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Introduction: Mutations affecting the RAS-MAPK pathway occur frequently in relapsed neuroblastoma tumors and are associated with response to MEK inhibition in vitro. However, these inhibitors alone do not lead to tumor regression in vivo, indicating the need for combination therapy. Methods and results: Via high-throughput combination screening, we identified that the MEK inhibitor trametinib can be combined with BCL-2 family member inhibitors, to efficiently inhibit growth of neuroblastoma cell lines with RAS-MAPK mutations. Suppressing the RAS-MAPK pathway with trametinib led to an increase in pro-apoptotic BIM, resulting in more BIM binding to anti-apoptotic BCL-2 family members. By favoring the formation of these complexes, trametinib treatment enhances sensitivity to compounds targeting anti-apoptotic BCL-2 family members. In vitro validation studies confirmed that this sensitizing effect is dependent on an active RAS-MAPK pathway. In vivo combination of trametinib with BCL-2 inhibitors led to tumor inhibition in NRAS-mutant and NF1-deleted xenografts. Conclusion: Together, these results show that combining MEK inhibition with BCL-2 family member inhibition could potentially improve therapeutic outcomes for RAS-MAPK-mutated neuroblastoma patients.
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Background: Despite (neo) adjuvant chemotherapy with cisplatin, doxorubicin and methotrexate, some patients with primary osteosarcoma progress during first-line systemic treatment and have a poor prognosis. In this study, we investigated whether patients with early disease progression (EDP), are characterized by a distinctive pharmacogenetic profile. Methods and Findings: Germline DNA from 287 Dutch high-grade osteosarcoma patients was genotyped using the DMET Plus array (containing 1,936 genetic markers in 231 drug metabolism and transporter genes). Associations between genetic variants and EDP were assessed using logistic regression models and associated variants (p <0.05) were validated in independent cohorts of 146 (Spain and United Kingdom) and 28 patients (Australia). In the association analyses, EDP was significantly associated with an SLC7A8 locus and was independently validated (meta-analysis validation cohorts: OR 0.19 [0.06-0.55], p = 0.002). The functional relevance of the top hits was explored by immunohistochemistry staining and an in vitro transport models. SLC7A8 encodes for the L-type amino acid transporter 2 (LAT2). Transport assays in HEK293 cells overexpressing LAT2 showed that doxorubicin, but not cisplatin and methotrexate, is a substrate for LAT2 (p < 0.0001). Finally, SLC7A8 mRNA expression analysis and LAT2 immunohistochemistry of osteosarcoma tissue showed that the lack of LAT2 expression is a prognostic factor of poor prognosis and reduced overall survival in patients without metastases (p = 0.0099 and p = 0.14, resp.). Conclusion: This study identified a novel locus in SLC7A8 to be associated with EDP in osteosarcoma. Functional studies indicate LAT2-mediates uptake of doxorubicin, which could give new opportunities to personalize treatment of osteosarcoma patients.
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Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value <10-5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5-2.7), p-value 5.0 × 10-7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity.
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Cancer remains the leading cause of disease-related death in children. For the many children who experience relapses of their malignant solid tumors, usually after very intensive first-line therapy, curative treatment options are scarce. Preclinical drug testing to identify promising treatment elements that match the molecular make-up of the tumor is hampered by the fact that (i) molecular genetic data on pediatric solid tumors from relapsed patients and thus our understanding of tumor evolution and therapy resistance are very limited to date and (ii) for many of the high-risk entities, no appropriate and molecularly well-characterized patient-derived models and/or genetic mouse models are currently available. However, recent regulatory changes enacted by the European Medicines Agency (class waiver changes) and the maturation of the RACE for Children act with the FDA, will require a significant increase in preclinical pediatric cancer research and clinical development must occur. We detail the outcome of a pediatric cancer international multistakeholder meeting whose output aims at defining an international consensus on minimum preclinical testing requirements for the development of innovative therapies for children and adolescents with cancer. Recommendations based on the experience of the NCI funded PPTP/C (www.ncipptc.org) and the EU funded ITCC-P4 public private partnership (www.itccp4.eu) are provided for the use of cell-based and mouse models for pediatric solid malignancies, as well as guidance on the scope and content of preclinical proof-of-concept data packages to inform clinical development dependent on clinical urgency. These recommendations can serve as a minimal guidance necessary to jumpstart preclinical pediatric research globally.
