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1.
Int J Pediatr Endocrinol ; 2020: 18, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33005196

RESUMO

Objective: The most common presentation of Klinefelter syndrome (KS) is infertility and features of hypogonadism. Currently no consensus exists on the risk of malignancy in this syndrome. Several case reports show an incidence of extragonadal germ cells tumors (eGCT) of 1.5 per 1000 KS patients (OR 50 against healthy population). Malignant germ cell tumors are rare in children. They account for 3% of all children cancers. Young patients with a germ cell tumor are not routinely tested for Klinefelter syndrome. This can therefore result in underdiagnosing. Literature data suggest a correlation between eGCT and KS. To the best of our knowledge there is no precise description of the primary locations of germ cell tumors in KS patients. The purpose of this study is to evaluate age groups and primary locations of extragonadal germ cell tumors in Klinefelter patients. With this data we investigate whether it is necessary to perform a cytogenetic analysis for KS in every eGCT patient. Study design: This study is based on case report publications in PubMed/Medline published until march 2020 that described "Klinefelter Syndrome (MeSH) AND/OR extragonadal germ cell tumors". Publications were included when patients age, location and histology of the germ cell tumor was known. Two double blinded reviewers selected the studies.Results: 141 KS patients with eGCTs were identified. Mean age at presentation was 17.3 years (StDev + - 10.2). In contrast to the extragonadal germ cell tumors in adults, most eGCT in children were mediastinal or in the central nervous system (respectively 90/141; 64% and 23/141; 16% of all tumors). Distribution of histologic subtypes showed that the largest fraction represented a teratoma, mixed-type-non-seminomateus GCT and germinoma, respectively 34/141; 24%, 26/141; 18% and 20/141; 14% of all tumors. Conclusion: These data suggest a correlation between primary extragonadal germ cell tumors and Klinefelter syndrome. There appears to be an indication for screening on KS in young patients with an eGCT in the mediastinum. A low threshold for radiologic examinations should be considered to discover eGCT. We emphasize the need for genetic analysis in all cases of a male with a mediastinal germ cell tumor for the underdiagnosed Klinefelter syndrome.

2.
Pediatr Res ; 2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33069162

RESUMO

BACKGROUND: Still 30-40% of pediatric acute myeloid leukemia (pedAML) patients relapse. Delineation of the transcriptomic profile of leukemic subpopulations could aid in a better understanding of molecular biology and provide novel biomarkers. METHODS: Using microarray profiling and quantitative PCR validation, transcript expression was measured in leukemic stem cells (LSC, n = 24) and leukemic blasts (L-blast, n = 25) from pedAML patients in comparison to hematopoietic stem cells (HSCs, n = 19) and control myeloblasts (C-blast, n = 20) sorted from healthy subjects. Gene set enrichment analysis was performed to identify relevant gene set enrichment signatures, and functional protein associations were identified by STRING analysis. RESULTS: Highly significantly overexpressed genes in LSC and L-blast were identified with a vast majority not studied in AML. CDKN1A, CFP, and CFD (LSC) and HOMER3, CTSA, and GADD45B (L-blast) represent potentially interesting biomarkers and therapeutic targets. Eleven LSC downregulated targets were identified that potentially qualify as tumor suppressor genes, with MYCT1, PBX1, and PTPRD of highest interest. Inflammatory and immune dysregulation appeared to be perturbed biological networks in LSC, whereas dysregulated metabolic profiles were observed in L-blast. CONCLUSION: Our study illustrates the power of taking into account cell population heterogeneity and reveals novel targets eligible for functional evaluation and therapy in pedAML. IMPACT: Novel transcriptional targets were discovered showing a significant differential expression in LSCs and blasts from pedAML patients compared to their normal counterparts from healthy controls. Deregulated pathways, including immune and metabolic dysregulation, were addressed for the first time in children, offering a deeper understanding of the molecular pathogenesis. These novel targets have the potential of acting as biomarkers for risk stratification, follow-up, and targeted therapy. Multiple LSC-downregulated targets endow tumor suppressor roles in other cancer entities, and further investigation whether hypomethylating therapy could result into LSC eradication in pedAML is warranted.

