RESUMO
Importance: The quality of routine care for children is rarely assessed, and then usually in single settings or for single clinical conditions. Objective: To estimate the quality of health care for children in Australia in inpatient and ambulatory health care settings. Design, Setting, and Participants: Multistage stratified sample with medical record review to assess adherence with quality indicators extracted from clinical practice guidelines for 17 common, high-burden clinical conditions (noncommunicable [n = 5], mental health [n = 4], acute infection [n = 7], and injury [n = 1]), such as asthma, attention-deficit/hyperactivity disorder, tonsillitis, and head injury. For these 17 conditions, 479 quality indicators were identified, with the number varying by condition, ranging from 9 for eczema to 54 for head injury. Four hundred medical records were targeted for sampling for each of 15 conditions while 267 records were targeted for anxiety and 133 for depression. Within each selected medical record, all visits for the 17 targeted conditions were identified, and separate quality assessments made for each. Care was evaluated for 6689 children 15 years of age and younger who had 15â¯240 visits to emergency departments, for inpatient admissions, or to pediatricians and general practitioners in selected urban and rural locations in 3 Australian states. These visits generated 160â¯202 quality indicator assessments. Exposures: Quality indicators were identified through a systematic search of local and international guidelines. Individual indicators were extracted from guidelines and assessed using a 2-stage Delphi process. Main Outcomes and Measures: Quality of care for each clinical condition and overall. Results: Of 6689 children with surveyed medical records, 53.6% were aged 0 to 4 years and 55.5% were male. Adherence to quality of care indicators was estimated at 59.8% (95% CI, 57.5%-62.0%; n = 160â¯202) across the 17 conditions, ranging from a high of 88.8% (95% CI, 83.0%-93.1%; n = 2638) for autism to a low of 43.5% (95% CI, 36.8%-50.4%; n = 2354) for tonsillitis. The mean adherence by condition category was estimated as 60.5% (95% CI, 57.2%-63.8%; n = 41â¯265) for noncommunicable conditions (range, 52.8%-75.8%); 82.4% (95% CI, 79.0%-85.5%; n = 14â¯622) for mental health conditions (range, 71.5%-88.8%); 56.3% (95% CI, 53.2%-59.4%; n = 94â¯037) for acute infections (range, 43.5%-69.8%); and 78.3% (95% CI, 75.1%-81.2%; n = 10â¯278) for injury. Conclusions and Relevance: Among a sample of children receiving care in Australia in 2012-2013, the overall prevalence of adherence to quality of care indicators for important conditions was not high. For many of these conditions, the quality of care may be inadequate.
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Serviços de Saúde da Criança/normas , Fidelidade a Diretrizes/estatística & dados numéricos , Indicadores de Qualidade em Assistência à Saúde , Qualidade da Assistência à Saúde/estatística & dados numéricos , Adolescente , Austrália , Criança , Pré-Escolar , Gerenciamento Clínico , Feminino , Humanos , Lactente , Recém-Nascido , MasculinoRESUMO
BACKGROUND: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner. METHODS: We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival. FINDINGS: We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084). INTERPRETATION: The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection. FUNDING: Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research.
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Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/cirurgia , Meduloblastoma/classificação , Meduloblastoma/cirurgia , Prognóstico , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Canadá , Criança , Pré-Escolar , Terapia Combinada , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Meduloblastoma/genética , Meduloblastoma/patologia , Estudos RetrospectivosRESUMO
Childhood acute myeloid leukaemia (AML) requires intensive therapy and is associated with survival rates that are substantially inferior to many other childhood malignancies. We undertook a retrospective analysis of Australian Paediatric Cancer Registry data from 1997 to 2008 together with a single-centre audit during the same period assessing burden on service delivery at a tertiary children's hospital (Royal Children's Hospital, Brisbane). Although survival improved from 54.3% (1997-2002) to 69.2% (2003-2008), childhood AML caused a disproportionate number of childhood cancer deaths, accounting for 5.5% of all childhood cancer diagnoses yet 7.9% of all childhood cancer mortality. Furthermore, treatment was associated with significant toxicity requiring intensive use of local health resources. Novel therapeutic strategies aimed at improving survival and reducing toxicity are urgently required.