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Antineoplásicos/farmacologia , Ensaios Clínicos como Assunto/métodos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/normas , Neoplasias/tratamento farmacológico , Terapias em Estudo/métodos , Adolescente , Animais , Criança , Consenso , Humanos , Agências InternacionaisRESUMO
PURPOSE: For localized, resectable neuroblastoma without MYCN amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome. PATIENTS AND METHODS: Diagnostic samples were obtained from 317 tumors, International Neuroblastoma Staging System stages 1/2A/2B, from 3 cohorts: Localized Neuroblastoma European Study Group I/II and Children's Oncology Group. Genomic data were analyzed using multi- and pangenomic techniques and fluorescence in-situ hybridization in 2 age groups (cutoff age, 18 months) and were quality controlled by the International Society of Pediatric Oncology European Neuroblastoma (SIOPEN) Biology Group. RESULTS: Patients with stage 1 tumors had an excellent outcome (5-year event-free survival [EFS] ± standard deviation [SD], 95% ± 2%; 5-year overall survival [OS], 99% ± 1%). In contrast, patients with stage 2 tumors had a reduced EFS in both age groups (5-year EFS ± SD, 84% ± 3% in patients < 18 months of age and 75% ± 7% in patients ≥ 18 months of age). However, OS was significantly decreased only in the latter group (5-year OS ± SD in < 18months and ≥ 18months, 96% ± 2% and 81% ± 7%, respectively; P = .001). In < 18months, relapses occurred independent of segmental chromosome aberrations (SCAs); only 1p loss decreased EFS (5-year EFS ± SD in patients 1p loss and no 1p loss, 62% ± 13% and 87% ± 3%, respectively; P = .019) but not OS (5-year OS ± SD, 92% ± 8% and 97% ± 2%, respectively). In patients ≥ 18 months, only SCAs led to relapse and death, with 11q loss as the strongest marker (11q loss and no 11q loss: 5-year EFS ± SD, 48% ± 16% and 85% ± 7%, P = .033; 5-year OS ± SD, 46% ± 22% and 92% ± 6%, P = .038). CONCLUSION: Genomic aberrations of resectable non-MYCN-amplified stage 2 neuroblastomas have a distinct age-dependent prognostic impact. Chromosome 1p loss is a risk factor for relapse but not for diminished OS in patients < 18 months, SCAs (especially 11q loss) are risk factors for reduced EFS and OS in those > 18months. In older patients with SCA, a randomized trial of postoperative chemotherapy compared with observation alone may be indicated.
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Aberrações Cromossômicas , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 1 , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/genética , Fatores Etários , Ensaios Clínicos como Assunto , Diploide , Amplificação de Genes , Genômica , Humanos , Lactente , Estadiamento de Neoplasias , Neuroblastoma/patologia , Neuroblastoma/cirurgia , Prognóstico , Intervalo Livre de Progressão , Taxa de SobrevidaRESUMO
PURPOSE: Targeted radiotherapy with 131iodine-meta-iodobenzylguanidine (131I-MIBG) is effective for neuroblastoma (NBL), although optimal scheduling during high-risk (HR) treatment is being investigated. We aimed to evaluate the feasibility of stem cell apheresis and study hematologic reconstitution after autologous stem cell transplantation (ASCT) in patients with HR-NBL treated with upfront 131I-MIBG-therapy. EXPERIMENTAL DESIGN: In two prospective multicenter cohort studies, newly diagnosed patients with HR-NBL were treated with two courses of 131I-MIBG-therapy, followed by an HR-induction protocol. Hematopoietic stem and progenitor cell (e.g., CD34+ cell) harvest yield, required number of apheresis sessions, and time to neutrophil (>0.5 × 109/L) and platelet (>20 × 109/L) reconstitution after ASCT were analyzed and compared with "chemotherapy-only"-treated patients. Moreover, harvested CD34+ cells were functionally (viability and clonogenic capacity) and phenotypically (CD33, CD41, and CD62L) tested before cryopreservation (n = 44) and/or after thawing (n = 19). RESULTS: Thirty-eight patients (47%) were treated with 131I-MIBG-therapy, 43 (53%) only with chemotherapy. Median cumulative 131I-MIBG dose/kg was 0.81 GBq (22.1 mCi). Median CD34+ cell harvest yield and apheresis days were comparable in both groups. Post ASCT, neutrophil recovery was similar (11 days vs. 10 days), whereas platelet recovery was delayed in 131I-MIBG- compared with chemotherapy-only-treated patients (29 days vs. 15 days, P = 0.037). Testing of harvested CD34+ cells revealed a reduced post-thaw viability in the 131I-MIBG-group. Moreover, the viable CD34+ population contained fewer cells expressing CD62L (L-selectin), a marker associated with rapid platelet recovery. CONCLUSIONS: Harvesting of CD34+ cells is feasible after 131I-MIBG. Platelet recovery after ASCT was delayed in 131I-MIBG-treated patients, possibly due to reinfusion of less viable and CD62L-expressing CD34+ cells, but without clinical complications. We provide evidence that peripheral stem cell apheresis is feasible after upfront 131I-MIBG-therapy in newly diagnosed patients with NBL. However, as the harvest of 131I-MIBG-treated patients contained lower viable CD34+ cell counts after thawing and platelet recovery after reinfusion was delayed, administration of 131I-MIBG after apheresis is preferred.
