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Leucemia Mieloide Aguda , Neoplasias do Mediastino , Neoplasias Embrionárias de Células Germinativas , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamento farmacológico , Neoplasias do Mediastino/patologia , Neoplasias do Mediastino/terapia , Neoplasias do Mediastino/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/terapia , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/terapia , Indução de Remissão , AdolescenteRESUMO
Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.
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Clofarabina , Histiocitose de Células de Langerhans , Humanos , Clofarabina/uso terapêutico , Clofarabina/administração & dosagem , Histiocitose de Células de Langerhans/tratamento farmacológico , Masculino , Feminino , Adulto , Adolescente , Criança , Pessoa de Meia-Idade , Pré-Escolar , Adulto Jovem , Idoso , Recidiva , Proteínas Proto-Oncogênicas B-raf/genética , Lactente , Resultado do Tratamento , Terapia de Salvação , Nucleotídeos de Adenina/uso terapêutico , Nucleotídeos de Adenina/administração & dosagem , Nucleotídeos de Adenina/efeitos adversos , Arabinonucleosídeos/uso terapêutico , Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/efeitos adversosRESUMO
BACKGROUND: The survival benefit observed in children with neuroblastoma (NB) and minimal residual disease who received treatment with anti-GD2 monoclonal antibodies prompted our investigation into the safety and potential clinical benefits of anti-CD3×anti-GD2 bispecific antibody (GD2Bi) armed T cells (GD2BATs). Preclinical studies demonstrated the high cytotoxicity of GD2BATs against GD2+cell lines, leading to the initiation of a phase I/II study in recurrent/refractory patients. METHODS: The 3+3 dose escalation phase I study (NCT02173093) encompassed nine evaluable patients with NB (n=5), osteosarcoma (n=3), and desmoplastic small round cell tumors (n=1). Patients received twice-weekly infusions of GD2BATs at 40, 80, or 160×106 GD2BATs/kg/infusion complemented by daily interleukin-2 (300,000 IU/m2) and twice-weekly granulocyte macrophage colony-stimulating factor (250 µg/m2). The phase II segment focused on patients with NB at the dose 3 level of 160×106 GD2BATs/kg/infusion. RESULTS: Of the 12 patients enrolled, 9 completed therapy in phase I with no dose-limiting toxicities. Mild and manageable cytokine release syndrome occurred in all patients, presenting as grade 2-3 fevers/chills, headaches, and occasional hypotension up to 72 hours after GD2BAT infusions. GD2-antibody-associated pain was minimal. Median overall survival (OS) for phase I and the limited phase II was 18.0 and 31.2 months, respectively, with a combined OS of 21.1 months. A phase I NB patient had a complete bone marrow response with overall stable disease. In phase II, 10 of 12 patients were evaluable: 1 achieved partial response, and 3 showed clinical benefit with prolonged stable disease. Over 50% of evaluable patients exhibited augmented immune responses to GD2+targets post-GD2BATs, as indicated by interferon-gamma (IFN-γ) EliSpots, Th1 cytokines, and/or chemokines. CONCLUSIONS: This study demonstrated the safety of GD2BATs up to 160×106 cells/kg/infusion. Coupled with evidence of post-treatment endogenous immune responses, our findings support further investigation of GD2BATs in larger phase II clinical trials.
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Antineoplásicos , Neuroblastoma , Osteossarcoma , Criança , Humanos , Linfócitos T/patologia , Neuroblastoma/patologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Osteossarcoma/tratamento farmacológicoRESUMO
Poikiloderma with neutropenia (PN) Clericuzio type (OMIM #604173) is a rare disease with areas of skin hyper- and hypopigmentation caused by biallelic USB1 variants. The current study was spurred by poor healing of a perianal tear wound in one affected child homozygous for c.266-1G>A (p.E90Sfster8) mutation, from a family reported previously. Treatment with G-CSF/CSF3 or GM-CSF/CSF2 transiently increased neutrophil/monocytes count with no effect on wound healing. Analysis of peripheral blood revealed a lack of non-classical (CD14+/- CD16+ ) monocytes, associated with a systemic inflammatory cytokine profile, in the two affected brothers. Importantly, despite normal expression of cognate receptors, monocytes from PN patients did not respond to M-CSF or IL-34 in vitro, as determined by cytokine secretion or CD16 expression. RNAseq of monocytes showed 293 differentially expressed genes, including significant downregulation of GATA2, AKAP6 and PDE4DIP that are associated with leucocyte differentiation and cyclic adenosine monophosphate (cAMP) signalling. Notably, the plasma cAMP was significantly low in the PN patients. Our study revealed a novel association of PN with a lack of non-classical monocyte population. The defects in monocyte plasticity may contribute to disease manifestations in PN and a defective cAMP signalling may be the primary effect of the splicing errors caused by USB1 mutation.