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Recursos em Saúde/estatística & dados numéricos , Leucemia Mieloide Aguda/epidemiologia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Austrália/epidemiologia , Criança , Pré-Escolar , Terapia Combinada , Efeitos Psicossociais da Doença , Infecção Hospitalar/epidemiologia , Feminino , Transplante de Células-Tronco Hematopoéticas , Hospitais Pediátricos/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Tempo de Internação/estatística & dados numéricos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/terapia , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Leucemia Mielomonocítica Aguda/epidemiologia , Leucemia Mielomonocítica Aguda/terapia , Masculino , Infecções Oportunistas/epidemiologia , Sistema de Registros , Estudos Retrospectivos , Taxa de Sobrevida , Centros de Atenção Terciária/estatística & dados numéricos , Resultado do TratamentoRESUMO
The mechanisms of retinoid activity in tumors remain largely unknown. Here we establish that retinoids cause extensive apoptosis of medulloblastoma cells. In a xenograft model, retinoids largely abrogated tumor growth. Using receptor-specific retinoid agonists, we defined a subset of mRNAs that were induced by all active retinoids in retinoid-sensitive cell lines. We also identified bone morphogenetic protein-2 (BMP-2) as a candidate mediator of retinoid activity. BMP-2 protein induced medulloblastoma cell apoptosis, whereas the BMP-2 antagonist noggin blocked both retinoid and BMP-2-induced apoptosis. BMP-2 also induced p38 mitogen-activated protein kinase (MAPK), which is necessary for BMP-2- and retinoid-induced apoptosis. Retinoid-resistant medulloblastoma cells underwent apoptosis when treated with BMP-2 or when cultured with retinoid-sensitive medulloblastoma cells. Retinoid-induced expression of BMP-2 is thus necessary and sufficient for apoptosis of retinoid-responsive cells, and expression of BMP-2 by retinoid-sensitive cells is sufficient to induce apoptosis in surrounding retinoid-resistant cells.
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Apoptose , Proteínas Morfogenéticas Ósseas/metabolismo , Neoplasias Encefálicas/metabolismo , Meduloblastoma/metabolismo , Comunicação Parácrina , Retinoides/farmacologia , Fator de Crescimento Transformador beta , Animais , Proteína Morfogenética Óssea 2 , Receptores de Proteínas Morfogenéticas Ósseas , Neoplasias Encefálicas/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Meduloblastoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Receptores de Fatores de Crescimento/genética , Receptores de Fatores de Crescimento/metabolismo , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
BACKGROUND: In order to determine the extent to which care delivered to children is appropriate (in line with evidence-based care and/or clinical practice guidelines (CPGs)) in Australia, we developed a set of clinical indicators for 21 common paediatric medical conditions for use across a range of primary, secondary and tertiary healthcare practice facilities. METHODS: Clinical indicators were extracted from recommendations found through systematic searches of national and international guidelines, and formatted with explicit criteria for inclusion, exclusion, time frame and setting. Experts reviewed the indicators using a multi-round modified Delphi process and collaborative online wiki to develop consensus on what constituted appropriate care. RESULTS: From 121 clinical practice guidelines, 1098 recommendations were used to draft 451 proposed appropriateness indicators. In total, 61 experts (n = 24 internal reviewers, n = 37 external reviewers) reviewed these indicators over 40 weeks. A final set of 234 indicators resulted, from which 597 indicator items were derived suitable for medical record audit. Most indicator items were geared towards capturing information about under-use in healthcare (n = 551, 92%) across emergency department (n = 457, 77%), hospital (n = 450, 75%) and general practice (n = 434, 73%) healthcare facilities, and based on consensus level recommendations (n = 451, 76%). The main reason for rejecting indicators was 'feasibility' (likely to be able to be used for determining compliance with 'appropriate care' from medical record audit). CONCLUSION: A set of indicators was developed for the appropriateness of care for 21 paediatric conditions. We describe the processes (methods), provenance (origins and evolution of indicators) and products (indicator characteristics) of creating clinical indicators within the context of Australian healthcare settings. Developing consensus on clinical appropriateness indicators using a Delphi approach and collaborative online wiki has methodological utility. The final indicator set can be used by clinicians and organisations to measure and reflect on their own practice.
