RESUMEN
PURPOSE: Chemotherapy for pediatric acute myeloid leukemia (AML) is very intensive and many, but not all centers, require extended hospitalization until neutrophil recovery. Child and family preferences, beliefs, and experiences around hospitalization have not been systematically assessed. PATIENTS AND METHODS: We recruited children with AML and their parents from nine pediatric cancer centers across the United States for a qualitative interview about their experiences of neutropenia management. Interviews were analyzed using a conventional content analysis approach. RESULTS: Of 116 eligible individuals, 86 (74.1%) agreed to participate. Interviews were conducted with 32 children and 54 parents from 57 families. Of these 57 families, 39 were cared for as inpatients and 18 were managed as outpatients. A very high proportion of respondents in both groups reported satisfaction with the discharge management strategy recommended by the treating institution: 86% (57 individuals) of respondents who experienced inpatient management and 85% (17 individuals) of respondents who experienced outpatient management expressed satisfaction. Respondent perceptions associated with satisfaction related to safety (access to emergency interventions, infection risk, close monitoring) and psychosocial concerns (family separation, low morale, social support). Respondents believed it could not be assumed that all children would have the same experience due to varied life circumstances. CONCLUSION: Children with AML and their parents express a very high degree of satisfaction with the discharge strategy recommended by their treating institution. Respondents saw a nuanced tradeoff between patient safety and psychosocial concerns that was mediated by a child's life circumstances.
Asunto(s)
Líquidos Corporales , Leucemia Mieloide Aguda , Neutropenia , Niño , Humanos , Neutropenia/terapia , Hospitalización , Padres , Satisfacción Personal , Leucemia Mieloide Aguda/terapiaRESUMEN
SevenChildren's Oncology Group phase 2 trials for patients with relapsed/progressive solid tumors were analyzed to estimate the event-free survival (EFS) for relapsed/progressive Ewing sarcoma. One hundred twenty-eight Ewing sarcoma patients were enrolled and 124 events occurred. The 6-month EFS was 12.7%, demonstrating the poor outcome of these patients. Only docetaxel achieved its protocol-specified radiographic response rate for activity; however, the EFS for docetaxel was similar to other agents, indicating that a higher radiographic response rate may not translate into superior disease control. This EFS benchmark could be utilized as an additional endpoint in trials for recurrent Ewing sarcoma.
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Neoplasias Óseas , Tumores Neuroectodérmicos Periféricos Primitivos , Sarcoma de Ewing , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/patología , Niño , Docetaxel/uso terapéutico , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Sarcoma de Ewing/patologíaRESUMEN
The COVID-19 pandemic impacted the health care system in unprecedented ways. We reviewed the registry of new cancer patients who presented to the Children's of Mississippi Center for Cancer and Blood Disorders and showed the average number of new pediatric cancer diagnoses dropped during the initial COVID-19 months and rose significantly in June 2020. We must encourage families to seek health care when needed and keep scheduled appointments for routine vaccinations and health maintenance as we know the long-term sequela of delaying health maintenance far outweighs risks at present.
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COVID-19/complicaciones , Diagnóstico Tardío/estadística & datos numéricos , Neoplasias/diagnóstico , SARS-CoV-2/aislamiento & purificación , Adolescente , Adulto , COVID-19/transmisión , COVID-19/virología , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Mississippi/epidemiología , Neoplasias/epidemiología , Neoplasias/virología , Adulto JovenRESUMEN
OBJECTIVES: The purpose of this study was to investigate the patient population and outcomes of synovial sarcoma at a single institution. METHODS: A retrospective review of the medical records of 28 patients with synovial sarcoma diagnosed from 1992 to 2017 was performed. Demographics, staging, disease location, treatment, and response to treatment were reviewed. RESULTS: Individuals with larger tumors at the time of presentation had an increased risk of death. An additional factor associated with poor prognosis in synovial sarcoma was increasing patient age. The patient population had a higher rate of nonextremity disease and lower overall survival when compared with national averages. CONCLUSIONS: Nonextremity disease and large size of tumor at presentation may have contributed to the disparity in institutional outcomes from the national averages. The advanced presentation of synovial sarcoma remains a significant challenge in improving patient survival.