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Neutropenia , Anormalidades da Pele , Masculino , Criança , Humanos , Monócitos/metabolismo , Anormalidades da Pele/genética , Anormalidades da Pele/metabolismo , Neutropenia/genética , Citocinas , Receptores de IgG , Diester Fosfórico Hidrolases/genéticaRESUMO
Background: Since treatment of neuroblastoma (NB) with anti-GD2 monoclonal antibodies provides a survival benefit in children with minimal residual disease and our preclinical study shows that anti-CD3 x anti-GD2 bispecific antibody (GD2Bi) armed T cells (GD2BATs) were highly cytotoxic to GD2+ cell lines, we conducted a phase I/II study in recurrent/refractory patients to establish safety and explore the clinical benefit of GD2BATs. Methods: The 3+3 dose escalation study (NCT02173093) phase I involved 9 evaluable patients with NB (n=5), osteosarcoma (OST) (n=3), and desmoplastic small round cell tumors (DSRCT) (n=1) with twice weekly infusions of GD2BATs at 40, 80, or 160 x 106 GD2BATs/kg/infusion with daily interleukin 2 (300,000 IU/m2) and twice weekly granulocyte-macrophage colony stimulating factor (250 µg/m2). Phase II portion of the trial was conducted in patients with NB at the dose 3 level of 160 x 106 GD2BATs/kg/infusion but failed to enroll the planned number of patients. Results: Nine of 12 patients in the phase I completed therapy. There were no dose limiting toxicities (DLTs). All patients developed mild and manageable cytokine release syndrome (CRS) with grade 2-3 fevers/chills, headaches, and occasional hypotension up to 72 hours after GD2BAT infusions. GD2-antibody associated pain was not significant in this study. The median OS for patients in the Phase I and limited Phase II was 18.0 and 31.2 months, respectively, whereas the combined OS was 21.1 months. There was a complete bone marrow response with overall stable disease in one of the phase I patients with NB. Ten of 12 phase II patients were evaluable for response: 1 had partial response. Three additional patients were deemed to have clinical benefit with prolonged stable disease. More than 50% of evaluable patients showed augmented immune responses to GD2+ targets after GD2BATs as measured by interferon-gamma (IFN-γ) EliSpots, Th1 cytokines, and/or chemokines. Conclusions: Our study demonstrated safety of up to 160 x 106 cells/kg/infusion of GD2BATs. Combined with evidence for the development of post treatment endogenous immune responses, this data supports further investigation of GD2 BATs in larger Phase II clinical trials.
RESUMO
Data on preservation of vaccine immunity following allogeneic HSCT in children is limited. We investigated vaccine titers and sought correlations with patient characteristics in this study. Twenty-eight cases were retrospectively analyzed. Antibody concentrations against hepatitis A, hepatitis B, 3 poliovirus serotypes, tetanus, diphtheria, measles, mumps, rubella, varicella, and 13 pneumococcus serotypes were measured as part of planned monitoring following HSCT. Protective antibody levels were found for hepatitis A in 79% of the recipients, measles in 54%, all poliovirus serotypes in 50%, tetanus in 50%, rubella in 50%, varicella in 46%, hepatitis B in 46%, mumps in 43%, diphtheria in 29%, and ≥7/13 pneumococcus serotypes in 46%; lowest level observed for diphtheria and highest for hepatitis A prior to starting post-HSCT immunizations. In univariate analysis, patients with non-malignant diseases (P = .03) and without GvHD (P = .04) had more protective titers. A significant positive association was found among vaccine titers against the microorganisms or the serotypes of the same microorganism, which were administered together in the same product, including polio serotypes, diphtheria and tetanus, mumps, measles, and rubella. Higher degrees of sero-positivity are likely to be due to lack of prior chemotherapy in non-malignant disease cases and lesser immunosuppression in patients without GvHD. Monitoring long-term vaccine titers and administering vaccines accordingly could be evaluated for post-HSCT re-immunization practice.