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3-Iodobenzilguanidina/uso terapêutico , Remoção de Componentes Sanguíneos/métodos , Neuroblastoma/terapia , Células-Tronco de Sangue Periférico/citologia , Transplante de Células-Tronco/métodos , Adolescente , Antígenos CD34/sangue , Quimiorradioterapia/métodos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Células-Tronco de Sangue Periférico/metabolismo , Estudos Prospectivos , Fatores de Risco , Transplante Autólogo , Resultado do TratamentoRESUMO
BACKGROUND: Head and neck rhabdomyosarcoma (HNRMS) survivors are at risk to develop adverse events (AEs). The impact of these AEs on psychosocial well-being is unclear. We aimed to assess psychosocial well-being of HNRMS survivors and examine whether psychosocial outcomes were associated with burden of therapy. PROCEDURE: Sixty-five HNRMS survivors (median follow-up: 11.5 years), treated in the Netherlands and the United Kingdom between 1990 and 2010 and alive ≥2 years after treatment visited the outpatient multidisciplinary follow-up clinic once, in which AEs were scored based on a predefined list according to the Common Terminology Criteria for Adverse Events. Survivors were asked to complete questionnaires on health-related quality of life (HRQoL; PedsQL and YQOL-FD), self-perception (KIDSCREEN), and satisfaction with appearances (SWA). HRQoL and self-perception scores were compared with reference values, and the correlation between physician-assessed AEs and psychosocial well-being was assessed. RESULTS: HNRMS survivors showed significantly lower scores on PedsQL school/work domain (P ≤ 0.01, P = 0.02, respectively), YQOL-FD domains negative self-image and positive consequences (P ≤ 0.01, P = 0.04, respectively) compared with norm data; scores on negative consequences domain were significantly higher (P = 0.03). Over 50% of survivors negatively rated their appearances on three or more items. Burden of AEs was not associated with generic HRQoL and self-perception scores, but was associated with disease-specific QoL (YQOL-FD). CONCLUSION: In general, HRQoL in HNRMS survivors was comparable to reference groups; however, survivors did report disease-specific consequences. We therefore recommend including specific questionnaires related to difficulties with facial appearance in a systematic monitoring program to determine the necessity for tailored care.
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Sobreviventes de Câncer/psicologia , Neoplasias de Cabeça e Pescoço/psicologia , Rabdomiossarcoma/psicologia , Adolescente , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
Patients with neuroblastoma in molecular remission remain at considerable risk for disease recurrence. Studies have found that neuroblastoma tissue contains adrenergic (ADRN) and mesenchymal (MES) cells; the latter express low levels of commonly used markers for minimal residual disease (MRD). We identified MES-specific MRD markers and studied the dynamics of these markers during treatment. PATIENTS AND METHODS: Microarray data were used to identify genes differentially expressed between ADRN and MES cell lines. Candidate genes were then studied using real-time quantitative polymerase chain reaction in cell lines and control bone marrow and peripheral blood samples. After selecting a panel of markers, serial bone marrow, peripheral blood, and peripheral blood stem cell samples were obtained from patients with high-risk neuroblastoma and tested for marker expression; survival analyses were also performed. RESULTS: PRRX1, POSTN, and FMO3 mRNAs were used as a panel for specifically detecting MES mRNA in patient samples. MES mRNA was detected only rarely in peripheral blood; moreover, the presence of MES mRNA in peripheral blood stem cell samples was associated with low event-free survival and overall survival. Of note, during treatment, serial bone marrow samples obtained from 29 patients revealed a difference in dynamics between MES mRNA markers and ADRN mRNA markers. Furthermore, MES mRNA was detected in a higher percentage of patients with recurrent disease than in those who remained disease free (53% v 32%, respectively; P = .03). CONCLUSION: We propose that the markers POSTN and PRRX1, in combination with FMO3, be used for real-time quantitative polymerase chain reaction-based detection of MES neuroblastoma mRNA in patient samples because these markers have a unique pattern during treatment and are more prevalent in patients with poor outcome. Together with existing markers of MRD, these new markers should be investigated further in large prospective studies.