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Medicina Baseada em Evidências , Pediatria/normas , Indicadores de Qualidade em Assistência à Saúde , Austrália , Criança , Humanos , Garantia da Qualidade dos Cuidados de SaúdeRESUMO
BACKGROUND: Alternative splicing of pre-messenger RNA results in RNA variants with combinations of selected exons. It is one of the essential biological functions and regulatory components in higher eukaryotic cells. Some of these variants are detectable with the Affymetrix GeneChip that uses multiple oligonucleotide probes (i.e. probe set), since the target sequences for the multiple probes are adjacent within each gene. Hybridization intensity from a probe correlates with abundance of the corresponding transcript. Although the multiple-probe feature in the current GeneChip was designed to assess expression values of individual genes, it also measures transcriptional abundance for a sub-region of a gene sequence. This additional capacity motivated us to develop a method to predict alternative splicing, taking advance of extensive repositories of GeneChip gene expression array data. RESULTS: We developed a two-step approach to predict alternative splicing from GeneChip data. First, we clustered the probes from a probe set into pseudo-exons based on similarity of probe intensities and physical adjacency. A pseudo-exon is defined as a sequence in the gene within which multiple probes have comparable probe intensity values. Second, for each pseudo-exon, we assessed the statistical significance of the difference in probe intensity between two groups of samples. Differentially expressed pseudo-exons are predicted to be alternatively spliced. We applied our method to empirical data generated from GeneChip Hu6800 arrays, which include 7129 probe sets and twenty probes per probe set. The dataset consists of sixty-nine medulloblastoma (27 metastatic and 42 non-metastatic) samples and four cerebellum samples as normal controls. We predicted that 577 genes would be alternatively spliced when we compared normal cerebellum samples to medulloblastomas, and predicted that thirteen genes would be alternatively spliced when we compared metastatic medulloblastomas to non-metastatic ones. We checked the consistency of some of our findings with information in UCSC Human Genome Browser. CONCLUSION: The two-step approach described in this paper is capable of predicting some alternative splicing from multiple oligonucleotide-based gene expression array data with GeneChip technology. Our method employs the extensive repositories of gene expression array data available and generates alternative splicing hypotheses, which can be further validated by experimental studies.
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Processamento Alternativo/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Algoritmos , Cerebelo/metabolismo , Simulação por Computador , Éxons/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Meduloblastoma/genética , RNA/genéticaRESUMO
To develop a genetically faithful model of medulloblastoma with increased tumor incidence compared with the current best model we activated the Sonic Hedgehog (Shh) pathway by transgenically expressing a constitutively active form of Smoothened in mouse cerebellar granule neuron precursors (ND2:SmoA1 mice). This resulted in early cerebellar granule cell hyper-proliferation and a 48% incidence of medulloblastoma formation. Gene expression studies showed an increase in the known Shh targets Gli1 and Nmyc that correlated with increasing hyperplasia and tumor formation. Notch2 and the Notch target gene, HES5, were also significantly elevated in Smoothened-induced tumors showing that Shh pathway activation is sufficient to induce Notch pathway signaling. In human medulloblastomas reverse transcription-PCR for Shh and Notch targets revealed activation of both of these pathways in most tumors when compared with normal cerebellum. Notch pathway inhibition with soluble Delta ligand or gamma secretase inhibitors resulted in a marked reduction of viable cell numbers in medulloblastoma cell lines and primary tumor cultures. Treatment of mice with D283 medulloblastoma xenografts with a gamma secretase inhibitor resulted in decreased proliferation and increased apoptosis, confirming that Notch signaling contributes to human medulloblastoma proliferation and survival. Medulloblastomas in ND2:SmoA1 mice and humans have concomitant increase in Shh and Notch pathway activities, both of which contribute to tumor survival.
