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1.
Nurs Open ; 10(4): 1942-1953, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36441641

RESUMO

AIM: The aim of this study is to assess effect of hospital walking programs on outcomes for older inpatients and to characterize hospital walking dose reported across studies. DESIGN: A systematic review and meta-analysis examining impact of hospital walking and/or reported walking dose among medical-surgical inpatients. For inclusion, studies were observational or experimental, published in English, enrolled inpatients aged ≥ 65 yrs hospitalized for medical or surgical reasons. METHODS: Searches of PubMed, CINAHL, Embase, Scopus, NICHSR, OneSearch, ClinicalTrials.gov, and PsycINFO were completed in December 2020. Two reviewers screened sources, extracted data, and performed quality bias appraisal. RESULTS: Hospital walking dose was reported in 6 studies and commonly as steps/24 hr. Length of stay (LOS) was a common outcome reported. Difference in combined mean LOS between walking and control groups was -5.89 days. Heterogeneity across studies was considerable (I2  = 96%) suggesting poor precision of estimates. Additional, high-quality trials examining hospital walking and patient outcomes of older patients is needed.


Assuntos
Hospitais , Pacientes Internados , Humanos , Tempo de Internação
2.
Neuro Oncol ; 24(6): 974-983, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34850169

RESUMO

BACKGROUND: The study aimed to evaluate whether simplified chemotherapy followed by dose-reduced irradiation was effective for treating patients (ages 3-21 years) with localized germinoma. The primary endpoint was 3-year progression-free survival (PFS) rate. METHODS: Patients with a complete response to chemotherapy with carboplatin and etoposide received 18 Gy WVI + 12 Gy boost to the tumor bed. Patients with partial response proceeded to 24 Gy WVI + 12 Gy. Longitudinal cognitive functioning was evaluated prospectively on ALTE07C1 and was a primary study aim. RESULTS: One hundred and fifty-one patients were enrolled; 137 were eligible. Among 90 evaluable patients, 74 were treated with 18 Gy and 16 with 24 Gy WVI. The study failed to demonstrate noninferiority of the 18 Gy WVI regimen compared to the design threshold of 95% 3-year PFS rate, where, per design, patients who could not be assessed for progression at 3 years were counted as failures. The Kaplan-Meier (KM)-based 3-year PFS estimates were 94.5 ± 2.7% and 93.75 ± 6.1% for the 18 Gy and 24 Gy WVI cohorts, respectively. Collectively, estimated mean IQ and attention/concentration were within normal range. A lower mean attention score was observed at 9 months for patients treated with 24 Gy. Acute effects in processing speed were observed in the 18 Gy cohort at 9 months which improved at 30-month assessment. CONCLUSIONS: While a failure according to the prospective statistical noninferiority design, this study demonstrated high rates of chemotherapy responses, favorable KM-based PFS and OS estimates in the context of reduced irradiation doses and holds promise for lower long-term morbidities for patients with germinoma.


Assuntos
Neoplasias Encefálicas , Germinoma , Glândula Pineal , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/patologia , Carboplatina/uso terapêutico , Criança , Pré-Escolar , Etoposídeo , Germinoma/tratamento farmacológico , Germinoma/patologia , Germinoma/radioterapia , Humanos , Glândula Pineal/patologia , Estudos Prospectivos , Adulto Jovem
3.
Front Cell Dev Biol ; 8: 610516, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33644031

RESUMO

Cardiovascular disease (CVD) is the leading cause of death in the U.S. and worldwide. Sex-related disparities have been identified in the presentation and incidence rate of CVD. Mitochondrial dysfunction plays a role in both the etiology and pathology of CVD. Recent work has suggested that the sex hormones play a role in regulating mitochondrial dynamics, metabolism, and cross talk with other organelles. Specifically, the female sex hormone, estrogen, has both a direct and an indirect role in regulating mitochondrial biogenesis via PGC-1α, dynamics through Opa1, Mfn1, Mfn2, and Drp1, as well as metabolism and redox signaling through the antioxidant response element. Furthermore, data suggests that testosterone is cardioprotective in males and may regulate mitochondrial biogenesis through PGC-1α and dynamics via Mfn1 and Drp1. These cell-signaling hubs are essential in maintaining mitochondrial integrity and cell viability, ultimately impacting CVD survival. PGC-1α also plays a crucial role in inter-organellar cross talk between the mitochondria and other organelles such as the peroxisome. This inter-organellar signaling is an avenue for ameliorating rampant ROS produced by dysregulated mitochondria and for regulating intrinsic apoptosis by modulating intracellular Ca2+ levels through interactions with the endoplasmic reticulum. There is a need for future research on the regulatory role of the sex hormones, particularly testosterone, and their cardioprotective effects. This review hopes to highlight the regulatory role of sex hormones on mitochondrial signaling and their function in the underlying disparities between men and women in CVD.