4.
Pediatr Res ; 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32645707

RESUMO

BACKGROUND: Children with serious illness suffer from symptoms at the end of life that often fail to be relieved. An overview is required of healthcare interventions improving and decreasing quality of life (QOL) for children with serious illness at the end of life. METHODS: A systematic review was performed in five databases, January 2000 to July 2018 without language limit. Reviewers selected quantitative studies with a healthcare intervention, for example, medication or treatment, and QOL outcomes or QOL-related measures, for example, symptoms, for children aged 1-17 years with serious illness. One author assessed outcomes with the QualSyst and GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) Framework; two authors checked a 25% sample. QOL improvement or reduction was categorized. RESULTS: Thirty-six studies met the eligibility criteria studying 20 unique interventions. Designs included 1 randomized controlled trial, 1 cross-sectional study, and 34 cohort studies. Patient-reported symptom monitoring increased QOL significantly in cancer patients in a randomized controlled trial. Dexmedetomidine, methadone, ventilation, pleurodesis, and palliative care were significantly associated with improved QOL, and chemotherapy, stem cell transplant, and hospitalization with reduced QOL, in cohort studies. CONCLUSIONS: Use of patient-controlled symptom feedback, multidisciplinary palliative care teams with full-time practical support, inhalation therapy, and off-label sedative medication may improve QOL. Curative therapy may reduce QOL. IMPACT: QOL for children at the end of life may be improved with patient-controlled symptom feedback, multidisciplinary palliative care teams with full-time practical support, inhalation therapy, and off-label sedative medication.QOL for children at the end of life may be reduced with therapy with a curative intent, such as curative chemotherapy or stem cell transplant.A comprehensive overview of current evidence to elevate currently often-failing QOL management for children at the end of life.New paradigm-level indicators for appropriate and inappropriate QOL management in children at the end of life.New hypotheses for future research, guided by the current knowledge within the field.Various healthcare interventions (as described above) could or might be employed as tools to provide relief in QOL management for children with serious illness, such as cancer, at the end of life, and therefore could be discussed in pediatrician end-of-life training to limit the often-failed QOL management in this population, cave the one-size-fits-all approach for individual cases.Multidisciplinary team efforts and 24/7 presence, especially practical support for parents, might characterize effective palliative care team interventions for children with serious illness at the end of life, suggesting a co-regulating link between well-being of the child partly to that of the parentsHypothesis-oriented research is needed, especially for children with nonmalignant disorders, such as genetic or neurological disorders at the end of life, as well as QOL outcomes for intervention research and psychosocial or spiritual outcomes.

5.
Cancers (Basel) ; 12(7)2020 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-32635465

RESUMO

Vincristine (VCR) is frequently used in pediatric oncology and can be administered intravenously through push injections or 1 h infusions. The effects of administration duration on population pharmacokinetics (PK) are unknown. We described PK differences related to administration duration and the relation between PK and VCR-induced peripheral neuropathy (VIPN). PK was assessed in 1-5 occasions (1-8 samples in 24 h per occasion). Samples were analyzed using high-performance liquid chromatography/tandem mass spectrometry. Population PK of VCR and its relationship with administration duration was determined using a non-linear mixed effect. We estimated individual post-hoc parameters: area under the concentration time curve (AUC) and maximum concentration (Cmax) in the plasma and peripheral compartment. VIPN was assessed using Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric-modified total neuropathy score (ped-mTNS). Overall, 70 PK assessments in 35 children were evaluated. The population estimated that the intercompartmental clearance (IC-Cl), volume of the peripheral compartment (V2), and Cmax were significantly higher in the push group. Furthermore, higher IC-Cl was significantly correlated with VIPN development. Administration of VCR by push led to increased IC-Cl, V2, and Cmax, but were similar to AUC, compared to 1 h infusions. Administration of VCR by 1 h infusions led to similar or higher exposure of VCR without increasing VIPN.

