studies using different end points. Taking unplanned Paediatric Intensive Care Unit admission as end point and only using data until 2 h prior to end point, we found a sensitivity of 0.67 and specificity of 0.88 to timely recognise patients. This proves that earlier identification is possible without a loss of sensitivity compared to other PEWS systems. When determining the corresponding clinical condition in patients with an elevated PEWS dichotomously as 'sick' or 'well', this resulted in a total of 27 % false-positive scores. This can cause motivational problems for caregivers to use the system but is a consequence of PEWS design to minimise false-negative rates because of high mortality associated with paediatric resuscitation. Using the need for emergency medical interventions as end point, sensitivity of PEWS is high and it seems, therefore, that it is also fit to alert health-care professionals that urgent interventions may be needed. CONCLUSION: These data show the effectiveness of a modified PEWS in identifying critically ill patients in an early phase making early interventions possible and hopefully reduce mortality.


Assuntos
Estado Terminal , Intervenção Médica Precoce/métodos , Avaliação de Resultados da Assistência ao Paciente , Índice de Gravidade de Doença , Criança , Criança Hospitalizada , Estudos de Coortes , Diagnóstico Precoce , Equipe de Respostas Rápidas de Hospitais/estatística & dados numéricos , Humanos , Unidades de Terapia Intensiva Pediátrica
15.
Eur J Pediatr ; 172(1): 31-7, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22991098

RESUMO

Although complementary and alternative medicine (CAM) is widely used in the pediatric population, research on the use of these therapies in the pediatric oncology population is of mixed quality. In this multicenter survey, we investigated the prevalence of CAM use, possible determinants of use, and parental attitude towards communication and research on CAM therapies. The prevalence of CAM use in the past 12 months was assessed by using a questionnaire based on the European guidelines on CAM research, filled out by parents of children visiting pediatric oncology outpatient clinics of six academic hospitals in the Netherlands. The questionnaire consisted of 26 questions on the child's clinical status, CAM use, and attitude towards communication and research on CAM therapies. One hundred and twenty-two of 288 respondents (42.4 %) reported CAM use. The most frequently used categories were homeopathy (18.8 %) and dietary supplements (11.5 %). Female gender and parental CAM use were significant predictors for the use of CAM (p < 0.001). Only one third of the parents had discussed CAM use with their pediatric oncologist. More than 80 % of the respondents identified a need for information about CAM from their pediatrician and 85.7 % was positive towards research on CAM. Half of the parents were interested in participating in future CAM trials. Conclusion, with more than 40 % of parents of Dutch pediatric oncology patients providing complementary and alternative medicine to their child and with lacking evidence on efficacy and safety of most CAM modalities, there is a clear need for high-quality research in this field. This study shows that most parents have an open attitude towards CAM research and that almost half of the parents would consider participating in future CAM trials, paving the way for research on CAM and aiming for its evidence-based use in pediatric oncology.


Assuntos
Terapias Complementares/estatística & dados numéricos , Neoplasias/terapia , Adolescente , Atitude Frente a Saúde , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Países Baixos/epidemiologia , Pais , Prevalência , Estudos Prospectivos , Inquéritos e Questionários , Adulto Jovem
16.
Anticancer Res ; 32(10): 4485-97, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23060577

RESUMO

BACKGROUND: The prognosis of rhabdomyosarcoma (RMS) in children and adolescents has improved since the introduction of multi-agent chemotherapy. However, outcome data of adults with RMS are scarce. This multicenter retrospective study investigated the effect of age on outcome of RMS. PATIENTS AND METHODS: Data were collected from three Dutch University Medical Centers between 1977-2009. The effect of age and clinical prognostic factors on relapse-free and disease-specific survival (DSS) were analyzed. RESULTS: Age as a continuous variable predicted poor survival in multivariate analysis. Five-year DSS was highest for non-metastatic embryonal RMS, followed by non-metastatic alveolar RMS and was poor in metastatic disease. Higher age correlated with unfavorable histological subtype (alveolar RMS) and with metastatic disease at presentation in embryonal RMS. In non-metastatic embryonal RMS and in all alveolar RMS, higher age was an adverse prognostic factor of outcome. CONCLUSION: This study indicates that age is a negative predictor of survival in patients with embryonal and alveolar RMS.