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Neoplasias Cerebelares/patologia , Meduloblastoma/patologia , Proteínas de Membrana/fisiologia , Transdução de Sinais/fisiologia , Transativadores/fisiologia , Adolescente , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Cerebelo/metabolismo , Cerebelo/patologia , Criança , Proteínas Hedgehog , Humanos , Hiperplasia , Camundongos , Camundongos Endogâmicos C57BL , Receptores NotchRESUMO
Recent studies show that activation of p38 mitogen-activated protein kinase (MAPK) results in cancer cell apoptosis initiated by retinoids, cisplatin and other chemotherapeutic agents. The observation that divergent therapies act through a common signal transduction pathway raises the possibility of developing new anti-cancer agents that lack the side-effects caused by events upstream of p38 MAPK. Here, we review p38-MAPK-mediated tumor cell apoptosis and implications for cancer therapeutics.
Assuntos
Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Cisplatino/farmacologia , Desenho de Fármacos , Ativação Enzimática , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias/enzimologia , Retinoides/farmacologia , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
Despite aggressive chemotherapy, approximately one-third of children with acute myeloid leukaemia (AML) relapse. More effective treatments are urgently needed. Survivin is an inhibitor-of-apoptosis protein with key roles in regulating cell division, proliferation and apoptosis. Furthermore, high expression of Survivin has been associated with poor clinical outcome in AML. The survivin suppressant YM155 (Sepantronium Bromide) has pre-clinical activity against a range of solid cancers and leukemias, although data in AML is limited. Therefore, we undertook a comprehensive pre-clinical evaluation of YM155 in paediatric AML. YM155 potently inhibited cell viability in a diverse panel of AML cell lines. All paediatric cell lines were particularly sensitive, with a median IC50 of 0.038 µM. Cell cycle analyses demonstrated concentration-dependent increases in a sub-G1 population with YM155 treatment, suggestive of apoptosis that was subsequently confirmed by an increase in annexin-V positivity. YM155-mediated apoptosis was confirmed across a panel of 8 diagnostic bone marrow samples from children with AML. Consistent with the proposed mechanism of action, YM155 treatment was associated with down-regulation of survivin mRNA and protein expression and induction of DNA damage. These data suggest that YM155-mediated inhibition of survivin is a potentially beneficial therapeutic strategy for AML, particularly paediatric disease, and warrants further evaluation.
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Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Imidazóis/farmacologia , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Naftoquinonas/farmacologia , Western Blotting , Criança , Citometria de Fluxo , Humanos , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Leucemia Mieloide Aguda/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Survivina , Células Tumorais CultivadasRESUMO
BACKGROUND: Conditional survival estimates take into account the time that a patient has remained alive following diagnosis to provide a realistic perspective on the probability of longer term survival. Such estimates are scarce for childhood cancer, particularly by age at diagnosis or stage of cancer. METHODS: De-identified population-based data were obtained from the Australian Paediatric Cancer Registry for children aged 0-14 years diagnosed with cancer between 1983 and 2010. Mortality status was followed up to the end of 2011. The hybrid period method was used to calculate relative survival estimates for those who were at risk during the period 2002-2011. Conditional survival stratified by diagnostic group or subgroup, age and stage at diagnosis was then obtained from the ratio of the relative survival estimates at different time points. RESULTS: A total of 13,537 children were eligible for inclusion. Five-year survival for all childhood cancers combined improved from 82% at diagnosis (95% confidence interval=81-83%) to 89% (88-90%) conditional on surviving one year, and 97% (97-98%) conditional on surviving five years after diagnosis. Conditional survival reached 95% within five years of diagnosis for nearly all types of cancer, regardless of a child's age or stage at diagnosis. CONCLUSION: Most children diagnosed with cancer who are alive five years after diagnosis can anticipate similar survival to children in the general population. This information may help alleviate some of the distress associated with childhood cancer, particularly for those with an initially poor prognosis.
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Neoplasias/mortalidade , Sistema de Registros , Adolescente , Fatores Etários , Austrália/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Projetos de Pesquisa , Taxa de Sobrevida , Fatores de TempoRESUMO
INTRODUCTION: A high-quality health system should deliver care that is free from harm. Few large-scale studies of adverse events have been undertaken in children's healthcare internationally, and none in Australia. The aim of this study is to measure the frequency and types of adverse events encountered in Australian paediatric care in a range of healthcare settings. METHODS AND ANALYSIS: A form of retrospective medical record review, the Institute of Healthcare Improvement's Global Trigger Tool, will be modified to collect data. Records of children aged <16â years managed during 2012 and 2013 will be reviewed. We aim to review 6000-8000 records from a sample of healthcare practices (hospitals, general practices and specialists). ETHICS AND DISSEMINATION: Human Research Ethics Committee approvals have been received from the Sydney Children's Hospital Network, Children's Health Queensland Hospital and Health Service, and the Women's and Children's Hospital Network in South Australia. An application is under review with the Royal Australian College of General Practitioners. The authors will submit the results of the study to relevant journals and undertake national and international oral presentations to researchers, clinicians and policymakers.