6.
Eur J Cancer ; 132: 11-16, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32305831

RESUMO

INTRODUCTION: Since the beginning of COVID-19 pandemic, it is known that the severe course of the disease occurs mostly among the elderly, whereas it is rare among children and young adults. Comorbidities, in particular, diabetes and hypertension, clearly associated with age, besides obesity and smoke, are strongly associated with the need for intensive treatment and a dismal outcome. A weaker immunity of the elderly has been proposed as a possible explanation of this uneven age distribution. Thus, there is concern that children treated for cancer may allso be at risk for an unfavourable course of infection. Along the same line, anecdotal information from Wuhan, China, mentioned a severe course of COVID-19 in a child treated for leukaemia. AIM AND METHODS: We made a flash survey on COVID-19 incidence and severity among children on anticancer treatment. Respondents were asked by email to fill in a short Web-based survey. RESULTS: We received reports from 25 countries, where approximately 10,000 patients at risk are followed up. At the time of the survey, more than 200 of these children were tested, nine of whom were positive for COVID-19. Eight of the nine cases had asymptomatic to mild disease, and one was just diagnosed with COVID-19. We also discuss preventive measures that are in place or should be taken and treatment options in immunocompromised children with COVID-19. CONCLUSION: Thus, even children receiving anticancer chemotherapy may have a mild or asymptomatic course of COVID-19. While we should not underestimate the risk of developing a more severe course of COVID-19 than that observed here, the intensity of preventive measures should not cause delays or obstructions in oncological treatment.


Assuntos
Antineoplásicos/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/complicações , Neoplasias/tratamento farmacológico , Pneumonia Viral/complicações , Adolescente , Criança , Infecções por Coronavirus/tratamento farmacológico , Feminino , Humanos , Masculino , Neoplasias/complicações , Pandemias , Pneumonia Viral/tratamento farmacológico , Inquéritos e Questionários
8.
Br J Haematol ; 190(1): 105-114, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32057100

RESUMO

Asparaginase (ASNase) is an important anti-leukaemic drug in the treatment of childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL). A substantial proportion of patients develop hypersensitivity reactions with anti-ASNase neutralising antibodies, resulting in allergic reactions or silent inactivation (SI), and characterised by inactivation and rapid clearance of ASNase. We report results of a prospective, real-time therapeutic drug monitoring of pegylated Escherichia coli (PEG-)ASNase and Erwinia ASNase in children treated for ALL and NHL in Belgium. Erwinia ASNase was given as second-line after hypersensitivity to PEG-ASNase. In total, 286 children were enrolled in the PEG-ASNase cohort. Allergy was seen in 11·2% and SI in 5·2% of patients. Of the 42 patients treated with Erwinia ASNase, 7·1% experienced allergy and 2·4% SI. The median trough PEG-ASNase activity was high in all patients without hypersensitivity. After Erwinia administration significantly more day 3 samples had activities <100 IU/l (62·5% vs. 10% at day 2 (D2)). The median D2 activity was significantly higher for intramuscular (IM; 347 IU/l) than for intravenous Erwinia administrations (159 IU/l). This prospective, multicentre study shows that monitoring of ASNase activity during treatment of children with ALL and NHL is feasible and informative. Treatment with Erwinia ASNase warrants close monitoring and optimally adherence to a 2-day interval of IM administrations.