4.
Am J Physiol Endocrinol Metab ; 317(2): E421-E432, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31237450

RESUMO

The purpose of this work was to determine the effect of resistance exercise (RE)-induced hormonal changes on the satellite cell (SC) myogenic state in response to muscle damage. Untrained men (n = 10, 22 ± 3 yr) and women (n = 9, 21 ± 4 yr) completed 2 sessions of 80 unilateral maximal eccentric knee extensions followed by either an upper body RE protocol (EX) or a 20-min rest (CON). Muscle samples were collected and analyzed for protein content of Pax7, MyoD, myogenin, cyclin D1, and p21 before (PRE), 12 h, and 24 h after the session was completed. Serum testosterone, growth hormone, cortisol, and myoglobin concentrations were analyzed at PRE, post-damage, immediately after (IP), and 15, 30, and 60 min after the session was completed. Testosterone was significantly (P < 0.05) higher immediately after the session in EX vs. CON for men. A significant time × sex × condition interaction was found for MyoD with an increase in EX (men) and CON (women) at 12 h. A significant time × condition interaction was found for Pax7, with a decrease in EX and increase in CON at 24 h. A significant time effect was found for myogenin, p21, and cyclin D1. Myogenin and p21 were increased at 12 and 24 h, and cyclin D1 was increased at 12 h. These results suggest that the acute RE-induced hormonal response can be important for men to promote SC proliferation after muscle damage but had no effect in women. Markers of SC differentiation appeared unaffected by the hormonal response but increased in response to muscle damage.


Assuntos
Proliferação de Células , Hormônio do Crescimento Humano/metabolismo , Hidrocortisona/metabolismo , Treinamento Resistido , Descanso/fisiologia , Células Satélites de Músculo Esquelético/fisiologia , Adolescente , Adulto , Exercício Físico/fisiologia , Feminino , Hormônio do Crescimento Humano/fisiologia , Humanos , Hidrocortisona/fisiologia , Masculino , Desenvolvimento Muscular/fisiologia , Fatores Sexuais , Adulto Jovem
5.
Pediatr Blood Cancer ; 65(2)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29090526

RESUMO

BACKGROUND: We conducted a phase II study of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy (RT) to assess progression-free survival (PFS) in children with newly diagnosed diffuse intrinsic pontine gliomas (DIPG). PATIENTS AND METHODS: Children 3-17 years with newly diagnosed DIPG were eligible. Capecitabine, 650 mg/m2 /dose BID (maximum tolerated dose [MTD] in children with concurrent radiation), was administered for 9 weeks starting the first day of RT. Following a 2-week break, three courses of capecitabine, 1,250 mg/m2 /dose BID for 14 days followed by a 7-day rest, were administered. As prospectively designed, 10 evaluable patients treated at the MTD on the phase I trial were included in the phase II analyses. The design was based on comparison of the PFS distribution to a contemporary historical control (n = 140) with 90% power to detect a 15% absolute improvement in the 1-year PFS with a type-1 error rate, α = 0.10. RESULTS: Forty-four patients were evaluable for the phase II objectives. Capecitabine and RT was well tolerated with low-grade palmar plantar erythrodyesthesia, increased alanine aminotransferase, cytopenias, and vomiting the most commonly reported toxicities. Findings were significant for earlier progression with 1-year PFS of 7.21% (SE = 3.47%) in the capecitabine-treated cohort versus 15.59% (SE = 3.05%) in the historical control (P = 0.007), but there was no difference for overall survival (OS) distributions (P = 0.30). Tumor enhancement at diagnosis was associated with shorter PFS and OS. Capecitabine was rapidly absorbed and converted to its metabolites. CONCLUSION: Capecitabine did not improve the outcome for children with newly diagnosed DIPG.


Assuntos
Neoplasias do Tronco Encefálico/terapia , Capecitabina/administração & dosagem , Quimiorradioterapia , Glioma/terapia , Administração Oral , Adolescente , Neoplasias do Tronco Encefálico/diagnóstico , Criança , Pré-Escolar , Feminino , Seguimentos , Glioma/diagnóstico , Humanos , Masculino , Estudos Prospectivos , Comprimidos
6.
Cancer Immunol Immunother ; 66(12): 1589-1595, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28825123