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Transplante de Células-Tronco Hematopoéticas , Imunidade Humoral , Vacinas/imunologia , Adolescente , Aloenxertos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Adulto JovemRESUMO
The use of G-CSF after myelotoxic chemotherapy accelerates neutrophil recovery reducing the risk of febrile neutropenia. Current guidelines recommend initiating G-CSF 24 hours after myelotoxic chemotherapy. However, the optimal timing of post-chemotherapy G-CSF administration has not been elucidated. Our previous work in murine models demonstrated that the reappearance of myeloid progenitors does not occur in bone marrow until 3-4 days after completion of chemotherapy suggesting that delayed G-CSF administration may be equally efficacious compared to current practice. We conducted a prospective, randomized, crossover study to compare the absolute neutrophil count (ANC) recovery after chemotherapy and a delayed G-CSF administration to a standard G-CSF administration schedule with early G-CSF start. A total of 21 children with solid tumors who received 2 identical cycles of myelotoxic chemotherapy were randomized to start receiving G-CSF either 24 hours after completion of chemotherapy or on the day that their ANC dropped below 1,000/mm3. There was no significant difference in the time to neutrophil recovery (ANC > 1,000/mm3 post nadir) between the two G-CSF administration schedules: 16.0 ± 0.5 days in the standard group compared to 16.7 ± 0.4 days in the delayed group (p = 0.36). The total number of G-CSF doses given, however, was significantly less in the delayed group: 6.7 ± 0.6 compared to 10.5 ± 0.6 doses in the standard group (p < 0.0001). Our data show that a delayed administration of post chemotherapy G-CSF resulted in a significant reduction in the number of G-CSF injections without compromising the G-CSF effects on neutrophil recovery.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Neoplasias/tratamento farmacológico , Neutropenia/complicações , Neutrófilos/metabolismo , Adolescente , Carcinoma/tratamento farmacológico , Criança , Neoplasias do Plexo Corióideo/tratamento farmacológico , Estudos Cross-Over , Esquema de Medicação , Feminino , Humanos , Infecções/complicações , Contagem de Leucócitos , Leucocitose/tratamento farmacológico , Masculino , Meduloblastoma/tratamento farmacológico , Neutrófilos/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Estudos Prospectivos , Fatores de TempoRESUMO
Severe veno-occlusive disease (VOD) following hematopoietic stem cell transplantation has a high mortality rate. The clinical course of VOD, role of preemptive and aggressive supportive care, and outcomes were investigated in a retrospective study from 2007 to 2014. Defibrotide was not available in all but one case with VOD at our center during the study. Forty-nine allogeneic transplants with intravenous busulfan-based or total body irradiation-based myeloablative conditioning were included. The median after hematopoietic stem cell transplantation day for suspicion of developing VOD (pre-VOD phase) was 6 due to weight gain, hepatomegaly, and/or mild increase in total bilirubin without fulfilling the modified Seattle criteria in 22 cases (45%). Despite fluid restriction, aggressive diuresis, and fresh frozen plasma infusions, 16 patients (33%) developed VOD by +10 days. Five cases (31%) had severe, 9 (56%) moderate, and 2 (13%) mild VOD. Eight cases (50%) required transfer to intensive care. One patient was given defibrotide, which was later discontinued due to concerns of adverse effects. Day +100 survival was 100% with complete resolution of VOD. Preemptive and aggressive supportive care could help achieve favorable outcomes in VOD and may have ameliorated the severity. This approach may be combined with other measures in the prevention/treatment of VOD.