9.
Disabil Rehabil ; : 1-11, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31910686

RESUMO

Purpose: The purpose of this study was to describe experiences of childhood brain tumor survivors (CBTS) and key figures in their environment after returning to school, using the International Classification of Functioning, Disability and Health - Children and Youth framework.Methods: We conducted semi-structured interviews with five children, nine parents, 28 teachers, and 14 health professionals at three predetermined times over a two-year period. A qualitative content analysis was performed by linking meaningful units from transcribed interviews to ICF codes.Results: Children experienced diverse body dysfunctions that could impede school participation, mostly related to knowledge acquisition and application, executive functioning and social life. Support at school and professional aftercare were essential to alleviate the child's difficulties. The teacher's attitude, parental involvement, and practices of collaboration belonging to the child's supportive network further influenced the reintegration process. Also, child-specific factors including emotional reactions to illness, age, and balance between school life and leisure time were considered to affect school readjustment.Conclusions: The International Classification of Functioning, Disability and Health framework is a useful instrument to systematically describe experiences of CBTS and key figures regarding school life, providing a common language to communicate for stakeholders in education and healthcare following the child's return.IMPLICATIONS FOR REHABILITATIONThe International Classification of Functioning, Disability and Health - Children and Youth framework is a useful instrument to describe experiences regarding school life of childhood brain tumor survivors (CBTS) and key figures in their environment.The ICF-CY model can be combined with a standardized assessment of neurocognition or performance to achieve a comprehensive view of the child's participation at school, by exploring both personal and environmental factors.Childhood brain tumor survivors mostly show impairments in acquiring and applying knowledge, executive functioning and social life, which may require increased support at school and professional aftercare.A positive attitude of school staff, high parental involvement in school life and adequate collaboration between parents, education and healthcare are important to prioritize in the context of reintegration into school of CBTS.

10.
Nucleic Acids Res ; 48(2): 770-787, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31799629

RESUMO

Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5'UTR of RPL9 (uL6). Additionally, we report two individuals from a family with multiple cancer incidences carrying a RPL9 missense variant. Analysis of cells from these individuals reveals that despite the variants both driving pre-rRNA processing defects and 80S monosome reduction, the downstream effects are remarkably different. Cells carrying the 5'UTR variant stabilize TP53 and impair the growth and differentiation of erythroid cells. In contrast, ribosomes incorporating the missense variant erroneously read through UAG and UGA stop codons of mRNAs. Metabolic profiles of cells carrying the 5'UTR variant reveal an increased metabolism of amino acids and a switch from glycolysis to gluconeogenesis while those of cells carrying the missense variant reveal a depletion of nucleotide pools. These findings indicate that variants in the same RP gene can drive similar ribosome biogenesis defects yet still have markedly different downstream consequences and clinical impacts.


Assuntos
Anemia de Diamond-Blackfan/genética , Processamento Pós-Transcricional do RNA/genética , Proteínas Ribossômicas/genética , Ribossomos/genética , Regiões 5' não Traduzidas/genética , Adolescente , Adulto , Anemia de Diamond-Blackfan/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Criança , Células Eritroides , Feminino , Humanos , Masculino , Mutação/genética , Precursores de RNA/genética , RNA Mensageiro/genética , Sequenciamento Completo do Exoma
11.
Br J Haematol ; 189(2): 351-362, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31837008

RESUMO

We investigated the long-term outcome, the incidence of second neoplasms (SN) and the rate of late adverse effects (LAE) in children with central nervous system (CNS) negative medium/high-risk de novo acute lymphoblastic leukaemia (ALL), in first complete remission (CR1) at end of late intensification, randomized to receive no cranial radiotherapy (No CRT, n = 92) versus CRT (standard arm, n = 84) in the non-inferiority EORTC 58832 study (1983-1989). Median follow-up was 20 years (range 4-32 years). The 25-year disease-free survival rate (±SE) was 67·4 ± 4·9% without CRT and 70·2 ± 5·0% with CRT. The 25-year incidence of isolated (6·5 ± 2·6% vs. 4·8 ± 2·3%) and any CNS relapse {8·7 ± 2·9% vs. 11·9 ± 3·5%; hazard ratio (HR) 0·71 [95% confidence interval (CI) 0·28-1·79]; test of non-inferiority: P = 0·01} was not increased without CRT. The 25-year SN incidence in CR1 was 7·9 ± 4·6% vs. 11·0 ± 4·2%. The 25-year event-free and overall survival rates were quite similar in both arms [59·5 ± 6·3% vs. 60·5 ± 5·9%, HR 0·94 (95% CI 0·57-1·52), and 78·1 ± 4·3% vs. 78·5 ± 4·5%, HR 1·00 (95% CI 0·53-1·88)]. Omission of CRT was associated with dramatic decrease in CNS and endocrine LAE rates. In conclusion, our data suggest that, with proper systemic and intrathecal CNS prophylaxis, CRT could totally be omitted in CR1 without jeopardizing survival, while decreasing LAE in childhood ALL.