RESUMO

BACKGROUND: We evaluated circulating levels of immunosuppressive regulatory T cells (Tregs) and other lymphocyte subsets in patients with newly diagnosed medulloblastoma (MBL) undergoing surgery compared to a control cohort of patients undergo craniectomy for correction of Chiari malformation (CM) and further determined the impact of standard irradiation and chemotherapy on this cell population. METHODS: Eligibility criteria for this biologic study included age 4-21 years, patients with CM undergoing craniectomy (as non-malignant surgical controls) and receiving dexamethasone for prevention of post-operative nausea, and those with newly diagnosed posterior fossa tumors (PFT) undergoing surgical resection and receiving dexamethasone as an anti-edema measure. Patients with confirmed MBL were also followed for longitudinal blood collection and analysis during radiotherapy and chemotherapy. RESULTS: A total of 54 subjects were enrolled on the study [22-CM, 18-MBL, and 14-PFT]. Absolute number and percentage Tregs (defined as CD4+CD25+FoxP3+CD127low/-) at baseline were decreased in MBL and PFT compared to CM [p = 0.0016 and 0.001, respectively). Patients with MBL and PFT had significantly reduced overall CD4+ T cell count (p = 0.0014 and 0.0054, respectively) compared to those with CM. Radiation and chemotherapy treatment in patients with MBL reduced overall lymphocyte counts; however, within the CD4+ T cell compartment, Tregs increased during treatment but gradually declined post therapy. CONCLUSIONS: Our results demonstrate that patients with MBL and PFT exhibit overall reduced CD4+ T cell counts at diagnosis but not an elevated proportion of Tregs. Standard treatment exacerbates lymphopenia in those with MBL while enriching for immunosuppressive Tregs over time.


Assuntos
Neoplasias Cerebelares/imunologia , Neoplasias Cerebelares/terapia , Meduloblastoma/imunologia , Meduloblastoma/terapia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Neoplasias Cerebelares/sangue , Quimiorradioterapia , Criança , Pré-Escolar , Craniotomia , Feminino , Humanos , Masculino , Meduloblastoma/sangue , Adulto Jovem
7.
Neuro Oncol ; 19(8): 1135-1144, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28339824

RESUMO

BACKGROUND: Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG. METHODS: Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course. BRAF aberrations in tumor tissue were determined by real-time polymerase chain reaction and fluorescence in situ hybridization. RESULTS: Thirty-eight eligible subjects were enrolled. Dose levels 1 and 2 (33 and 43 mg/m2/dose b.i.d.) were excessively toxic. DLTs included grade 3 elevated amylase/lipase (n = 1), headache (n = 1), mucositis (n = 2), and grades 2-3 rash (n = 6). At dose level 0 (25 mg/m2/dose b.i.d, the RP2D), only 3 of 24 subjects experienced DLTs (elevated amylase/lipase, rash, and mucositis). At the R2PD, the median (range) area under the curve (AUC0-∞) and apparent oral clearance of selumetinib were 3855 ng*h/mL (1780 to 7250 ng × h/mL) and 6.5 L × h-1 × m-2 (3.4 to 14.0 L × h-1 × m-2), respectively. Thirteen of 19 tumors had BRAF abnormalities. Among the 5 (20%) of 25 subjects with sustained partial responses, all at the RP2D, 4 had BRAF aberrations, 1 had insufficient tissue. Subjects received a median of 13 cycles (range: 1-26). Fourteen (37%) completed all protocol treatment (26 cycles [n = 13], 13 cycles [n = 1]) with at least stable disease; 2-year progression-free survival at the RP2D was 69 ± SE 9.8%. CONCLUSION: Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.


Assuntos
Benzimidazóis/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Benzimidazóis/farmacocinética , Criança , Pré-Escolar , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Gradação de Tumores , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacocinética
8.
Nutrients ; 8(10)2016 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-27754419

RESUMO

This project was designed to assess the effects of time of day and training status on the benefits of caffeine supplementation for cycling performance. Twenty male subjects (Age, 25 years; Peak oxygen consumption, 57 mL·kg-1·min-1) were divided into tertiles based on training levels, with top and bottom tertiles designated as 'trained' (n = 7) and 'untrained' (n = 7). Subjects completed two familiarization trials and four experimental trials consisting of a computer-simulated 3-km cycling time trial (TT). The trials were performed in randomized order for each combination of time of day (morning and evening) and treatment (6mg/kg of caffeine or placebo). Magnitude-based inferences were used to evaluate all treatment effects. For all subjects, caffeine enhanced TT performance in the morning (2.3% ± 1.7%, 'very likely') and evening (1.4% ± 1.1%, 'likely'). Both untrained and trained subjects improved performance with caffeine supplementation in the morning (5.5% ± 4.3%, 'likely'; 1.0% ± 1.7%, 'likely', respectively), but only untrained subjects rode faster in the evening (2.9% ± 2.6%, 'likely'). Altogether, our observations indicate that trained athletes are more likely to derive ergogenic effects from caffeine in the morning than the evening. Further, untrained individuals appear to receive larger gains from caffeine in the evening than their trained counterparts.