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Sarcoma Sinovial/mortalidad , Adulto , Factores de Edad , Femenino , Disparidades en el Estado de Salud , Humanos , Masculino , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Sarcoma Sinovial/patología , Tasa de SupervivenciaRESUMEN
Complex relationships between race and socioeconomic status have a poorly understood influence on psychologic outcomes in pediatric oncology. The Family Symptom Inventory was used to assess symptoms of depression and anxiety in pediatric patients with cancer and their caregivers. Separate hierarchical linear regression models examined the relationship between demographic variables, cancer characteristics, socioeconomic status, and access to care and patient or caregiver depression/anxiety. Participants included 196 pediatric patients with cancer (mean age, 11.21 y; 49% African American) and their caregivers. On average, caregivers reported low levels of depression/anxiety. Symptoms of depression and anxiety in patients were correlated with poorer mental health in caregivers (r=0.62; P<0.01). Self-reported financial difficulty (ß=0.49; P<0.001) and brain cancer diagnosis for their child (ß=0.42; P=0.008) were significantly associated with depression and anxiety in caregivers. Analysis did not reveal significant associations between race, household income, or access to care and patient or caregiver depression/anxiety. Perception of financial hardship can adversely impact mental health in caregivers of children with cancer. Psychosocial assessment and interventions may be especially important for caregivers of patients with brain tumors and caregivers who report feeling financial difficulty.
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Cuidadores/psicología , Neoplasias/psicología , Calidad de Vida , Grupos Raciales/psicología , Autoinforme , Clase Social , Adolescente , Adulto , Niño , Preescolar , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Pronóstico , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Efficacy of therapeutic strategies relative to patient- and family-centered outcomes in pediatric oncology must be assessed. We sought to identify outcomes important to children with acute myeloid leukemia and their families related to inpatient versus at-home management of neutropenia. We conducted qualitative interviews with 32 children ≥8 years old and 54 parents. Analysis revealed the impact of neutropenia management strategy on siblings, parent anxiety, and child sleep quality as being outcomes of concern across respondents. These themes were used to inform the design of a questionnaire that is currently being used in a prospective, multiinstitutional comparative effectiveness trial.
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Ansiedad , Pacientes Internos , Leucemia Mieloide Aguda , Neutropenia , Relaciones Padres-Hijo , Hermanos , Adolescente , Adulto , Ansiedad/fisiopatología , Ansiedad/psicología , Ansiedad/terapia , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/fisiopatología , Leucemia Mieloide Aguda/psicología , Leucemia Mieloide Aguda/terapia , Neutropenia/fisiopatología , Neutropenia/psicología , Neutropenia/terapia , Estudios ProspectivosRESUMEN
The increasing use of serial multimodality imaging in the management of pediatric osteosarcoma raises concern of over exposure to ionizing radiation in children, especially from repeated computed tomographic (CT) scans. This study reviews the utilization of multimodality imaging in patients with osteosarcoma at our institution and analyzes any potential radiation-related complications. Twenty-eight patients were identified. Three patients developed late complications-acute myeloid leukemia, myelodysplastic syndrome, and early menopause. Using the patient's age and body part imaged, CT dose length product and effective dose was estimated with the use of a conversion factor for 19 patients. The effective doses were higher in the 3 patients with late complications than the other patients in the cohort (P=0.018). These results suggest an increased risk for adverse effects with higher CT exposures and effective doses. On the basis of our data and published data, methods to decrease the doses of radiation from medical imaging need to be explored. The number of CT scans may be limited. Implementing the Image Gently concept to decrease radiation exposure can be beneficial in modification of CT acquisition parameters.