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Serviços de Saúde da Criança/normas , Erros Médicos , Segurança do Paciente , Garantia da Qualidade dos Cuidados de Saúde , Indicadores de Qualidade em Assistência à Saúde , Adolescente , Austrália , Criança , Pré-Escolar , Protocolos Clínicos , Humanos , Lactente , Recém-Nascido , Erros Médicos/prevenção & controle , Prontuários Médicos , Estudos RetrospectivosRESUMO
Genomic characterization of medulloblastoma has improved molecular risk classification but struggles to define functional biological processes, particularly for the most aggressive subgroups. We present here a novel proteomic approach to this problem using a reference library of stable isotope labeled medulloblastoma-specific proteins as a spike-in standard for accurate quantification of the tumor proteome. Utilizing high-resolution mass spectrometry, we quantified the tumor proteome of group 3 medulloblastoma cells and demonstrate that high-risk MYC amplified tumors can be segregated based on protein expression patterns. We cross-validated the differentially expressed protein candidates using an independent transcriptomic data set and further confirmed them in a separate cohort of medulloblastoma tissue samples to identify the most robust proteogenomic differences. Interestingly, highly expressed proteins associated with MYC-amplified tumors were significantly related to glycolytic metabolic pathways via alternative splicing of pyruvate kinase (PKM) by heterogeneous ribonucleoproteins (HNRNPs). Furthermore, when maintained under hypoxic conditions, these MYC-amplified tumors demonstrated increased viability compared to non-amplified tumors within the same subgroup. Taken together, these findings highlight the power of proteomics as an integrative platform to help prioritize genetic and molecular drivers of cancer biology and behavior.
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Biomarcadores Tumorais/genética , Neoplasias Cerebelares/genética , Meduloblastoma/genética , Proteômica/métodos , Linhagem Celular Tumoral , Neoplasias Cerebelares/patologia , Humanos , Espectrometria de Massas , Meduloblastoma/patologia , Fatores de RiscoRESUMO
INTRODUCTION: Australian and international clinical practice guidelines are available for common paediatric conditions. Yet there is evidence that there are substantial variations between the guidelines, recommendations (appropriate care) and the care delivered. This paper describes a study protocol to determine the appropriateness of the healthcare delivered to Australian children for 16 common paediatric conditions in acute and primary healthcare settings. METHODS AND ANALYSIS: A random sample of 6000-8000 medical records representing a cross-section of the Australian paediatric population will be reviewed for appropriateness of care against a set of indicators within three Australian states (New South Wales, Queensland and South Australia) using multistage, stratified sampling. Medical records of children aged <16â years who presented with at least one of the study conditions during 2012 and 2013 will be reviewed. ETHICS AND DISSEMINATION: Human Research Ethics Committee approvals have been received from the Sydney Children's Hospital Network, Children's Health Queensland Hospital and Health Service and Women's and Children's Hospital Network (South Australia). An application is under review for the Royal Australian College of General Practitioners. The authors will submit the results of the study to relevant journals and offer oral presentations to researchers, clinicians and policymakers at national and international conferences.