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INTRODUCTION: Radiotherapy is essential for achieving and maintaining local control in head and neck rhabdomyosarcoma (HNRMS) patients. However, radiotherapy may cause outgrowth disturbances of facial bone and soft tissue, resulting in facial asymmetry. The aim of this study was to develop a method to visualize and measure facial asymmetry in HNRMS survivors using three-dimensional (3D) imaging techniques. METHODS: Facial deformity was evaluated in a multidisciplinary clinical assessment of 75 HNRMS survivors, treated with external beam radiotherapy (EBRT, n = 26) or Ablative surgery, MOulage brachytherapy, and REconstruction (AMORE, n = 49). Individual facial asymmetry was measured using 3D photogrammetry and expressed in a raw asymmetry index and a normalized sex-age-ethnicity-matched asymmetry signature weight. Facial asymmetry was also compared between British and Dutch controls and between survivors and their matched controls. RESULTS: Facial asymmetry was more pronounced with increasing age (P < 0.01) in British controls compared with Dutch controls (P = 0.04). Survivors developed more facial asymmetry than matched controls (P < 0.001). The clinical assessment of facial deformity correlated with the raw asymmetry index (r = 0.60, P < 0.001). DISCUSSION: 3D imaging can be used for objective measurement of facial asymmetry in HNRMS survivors. The raw asymmetry index correlated with a clinical assessment of facial deformity. Comparisons between treatment groups seemed inappropriate given the differences in facial asymmetry between British and Dutch controls. In future studies, pretreatment images could act as matched controls for posttreatment evaluation.
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Assimetria Facial , Neoplasias de Cabeça e Pescoço/radioterapia , Imageamento Tridimensional , Rabdomiossarcoma/radioterapia , Sobreviventes , Adolescente , Adulto , Criança , Pré-Escolar , Assimetria Facial/etiologia , Assimetria Facial/patologia , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Rabdomiossarcoma/patologiaRESUMO
We performed a systematic review to define the long-term health problems and optimal treatment strategy for patients with neuroblastoma with intraspinal extension. Of 685 identified studies, 28 were included in this review. The burden of long-term health problems is high; a median of 50% of patients suffered from neurological motor deficit, 34% from sphincter dysfunction, and 30% from spinal deformity. The currently available literature remains suboptimal as a guide for treatment of NBL with intraspinal extension. More well-designed, prospective studies are needed to determine the optimal treatment strategy.
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Neuroblastoma/patologia , Neuroblastoma/terapia , Humanos , Recém-Nascido , Neuroblastoma/complicações , Compressão da Medula Espinal/etiologia , Compressão da Medula Espinal/terapiaRESUMO
Neuroblastoma is predominantly characterised by chromosomal rearrangements. Next to V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma Derived Homolog (MYCN) amplification, chromosome 7 and 17q gains are frequently observed. We identified a neuroblastoma patient with a regional 7q36 gain, encompassing the enhancer of zeste homologue 2 (EZH2) gene. EZH2 is the histone methyltransferase of lysine 27 of histone H3 (H3K27me3) that forms the catalytic subunit of the polycomb repressive complex 2. H3K27me3 is commonly associated with the silencing of genes involved in cellular processes such as cell cycle regulation, cellular differentiation and cancer. High EZH2 expression correlated with poor prognosis and overall survival independent of MYCN amplification status. Unexpectedly, treatment of 3 EZH2-high expressing neuroblastoma cell lines (IMR32, CHP134 and NMB), with EZH2-specific inhibitors (GSK126 and EPZ6438) resulted in only a slight G1 arrest, despite maximum histone methyltransferase activity inhibition. Furthermore, colony formation in cell lines treated with the inhibitors was reduced only at concentrations much higher than necessary for complete inhibition of EZH2 histone methyltransferase activity. Knockdown of the complete protein with three independent shRNAs resulted in a strong apoptotic response and decreased cyclin D1 levels. This apoptotic response could be rescued by overexpressing EZH2ΔSET, a truncated form of wild-type EZH2 lacking the SET transactivation domain necessary for histone methyltransferase activity. Our findings suggest that high EZH2 expression, at least in neuroblastoma, has a survival function independent of its methyltransferase activity. This important finding highlights the need for studies on EZH2 beyond its methyltransferase function and the requirement for compounds that will target EZH2 as a complete protein.