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Doenças Hematológicas/mortalidade , Transplante de Células-Tronco Hematopoéticas/mortalidade , Hepatopatia Veno-Oclusiva/diagnóstico , Agonistas Mieloablativos/uso terapêutico , Cuidados Paliativos/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Doenças Hematológicas/patologia , Doenças Hematológicas/terapia , Humanos , Lactente , Masculino , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Condicionamento Pré-Transplante , Transplante Homólogo , Adulto JovemAssuntos
Bacteriemia , Infecções Relacionadas a Cateter , Cateterismo Venoso Central , Neoplasias , Criança , Método Duplo-Cego , Etanol , HumanosRESUMO
Hematopoietic stem cell transplant (HSCT) is a therapeutic option for patients with sickle cell disease (SCD) and severe acquired aplastic anemia (SAA). HSCT may have beneficial effects on ventricular function in damaged myocardium. We hypothesized improvement in ventricular performance and pulmonary hypertension following HSCT with strain echocardiography in SCD and SAA. Echocardiographic strain and other standard functional data were obtained via retrospective cohort analysis of patients (n = 23) with SCD and SAA who underwent HSCT and were followed at a single center between 2000 and 2014. Left ventricular global longitudinal strain was below normal at baseline, and decreased significantly (from - 16.6 to - 11.1, P = 0.05) from pre-HSCT to the initial post-HSCT echocardiogram at 109 (SD ± 83) days. At 351 (SD ± 115) days, longitudinal strain improved significantly from initial decline (from - 11.1 to - 17.5, P = 0.009) but was comparable to baseline (P = 0.43). Other measurements of bi-ventricular function did not change significantly. Tricuspid regurgitation velocities as surrogates for pulmonary hypertension improved in the subset of patients with baseline elevated values although data points were limited. Abnormal myocardial systolic function was detected at baseline with strain imaging. HSCT was associated with initial worsening longitudinal strain values, followed by improvement to baseline levels by 1 year. Insufficient data exist on whether pulmonary hypertension improves after HSCT.
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Anemia Aplástica/cirurgia , Anemia Falciforme/cirurgia , Ecocardiografia/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Hipertensão Pulmonar/fisiopatologia , Função Ventricular/fisiologia , Adolescente , Anemia Aplástica/fisiopatologia , Anemia Falciforme/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Hipertensão Pulmonar/diagnóstico por imagem , Masculino , Estudos Retrospectivos , Insuficiência da Valva Tricúspide/complicaçõesRESUMO
Cumulative myelosuppression is the main limiting factor for administration of repeated cycles of chemotherapy. We present a case series of five pediatric patients with high-risk solid malignancies who received small split peripheral blood stem cells (PBSC) doses of less than 1 × 106/kg CD34+ cells obtained after a single leukapheresis procedure and given after repeated cycles of ICE (ifosfamide, carboplatin, and etoposide) chemotherapy. Mean duration to absolute neutrophil count (ANC) recovery to >1000/mm3 and platelet recovery to >50 × 103/mm3 was 17.1 and 24.3 days. Using split doses of PBSC prevented prolonged neutropenia after repeated cycles of submyeloablative chemotherapy.
RESUMO
Acute myeloid leukemia (AML) continues to be a challenging disease to treat, thus new treatment strategies are needed. In this study, we investigated the antileukemic effects of ATR inhibition alone or combined with cytarabine in AML cells. Treatment with the ATR-selective inhibitor AZ20 caused proliferation inhibition in AML cell lines and primary patient samples. It partially abolished the G2 cell cycle checkpoint and caused DNA replication stress and damage, accompanied by CDK1-independent apoptosis and downregulation of RRM1 and RRM2. AZ20 synergistically enhanced cytarabine-induced proliferation inhibition and apoptosis, abolished cytarabine-induced S and G2/M cell cycle arrest, and cooperated with cytarabine in inducing DNA replication stress and damage in AML cell lines. These key findings were confirmed with another ATR-selective inhibitor AZD6738. Therefore, the cooperative induction of DNA replication stress and damage by ATR inhibition and cytarabine, and the ability of ATR inhibition to abrogate the G2 cell cycle checkpoint both contributed to the synergistic induction of apoptosis and proliferation inhibition in AML cell lines. Synergistic antileukemic interactions between AZ20 and cytarabine were confirmed in primary AML patient samples. Our findings provide insight into the mechanism of action underlying the synergistic antileukemic activity of ATR inhibition in combination with cytarabine in AML.