Assuntos
Desempenho Atlético , Ciclismo/fisiologia , Cafeína/farmacologia , Ritmo Circadiano , Suplementos Nutricionais , Condicionamento Físico Humano/fisiologia , Adolescente , Adulto , Método Duplo-Cego , Humanos , Masculino , Educação Física e Treinamento , Resultado do Tratamento , Adulto Jovem
9.
J Neurooncol ; 129(3): 443-451, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27350411

RESUMO

Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, inhibiting its enzymatic activity. We conducted an investigator-sponsored molecular biology (MB) and phase II study to estimate inhibition of tumor telomerase activity and sustained responses by imetelstat in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose of imetelstat as a 2-h intravenous infusion at 285 mg/m(2), 12-24 h before surgery. Telomerase activity was evaluated in fresh tumor from surgery. Post-surgery and in the phase II study, patients received imetelstat IV (days 1 and 8 q21-days) at 285 mg/m(2). Imetelstat pharmacokinetic and pharmacodynamic studies were performed. Of two evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95 % compared to baseline archival tissue in one patient and was inevaluable in one patient. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. Most common grade 3/4 toxicities included thrombocytopenia (32.5 %), lymphopenia (17.5 %), neutropenia (12.5 %), ALT (7.5 %) and AST (5 %) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Glioma/tratamento farmacológico , Indóis/uso terapêutico , Niacinamida/análogos & derivados , Telomerase/metabolismo , Adolescente , Alanina Transaminase/metabolismo , Contagem de Células Sanguíneas , Neoplasias do Sistema Nervoso Central/cirurgia , Criança , Pré-Escolar , Feminino , Glioma/cirurgia , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Niacinamida/uso terapêutico , Oligonucleotídeos , Telomerase/genética , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
10.
Pediatr Blood Cancer ; 63(9): 1563-70, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27203542

RESUMO

BACKGROUND: The outcomes with high-risk central nervous system (CNS) embryonal tumors remain relatively poor despite aggressive treatment. The purposes of this study using postirradiation myeloablative chemotherapy with autologous hematopoietic stem cell rescue (ASCR) were to document feasibility and describe toxicities of the regimen, establish the appropriate dose of thiotepa, and estimate the overall survival (OS) and event-free survival (EFS). PROCEDURE: The Children's Cancer Group conducted this pilot study in children and adolescents with CNS embryonal tumors. The treatment consisted of induction chemotherapy to mobilize hematopoietic stem cells, chemoradiotherapy, and myeloablative consolidation chemotherapy with ASCR. RESULTS: The study accrued 25 subjects in 40 months and was closed early due to toxicity, namely, veno-occlusive disease (VOD) of the liver, more recently termed sinusoidal obstructive syndrome (SOS). Of 24 eligible subjects, three of 11 (27%) receiving thiotepa Dose Level 1 (150 mg/m(2) /day × 3 days) and three of 12 (25%) receiving de-escalated Dose Level 0 (100 mg/m(2) /day × 3 days) experienced VOD/SOS. One additional subject experienced toxic death attributed to septic shock; postmortem examination revealed clinically undiagnosed VOD/SOS. The 2-year EFS and OS were 54 ± 10% and 71 ± 9%, respectively. The 5-year EFS and OS were 46 ± 11% and 50 ± 11%. CONCLUSIONS: The treatment regimen was deemed to have an unacceptable rate of VOD/SOS. There was complete recovery in all six cases. The overall therapeutic strategy using a regimen less likely to cause VOD/SOS may merit further evaluation for the highest risk patients.


Assuntos
Neoplasias do Sistema Nervoso Central/terapia , Radiação Cranioespinal , Hepatopatia Veno-Oclusiva/epidemiologia , Neoplasias Embrionárias de Células Germinativas/terapia , Adolescente , Neoplasias do Sistema Nervoso Central/mortalidade , Quimiorradioterapia/efeitos adversos , Criança , Pré-Escolar , Radiação Cranioespinal/efeitos adversos , Feminino , Humanos , Incidência , Quimioterapia de Indução/efeitos adversos , Masculino , Neoplasias Embrionárias de Células Germinativas/mortalidade
11.
Cancer Med ; 5(7): 1416-24, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27109549

RESUMO

Sunitinib malate is a small multi-targeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and stem cell factor receptor (KIT), which are highly expressed by some high-grade brain tumors. We conducted a phase II study to estimate the efficacy and further characterize the pharmacokinetics of sunitinib in pediatric patients with recurrent or refractory high-grade glioma (Stratum A) or ependymoma (Stratum B). This was a prospective, multicenter Phase II trial conducted through the Children's Oncology Group (ClinicalTrials.gov Identifier NCT01462695). Sunitinib, 15 mg/m2, was orally administered once daily for 4 weeks every 6 weeks. The safety and tolerability of sunitinib, an estimate of progression-free survival (PFS), analyses of sunitinib pharmacokinetics (PK) and pharmacodynamics modulation of plasma VEGF and VEGFR2 were also assessed. Thirty eligible patients (17 patients on Stratum A, 13 patients on Stratum B) were enrolled and 29 patients were evaluable for response. Sunitinib was reasonably well tolerated in children with recurrent ependymoma or high-grade glioma. Most adverse events were of mild-to-moderate severity and manageable with supportive treatment. While there was a statistically significant modulation of plasma VEGFR2 with sunitinib exposure, there were no sustained tumor responses. Both strata were closed at time of planned interim analysis as there was not sufficient efficacy associated with sunitinib in children with recurrent brain tumors. Sunitinib was well tolerated in children and young adults with recurrent high-grade glioma or ependymoma but had no single agent objective antitumor activity in these patients.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Ependimoma/tratamento farmacológico , Glioma/tratamento farmacológico , Indóis/uso terapêutico , Pirróis/uso terapêutico , Adolescente , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Criança , Pré-Escolar , Terapia Combinada , Monitoramento de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ependimoma/mortalidade , Ependimoma/patologia , Feminino , Glioma/mortalidade , Glioma/patologia , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/farmacocinética , Masculino , Gradação de Tumores , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/uso terapêutico , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Pirróis/farmacocinética , Retratamento , Sunitinibe , Resultado do Tratamento , Adulto Jovem
12.
Neuro Oncol ; 18(9): 1319-25, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27022131

