RESUMEN
The contribution of genetic predisposing factors to the development of pediatric acute lymphoblastic leukemia (ALL), the most frequently diagnosed cancer in childhood, has not been fully elucidated. Children presenting with multiple de novo leukemias are more likely to suffer from genetic predisposition. Here, we selected five of these patients and analyzed the mutational spectrum of normal and malignant tissues. In two patients, we identified germline mutations in TYK2, a member of the JAK tyrosine kinase family. These mutations were located in two adjacent codons of the pseudokinase domain (p.Pro760Leu and p.Gly761Val). In silico modeling revealed that both mutations affect the conformation of this autoregulatory domain. Consistent with this notion, both germline mutations promote TYK2 autophosphorylation and activate downstream STAT family members, which could be blocked with the JAK kinase inhibitor I. These data indicate that germline activating TYK2 mutations predispose to the development of ALL.
Asunto(s)
Mutación de Línea Germinal , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , TYK2 Quinasa/genética , Alelos , Sustitución de Aminoácidos , Exoma , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Modelos Moleculares , Fosforilación , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Unión Proteica , Conformación Proteica , Dominios y Motivos de Interacción de Proteínas , Factores de Transcripción STAT/metabolismo , TYK2 Quinasa/química , TYK2 Quinasa/metabolismoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Estudios de Casos y Controles , Terapia Combinada , Femenino , Estudios de Seguimiento , Trastornos Histiocíticos Malignos , Humanos , Técnicas para Inmunoenzimas , Inmunofenotipificación , Metástasis Linfática , Linfoma de Células B Grandes Difuso , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Neoplasias/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
Several studies in adults have shown patient reported outcomes (PROs) to be effective in enhancing patient-physician communication and discussion of Health Related Quality of Life outcomes. Although less studied, positive results have been demonstrated in children. A PRO-intervention needs to be feasible in clinical practice to be successful. In the current study, 74 parents of children who successfully completed their cancer treatment and 21 pediatric oncologists (POs) evaluated a PRO-intervention and gave recommendations for future use in their practice. Most parents and POs suggested PROs to be an important part of standard care, starting during treatment, with an assessment frequency of every 3 months.
Asunto(s)
Oncología Médica , Padres/psicología , Evaluación del Resultado de la Atención al Paciente , Médicos/psicología , Pautas de la Práctica en Medicina , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Atención al Paciente , Pronóstico , Calidad de VidaRESUMEN
Methotrexate (MTX), one of the important pillars in the treatment of different forms of cancer, is associated with the development of hepatotoxicity. The 677C>T variant (rs1801133) in the methylenetetrahydrofolate reductase (MTHFR) gene might affect the development of hepatotoxicity. Results in literature are, however, contradictive. The aim of this study was to evaluate the role of the MTHFR 677C>T polymorphism in MTX-induced hepatotoxicity by analyzing a Dutch cohort of pediatric patients treated with high doses of MTX and subsequently performing a meta-analysis. Ninety-eight patients receiving 542 courses of high-dose MTX were genotyped for the MTHFR 677C>T variant. Hepatotoxicity was evaluated retrospectively according to common terminology criteria for adverse events-National Cancer Institute criteria. The influence of MTHFR 677C>T on hepatotoxicity was examined using a generalized estimating equation (GEE) analysis. A fixed-effect meta-analysis based on this and previous studies investigating the association between the MTHFR 677C>T polymorphism and uniformly coded hepatotoxicity was performed. The GEE analysis showed an increased risk of developing hepatotoxicity for T versus C allele (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.0-3.2, P=0.04). This finding was not supported by the meta-analysis including seven studies and 1044 patients; the OR for the 677T versus C allele was 1.1 (95% CI 0.84-1.5, P=0.25). Heterogeneity between studies was observed, possibly related to differences in MTX dose and leucovorin rescue. In conclusion, in patients with cancer, the MTHFR 677T allele has only a minor role in the development of MTX-induced hepatotoxicity. Observed heterogeneity between studies warrants further study into (tailored) leucovorin rescue.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Metotrexato/efectos adversos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Niño , Femenino , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Masculino , Metotrexato/administración & dosificación , Polimorfismo de Nucleótido SimpleRESUMEN