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Citarabina/farmacologia , Interações Medicamentosas , Sinergismo Farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Morfolinas/farmacologia , Pirimidinas/farmacologia , Adolescente , Adulto , Idoso , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Criança , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Células Tumorais Cultivadas , Adulto JovemRESUMO
INTRODUCTION: Pediatric patients with hemophagocytic lymphohistiocytosis (HLH) may develop refractory respiratory or cardiac failure that warrants consideration for extracorporeal membrane oxygenation (ECMO) support. The purposes of this study were to describe the use and outcomes of ECMO in pediatric HLH patients, to identify risk factors for hospital mortality and to compare their ECMO use and outcomes to the ECMO population as a whole. METHODS: Pediatric patients (⩽ 18 years) with a diagnosis of HLH in the Extracorporeal Life Support Organization (ELSO) Registry were included. RESULTS: Between 1983 and 2014, data for 30 children with HLH were available in the ELSO registry and all were included in this study. All cases occurred in the last decade. Of the 30 HLH patients, 24 (80%) had a respiratory indication for ECMO and six (20%) had a cardiac indication (of which 4 were E-CPR and 2 cardiac failure). Of the 24 respiratory ECMO patients, 63% were placed on VA ECMO. Compared with all pediatric patients in the ELSO registry during the study period (n=17,007), HLH patients had worse hospital survival (non-HLH 59% vs HLH 30%, p=0.001). In pediatric HLH patients, no pre-ECMO risk factors for mortality were identified. The development of a hemorrhagic complication on ECMO was associated with decreased mortality (p=0.01). Comparing HLH patients with respiratory failure to patients with other immune compromised conditions, the overall survival rate is similar (HLH 38% vs. non-HLH immune compromised 31%, p=0.64). CONCLUSIONS: HLH is an uncommon indication for ECMO and these patients have increased mortality compared to the overall pediatric ECMO population. These data should be factored into decision-making when considering ECMO for pediatric HLH patients.
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Oxigenação por Membrana Extracorpórea/métodos , Linfo-Histiocitose Hemofagocítica/terapia , Adolescente , Criança , Pré-Escolar , Oxigenação por Membrana Extracorpórea/efeitos adversos , Feminino , Hemorragia/etiologia , Humanos , Lactente , Recém-Nascido , Linfo-Histiocitose Hemofagocítica/epidemiologia , Masculino , Análise de Sobrevida , Resultado do TratamentoRESUMO
In this study we sought to identify genetic factors associated with the presenting white blood cell (WBC) count in B-precursor acute lymphoblastic leukemia (BP-ALL). Using ETV6-RUNX1-positive BP-ALL patient samples, a homogeneous subtype, we identified 16 differentially expressed genes based on the presenting WBC count (< 50,000/cumm vs > 50,000). We further confirmed that IL1R1, BCAR3, KCNH2, PIR, and ZDHHC23 were differentially expressed in a larger cohort of ETV6-RUNX1-negative BP-ALL patient samples. Statistical analysis demonstrated that expression levels of these genes could accurately categorize high and low WBC count subjects using two independent patient sets, representing positive and negative ETV6-RUNX1 cases. Further studies in leukemia cell line models will better delineate the role of these genes in regulating the white blood cell count and potentially identify new therapeutic targets.
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Contagem de Leucócitos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas de Transporte/genética , Proteínas de Transporte/fisiologia , Criança , Pré-Escolar , Dioxigenases , Canal de Potássio ERG1/genética , Canal de Potássio ERG1/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Marcadores Genéticos/genética , Fatores de Troca do Nucleotídeo Guanina , Humanos , Masculino , Proteínas Nucleares/genética , Proteínas Nucleares/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Mapas de Interação de Proteínas/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/fisiologiaRESUMO
PURPOSE: To investigate the molecular mechanism underlying intrinsic resistance to ABT-199. EXPERIMENTAL DESIGN: Western blots and real-time RT-PCR were used to determine levels of Mcl-1 after ABT-199 treatment alone or in combination with cytarabine or daunorubicin. Immunoprecipitation of Bim and Mcl-1 were used to determine the effect of ABT-199 treatment on their interactions with Bcl-2 family members. Lentiviral short hairpin RNA knockdown of Bim and CRISPR knockdown of Mcl-1 were used to confirm their role in resistance to ABT-199. JC-1 assays and flow cytometry were used to determine drug-induced apoptosis. RESULTS: Immunoprecipitation of Bim from ABT-199-treated cell lines and a primary patient sample demonstrated decreased association with Bcl-2, but increased association with Mcl-1 without corresponding change in mitochondrial outer membrane potential. ABT-199 treatment resulted in increased levels of Mcl-1 protein, unchanged or decreased Mcl-1 transcript levels, and increased Mcl-1 protein half-life, suggesting that the association with Bim plays a role in stabilizing Mcl-1 protein. Combining conventional chemotherapeutic agent cytarabine or daunorubicin with ABT-199 resulted in increased DNA damage along with decreased Mcl-1 protein levels, compared with ABT-199 alone, and synergistic induction of cell death in both AML cell lines and primary patient samples obtained from AML patients at diagnosis. CONCLUSIONS: Our results demonstrate that sequestration of Bim by Mcl-1 is a mechanism of intrinsic ABT-199 resistance and supports the clinical development of ABT-199 in combination with cytarabine or daunorubicin for the treatment of AML. Clin Cancer Res; 22(17); 4440-51. ©2016 AACR.