RESUMO

BACKGROUND: p53 is a promising target in human cancer. p28 is a cell-penetrating peptide that preferentially enters cancer cells and binds to both wild-type and mutant p53 protein, inhibiting COP1-mediated ubiquitination and proteasomal degradation. This results in increased levels of p53, which induces cell cycle arrest at G2/M. We conducted a phase I study to determine the maximum-tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) and pharmacokinetics (PKs) of p28 in children. METHODS: Children aged 3-21 years with recurrent or progressive central nervous system tumors were eligible. Intravenous p28 was administered 3 times weekly for 4 consecutive weeks of a 6-week cycle at 4.16 mg/kg/dose (the adult recommended phase II dose) using a rolling-6 study design. Expression status of p53 was characterized by immunohistochemistry, and serum PK parameters were established on the second dose. RESULTS: Of the 18 eligible patients enrolled in the study, 12 completed the DLT monitoring period and were evaluable for toxicity. p28 was well-tolerated; 7 participants received ≥2 courses, and the most common adverse event attributed to the drug was transient grade 1 infusion-related reaction. PK analysis revealed a profile similar to adults; however, an increased area under the curve was observed in pediatric patients. High p53 expression in tumor cell nuclei was observed in 6 of 12 available tissue samples. There were no objective responses; 2 participants remained stable on the study for >4 cycles. CONCLUSIONS: This phase I study demonstrated that p28 is well-tolerated in children with recurrent CNS malignancies at the adult recommended phase II dose.


Assuntos
Antineoplásicos/uso terapêutico , Azurina/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Ubiquitinação/efeitos dos fármacos , Adolescente , Adulto , Antineoplásicos/farmacocinética , Azurina/farmacocinética , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Fragmentos de Peptídeos/farmacocinética , Prognóstico , Adulto Jovem
13.
Neuro Oncol ; 18(5): 725-34, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26487690

RESUMO

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is associated with poor survival regardless of therapy. We used volumetric apparent diffusion coefficient (ADC) histogram metrics to determine associations with progression-free survival (PFS) and overall survival (OS) at baseline and after radiation therapy (RT). METHODS: Baseline and post-RT quantitative ADC histograms were generated from fluid-attenuated inversion recovery (FLAIR) images and enhancement regions of interest. Metrics assessed included number of peaks (ie, unimodal or bimodal), mean and median ADC, standard deviation, mode, skewness, and kurtosis. RESULTS: Based on FLAIR images, the majority of tumors had unimodal peaks with significantly shorter average survival. Pre-RT FLAIR mean, mode, and median values were significantly associated with decreased risk of progression; higher pre-RT ADC values had longer PFS on average. Pre-RT FLAIR skewness and standard deviation were significantly associated with increased risk of progression; higher pre-RT FLAIR skewness and standard deviation had shorter PFS. Nonenhancing tumors at baseline showed higher ADC FLAIR mean values, lower kurtosis, and higher PFS. For enhancing tumors at baseline, bimodal enhancement histograms had much worse PFS and OS than unimodal cases and significantly lower mean peak values. Enhancement in tumors only after RT led to significantly shorter PFS and OS than in patients with baseline or no baseline enhancement. CONCLUSIONS: ADC histogram metrics in DIPG demonstrate significant correlations between diffusion metrics and survival, with lower diffusion values (increased cellularity), increased skewness, and enhancement associated with shorter survival, requiring future investigations in large DIPG clinical trials.