Children with acute lymphoblastic leukemia (ALL) and high minimal residual disease (MRD) levels after initial chemotherapy have a poor clinical outcome. In this prospective, single arm, Phase 2 trial, 111 Dutch and Australian children aged 1-18 years with newly diagnosed, t(9;22)-negative ALL, were identified among 1041 consecutively enrolled patients as high risk (HR) based on clinical features or high MRD. The HR cohort received the AIEOP-BFM (Associazione Italiana di Ematologia ed Oncologia Pediatrica (Italy)-Berlin-Frankfurt-Münster ALL Study Group) 2000 ALL Protocol I, then three novel HR chemotherapy blocks, followed by allogeneic transplant or chemotherapy. Of the 111 HR patients, 91 began HR treatment blocks, while 79 completed the protocol. There were 3 remission failures, 12 relapses, 7 toxic deaths in remission and 10 patients who changed protocol due to toxicity or clinician/parent preference. For the 111 HR patients, 5-year event-free survival (EFS) was 66.8% (±5.5) and overall survival (OS) was 75.6% (±4.3). The 30 patients treated as HR solely on the basis of high MRD levels had a 5-year EFS of 63% (±9.4%). All patients experienced grade 3 or 4 toxicities during HR block therapy. Although cure rates were improved compared with previous studies, high treatment toxicity suggested that novel agents are needed to achieve further improvement.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Asparaginasa/administración & dosificación , Asparaginasa/efectos adversos , Niño , Preescolar , Terapia Combinada , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Daunorrubicina/administración & dosificación , Daunorrubicina/efectos adversos , Femenino , Humanos , Lactante , Estimación de Kaplan-Meier , Masculino , Mercaptopurina/administración & dosificación , Mercaptopurina/efectos adversos , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Prednisona/administración & dosificación , Prednisona/efectos adversos , Estudios Prospectivos , Inducción de Remisión , Factores de Riesgo , Trasplante Homólogo , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/efectos adversosRESUMEN
BACKGROUND: We report on the treatment of children and adolescents with acute lymphoblastic leukemia (ALL) in first relapse. The protocol focused on: (1) Intensive chemotherapy preceding allogeneic stem cell transplantation (SCT) in early bone marrow relapse; (2) Rotational chemotherapy in late relapse, without donor; (3) Postponement of cerebro-spinal irradiation in late isolated CNS relapse; and (4) Treatment in very late bone marrow relapse with chemotherapy only. METHODS: From January 1999 until July 2006 all 158 Dutch pediatric patients with ALL in first relapse were recorded. Ninety-nine patients were eligible; 54 patients with early and 45 with late relapse. Eighteen patients had an isolated extra-medullary relapse; 69 patients had bone marrow involvement only. RESULTS: Five-years EFS rates for early and late relapses were 12% and 35%, respectively. For early relapses 5 years EFSs were 25% for patients transplanted; 0% for non-transplanted patients. For late relapses 5 years EFS was 64% for patients treated with chemotherapy only, and 16% for transplanted patients. For very late relapses EFS was 58%. CONCLUSIONS: Our data suggest the superiority of SCT for early relapse patients. For late relapses a better outcome is achieved with chemotherapy only using the rotational chemotherapy scheme. The most important factor for survival was interval between first CR and occurrence of the first relapse.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Trasplante de Células Madre , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Médula Ósea/terapia , Neoplasias del Sistema Nervioso Central/terapia , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Masculino , Análisis Multivariante , Países Bajos , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Modelos de Riesgos Proporcionales , Recurrencia , Inducción de Remisión , Análisis de Supervivencia , Neoplasias Testiculares/terapiaRESUMEN
Response to therapy as determined by minimal residual disease (MRD) is currently used for stratification in treatment protocols for pediatric acute lymphoblastic leukemia (ALL). However, the large MRD-based medium risk group (MRD-M; 50-60% of the patients) harbors many relapses. We analyzed MRD in 131 uniformly treated precursor-B-ALL patients and evaluated whether combined MRD and IKZF1 (Ikaros zinc finger-1) alteration status can improve risk stratification. We confirmed the strong prognostic significance of MRD classification, which was independent of IKZF1 alterations. Notably, 8 of the 11 relapsed cases in the large MRD-M group (n=81; 62%) harbored an IKZF1 alteration. Integration of both MRD and IKZF1 status resulted in a favorable outcome group (n=104; 5 relapses) and a poor outcome group (n=27; 19 relapses), and showed a stronger prognostic value than each of the established risk factors alone (hazard ratio (95%CI): 24.98 (8.29-75.31)). Importantly, whereas MRD and IKZF1 status alone identified only 46 and 54% of the relapses, respectively, their integrated use allowed prediction of 79% of all the relapses with 93% specificity. Because of the unprecedented sensitivity in upfront relapse prediction, the combined parameters have high potential for future risk stratification, particularly for patients originally classified as non-high risk, such as the large group of MRD-M patients.