12.
Proc Natl Acad Sci U S A ; 116(38): 19055-19063, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31484767

RESUMO

Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1ß secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1ß at baseline. Finally, both patients displayed elevated levels of inflammasome-induced cytokines in the serum. Six NLRP1 GOF mutations have previously been described to underlie 3 allelic Mendelian diseases with differing phenotypes and modes of inheritance. Our results demonstrate that an autosomal recessive, syndromic form of JRRP can be associated with an NLRP1 GOF mutation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Mutação com Ganho de Função , Homozigoto , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções Respiratórias/genética , Infecções Respiratórias/patologia , Pré-Escolar , Citocinas/metabolismo , Feminino , Humanos , Lactente , Inflamassomos , Queratinócitos/citologia , Queratinócitos/imunologia , Queratinócitos/metabolismo , Masculino , Linhagem , Irmãos , Síndrome
13.
Glob Pediatr Health ; 6: 2333794X19860659, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31321257

RESUMO

This multiple case study investigated perspectives of childhood brain tumor survivors on reintegration into school over a 2-year period. Semistructured interviews were conducted with 5 children at 3 times to obtain an extensive view of their overall school experience. Thematic analysis of data resulted in 4 themes: "school life and participation," "peer relations and friendships," "performance and difficulties," and "support and follow-up." Childhood brain tumor survivors consider school attendance as part of a normal disease-free life. Social contact and friendships represent their main motivating factors for returning to school. Attitudes and feelings regarding performance, difficulties, and support vary among survivors and change over time. In conclusion, continuity in learning and social contact established before the return facilitate the reintegration process. A comprehensive assessment of their academic and psychosocial functioning should be organized on reentry. Systematic follow-up by parents, school staff, and health professionals throughout the child's school career is required.

14.
Syst Rev ; 8(1): 165, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296266

RESUMO

BACKGROUND: Seriously ill children suffer from numerous symptoms at the end of their lives, including pain, anxiety, and restricted communication. There are currently no comprehensive overviews of which health interventions have proven benefits and which have proven detrimental effects on the quality of life of children in an end-of-life context. In order to identify potential quality indicators to eventually improve care, a systematic review of available evidence is needed. The aim of the current systematic review will be to make an overview of the influence of health interventions on associated outcomes related to quality of life at the end of life in seriously ill children. METHODS: A systematic search will be conducted in MEDLINE, Embase, CENTRAL, CINAHL, and Web of Science. We will include quantitative empirical designs looking into the influence of a health intervention on (proxies of) quality of life at the end of life in seriously ill children. Three independent authors will review titles and abstracts and screen full texts against eligibility criteria. One reviewer will carry out full data extraction and quality assessment, and a 20% random sample will be extracted and assessed by two independent reviewers. We will use the QualSyst Tool for assessment of the quality of the included studies (QualSyst Tool) for quality assessment; overall strength of the body of evidence will be assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. An overview table of health interventions will be discussed through narrative synthesis. Should sufficient homogeneous publications arise, we will perform meta-analyses with a random-effects model. Our protocol adheres to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) checklist for study protocols. DISCUSSION: As part of a larger project, we will use the results of this review to identify a first set of quality indicators for the care for children at the end of life. Reviewing the current span of evidence and identifying research gaps will uncover future research priorities into the care for children at the end of life. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018105109.


Assuntos
Adaptação Psicológica , Estado Terminal/psicologia , Qualidade de Vida , Assistência Terminal/métodos , Criança , Humanos
15.
Br J Haematol ; 186(5): 741-753, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31124581