Assuntos
Neoplasias do Tronco Encefálico/patologia , Glioma/patologia , Interpretação de Imagem Assistida por Computador/métodos , Neoplasias do Tronco Encefálico/mortalidade , Neoplasias do Tronco Encefálico/radioterapia , Criança , Imagem de Difusão por Ressonância Magnética , Progressão da Doença , Intervalo Livre de Doença , Feminino , Glioma/mortalidade , Glioma/radioterapia , Humanos , Estimativa de Kaplan-Meier , Masculino , Prognóstico
14.
J Neurosurg Pediatr ; 17(4): 453-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26684767

RESUMO

OBJECT The impact of central pathology review on outcome has been described in pediatric patients with high-grade glioma (HGG). The objective of this report was to analyze the impact of the central pathology review on outcome in the subgroup of patients with institutional diagnosis of HGG of the spinal cord enrolled in the Children's Cancer Group 945 cooperative study. METHODS Five neuropathologists centrally reviewed the pathology of the 18 patients with HGG of the spinal cord who were enrolled in the study. These reviews were independent, and reviewers were blinded to clinical history and outcomes. A consensus diagnosis was established for each patient, based on the outcome of the review. RESULTS Of 18 patients, only 10 were confirmed to have HGG on central review. At a median follow-up of 12 years, event-free and overall survival for all 18 patients was 43.2% ± 13.3% and 50% ± 13.4%, respectively. After central review, 10-year event-free and overall survival for confirmed HGGs and discordant diagnoses was 30% ± 12.5% versus 58.3% ± 18.8% (p = 0.108) and 30% ± 12.5% versus 75% ± 14.2% (p = 0.0757), respectively. CONCLUSIONS The level of discordant diagnoses in children and adolescents with institutional diagnosis of HGG of the spinal cord was 44% in this experience. However, there was no significant difference in outcome between patients with confirmed and discordant diagnosis. This group of tumor deserves a specific attention in future trials.


Assuntos
Glioma/diagnóstico , Avaliação de Resultados em Cuidados de Saúde , Neoplasias da Medula Espinal/diagnóstico , Adolescente , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Glioma/terapia , Humanos , Lactente , Masculino , Gradação de Tumores , Estudos Retrospectivos , Método Simples-Cego , Neoplasias da Medula Espinal/terapia
15.
Am J Hematol ; 90(12): 1099-105, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26414435

RESUMO

Children with sickle cell anemia (SCA) and conditional transcranial Doppler (TCD) ultrasound velocities (170-199 cm/sec) may develop stroke. However, with limited available clinical data, the current standard of care for conditional TCD velocities is observation. The efficacy of hydroxyurea in preventing conversion from conditional to abnormal TCD (≥200 cm/sec), which confers a higher stroke risk, has not been studied prospectively in a randomized trial. Sparing Conversion to Abnormal TCD Elevation (SCATE #NCT01531387) was a National Heart, Lung, and Blood Institute-funded Phase III multicenter international clinical trial comparing alternative therapy (hydroxyurea) to standard care (observation) to prevent conversion from conditional to abnormal TCD velocity in children with SCA. SCATE enrolled 38 children from the United States, Jamaica, and Brazil [HbSS (36), HbSß(0) -thalassemia (1), and HbSD (1), median age = 5.4 years (range, 2.7-9.8)]. Because of the slow patient accrual and administrative delays, SCATE was terminated early. In an intention-to-treat analysis, the cumulative incidence of abnormal conversion was 9% (95% CI = 0-35%) in the hydroxyurea arm and 47% (95% CI = 6-81%) in observation arm at 15 months (P = 0.16). In post hoc analysis according to treatment received, significantly fewer children on hydroxyurea converted to abnormal TCD velocities when compared with observation (0% vs. 50%, P = 0.02). After a mean of 10.1 months, a significant change in mean TCD velocity was observed with hydroxyurea treatment (-15.5 vs. +10.2 cm/sec, P = 0.02). No stroke events occurred in either arm. Hydroxyurea reduces TCD velocities in children with SCA and conditional velocities.


Assuntos
Anemia Falciforme/tratamento farmacológico , Antineoplásicos/uso terapêutico , Hidroxiureia/uso terapêutico , Antineoplásicos/administração & dosagem , Criança , Pré-Escolar , Feminino , Humanos , Hidroxiureia/administração & dosagem , Masculino , Ultrassonografia Doppler Transcraniana
16.
Childs Nerv Syst ; 31(9): 1433-45, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26188774

RESUMO

BACKGROUND: Cediranib (AZD2171), an oral pan-vascular endothelial growth factor (VEGF) inhibitor, was evaluated in this phase I study to determine its toxicity profile, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics in children and adolescents with recurrent or refractory primary central nervous system (CNS) tumors. METHODS: Children and adolescents <22 years were enrolled into one of two strata: stratum I­those not receiving enzyme-inducing anticonvulsant drugs (EIACD) and stratum II­those receiving EIACDs. Dose-level selection was based on the continual reassessment method (CRM). RESULTS: Thirty-six eligible patients with median age of 12.7 years (range, 5.4-21.7 years) in stratum I (24 males) and 12 patients (7 males) in stratum II with median age of 13.4 years (range, 8.9-19.5 years) were initially assessed over a 4-week DLT evaluation period, modified to 6 weeks during the study. An MTD of 32 mg/m(2)/day was declared; however, excessive toxicities (transaminitis, proteinuria, diarrhea, hemorrhage, palmer-planter syndrome, reversible posterior leukoencephalopathy) in the expansion cohort treated at this dose suggested that it might not be tolerated over a longer time period. An expansion cohort at 20 mg/m(2)/day also demonstrated poor longer-term tolerability. Diffusion and perfusion MRI and PET imaging variables as well as biomarker analysis were performed and correlated with outcome. At 20 mg/m(2)/day, the median plasma area under the concentration-time curve at steady state was lower than that observed in adults at similar dosages. CONCLUSIONS: While the MTD of once daily oral cediranib in children with recurrent or progressive CNS tumors was initially defined as 32 mg/m(2)/day, this dose and 20 mg/m(2)/day were not considered tolerable over a protracted time period.