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Antineoplásicos/farmacologia , Proteína 11 Semelhante a Bcl-2/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Sulfonamidas/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Citarabina/farmacologia , Daunorrubicina/farmacologia , Sinergismo Farmacológico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Estabilidade Proteica/efeitos dos fármacosRESUMO
MK-1775 is the first-in-class selective Wee1 inhibitor which has been demonstrated to synergize with CHK1 inhibitors in various malignancies. In this study, we report that the pan-histone deacetylase inhibitor (HDACI) panobinostat synergizes with MK-1775 in acute myeloid leukemia (AML), a malignancy which remains a clinical challenge and requires more effective therapies. Using both AML cell line models and primary patient samples, we demonstrated that panobinostat and MK-1775 synergistically induced proliferation arrest and cell death. We also demonstrated that panobinostat had equal anti-leukemic activities against primary AML blasts derived from patients either at initial diagnosis or at relapse. Interestingly, treatment with panobinostat alone or in combination with MK-1775 resulted in decreased Wee1 protein levels as well as downregulation of the CHK1 pathway. shRNA knockdown of CHK1 significantly sensitized AML cells to MK-1775 treatment, while knockdown of Wee1 significantly enhanced both MK-1775- and panobinostat-induced cell death. Our results demonstrate that panobinostat synergizes with MK-1775 in AML cells, at least in part through downregulation of CHK1 and/or Wee1, providing compelling evidence for the clinical development of the combination treatment in AML.
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Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 1 do Ponto de Checagem , Sinergismo Farmacológico , Humanos , Concentração Inibidora 50 , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Proteínas Nucleares/antagonistas & inibidores , Panobinostat , Proteínas Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , PirimidinonasRESUMO
PURPOSE: Physicians play a critical role in delivering effective treatment and enabling successful transition to survivorship among adolescent and young adult (AYA) cancer patients. However, with no AYA cancer medical specialty, information on where and by whom AYAs with cancer are treated is limited. METHODS: Using the National Cancer Institute's population-based AYA HOPE Study, 464 AYAs aged 15-39 at diagnosis treated by 903 physicians were identified. Differences in physician and hospital characteristics were examined by age at diagnosis and cancer type (germ cell cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, acute lymphocytic leukemia [ALL], and sarcoma) using chi-square tests. RESULTS: Treating physicians were predominately 51-64 years old, male, United States-trained in non-pediatric specialties, and in group practices within large metropolitan areas. Older patients were less often treated by pediatric physicians (p < 0.01) and more likely to be treated by United States-trained physicians without research/teaching responsibilities and in hospitals without residency programs (p < 0.05). The majority of the few pediatricians (n = 44) treated ALL patients. Physicians with research/teaching responsibilities and those based in medical schools were more likely to treat patients with ALL and sarcoma compared with other cancer types (p < 0.01). Of HL patients, 73% were treated at a cancer center compared with 56% of patients with germ cell cancer (p < 0.01), while ALL (85%) and sarcoma (87%) patients were more likely to be treated in hospitals with residency programs (p < 0.01). CONCLUSIONS: Most AYAs with cancer were treated by non-pediatric physicians in community settings, although physician characteristics varied significantly by patient cancer type and age at diagnosis.