RESUMO

Outcomes in childhood T-cell acute lymphoblastic leukaemia (T-ALL) are steadily improving due to intensive therapy. Between 1989 and 2008, 599 children with newly diagnosed T-ALL were enrolled in two successive European Organization for Research and Treatment of Cancer - Children's Leukaemia Group trials (58881 and 58951), both based on the Berlin-Frankfurt-Munster protocol and without cranial irradiation. In the latter trial induction chemotherapy was intensified. The most important randomizations were Medac Escherichia coli asparaginase versus Erwinia asparaginase in trial 58881, and dexamethasone (6 mg/m2 /day) versus prednisolone (60 mg/m2 /day) and prolonged versus conventional asparaginase duration in trial 58951. 8-year event-free survival (EFS) increased from 65·1% to 74·0% in trial 58951. Improvement was most profound for patients with white blood cell (WBC) counts <100 × 109 /l and "good responders" to prephase. Medac E. coli asparaginase was associated with longer EFS [hazard ratio (HR) 0·54, P = 0·0015] and overall survival (HR 0·51, P = 0·0018). Induction therapy with dexamethasone did not improve EFS compared to prednisolone. Remarkably, intensification of central nervous system (CNS)-directed therapy in trial 58951 resulted in fewer bone marrow relapses, while the incidence of CNS relapses remained low. In summary, we showed that adequate asparaginase therapy, intensified induction treatment and intensification of CNS-directed chemotherapy can result in an improvement of outcome in T-ALL patients with good prephase response and initial WBC counts <100 × 109 /l, representing approximately 50% of T-ALL patients.


Assuntos
Ensaios Clínicos como Assunto/métodos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Análise de Sobrevida , Resultado do Tratamento
16.
Pediatr Blood Cancer ; 66(5): e27605, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30623572

RESUMO

BACKGROUND: Children with acute myeloid leukemia (AML) have a 70% survival rate with treatment regimens containing high doses of cytarabine and anthracyclines and, in some, hematopoietic stem cell transplantation (allo-HSCT). PROCEDURE: In this multicenter Dutch-Belgian protocol (DB AML-01), 112 children with de novo AML were included. Treatment was stratified according to day 15 bone marrow response after the first induction course. Poor responders received a second course without delay while good responders awaited hematological recovery. Patients achieving CR after two induction courses continued with three consolidation courses without HSCT in CR1. RESULTS: The overall remission rate was 93.5%. After a median follow-up of 4.1 years, three-year event-free survival (EFS) was 52.6% (95% CI, 42.9%-61.3%), three-year cumulative incidence of relapse 39.7% (95% CI, 30.1%-49.0%), and three-year overall survival (OS) 74.0% (95% CI, 64.8%-81.2%). Significantly more events occurred in patients with high WBC at diagnosis or FLT3-ITD/NPM1-WT, whereas core binding factor (CBF) leukemia had a significantly better EFS. KMT2A rearrangements and age > 10 years negatively impacted OS. CONCLUSIONS: DB AML-01 response-guided therapy results in a favorable OS, particularly for children with CBF leukemia, children younger than 10 years or with initial WBC counts below 100 × 109 /L. Outcome of patients with FLT3-ITD/NPM1-WT remains poor and warrants alternative treatment strategies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Antraciclinas/administração & dosagem , Criança , Pré-Escolar , Citarabina/administração & dosagem , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/patologia , Masculino , Prognóstico , Estudos Prospectivos , Indução de Remissão , Taxa de Sobrevida
17.
Mol Cell Proteomics ; 18(4): 760-772, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30630937

RESUMO

Neutrophil granulocytes are critical mediators of innate immunity and tissue regeneration. Rare diseases of neutrophil granulocytes may affect their differentiation and/or functions. However, there are very few validated diagnostic tests assessing the functions of neutrophil granulocytes in these diseases. Here, we set out to probe omics analysis as a novel diagnostic platform for patients with defective differentiation and function of neutrophil granulocytes. We analyzed highly purified neutrophil granulocytes from 68 healthy individuals and 16 patients with rare monogenic diseases. Cells were isolated from fresh venous blood (purity >99%) and used to create a spectral library covering almost 8000 proteins using strong cation exchange fractionation. Patient neutrophil samples were then analyzed by data-independent acquisition proteomics, quantifying 4154 proteins in each sample. Neutrophils with mutations in the neutrophil elastase gene ELANE showed large proteome changes that suggest these mutations may affect maturation of neutrophil granulocytes and initiate misfolded protein response and cellular stress mechanisms. In contrast, only few proteins changed in patients with leukocyte adhesion deficiency (LAD) and chronic granulomatous disease (CGD). Strikingly, neutrophil transcriptome analysis showed no correlation with its proteome. In case of two patients with undetermined genetic causes, proteome analysis guided the targeted genetic diagnostics and uncovered the underlying genomic mutations. Data-independent acquisition proteomics may help to define novel pathomechanisms in neutrophil diseases and provide a clinically useful diagnostic dimension.