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Proteína Potenciadora do Homólogo 2 de Zeste/fisiologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Neuroblastoma/enzimologia , Benzamidas/farmacologia , Compostos de Bifenilo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Aberrações Cromossômicas , Cromossomos Humanos Par 7 , Regulação para Baixo/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Inibidores Enzimáticos/farmacologia , Técnicas de Silenciamento de Genes , Rearranjo Gênico , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/fisiologia , Humanos , Indóis/farmacologia , Morfolinas , Neuroblastoma/fisiopatologia , Prognóstico , Piridonas/farmacologiaRESUMO
INTRODUCTION: Neuroblastoma (NBL) accounts for 10% of the paediatric malignancies and is responsible for 15% of the paediatric cancer-related deaths. Vanillylmandelic acid (VMA) and homovanillic acid (HVA) are most commonly analysed in urine of NBL patients. However, their diagnostic sensitivity is suboptimal (82%). Therefore, we performed in-depth analysis of the diagnostic sensitivity of a panel of urinary catecholamine metabolites. PATIENTS AND METHODS: Retrospective study of a panel of 8 urinary catecholamine metabolites (VMA, HVA, 3-methoxytyramine [3MT], dopamine, epinephrine, metanephrine, norepinephrine and normetanephrine [NMN]) from 301 NBL patients at diagnosis. Special attention was given to subgroups, metaiodobenzylguanidine (MIBG) non-avid tumours and VMA/HVA negative patients. RESULTS: Elevated catecholamine metabolites, especially 3MT, correlated with nine out of 12 NBL characteristics such as stage, age, MYCN amplification, loss of heterozygosity for 1p and bone-marrow invasion. The combination of the classical markers VMA and HVA had a diagnostic sensitivity of 84%. NMN was the most sensitive single diagnostic metabolite with overall sensitivity of 89%. When all 8 metabolites were combined, a diagnostic sensitivity of 95% was achieved. Among the VMA and HVA negative patients, were also 29% with stage 4 disease, which usually had elevation of other catecholamine metabolites (93%). Diagnostic sensitivity for patients with MIBG non-avid tumour was improved from 33% (VMA and/or HVA) to 89% by measuring the panel. CONCLUSIONS: Our study demonstrates that analysis of a urinary catecholamine metabolite panel, comprising 8 metabolites, ensures the highest sensitivity to diagnose NBL patients.
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Biomarcadores Tumorais/urina , Catecolaminas/urina , Neuroblastoma/urina , Adolescente , Catecolaminas/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Case management is a subject of interest within pediatric palliative care. Detailed descriptions of the content of this type of case management are lacking. We aim to describe the contents of care provided, utilization of different disciplines, and times of usage of a pediatric palliative care case management program compared for patients with malignant disease (MD) and non-malignant disease (NMD). METHODS: A three-month prospective study, with questionnaires filled in by members of a pediatric palliative care team (PPCT) for each contact with parents. RESULTS: Four hundred fifty-five contacts took place with parents of 70 patients (27MD, 43NMD). Sixty-two percent of all contacts were with the specialized nurse. The child life specialists, psychologist and social worker were also regularly consulted, the chaplain was not consulted. Ninety-five percent of all contacts took place between 8 am and 6 pm during weekdays, a limited number between 6 pm and 9 pm. Twenty-five percent of all contacts were proactively initiated by the PPCT, 25 % were initiated by parents. In these care characteristics, no differences were seen for MD and NMD patients. Psychosocial topics were addressed most frequently. MD patients consulted the PPCT more often about school and NMD patients about socio-economic issues. CONCLUSIONS: All different disciplines of the PPCT were regularly consulted, except for the chaplain. With an easy accessible team with a highly pro-active approach, availability from 8 am to 9 pm seems sufficient to accommodate patient's and parent's needs. More anticipation seems required for socio-economic topics. This insight in pediatric palliative case management can provide guidance in the development of a new PPCT.