Asunto(s)
Neoplasias Óseas/diagnóstico por imagen , Osteosarcoma/diagnóstico por imagen , Traumatismos por Radiación/epidemiología , Tomografía Computarizada por Rayos X/efectos adversos , Adolescente , Adulto , Niño , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Imagen Multimodal/efectos adversos , Imagen Multimodal/métodos , Tomografía de Emisión de Positrones , Dosis de Radiación , Estudios Retrospectivos , Medición de Riesgo , Adulto JovenRESUMEN
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although curable, approximately 20% of patients relapse. In an effort to detect relapse earlier, our institution performed surveillance bone marrow (BM) and cerebrospinal fluid (CSF) evaluations every 3 months from the end of therapy to 1 year off. This study retrospectively reviewed all patients with B-cell ALL (B-ALL) from September 2005 to September 2010 to determine the benefit and cost of these procedures. Forty-one patients completed therapy and had 190 BMs and 190 lumbar punctures (LPs) performed. Four of 41 patients (9.8%) experienced a relapse. Relapse was detected in only 1 patient by routine BM evaluation (0.5%). Zero LPs were positive. The professional fees for the procedures were $8,738/patient. Therefore, off-therapy BM and CSF evaluations are not effective at detecting relapse and are expensive. Our institution has abandoned off-therapy surveillance for ALL.
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Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Adolescente , Examen de la Médula Ósea , Niño , Preescolar , Femenino , Costos de la Atención en Salud , Humanos , Lactante , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/líquido cefalorraquídeo , RecurrenciaRESUMEN
Hemoglobin (Hb) variants may be associated with low oxygen saturation and exacerbated episodes of anemia from common stressors such as viral infections. These attributes frequently cause increased clinical concern and unnecessary and expensive testing if not considered early in the evaluation of the patient. Some clinically significant Hb variants result in a normal Hb electrophoresis result, which can be method-dependent. Herein we describe a patient with low oxygen saturation and a history of hemolytic anemia who was subsequently found to carry a novel, unstable ß-globin variant that we have named Hb Allentown [ß137(H15)ValâTrp (GTG>TGG) HBB: c.412_413delinsTG, p.Val138Trp] for the place of identification of the variant. Hb Allentown is formed by a rare double nucleotide substitution within the same codon. Additionally, positive identification of rare Hb variants characterized by a single method is discouraged, as the Hb variant was misclassified as Hb S-South End or ß6(A3)GluâVal;ß132(H10)LysâAsn (HBB: c.[20A > T;399A > C]) by the initial laboratory.
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Anemia/diagnóstico , Anemia/genética , Hemoglobinas Anormales/genética , Hemoglobinas Anormales/metabolismo , Globinas beta/genética , Globinas beta/metabolismo , Sustitución de Aminoácidos , Anemia/sangre , Cromatografía Líquida de Alta Presión , Codón , Análisis Mutacional de ADN , Genotipo , Hemoglobinas Anormales/química , Humanos , Hipoxia/sangre , Modelos Moleculares , Conformación Molecular , Esplenomegalia , Globinas beta/químicaRESUMEN
Chondrosarcoma is a malignant bone tumour common in adults, third to myeloma and osteosarcoma, but is exceptionally rare in children. Here we discuss a 9-year-old girl presenting with occlusive right pulmonary artery neoplastic embolus, resulting from a primary right proximal humerus chondrosarcoma. To the best of our knowledge, this the first pediatric and only second overall case reported in the United States of a neoplastic pulmonary embolus resulting from a primary chondrosarcoma.