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Serviços de Saúde da Criança/normas , Fidelidade a Diretrizes , Pediatria/normas , Padrões de Prática Médica/normas , Garantia da Qualidade dos Cuidados de Saúde , Adolescente , Austrália , Criança , Pré-Escolar , Protocolos Clínicos , Humanos , Lactente , Recém-Nascido , Prontuários Médicos , Indicadores de Qualidade em Assistência à Saúde , Estudos RetrospectivosRESUMO
INTRODUCTION: Despite the widespread availability of clinical guidelines, considerable gaps remain between the care that is recommended (appropriate care) and the care provided. This protocol describes a research methodology to develop clinical indicators for appropriate care for common paediatric conditions. METHODS AND ANALYSIS: We will identify conditions amenable to population-level appropriateness of care research and develop clinical indicators for each condition. Candidate conditions have been identified from published research; burden of disease, prevalence and frequency of presentation data; and quality of care priority lists. Clinical indicators will be developed through searches of national and international guidelines, and formatted with explicit criteria for inclusion, exclusion, time frame and setting. Experts will review the indicators using a wiki-based approach and modified Delphi process. A formative evaluation of the wiki process will be undertaken. ETHICS AND DISSEMINATION: Human Research Ethics Committee approvals have been received from Sydney Children's Hospital Network, Children's Health Queensland Hospital and Health Service, and the Women's and Children's Health Network (South Australia). Applications are under review with Macquarie University and the Royal Australian College of General Practitioners. We will submit the results of the study to relevant journals and offer national and international presentations.
Assuntos
Serviços de Saúde da Criança/normas , Pediatria/normas , Garantia da Qualidade dos Cuidados de Saúde/métodos , Indicadores de Qualidade em Assistência à Saúde , Adolescente , Austrália , Criança , Pré-Escolar , Protocolos Clínicos , Humanos , Lactente , Recém-NascidoRESUMO
BACKGROUND: Resistance to radiation treatment remains a major clinical problem for patients with brain cancer. Medulloblastoma is the most common malignant brain tumor of childhood, and occurs in the cerebellum. Though radiation treatment has been critical in increasing survival rates in recent decades, the presence of resistant cells in a substantial number of medulloblastoma patients leads to relapse and death. METHODS: Using the established medulloblastoma cell lines UW228 and Daoy, we developed a novel model system to enrich for and study radiation tolerant cells early after radiation exposure. Using fluorescence-activated cell sorting, dead cells and cells that had initiated apoptosis were removed, allowing surviving cells to be investigated before extensive proliferation took place. RESULTS: Isolated surviving cells were tumorigenic in vivo and displayed elevated levels of ABCG2, an ABC transporter linked to stem cell behavior and drug resistance. Further investigation showed another family member, ABCA1, was also elevated in surviving cells in these lines, as well as in early passage cultures from pediatric medulloblastoma patients. We discovered that the multi-ABC transporter inhibitors verapamil and reserpine sensitized cells from particular patients to radiation, suggesting that ABC transporters have a functional role in cellular radiation protection. Additionally, verapamil had an intrinsic anti-proliferative effect, with transient exposure in vitro slowing subsequent in vivo tumor formation. When expression of key ABC transporter genes was assessed in medulloblastoma tissue from 34 patients, levels were frequently elevated compared with normal cerebellum. Analysis of microarray data from independent cohorts (n = 428 patients) showed expression of a number of ABC transporters to be strongly correlated with certain medulloblastoma subtypes, which in turn are associated with clinical outcome. CONCLUSIONS: ABC transporter inhibitors are already being trialed clinically, with the aim of decreasing chemotherapy resistance. Our findings suggest that the inhibition of ABC transporters could also increase the efficacy of radiation treatment for medulloblastoma patients. Additionally, the finding that certain family members are associated with particular molecular subtypes (most notably high ABCA8 and ABCB4 expression in Sonic Hedgehog pathway driven tumors), along with cell membrane location, suggests ABC transporters are worthy of consideration for the diagnostic classification of medulloblastoma.