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Cuidados Paliativos/estatística & dados numéricos , Adolescente , Administração de Caso/estatística & dados numéricos , Criança , Saúde da Criança/estatística & dados numéricos , Pré-Escolar , Hospitalização/estatística & dados numéricos , Humanos , Países Baixos , Pais , Planejamento de Assistência ao Paciente , Equipe de Assistência ao Paciente/estatística & dados numéricos , Relações Profissional-Família , Estudos Prospectivos , Apoio Social , Fatores de Tempo , Adulto JovemRESUMO
OBJECTIVE: The KLIK method is an online tool that monitors and discusses electronic patient-reported outcomes (ePROs), which has been shown to enhance outcomes. This study aimed (1) to determine the fidelity (ie, extent to which used as intended) of the KLIK method as implemented in outpatient pediatric cancer care and (2) to study health care professional (HCP)-reported barriers and facilitators for implementation. METHODS: Two hundred five children with newly diagnosed cancer (enrollment rate 85%) participated. At 1 (T1), 3 (T2), and 6 (T3) months after diagnosis, patients (8-18 years) or parents (of patients 0-7 years) completed health-related quality of life (HRQoL) questionnaires, which were transformed into an ePROfile and discussed by their HCP during consultations. Fidelity was determined by the following: percentage of website registrations, HRQoL questionnaires completed, and ePROfiles discussed. Implementation determinants were assessed with HCPs after the final T3 with the Measurement Instrument for Determinants of Innovations. RESULTS: Depending on the time point (T1-T3), fidelity was 86% to 89% for website registration, 66-85% for completed HRQoL questionnaires, and 56% to 62% for ePROfile discussion. Barriers were mainly related to organizational issues (eg, organizational change) and less frequently to users (eg, motivation to comply) or the intervention (compatibility). Facilitators were related to the user (eg, positive outcome expectations) and intervention (simplicity) but not to the organization. CONCLUSIONS: When implementing ePROs in outpatient pediatric oncology practice, HCPs report determinants that influence ePRO integration. To improve implementation and outcomes, tailored organizational (eg, formal ratification by management and time) and specific local (eg, individualized assessments) strategies should be developed to achieve optimal ePRO discussion.
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Assistência Ambulatorial , Registros Eletrônicos de Saúde/organização & administração , Neoplasias/terapia , Medidas de Resultados Relatados pelo Paciente , Pediatria , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Inquéritos e QuestionáriosRESUMO
INTRODUCTION: To date, oncology patients are more dependent on non-cellular host defense against pathogens due to intensive (chemo)therapy-related bone marrow suppression. Since data on complement functionality in oncology patients are limited, we aimed to investigate the innate complement function in relation to the type of malignancy and therapy in a longitudinal cohort of patients. METHODS: A large single-center, prospective non-intervention study was conducted, in which blood samples were taken from patients before, during, and after treatment with chemotherapy and/or subsequent admittance for (febrile) neutropenia. RESULTS/FINDINGS: Analysis of 48 patients showed a high percentage of defects in complement activity of the alternative pathway (19.1%), the classical pathway (4.3%), or both (42.6%). Post hoc analysis of six different treatment protocols with more than three patients each showed distinct effects of specific therapies. Whereas patients treated according to the Ewing, EpSSG-rhabdomyosarcoma, or SIOP CNS germ cell tumor protocol showed no defects, patients treated according to the ALL-11 (leukemia), the EURAMOS I (osteosarcoma), or the ACNS (medulloblastoma) protocols showed an almost universal reduction in complement function. Although we could not explain the reduced complement functionality under all conditions, a strong effect was observed following high-dose methotrexate or ifosfamide. CONCLUSION: Acquired complement defects were commonly observed in more than 50% of oncology patients, some of which associated with certain chemotherapeutic drugs. Additional studies are needed to determine the clinical and therapeutic context of complement defects and their possible effect on treatment outcome or the increased risk of infection.
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Hospitalization rates over time of childhood cancer survivors (CCS) provide insight into the burden of unfavorable health conditions on CCS and health care resources. The objective of our study was to examine trends in hospitalizations of CCS and risk factors in comparison with the general population. We performed a medical record linkage study of a cohort of 1564 ≥five-year CCS with national registers. We obtained a random sample of the general population matched on year of birth, gender and calendar year per CCS retrieved. We quantified and compared hospitalization rates of CCS and reference persons from 1995 until 2005, and we analyzed risk factors for hospitalization within the CCS cohort with multivariable Poisson models. We retrieved hospitalization information from 1382 CCS and 25583 reference persons. The overall relative hospitalization rate (RHR) was 2.2 (95%CI:1.9-2.5) for CCS compared to reference persons. CCS with central nervous system and solid tumors had highest RHRs. Hospitalization rates in CCS were increased compared to reference persons up to at least 30 years after primary diagnosis, with highest rates 5-10 and 20-30 years after primary cancer. RHRs were highest for hospitalizations due to neoplasms (10.7; 95%CI:7.1-16.3) and endocrine/nutritional/metabolic disorders (7.3; 95%CI:4.6-11.7). Female gender (P<0.001), radiotherapy to head and/or neck (P<0.001) or thorax and/or abdomen (P = 0.03) and surgery (P = 0.01) were associated with higher hospitalization rates in CCS. In conclusion, CCS have increased hospitalization rates compared to the general population, up to at least 30 years after primary cancer treatment. These findings imply a high and long-term burden of unfavorable health conditions after childhood cancer on survivors and health care resources.