Asunto(s)
Neoplasias Óseas/diagnóstico , Condrosarcoma/diagnóstico , Húmero , Células Neoplásicas Circulantes , Arteria Pulmonar/diagnóstico por imagen , Embolia Pulmonar/diagnóstico , Neoplasias Óseas/complicaciones , Niño , Condrosarcoma/complicaciones , Ecocardiografía , Femenino , Humanos , Embolia Pulmonar/etiología , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Bloodstream infections (BSIs) are a frequent cause of morbidity in patients with acute myeloid leukemia (AML), due in part to the presence of central venous access devices (CVADs) required to deliver therapy. OBJECTIVE: To determine the differential risk of bacterial BSI during neutropenia by CVAD type in pediatric patients with AML. METHODS: We performed a secondary analysis in a cohort of 560 pediatric patients (1,828 chemotherapy courses) receiving frontline AML chemotherapy at 17 US centers. The exposure was CVAD type at course start: tunneled externalized catheter (TEC), peripherally inserted central catheter (PICC), or totally implanted catheter (TIC). The primary outcome was course-specific incident bacterial BSI; secondary outcomes included mucosal barrier injury (MBI)-BSI and non-MBI BSI. Poisson regression was used to compute adjusted rate ratios comparing BSI occurrence during neutropenia by line type, controlling for demographic, clinical, and hospital-level characteristics. RESULTS: The rate of BSI did not differ by CVAD type: 11 BSIs per 1,000 neutropenic days for TECs, 13.7 for PICCs, and 10.7 for TICs. After adjustment, there was no statistically significant association between CVAD type and BSI: PICC incident rate ratio [IRR] = 1.00 (95% confidence interval [CI], 0.75-1.32) and TIC IRR = 0.83 (95% CI, 0.49-1.41) compared to TEC. When MBI and non-MBI were examined separately, results were similar. CONCLUSIONS: In this large, multicenter cohort of pediatric AML patients, we found no difference in the rate of BSI during neutropenia by CVAD type. This may be due to a risk-profile for BSI that is unique to AML patients.
Asunto(s)
Infecciones Bacterianas , Infecciones Relacionadas con Catéteres , Cateterismo Venoso Central , Catéteres Venosos Centrales , Leucemia Mieloide Aguda , Neutropenia , Sepsis , Humanos , Niño , Sepsis/epidemiología , Catéteres Venosos Centrales/efectos adversos , Leucemia Mieloide Aguda/complicaciones , Neutropenia/complicaciones , Neutropenia/epidemiología , Doxorrubicina , Cateterismo Venoso Central/efectos adversos , Factores de Riesgo , Infecciones Relacionadas con Catéteres/etiologíaRESUMEN
To determine the contribution of susceptibility loci in explaining the genetic basis of acute lymphoblastic leukemia (ALL), we genotyped 29 high-potential candidate genes with 672 tagged single-nucleotide polymorphisms (SNPs) in a sample (163 cases and 251 healthy controls) of Caucasian children. Fifty SNPs in 15 genes were significantly associated with ALL risk at the P < 0.05 level. After correction for multiple testing, rs442264 within the LIM domain only 1 (LMO1) gene at 11p15 remained significant [odds ratio (OR) = 1.90, P = 3 × 10(-5)]. In addition, a major haplotype within LMO1 comprising 14 SNPs with individual risk associations was found to significantly increase ALL risk (OR = 1.79, P = 0.0006). A stratified analysis on subtype indicated that risk associations of LMO1 variants are significant in children with precursor B-cell leukemia. These data show that genetic variants within LMO1 are associated with ALL and identify this gene as a strong candidate for precursor B-cell leukemogenesis.
Asunto(s)
Cromosomas Humanos Par 11 , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Factores de Transcripción/genética , Adolescente , Adulto , Niño , Preescolar , Mapeo Cromosómico , Femenino , Frecuencia de los Genes , Haplotipos , Humanos , Lactante , Proteínas con Dominio LIM , Desequilibrio de Ligamiento , Masculino , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Control de CalidadRESUMEN
Cutaneous Ewing sarcoma is a rare variant that has been poorly characterized and has no standard therapy. We report 2 patients with cutaneous Ewing sarcoma and review 76 other cases reported in the literature for demographics, presentation, treatment, and outcome. Only 2 patients presented with metastatic disease, and only 8 patients developed metastatic disease. Ninety-one percent of all patients are alive despite wide variations in treatment regimens. On the basis of this summary, treatment consisting of local control with surgery and/or radiation and abbreviated chemotherapy is proposed as a treatment option for this less aggressive Ewing sarcoma.