Asunto(s)
Factor de Transcripción Ikaros/genética , Neoplasia Residual/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Valor Predictivo de las Pruebas , Niño , Reordenamiento Génico , Humanos , Estimación de Kaplan-Meier , Mutación , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Recurrencia , Medición de Riesgo , Sensibilidad y EspecificidadRESUMEN
Relapse is the most common cause of treatment failure in pediatric acute lymphoblastic leukemia (ALL) and is often difficult to predict. To explore the prognostic impact of recurrent DNA copy number abnormalities on relapse, we performed high-resolution genomic profiling of 34 paired diagnosis and relapse ALL samples. Recurrent lesions detected at diagnosis, including PAX5, CDKN2A and EBF1, were frequently absent at relapse, indicating that they represent secondary events that may be absent in the relapse-prone therapy-resistant progenitor cell. In contrast, deletions and nonsense mutations in IKZF1 (IKAROS) were highly enriched and consistently preserved at the time of relapse. A targeted copy number screen in an unselected cohort of 131 precursor B-ALL cases, enrolled in the dexamethasone-based Dutch Childhood Oncology Group treatment protocol ALL9, revealed that IKZF1 deletions are significantly associated with poor relapse-free and overall survival rates. Separate analysis of ALL9-treatment subgroups revealed that non-high-risk (NHR) patients with IKZF1 deletions exhibited a approximately 12-fold higher relative relapse rate than those without IKZF1 deletions. Consequently, IKZF1 deletion status allowed the prospective identification of 53% of the relapse-prone NHR-classified patients within this subgroup and, therefore, serves as one of the strongest predictors of relapse at the time of diagnosis with high potential for future risk stratification.
Asunto(s)
Eliminación de Gen , Factor de Transcripción Ikaros/genética , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Biomarcadores de Tumor/genética , Niño , Preescolar , Codón sin Sentido/genética , Hibridación Genómica Comparativa , Femenino , Dosificación de Gen , Perfilación de la Expresión Génica , Humanos , Lactante , Masculino , Recurrencia Local de Neoplasia/terapia , Análisis de Secuencia por Matrices de Oligonucleótidos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Pronóstico , Tasa de Supervivencia , Resultado del TratamientoAsunto(s)
Trastornos de las Plaquetas Sanguíneas/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Leucemia Mieloide Aguda/genética , Mutación , Trastornos de las Plaquetas Sanguíneas/diagnóstico , Niño , Preescolar , Femenino , Eliminación de Gen , Humanos , Leucemia Mieloide Aguda/diagnóstico , MasculinoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Rabdomiosarcoma/terapia , Niño , Terapia Combinada , Femenino , Humanos , Metástasis de la Neoplasia , Inducción de Remisión , Rabdomiosarcoma/tratamiento farmacológico , Rabdomiosarcoma/patología , Rabdomiosarcoma/cirugía , Acondicionamiento PretrasplanteRESUMEN
The potential role of antibodies and T lymphocytes in the eradication of cancer has been demonstrated in numerous animal models and clinical trials. In the last decennia new strategies have been developed for the use of tumor-specific T cells and antibodies in cancer therapy. Effective anti-tumor immunotherapy requires the identification of suitable target antigens. The expression of tumor-specific antigens has been extensively studied for most types of adult tumors. Pediatric patients should be excellent candidates for immunotherapy since their immune system is more potent and flexible as compared to that of adults. So far, these patients do not benefit enough from the progresses in cancer immunotherapy, and one of the reasons is the paucity of tumor-specific antigens identified on pediatric tumors. In this review we discuss the current status of cancer immunotherapy in children, focusing on the identification of tumor-specific antigens on pediatric solid tumors.