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Neoplasias/terapia , Sobreviventes , Adolescente , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , National Cancer Institute (U.S.) , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: Ethanol lock therapy (ELT) with systemic antimicrobial therapy (SAT) is a treatment for catheter-associated bloodstream infections (CABSI). However, its impact on hospital length of stay (LOS) is unknown. OBJECTIVES: Assess the impact of ELT on LOS, LOS attributable to CABSI (ALOS), and catheter salvage in pediatric hematology, oncology, stem cell transplant (HOSCT) CABSI. METHODS: Retrospective review of HOSCT CABSI from January 2009 to July 2011. RESULTS: A total of 124 CABSI episodes were reviewed in 66 patients. Mean LOS with ELT after 1 positive blood culture (BC) was 7.1 versus 12.3 days after ≥2 positive BC (P = .014). Mean ALOS was 1.6 days with ELT versus 2.9 days without ELT (P = .018). Mean ALOS with ELT after 1 positive BC was 3.75 days versus 5.8 days after ≥2 positive BC (P = .022). Catheter salvage rate: 41 of 48 (85%) with ELT versus 49 of 68 (72%) without ELT (P = .169). CONCLUSION: Earlier initiation of ELT may decrease ALOS.
Assuntos
Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Infecções Relacionadas a Cateter/complicações , Infecções Relacionadas a Cateter/tratamento farmacológico , Cateterismo Venoso Central/efeitos adversos , Etanol/administração & dosagem , Tempo de Internação/estatística & dados numéricos , Anti-Infecciosos Locais/administração & dosagem , Bacteriemia/etiologia , Cateteres de Demora/efeitos adversos , Estudos de Coortes , Humanos , Michigan , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE: Adolescent and young adult (AYA) cancer survivors experience barriers to utilizing healthcare, but the determinants of cancer-related medical care of AYAs has not been fully explored. METHODS: We studied factors associated with medical care utilization among 465 AYA cancer survivors in the AYA Health Outcomes and Patient Experience Study, a cohort of 15 to 39 year olds recently diagnosed with germ cell cancer, lymphoma, sarcoma, or acute lymphocytic leukemia. Descriptive statistics and multivariate logistic regression methods were used. RESULTS: Most AYA cancer survivors (95%), who were 15-35 months post diagnosis, received medical care in the past 12 months and 17% were undergoing cancer treatment. In multivariate analyses, compared with AYAs with no cancer-related medical visits in the previous year, AYAs receiving cancer-related care were more likely to currently have health insurance (odds ratio (OR) = 4.9; 95% confidence interval (CI) = 1.7-13.8) or have had health insurance in the past year (OR = 4.0; 95% CI = 0.99-16.3). Cancer recurrence, lacking employment, and negative changes in self-reported general health were associated with ongoing cancer treatment versus other cancer-related medical care. Eleven percent of all AYAs and 25% of AYAs who did not receive medical care in the past 12 months lost health insurance between the initial and follow-up surveys. CONCLUSION: AYA cancer survivors with health insurance were much more likely to receive cancer-related medical care than those without insurance. IMPLICATIONS FOR CANCER SURVIVORS: Despite the need for post-treatment medical care, lacking health insurance is a barrier to receiving any medical care among AYAs.
Assuntos
Acessibilidade aos Serviços de Saúde , Neoplasias/mortalidade , Neoplasias/terapia , Sobreviventes , Adolescente , Adulto , Feminino , Nível de Saúde , Humanos , Seguro Saúde , Modelos Logísticos , Masculino , Adulto JovemRESUMO
BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a treatment modality for many oncologic as well as non-oncologic disorders. Although the side effects of different chemotherapy regimens have been well studied by several oncology consortiums, limited data is available regarding the late adverse effects of HSCT. Furthermore, pediatric-focused post-HSCT follow-up guidelines for primary care pediatricians do not exist. OBJECTIVE: To provide a summary of the most common late adverse effects of HSCT and give the primary care pediatrician guidance and evidence-based information for the screening and management of this patient population. DESIGN: The literature was searched using PubMed using keywords, including pediatric bone marrow transplant, hematopoietic stem cell transplant guidelines, pediatric bone marrow transplant guidelines, and pediatric bone marrow transplant immunizations. The most relevant articles out of the hundreds of results were reviewed. RESULTS: Based on 9 review articles from the Pediatric Clinics of North America and 3 articles from the Biology of Blood and Marrow Transplant Journal as well as their original references, a summary of the most common late adverse effects after HSCT was constructed. Pediatric HSCT patients have a high incidence of late adverse effects, with 93% of survivors having at least 1 late adverse effect after 7 years of follow-up. CONCLUSION: Late adverse effects after pediatric HSCT are common and require close screening and monitoring, which can be done by the primary care provider along with the oncologist.