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Quimioradioterapia , Sarcoma de Ewing , Neoplasias Cutáneas , Adolescente , Niño , Femenino , Humanos , Inducción de Remisión , Sarcoma de Ewing/patología , Sarcoma de Ewing/cirugía , Sarcoma de Ewing/terapia , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugía , Neoplasias Cutáneas/terapia , Resultado del TratamientoRESUMEN
Importance: Pediatric acute myeloid leukemia (AML) requires multiple courses of intensive chemotherapy that result in neutropenia, with significant risk for infectious complications. Supportive care guidelines recommend hospitalization until neutrophil recovery. However, there are little data to support inpatient over outpatient management. Objective: To evaluate outpatient vs inpatient neutropenia management for pediatric AML. Design, Setting, and Participants: This cohort study used qualitative and quantitative methods to compare medical outcomes, patient health-related quality of life (HRQOL), and patient and family perceptions between outpatient and inpatient neutropenia management. The study included patients from 17 US pediatric hospitals with frontline chemotherapy start dates ranging from January 2011 to July 2019, although the specific date ranges differed for the individual analyses by design and relative timing. Data were analyzed from August 2019 to February 2020. Exposures: Discharge to outpatient vs inpatient neutropenia management. Main Outcomes and Measures: The primary outcomes of interest were course-specific bacteremia incidence, times to next course, and patient HRQOL. Course-specific mortality was a secondary medical outcome. Results: Primary quantitative analyses included 554 patients (272 [49.1%] girls and 282 [50.9%] boys; mean [SD] age, 8.2 [6.1] years). Bacteremia incidence was not significantly different during outpatient vs inpatient management (67 courses [23.8%] vs 265 courses [29.0%]; adjusted rate ratio, 0.73; 95% CI, 0.56 to 1.06; P = .08). Outpatient management was not associated with delays to the next course compared with inpatient management (mean [SD] 30.7 [12.2] days vs 32.8 [9.7] days; adjusted mean difference, -2.2; 95% CI, -4.1 to -0.2, P = .03). Mortality during intensification II was higher for patients who received outpatient management compared with those who received inpatient management (3 patients [5.4%] vs 1 patient [0.5%]; P = .03), but comparable with inpatient management at other courses (eg, 0 patients vs 5 patients [1.3%] during induction I; P = .59). Among 97 patients evaluated for HRQOL, outcomes did not differ between outpatient and inpatient management (mean [SD] Pediatric Quality of Life Inventory total score, 70.1 [18.9] vs 68.7 [19.4]; adjusted mean difference, -2.8; 95% CI, -11.2 to 5.6). A total of 86 respondents (20 [23.3%] in outpatient management, 66 [76.7%] in inpatient management) completed qualitative interviews. Independent of management strategy received, 74 respondents (86.0%) expressed satisfaction with their experience. Concerns for hospital-associated infections among caregivers (6 of 7 caregiver respondents [85.7%] who were dissatisfied with inpatient management) and family separation (2 of 2 patient respondents [100%] who were dissatisfied with inpatient management) drove dissatisfaction with inpatient management. Stress of caring for a neutropenic child at home (3 of 3 respondents [100%] who were dissatisfied with outpatient management) drove dissatisfaction with outpatient management. Conclusions and Relevance: This cohort study found that outpatient neutropenia management was not associated with higher bacteremia incidence, treatment delays, or worse HRQOL compared with inpatient neutropenia management among pediatric patients with AML. While outpatient management may be safe for many patients, course-specific mortality differences suggest that outpatient management in intensification II should be approached with caution. Patient and family experiences varied, suggesting that outpatient management may be preferred by some but may not be feasible for all families. Further studies to refine and standardize safe outpatient management practices are warranted.