Asunto(s)
Inmunoterapia Activa , Neoplasias/terapia , Antígenos de Neoplasias/inmunología , Niño , Ensayos Clínicos como Asunto , Humanos , Neoplasias/inmunologíaAsunto(s)
Trasplante de Médula Ósea/efectos adversos , Leucemia Mieloide/etiología , Leucemia Mieloide/terapia , Neoplasias Primarias Secundarias/terapia , Enfermedad Aguda , Análisis Citogenético , Reordenamiento Génico , Humanos , Lactante , Leucemia Mieloide/genética , Masculino , Neoplasias Primarias Secundarias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Donantes de Tejidos , Trasplante HomólogoRESUMEN
Gross cytogenetic anomalies are traditionally being used as diagnostic, prognostic and therapeutic markers in the clinical management of cancer, including childhood acute lymphoblastic leukemia (ALL). Recently, it has become increasingly clear that genetic lesions driving tumorigenesis frequently occur at the submicroscopic level and, consequently, escape standard cytogenetic observations. Therefore, we profiled the genomes of 40 childhood ALLs at high resolution. We detected multiple de novo genetic lesions, including gross aneuploidies and segmental gains and losses, some of which were subtle and affected single genes. Many of these lesions involved recurrent (partially) overlapping deletions and duplications, containing various established leukemia-associated genes, such as ETV6, RUNX1 and MLL. Importantly, the most frequently affected genes were those controlling G1/S cell cycle progression (e.g. CDKN2A, CDKN1B and RB1), followed by genes associated with B-cell development. The latter group includes microdeletions of the B-lineage transcription factors PAX5, EBF, E2-2 and IKZF1 (Ikaros), as well as genes with other established roles in B-cell development, that is RAG1 and RAG2, FYN, PBEF1 or CBP/PAG. The fact that we frequently encountered multiple lesions affecting genes involved in cell cycle regulation and B-cell differentiation strongly suggests that both these processes need to be targeted independently and simultaneously to trigger ALL development.
Asunto(s)
Ciclo Celular/genética , Diferenciación Celular/genética , Genes Relacionados con las Neoplasias , Linfocitos/citología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Linfocitos B/citología , Aberraciones Cromosómicas , Femenino , Dosificación de Gen , Perfilación de la Expresión Génica/métodos , Genómica/métodos , Humanos , Masculino , Hibridación de Ácido Nucleico , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Factores de TranscripciónRESUMEN
BACKGROUND: The aim of the study was to make a comprehensive inventory of the physical, psychological, and social symptoms of children with cancer and their parents during the palliative phase and the extent to which health professionals address those symptoms. PROCEDURE: Forty parents of children who died 1-3 years prior to data collection (structured questionnaire) were invited to participate in the study. RESULTS: The response rate was 32 out of 40 parents (80%). Most frequently mentioned physical symptoms were pain, poor appetite, and fatigue. The children's most mentioned psychological symptoms were sadness, difficulty in talking to their parents about their feelings regarding illness and death and fear of being alone. The symptoms of fear of death of the child and fear of physical symptoms were most frequently mentioned parents' psychological symptoms. Health professionals addressed 82% of the children's physical symptoms, 43% of the children's psychological symptoms, and 56% of the parents' psychological symptoms. Parents indicated that after professional attention the proportion of children's physical symptoms that were completely or partially resolved was 18 and 26%, respectively. For children's psychological symptoms the figures were 9 and 25%, respectively, and for parents' psychological symptoms 2 and 23%, respectively. CONCLUSIONS: The burden of symptoms of the child with cancer during the palliative phase and their parents is high. Health professionals focus mainly on the physical symptoms of the child. Relief of symptoms could not be achieved for a large proportion of symptoms. Further prospective research is necessary to investigate the kind, frequency and intensity of symptoms in order to tailor optimal palliative care to the needs of both child and parent.