Assuntos
Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Administração Oral , Adolescente , Disponibilidade Biológica , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Estatística como Assunto , Fatores de Tempo , Adulto Jovem
17.
J Clin Oncol ; 33(24): 2646-54, 2015 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-26169613

RESUMO

PURPOSE: Two phase II studies assessed the efficacy of vismodegib, a sonic hedgehog (SHH) pathway inhibitor that binds smoothened (SMO), in pediatric and adult recurrent medulloblastoma (MB). PATIENTS AND METHODS: Adult patients enrolled onto PBTC-025B and pediatric patients enrolled onto PBTC-032 were treated with vismodegib (150 to 300 mg/d). Protocol-defined response, which had to be sustained for 8 weeks, was confirmed by central neuroimaging review. Molecular tests to identify patterns of response and insensitivity were performed when tissue was available. RESULTS: A total of 31 patients were enrolled onto PBTC-025B, and 12 were enrolled onto PBTC-032. Three patients in PBTC-025B and one in PBTC-032, all with SHH-subgroup MB (SHH-MB), exhibited protocol-defined responses. Progression-free survival (PFS) was longer in those with SHH-MB than in those with non-SHH-MB, and prolonged disease stabilization occurred in 41% of patient cases of SHH-MB. Among those with SHH-MB, loss of heterozygosity of PTCH1 was associated with prolonged PFS, and diffuse staining of P53 was associated with reduced PFS. Whole-exome sequencing identified mutations in SHH genes downstream from SMO in four of four tissue samples from nonresponders and upstream of SMO in two of four patients with favorable responses. CONCLUSION: Vismodegib exhibits activity against adult recurrent SHH-MB but not against recurrent non-SHH-MB. Inadequate accrual of pediatric patients precluded conclusions in this population. Molecular analyses support the hypothesis that SMO inhibitor activity depends on the genomic aberrations within the tumor. Such inhibitors should be advanced in SHH-MB studies; however, molecular and genomic work remains imperative to identify target populations that will truly benefit.


Assuntos
Anilidas/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Proteínas Hedgehog/metabolismo , Meduloblastoma/tratamento farmacológico , Piridinas/uso terapêutico , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Feminino , Proteínas Hedgehog/genética , Humanos , Masculino , Meduloblastoma/genética , Meduloblastoma/metabolismo , Pessoa de Meia-Idade , Adulto Jovem
18.
Childs Nerv Syst ; 31(8): 1283-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25930724

RESUMO

PURPOSE: Amplification and high levels of NOTCH ligand expression have been identified in several types of pediatric brain tumors. A phase I trial of weekly MK-0752, an oral inhibitor of gamma-secretase, was conducted in children with recurrent central nervous system (CNS) malignancies to estimate the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics of weekly MK-0752. METHODS: MK-0752 was administered once weekly at 1000 and 1400 mg/m(2) using a rolling-6 design. PK analysis was performed during the first course. NOTCH and HES expression was assessed by immunohistochemistry and Western blot. RESULTS: Ten eligible patients were enrolled (median age 8.8 years; range 3.1-19.2) with diagnoses of brain stem glioma (n = 3), ependymoma (n = 2), anaplastic astrocytoma (n = 1), choroid plexus carcinoma (n = 2), medulloblastoma (n = 1), and primitive neuroectodermal tumor (n = 1). Nine were evaluable for toxicity. One DLT of fatigue occurred in the six evaluable patients enrolled at 1000 mg/m(2)/dose. No DLTs were experienced by three patients treated at 1400 mg/m(2)/dose. Non-dose-limiting grade 3 toxicities included lymphopenia, neutropenia, and anemia. Median number of treatment courses was 2 (range 1-10). Two patients continued on therapy for at least 6 months. The median (range) C(max) of MK-0752 was 88.2 µg/mL (40.6 to 109 µg/mL) and 60.3 µg/mL (59.2 to 91.9 µg/mL) in patients receiving 1000 and 1400 mg/m(2)/week, respectively. NOTCH expression was decreased in six of seven patients for whom tissue was available at 24 h post-MK-0752. CONCLUSION: MK-0752 is well tolerated and exhibits target inhibition at 1000 and 1400 mg/m(2)/week in children with recurrent CNS malignancies.