Asunto(s)
Leucemia Mieloide Aguda/terapia , Neutropenia/etiología , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Calidad de Vida/psicología , Adolescente , Niño , Preescolar , Estudios de Cohortes , Quimioterapia/métodos , Quimioterapia/psicología , Quimioterapia/estadística & datos numéricos , Familia/psicología , Femenino , Humanos , Entrevistas como Asunto/métodos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/epidemiología , Masculino , Neutropenia/epidemiología , Evaluación de Resultado en la Atención de Salud/métodos , Pediatría/métodos , Pediatría/estadística & datos numéricos , Investigación CualitativaRESUMEN
BACKGROUND: Lack of health insurance coverage is associated with poor access and receipt of cancer care and survival in the United States. Disruptions in coverage are common among low-income populations, but little is known about associations of disruptions with cancer care, including prevention, screening, and treatment, as well as outcomes of stage at diagnosis and survival. METHODS: We conducted a systematic review of studies of health insurance coverage disruptions and cancer care and outcomes published between 1980 and 2019. We used the PubMed, EMBASE, Scopus, and CINAHL databases and identified 29 observational studies. Study characteristics and key findings were abstracted and synthesized qualitatively. RESULTS: Studies evaluated associations between coverage disruptions and prevention or screening (31.0%), treatment (13.8%), end-of-life care (10.3%), stage at diagnosis (44.8%), and survival (20.7%). Coverage disruptions ranged from 4.3% to 32.8% of patients age-eligible for breast, cervical, or colorectal cancer screening. Between 22.1% and 59.5% of patients with Medicaid gained coverage only at or after cancer diagnosis. Coverage disruptions were consistently statistically significantly associated with lower receipt of prevention, screening, and treatment. Among patients with cancer, those with Medicaid disruptions were statistically significantly more likely to have advanced stage (odds ratios = 1.2-3.8) and worse survival (hazard ratios = 1.28-2.43) than patients without disruptions. CONCLUSIONS: Health insurance coverage disruptions are common and adversely associated with receipt of cancer care and survival. Improved data infrastructure and quasi-experimental study designs will be important for evaluating the associations of federal and state policies on coverage disruptions and care and outcomes.
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Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Cobertura del Seguro/estadística & datos numéricos , Neoplasias/economía , Neoplasias/terapia , Detección Precoz del Cáncer/estadística & datos numéricos , Humanos , Seguro de Salud/estadística & datos numéricos , Medicaid/estadística & datos numéricos , Pacientes no Asegurados/estadística & datos numéricos , Neoplasias/diagnóstico , Estudios Observacionales como Asunto , Patient Protection and Affordable Care Act/estadística & datos numéricos , Pobreza/estadística & datos numéricos , Publicaciones/estadística & datos numéricos , Estados UnidosRESUMEN
Histone deacetylase inhibitors (HDACi) have been evaluated in patients with Ewing sarcoma (EWS) but demonstrated limited activity. To better understand the potential for HDACi in EWS, we evaluated the combination of the HDACi vorinostat, with DNA damaging agents SN-38 (the active metabolite of irinotecan and topoisomerase 1 inhibitor) plus the alkylating agent temozolomide (ST). Drugs were evaluated in sequential and simultaneous combinations in two EWS cell lines. Results demonstrate that cell viability, DNA damage and reactive oxygen species (ROS) production are dependent on the sequence of drug administration. Enhanced cytotoxicity is exhibited in vitro in EWS cell lines treated with ST administered before vorinostat, which was modestly higher than concomitant treatment and superior to vorinostat administered before ST. Drug combinations downregulate cyclin D1 to induce G0/G1 arrest and promote apoptosis by cleavage of caspase-3 and PARP. When ST is administered before or concomitantly with vorinostat there is activation of STAT3, MAPK and the p53 pathway. In contrast, when vorinostat is administered before ST, there is DNA repair, increased AKT phosphorylation and reduced H2B acetylation. Inhibition of AKT using the small molecule inhibitor MK-2206 did not restore H2B acetylation. Combining ST with the dual ALK and IGF-1R inhibitor, AZD3463 simultaneously inhibited STAT3 and AKT to enhance the cytotoxic effects of ST and further reduce cell growth suggesting that STAT3 and AKT activation were in part mediated by ALK and IGF-1R signaling. In summary, potent antiproliferative and proapoptotic activity were demonstrated for ST induced DNA damage before or simultaneous with HDAC inhibition and cell death was mediated through the p53 pathway. These observations may aid in designing new protocols for treating pediatric patients with high-risk EWS.