Assuntos
Rabdomiossarcoma Alveolar/mortalidade , Rabdomiossarcoma Embrionário/mortalidade , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Rabdomiossarcoma Alveolar/secundário , Rabdomiossarcoma Embrionário/secundário , Resultado do Tratamento , Adulto Jovem
17.
Int J Pediatr ; 2012: 709569, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22518181

RESUMO

Background. Video-assisted real-time simulation (VARS) offers the possibility of developing competence in acute medicine in a realistic and safe environment. We investigated the effectiveness of the VARS model and compared it with educational methods like Problem-Based Learning (PBL) and Pediatric Advanced Life Support (PALS). Methods. 45 fourth-year medical students were randomized for three educational methods. Level of knowledge and self-efficacy were measured before and after intervention. Clinical performance was measured by a blinded observer using a video checklist of prescripted scenarios on a high-fidelity simulator. Results. Knowledge test and self-efficacy scores improved significantly (P < 0.001) without differences between educational groups. The VARS group showed significantly (P < 0.05) higher scores on both postintervention scenarios concerning structure and time. Conclusion. VARS training is an effective educational method teaching pediatric acute care skills in the undergraduate curriculum. When compared to PBL and PALS training, VARS training appears to be superior in enhancing short-term clinical performance.

18.
Pediatr Blood Cancer ; 58(4): 598-605, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21755595

RESUMO

BACKGROUND: UNC13D, encoding the protein munc13-4, is essential in intracellular trafficking and exocytosis of lytic granules. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis type 3 (FHL3), a genetically heterogeneous, rare autosomal recessive immune disorder. How mutations affect function of munc13-4 is poorly understood. Since 2006 we genetically identified seven FHL patients with mutations in UNC13D. PROCEDURES: Here, we report for the first time a c.2695C>T (p.Arg899X) mutation in exon 28 of UNC13D in three young unrelated Dutch patients. The mutation causes a premature stop codon and encodes munc13-4(1-899), which lacks the C-terminal C2 domain. Genealogical research and haplotyping of the patient families demonstrated that a single ancestral founder introduced the mutation in the Netherlands. We then characterized the mutant protein phenotypically in cell biological and immunological assays. RESULTS: Munc13-4(1-899) was correctly targeted to CD63-positive secretory lysosomes, although its stability was reduced and dynamic turnover on the granule membrane became uncoupled from receptor signaling. In accord, and in contrast to wild-type munc13-4, ectopically expressed mutant failed to rescue degranulation in cells with silenced endogenous munc13-4. CONCLUSIONS: The functional and clinical data showed that this novel Dutch founder mutation leads to severe early onset of FHL3 due to misfolding and degradation of munc13-4(1-899).


Assuntos
Códon de Terminação , Linfo-Histiocitose Hemofagocítica , Proteínas de Membrana , Mutação Puntual , Dobramento de Proteína , Proteínas , Proteólise , Animais , Degranulação Celular/genética , Linhagem Celular Tumoral , Humanos , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/metabolismo , Lisossomos/genética , Lisossomos/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Países Baixos , Estrutura Terciária de Proteína , Proteínas/genética , Proteínas/metabolismo , Ratos , Tetraspanina 30/genética , Tetraspanina 30/metabolismo
20.
Pediatr Blood Cancer ; 50(4): 886-8, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17668865

RESUMO

Post-transplant lymphoproliferative disorder (PTLD) in the central nervous system (CNS) has a poor prognosis. New therapeutic approaches should be explored. We report our experience with intrathecal administration of rituximab in a 10-year-old kidney allograft recipient with PTLD in the CNS. After standard treatment had failed, we tried to treat the patient by administering rituximab directly into the cerebral ventricle through an Omaya reservoir, in addition to conventional intrathecal and systemic chemotherapy. This strategy resulted in a disappearance of clinical symptoms and a negative positron emission tomogram. Intrathecal administration of rituximab may be a feasible approach in children with PTLD in the CNS. However, its specific role in our patient remains uncertain.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Transplante de Rim/efeitos adversos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Anticorpos Monoclonais Murinos , Neoplasias Encefálicas/virologia , Criança , Infecções por Vírus Epstein-Barr/complicações , Feminino , Humanos , Injeções Intraventriculares , Injeções Espinhais , Linfoma Difuso de Grandes Células B/virologia , Síndrome Nefrótica/cirurgia , Complicações Pós-Operatórias , Rituximab
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