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Efeitos Psicossociais da Doença , Hospitalização/estatística & dados numéricos , Modelos Estatísticos , Neoplasias/reabilitação , Sistema de Registros , Sobreviventes/estatística & dados numéricos , Adulto , Estudos de Casos e Controles , Feminino , Cabeça/efeitos da radiação , Humanos , Estudos Longitudinais , Masculino , Registro Médico Coordenado , Pessoa de Meia-Idade , Pescoço/efeitos da radiação , Neoplasias/classificação , Neoplasias/patologia , Neoplasias/terapia , Países Baixos , Fatores de Risco , Fatores Sexuais , Tórax/efeitos da radiaçãoRESUMO
PURPOSE: Long-term childhood cancer survivors are at high risk of late adverse effects, including stroke. We aimed to determine the cumulative incidence of clinically validated symptomatic stroke (transient ischemic attack [TIA], cerebral infarction, and intracerebral hemorrhage [ICH]) and to quantify dose-effect relationships for cranial radiation therapy (CRT) and supradiaphragmatic radiation therapy (SDRT). METHODS AND MATERIALS: Our single-center study cohort included 1362 survivors of childhood cancer that were diagnosed between 1966 and 1996. Prescribed CRT and SDRT doses were converted into the equivalent dose in 2-Gy fractions (EQD2). Multivariate Cox regression models were used to analyze the relationship between the EQD2 and stroke. RESULTS: After a median latency time of 24.9 years and at a median age of 31.2 years, 28 survivors had experienced a first stroke: TIA (n=5), infarction (n=13), and ICH (n=10). At an attained age of 45 years, the estimated cumulative incidences, with death as competing risk, among survivors treated with CRT only, SDRT only, both CRT and SDRT, and neither CRT nor SDRT were, respectively, 10.0% (95% confidence interval [CI], 2.5%-17.0%), 5.4% (95% CI, 0%-17.0%), 12.5% (95% CI, 5.5%-18.9%), and 0.1% (95% CI, 0%-0.4%). Radiation at both locations significantly increased the risk of stroke in a dose-dependent manner (hazard ratios: HRCRT 1.02 Gy(-1); 95% CI, 1.01-1.03, and HRSDRT 1.04 Gy(-1); 95% CI, 1.02-1.05). CONCLUSIONS: Childhood cancer survivors treated with CRT, SDRT, or both have a high stroke risk. One in 8 survivors treated at both locations will have experienced a symptomatic stroke at an attained age of 45 years. Further research on the pathophysiologic processes involved in stroke in this specific group of patients is needed to enable the development of tailored secondary prevention strategies.
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Irradiação Craniana/mortalidade , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/radioterapia , Lesões por Radiação/mortalidade , Sistema de Registros , Acidente Vascular Cerebral/mortalidade , Adolescente , Adulto , Causalidade , Criança , Pré-Escolar , Estudos de Coortes , Comorbidade , Irradiação Craniana/estatística & dados numéricos , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Lesões por Radiação/diagnóstico , Dosagem Radioterapêutica , Medição de Risco , Acidente Vascular Cerebral/diagnóstico , Taxa de Sobrevida , Sobreviventes , Avaliação de Sintomas/estatística & dados numéricos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Many paediatric brain tumour survivors (PBTS) suffer from neurocognitive impairments. Promising effects of neurofeedback (NF) on neurocognitive functioning have been reported, however research into NF for PBTS has not been conducted. We investigated the effects of NF on neurocognitive functioning in PBTS using a double-blind randomised placebo-controlled trial with a parallel-group design (Pediatric Research on Improving Speed, Memory, and Attention; the PRISMA study). METHODS: Eligible for inclusion were PBTS with neurocognitive complaints, aged 8-18 years, >2 years post-treatment. They were recruited from five medical centres in the Netherlands. A randomisation table assigned participants to 30 sessions (two per week) of either NF or placebo feedback (PF) (ratio 1:1). Participants, parents, trainers, and researchers handling the data were blinded to group assignment. Participants were assessed pre-, post- and 6 months post-training to determine whether NF training would lead to improved functioning as compared with PF training. Primary outcome measures were attention, processing speed, memory, executive functioning, visuomotor integration, and intelligence. Linear mixed models analyses were used to test differences between NF and PF training over time. RESULTS: A total of 82 children were enrolled (mean age 13.9 years, standard deviation = 3.2, 49% males); 80 participants were randomised (NF: n = 40, PF n = 40); 71 participants completed the training (NF: n = 34, PF: n = 37); 68 participants completed training and 6 months post-training assessment (NF: n = 33, PF: n = 35). Similar improvements were found over time for the two treatment groups on the primary outcomes (all p's > 0.15). CONCLUSION: Results indicated no specific treatment-effects of NF on neurocognitive functioning of PBTS.