Asunto(s)
Neoplasias/complicaciones , Cuidados Paliativos/psicología , Padres/psicología , Cuidado Terminal/psicología , Adolescente , Factores de Edad , Anorexia/etiología , Anorexia/psicología , Anorexia/terapia , Actitud Frente a la Muerte , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/fisiopatología , Neoplasias Encefálicas/psicología , Cuidadores/psicología , Niño , Preescolar , Emociones , Fatiga/etiología , Fatiga/psicología , Fatiga/terapia , Miedo , Femenino , Enfermedades Gastrointestinales/etiología , Enfermedades Gastrointestinales/psicología , Enfermedades Gastrointestinales/terapia , Humanos , Lactante , Leucemia/complicaciones , Leucemia/fisiopatología , Leucemia/psicología , Masculino , Limitación de la Movilidad , Neoplasias/economía , Neoplasias/fisiopatología , Neoplasias/psicología , Neoplasias/terapia , Dolor/fisiopatología , Manejo del Dolor , Cuidados Paliativos/economía , Relaciones Padres-Hijo , Relaciones Médico-Paciente , Relaciones Profesional-Familia , Estudios Retrospectivos , Apoyo Social , Estrés Psicológico/etiología , Estrés Psicológico/psicología , Estrés Psicológico/terapia , Encuestas y Cuestionarios , Cuidado Terminal/economía , Insuficiencia del TratamientoRESUMEN
The dog is an important animal model for solid organ as well as stem cell allo transplantation. Methods such as cellular and serological typing and more recently sequence-based typing (SBT) have been used to discriminate tissue antigen disparity of donor and recipient. We applied SBT for the canine class I (DLA-88) and class II (DLA-DRB1) genes in beagle families prior stem cell transplantation. A novel DLA-88 (DLA-88*04501) allele in combination with a DLA-DRB1*01901 allele was found. Sequence comparison of exons 2 and 3 of the novel allele revealed most sequence identity to the DLA-88*01301 allele (96.15% identity at the nucleotide and 90.65% identity at the protein level).
Asunto(s)
Alelos , Perros/genética , Antígenos de Histocompatibilidad/genética , Complejo Mayor de Histocompatibilidad/genética , Análisis de Secuencia de ADN , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Perros/inmunología , Variación Genética , Haplotipos , Repeticiones de Microsatélite , Datos de Secuencia Molecular , Linaje , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo Genético , Homología de Secuencia , HermanosRESUMEN
Many patients do not reach haematopoietic stem cell transplantation. Shortage of unrelated donors (UDs) is still seen as the main cause. However, with a worldwide UD pool containing more than 8 million donors, it is possible that other impediments are becoming more important. We analysed 549 UD searches for Dutch patients, performed between 1987 and 2000, in order to find the reasons for failure or success to reach transplantation. Between 1996 and 2000, 59% of the patients of Northwest European origin received a graft from an UD with a median time span of 4.4 months from the start of the search. In all, 11% of the patients lacked a compatible donor, while 30% became medically unfit for transplantation. This is in contrast to the patients of non-Northwest European origin for whom UD shortage is still the most important impediment; only 32% were transplanted while 50% lacked a compatible donor. We conclude that the shortage of donors is no longer the biggest constraint in unrelated stem cell transplantation for patients of Northwest European origin. It may be more effective to optimize the chance on transplantation by making the search process more efficient.