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Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Camptotecina/análogos & derivados , Dacarbazina/análogos & derivados , Inhibidores de Histona Desacetilasas/toxicidad , Ácidos Hidroxámicos/toxicidad , Transducción de Señal/efectos de los fármacos , Acetilación/efectos de los fármacos , Camptotecina/toxicidad , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Dacarbazina/toxicidad , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Irinotecán , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patología , Temozolomida , Proteína p53 Supresora de Tumor/metabolismo , VorinostatRESUMEN
BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. The U.S. Surveillance Epidemiology and End Results (SEER) registry reports that Hispanic children have the highest incidence of ALL, however, it is unclear if this is due to genetic factors, unique environmental exposures, or both. Previous reports have shown an association between CYP1A1 variants and ALL. METHODS: To explore the contribution of CYP1A1 polymorphisms to ALL susceptibility in different ethnic groups, we conducted a case-control analysis in Caucasian, Hispanic, and African-American children. RESULTS: Increased risk of developing ALL was found in the whole sample group for homozygosity of variant alleles at CYP1A1*2C (OR 2.51, 95% CI 1.18-5.33, P = 0.016) and CYP1A1*2B (OR 3.24, 95% CI 1.43-7.34, P = 0.005). Stratified analyses showed increased risks in the Hispanic group (CYP1A1*2A, OR 2.70, 95% CI 1.27-5.74, P = 0.010; CYP1A1*2C, OR 2.47, 95% CI 1.13-5.38, P = 0.023; and CYP1A1*2B, OR 3.28, 95% CI 1.40-7.69, P = 0.006) but not for the other ethnic groups. Hispanic control subjects were significantly more likely to be carriers of variant alleles as compared to Caucasians (P < 0.0001) and African Americans (P = 0.005). CONCLUSIONS: Our study suggests that polymorphisms in CYP1A1 may contribute to the increased risk of ALL in Hispanic children due to both their impact on leukemia susceptibility and the increased prevalence of the at-risk alleles in the Hispanic population. IMPACT: Our study provides a novel and specific link between CYP1A1 polymorphisms and ethnic influence on ALL risk that may help explain varying susceptibilities across groups to environmental toxins.
Asunto(s)
Citocromo P-450 CYP1A1/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/etnología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Negro o Afroamericano/etnología , Negro o Afroamericano/genética , Estudios de Casos y Controles , Niño , Genotipo , Hispánicos o Latinos/etnología , Hispánicos o Latinos/genética , Humanos , Población Blanca/etnología , Población Blanca/genéticaRESUMEN
BACKGROUND: Hispanic children have both a higher incidence and a poorer outcome in acute lymphoblastic leukemia (ALL). Moreover, a higher incidence for therapy-related acute myeloid leukemia with 11q23 translocations after treatment with topoisomerase II (topo II) inhibitors has been observed in Hispanic children with ALL. We sought to determine the potential role of genetic variants within the topoisomerase IIα gene (TOP2A), within the mixed lineage leukemia gene (MLL) and two of its translocation partners, cyclin AMP response element-binding protein gene (CREBBP) and E1A binding protein gene (EP300) in the increased sensitivity of Hispanic children with ALL to topo II inhibitors. METHODS: Fifty-two tagged single nucleotide polymorphisms (SNP) covering the four genes were genotyped in 241 samples (66 children with ALL and 175 age matched controls) of self-identified Hispanic origin. RESULTS: Two SNPs within MLL (rs525549 and rs6589664) and three SNPs within EP300 (rs5758222, rs7286979, and rs20551) were significantly associated with ALL (P = 0.001-0.04). A significant gene-dosage effect for increasing numbers of potential high-risk genotypes (OR = 16.66; P = 2 × 10(-5)) and a major haplotype significantly associated with ALL (OR = 5.68; P = 2 × 10(-6)) were found. Replication in a sample of 137 affected White children and 239 controls showed that only rs6589664 (MLL) was significantly associated in this ethnic group. CONCLUSIONS: Our findings indicate that the association between ALL and common genetic variants within MLL and EP300 is population specific. IMPACT: Replication of our findings in independent Hispanic populations is warranted to elucidate the role of these variants in ALL susceptibility and define their importance in the ethnic specific differences in ALL risk.