RESUMO
Medulloblastoma is the most common malignant brain tumor of childhood. Novel therapeutic strategies are urgently needed to overcome cytotoxic resistance. We hypothesized that antiapoptotic signals contribute to resistance and that treatment with proapoptotic agents could increase the efficacy of conventional therapies. A PCR array was used to assess the status of the apoptotic signaling pathway in medulloblastoma cells after treatment with cytotoxic chemotherapy. Treatment with cisplatin led to the upregulation of antiapoptotic signals, including inhibitor of apoptosis proteins (IAP), in medulloblastoma cells. We subsequently investigated the synergistic effect of a small-molecule IAP inhibitor, LBW242, in combination with cisplatin and/or radiotherapy in three human medulloblastoma cell lines and 5 short term primary patient medulloblastoma cultures. The addition of LBW242 to chemotherapy resulted in significantly increased antitumor activity with a similar effect observed in combination with radiotherapy. Measurement of caspase-8 and -9 activity indicated that the synergy resulted from induction of both the intrinsic and extrinsic apoptotic pathways. Apoptosis was confirmed by Annexin V staining and activation of caspases 3/7. Xenograft models were used to evaluate the mechanism of action and efficacy in vivo. The combination therapy significantly reduced the tumor burden in a medulloblastoma xenograft model and TUNEL analysis in a medulloblastoma orthograft confirmed in vivo induction of apoptosis. These findings support the strategy of targeting IAPs in combination with cytotoxic therapy as a novel treatment strategy for patients with medulloblastoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Cerebelares/tratamento farmacológico , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Inibidoras de Apoptose/uso terapêutico , Meduloblastoma/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Cisplatino/administração & dosagem , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Inibidoras de Apoptose/farmacologia , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Oligopeptídeos/administração & dosagem , Transdução de Sinais , Vincristina/administração & dosagem , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The Notch signalling pathway plays crucial roles in neural development, functioning by preventing premature differentiation and promotion of glial cell fates. In the developing cerebellum Notch pathway components are expressed in granule neuron progenitors of the external germinal layer (EGL) but the precise function of Notch in these cells is unclear. The Hedgehog pathway is also crucial in cerebellar development, mainly via control of the cell cycle, and persistent activation of the pathways leads to the cerebellar tumour medulloblastoma. Interactions between Hedgehog and Notch have been reported in normal brain development as well as in Hedgehog pathway induced medulloblastoma but the molecular details of this interaction are not known and we investigate here the role of Notch signalling in the development of the EGL and the intersection between the two pathways in cerebellar granule neuron progenitors and in medulloblastoma. RESULTS: RBP-J is the major downstream effector of all four mammalian Notch receptors and the RBP-J conditional mouse facilitates inactivation of canonical Notch signals. Patched1 is a negative regulator of Hedgehog signalling and the Patched1 conditional mouse is widely used to activate Hedgehog signalling via Patched1 deletion in specific cell types. The conditional mouse lines were crossed with a Math1-Cre line to delete the two genes in granule neuron progenitors from embryonic day 10.5. While deletion of only Patched1 as well as Patched1 together with RBP-J leads to formation of medulloblastoma concomitant with disorganisation of cell layers, loss of RBP-J from granule neuron progenitors has no obvious effect on overall cerebellar morphology or differentiation and maturation of the different cerebellar cell types. CONCLUSIONS: Our results suggest that even though Notch signalling has been shown to play important roles in cerebellar development, signalling via RBP-J is surprisingly not required in granule neuron progenitors. Furthermore, RBP-J inactivation in these cells does not influence the formation of medulloblastoma initiated by Hedgehog pathway activation. This may suggest a requirement of Notch in cerebellar development at a different developmental stage or in a different cell type than examined here - for example, in the neural stem cells of the ventricular zone. In addition, it remains a possibility that, in granule neuron progenitors, Notch may signal via an alternative pathway without the requirement for RBP-J.