Assuntos
Neoplasias Encefálicas/complicações , Transtornos Neurocognitivos/terapia , Neurorretroalimentação/métodos , Sobreviventes , Adolescente , Atenção/fisiologia , Neoplasias Encefálicas/psicologia , Criança , Transtornos Cognitivos/terapia , Método Duplo-Cego , Função Executiva/fisiologia , Feminino , Humanos , Masculino , Memória/fisiologia , Países Baixos , Transtornos Neurocognitivos/etiologia , Transtornos Neurocognitivos/fisiopatologia , Tempo de Reação/fisiologia , Resultado do TratamentoRESUMO
The anti-apoptotic protein B cell lymphoma/leukaemia 2 (BCL-2) is highly expressed in neuroblastoma and plays an important role in oncogenesis. In this study, the selective BCL-2 inhibitor ABT199 was tested in a panel of neuroblastoma cell lines with diverse expression levels of BCL-2 and other BCL-2 family proteins. ABT199 caused apoptosis more potently in neuroblastoma cell lines expressing high BCL-2 and BIM/BCL-2 complex levels than low expressing cell lines. Effects on cell viability correlated with effects on BIM displacement from BCL-2 and cytochrome c release from the mitochondria. ABT199 treatment of mice with neuroblastoma tumors expressing high BCL-2 levels only resulted in growth inhibition, despite maximum BIM displacement from BCL-2 and the induction of a strong apoptotic response. We showed that neuroblastoma cells might survive ABT199 treatment due to its acute upregulation of the anti-apoptotic BCL-2 family protein myeloid cell leukaemia sequence 1 (MCL-1) and BIM sequestration by MCL-1. In vitro inhibition of MCL-1 sensitized neuroblastoma cell lines to ABT199, confirming the pivotal role of MCL-1 in ABT199 resistance. Our findings suggest that neuroblastoma patients with high BCL-2 and BIM/BCL-2 complex levels might benefit from combination treatment with ABT199 and compounds that inhibit MCL-1 expression.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Neuroblastoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Proteína 11 Semelhante a Bcl-2/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Concentração Inibidora 50 , Camundongos , Mitocôndrias/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Neuroblastoma/patologia , Sulfonamidas/farmacologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AIM: To evaluate the prevalence of health problems in 5-year survivors treated for neuroblastoma (NBL) with intraspinal extension. PATIENTS AND METHODS: Retrospective, single center cohort study (using data from Childhood Cancer Registry and medical records) of patients treated for NBL with intraspinal extension (between 1980 and 2007) who survived ≥ 5 years after diagnosis. Health problems were graded according to the Common Terminology Criteria for Adverse Events (CTCAEv.3.0). RESULTS: All eligible patients (n = 19) were included (n = 7 no neurological symptoms at diagnosis), median age at diagnosis was 1.2 years (0.6-10.8 years), and median follow-up time was 15.6 years (6.3-29.5 years). Ninety-five percent of survivors had ≥1 health problem and 48% of survivors had ≥4 health problem with a mean of 3.8 per survivor. Fifty-three percent of survivors had at least one severe (grade 3) or life-threatening/disabling (grade 4) health problem. The three most prevalent health problems were kyphosis and/or scoliosis (68% of patients), motor neuropathy (32% of patients), and sensory neuropathy (26% of patients). Of the 13 patients who underwent a laminectomy, 54% (seven of 13) developed a grade 3 and 23% (three of 13) developed a grade 4 health problem. Among six patients, without laminectomy, 17% developed (one of six) a grade 3 and in 17% developed (one of six) a grade 4 health problem. CONCLUSIONS: Ninety-five percent of 5-year survivors treated for a childhood intraspinal NBL have health problems. The high prevalence of grade 3 and 4 health problems (especially in the laminectomy group) emphasizes the importance of specialized long-term multidisciplinary follow-up and identifies optimal treatment with limited morbidity and maximal efficacy.