Assuntos
Doença , Neutrófilos/metabolismo , Proteoma/metabolismo , Proteômica , Sequência de Bases , Doença/genética , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
18.
Dev Neurorehabil ; 22(5): 321-328, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30015543

RESUMO

Objective: To discover short-term changes in perspectives of parents and teachers of childhood brain tumour survivors on school reintegration, in order to reveal similarities and differences between them over time. Methods: Semi-structured interviews were conducted with parents and teachers of five children at the start and the end of a 1-year period following the child's school re-entry. Results: Thematic analysis of data resulted in three main themes: 'the child's performance and wellbeing', 'the school's attitude and approach' and 'communication and working together'. Parental concerns about child-specific changes and the school's approach to the child could either decrease or increase over time. Teachers remained focused on assessing their pupil's learning potential and finding ways of appropriate support. Their different perspectives on communication and working together became more pronounced. Conclusions: This study emphasizes the importance of clear communication and collaboration, coordinated follow-up and availability of healthcare professionals during the child's school reintegration.


Assuntos
Atitude , Neoplasias Encefálicas/reabilitação , Reabilitação Neurológica/psicologia , Pais/psicologia , Professores Escolares/psicologia , Adulto , Neoplasias Encefálicas/psicologia , Criança , Feminino , Humanos , Masculino
19.
J Health Psychol ; 24(10): 1436-1447, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-28988492

RESUMO

Reintegration into school is a milestone for childhood brain tumor survivors, as well as for their parents, teachers, and healthcare providers. We explored their experiences following the school re-entry by conducting semi-structured interviews. Thematic analysis resulted in four main themes: "school performance," "psychosocial well-being," "support and approach," and "communication and collaboration." Children were pleased to return to school despite confrontation with adverse outcomes. Parents, teachers, and healthcare providers identified current and future concerns and challenges, as well as opportunities for academic and personal development. Their experiences highlight the importance of coordinated and systematic follow-up in close collaboration with healthcare providers.


Assuntos
Neoplasias Encefálicas/psicologia , Sobreviventes de Câncer/psicologia , Instituições Acadêmicas , Desempenho Acadêmico/psicologia , Adaptação Psicológica , Neoplasias Encefálicas/terapia , Criança , Desenvolvimento Infantil , Comunicação , Comportamento Cooperativo , Feminino , Pessoal de Saúde/psicologia , Humanos , Relações Interpessoais , Entrevistas como Assunto , Masculino , Pais/psicologia , Pesquisa Qualitativa , Professores Escolares/psicologia , Apoio Social
20.
Int Med Case Rep J ; 11: 333-337, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30532602

RESUMO

Neonatal neutropenia is regularly seen with variable etiology. We describe a breastfed infant with maternal medication use as a probable cause of neonatal neutropenia. An 8 days old exclusively breastfed female infant of Arab-Berber descent was referred to our hospital because of an infection of the umbilicus. Complete blood count showed a picture of severe isolated neutropenia. After initiating intravenous antibiotic treatment, the infection quickly resolved, but the isolated neutropenia persisted. Bone marrow aspiration indicated severe congenital neutropenia. The mother was known to have Crohn's disease, treated with methylprednisolone and adalimumab up to 3 months before delivery, and latent tuberculosis, for which she used isoniazid postnatally. Breast-feeding was terminated and filgrastim was started, with an increase of the neutrophilic count. After several weeks, filgrastim could be terminated. Bone marrow and complete blood count were repeated and were completely normal. This case report describes a very young breastfed female infant with severe neutropenia, causing an infection, in which maternal adalimumab use could not be excluded as a possible cause. Maternal isoniazid use is highly unlikely.

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