Assuntos
Cerebelo/citologia , Cerebelo/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas Hedgehog/metabolismo , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Células-Tronco Neurais/fisiologia , Transdução de Sinais/fisiologia , Animais , Animais Recém-Nascidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Diferenciação Celular/genética , Células Cultivadas , Embrião não Mamífero , Proteínas do Olho/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Homeodomínio/metabolismo , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Meduloblastoma/etiologia , Meduloblastoma/genética , Meduloblastoma/metabolismo , Camundongos , Camundongos Transgênicos , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/metabolismo , Receptores Patched , Receptor Patched-1 , Antígeno Nuclear de Célula em Proliferação/metabolismo , Receptores de Superfície Celular/deficiência , Receptores Notch/metabolismo , Proteínas Repressoras/metabolismoRESUMO
OBJECTIVE: To document haemopoietic stem cell transplantation (HSCT) activity and trends among paediatric patients in Australia and New Zealand. DESIGN, SETTING AND PARTICIPANTS: A retrospective analysis of data reported to the Australasian Bone Marrow Transplant Recipient Registry by the seven paediatric HSCT institutions in Australia and New Zealand over the 9-year period 1998-2006, with particular focus on the most recent years (2002-2006). MAIN OUTCOME MEASURES: Types of HSCT performed; transplant-related mortality (TRM); stem cell sources; indications for HSCT; causes of death after HSCT. RESULTS: Over the period 1998-2006, 522 autologous HSCT procedures (41%) and 737 allogeneic procedures (59%) were performed. About 60% of allogeneic transplants involved alternative donors (donors other than a human leukocyte antigen-matched sibling). The use of umbilical cord blood as a source of haemopoietic stem cells has doubled since 1998, with 34% of allogeneic transplants in 2006 using cord blood. Over the period 2002-2006, the median age of patients receiving transplants was 7 years (range, 0-19 years). The most common indications for allogeneic HSCT were acute lymphoblastic leukaemia (33%) and acute myeloid leukaemia (24%). The most common indications for autologous HSCT were neuroblastoma (23%), medulloblastoma (21%) and Ewing sarcoma (10%). TRM at 1 year after transplant was 22% for alternative donor transplants, 7% for matched-sibling transplants and 5% for autologous transplants. Relapse or persistence of a child's underlying condition accounted for 54% of all deaths within 1 year after transplant. CONCLUSIONS: HSCT is an important procedure for children with a range of life-threatening illnesses. Local trends in the indications for HSCT, donor selection and TRM reflect contemporary international practice.
Assuntos
Transplante de Medula Óssea/estatística & dados numéricos , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Adolescente , Adulto , Austrália , Transplante de Medula Óssea/mortalidade , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/terapia , Masculino , Nova Zelândia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Sistema de Registros , Estudos Retrospectivos , Sobreviventes , Adulto JovemRESUMO
Toward the goal of generating a mouse medulloblastoma model with increased tumor incidence, we developed a homozygous version of our ND2:SmoA1 model. Medulloblastomas form in 94% of homozygous Smo/Smo mice by 2 months of age. Tumor formation is, thus, predictable by age, before the symptomatic appearance of larger lesions. This high incidence and early onset of tumors is ideal for preclinical studies because mice can be enrolled before symptom onset and with a greater latency period before late-stage disease. Smo/Smo tumors also display leptomeningeal dissemination of neoplastic cells to the brain and spine, which occurs in many human cases. Despite an extended proliferation of granule neuron precursors (GNP) in the postnatal external granular layer (EGL), the internal granular layer formed normally in Smo/Smo mice and tumor formation occurred only in localized foci on the superficial surface of the molecular layer. Thus, tumor formation is not simply the result of over proliferation of GNPs within the EGL. Moreover, Smo/Smo medulloblastomas were transplantable and serially passaged in vivo, demonstrating the aggressiveness of tumor cells and their transformation beyond a hyperplastic state. The Smo/Smo model is the first mouse medulloblastoma model to show leptomeningeal spread. The adherence to human pathology, high incidence, and early onset of tumors thus make Smo/Smo mice an efficient model for preclinical studies.
Assuntos
Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Proteínas Hedgehog/genética , Meduloblastoma/genética , Meduloblastoma/patologia , Neoplasias Meníngeas/patologia , Receptores Acoplados a Proteínas G/genética , Animais , Modelos Animais de Doenças , Neoplasias Meníngeas/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos Transgênicos , Receptor Smoothened , TransgenesRESUMO
Constitutive Hedgehog (Hh) pathway activity is associated with initiation of neoplasia, but its role in the continued growth of established tumors is unclear. Here, we investigate the therapeutic efficacy of the Hh pathway antagonist cyclopamine in preclinical models of medulloblastoma, the most common malignant brain tumor in children. Cyclopamine treatment of murine medulloblastoma cells blocked proliferation in vitro and induced changes in gene expression consistent with initiation of neuronal differentiation and loss of neuronal stem cell-like character. This compound also caused regression of murine tumor allografts in vivo and induced rapid death of cells from freshly resected human medulloblastomas, but not from other brain tumors, thus establishing a specific role for Hh pathway activity in medulloblastoma growth.