Assuntos
Derivados de Benzeno/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Doenças do Sistema Nervoso Central/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Propionatos/uso terapêutico , Sulfonas/uso terapêutico , Administração Oral , Adolescente , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Área Sob a Curva , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Derivados de Benzeno/sangue , Doenças do Sistema Nervoso Central/sangue , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/sangue , Feminino , Seguimentos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Propionatos/sangue , Receptor Notch1/metabolismo , Proteínas Repressoras/metabolismo , Sulfonas/sangue , Fatores de Tempo , Fatores de Transcrição HES-1 , Adulto Jovem
19.
Neuro Oncol ; 17(6): 882-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25688119

RESUMO

BACKGROUND: Aurora Kinase A (AURKA) encodes a protein that regulates the formation and stability of the mitotic spindle and is highly active in atypical teratoid rhabdoid tumors (ATRT) through loss of the INI1 tumor suppressor gene. Alisertib (MLN8237) inhibits AURKA in vitro and in vivo. Given the strong preclinical data supporting the use of alisertib for ATRT patients, we sought and obtained permission to use alisertib in single patient treatment plans for 4 recurrent pediatric ATRT patients. METHODS: Patients with recurrent or progressive ATRT received alisertib 80 mg/m(2) by mouth once daily for 7 days of a 21-day treatment cycle. Disease evaluation (MRI of brain and spine and lumbar puncture) was done after 2 cycles of alisertib and every 2-3 cycles thereafter for as long as the patients remained free from tumor progression. RESULTS: Four patients with median age of 2.5 years (range, 1.39-4.87 y) at diagnosis received alisertib 80 mg/m(2) by mouth once daily for 7 days of a 21-day treatment cycle, and all 4 patients had disease stabilization and/or regression after 3 cycles of alisertib therapy. Two patients continued to have stable disease regression for 1 and 2 years, respectively, on therapy. CONCLUSIONS: Single-agent alisertib produced marked and durable regression in disease burden, as detected by brain and spine MRI and by evaluation of spinal fluid cytology. Alisertib has moderate but manageable toxicities, and its chronic administration appears feasible in this pediatric population. These novel data support the incorporation of alisertib in future therapeutic trials for children with ATRT.


Assuntos
Antineoplásicos/uso terapêutico , Azepinas/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Pirimidinas/uso terapêutico , Tumor Rabdoide/tratamento farmacológico , Teratoma/tratamento farmacológico , Antineoplásicos/efeitos adversos , Aurora Quinase A/antagonistas & inibidores , Aurora Quinase A/metabolismo , Azepinas/efeitos adversos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Neoplasias Encefálicas/metabolismo , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pirimidinas/efeitos adversos , Tumor Rabdoide/metabolismo , Teratoma/metabolismo , Resultado do Tratamento
20.
Pediatr Blood Cancer ; 62(5): 776-83, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25704363

RESUMO

BACKGROUND: Supratentorial PNETs (sPNET) are uncommon embryonal malignancies of the central nervous system whose prognosis has historically been poor. We evaluated the outcome and prognostic factors of children with sPNET treated prospectively on a Children's Oncology Group trial. PROCEDURE: Following surgery, patients received craniospinal radiotherapy with concurrent carboplatin followed by six months of maintenance chemotherapy with cyclophosphamide and vincristine. RESULTS: Five-year overall survival (OS) and progression-free survival (PFS) for all patients was 58 ± 7% and 48 ± 7%. For patients with pineoblastoma (n = 23), five-year OS and PFS was 81 ± 9% and 62 ± 11%. Extent of resection but not M-stage was prognostic. Five-year OS and PFS for 37 patients with non-pineal tumors (NPsPNET) was 44 ± 8% and 39 ± 8%, significantly worse than for PB (P = 0.055 and 0.009 respectively). Extent of resection and major radiotherapy deviations were prognostic. Five year OS was 59 +/- 11.4% for those undergoing complete resection versus 10.4 +/- 7% for those who did not (P = 0.017). Central pathologic review called 14 (38%) "classic" sPNET, 8 (22%) "undifferentiated" and 13 (35%) "malignant gliomas." There was no significant difference between the subgroups, although survival distributions approached significance when the combined "classic" and "undifferentiated" group was compared to the "malignant gliomas." CONCLUSIONS: Carboplatin during RT followed by 6 months of non-intensive chemotherapy is a feasible treatment strategy for patients with sPNET. Aggressive surgical resection should be attempted if feasible. The classification of supratentorial small cell malignancies can be difficult.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Tumores Neuroectodérmicos Primitivos/terapia , Neoplasias Supratentoriais/terapia , Adolescente , Adulto , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Carboplatina/administração & dosagem , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Estadiamento de Neoplasias , Tumores Neuroectodérmicos Primitivos/mortalidade , Tumores Neuroectodérmicos Primitivos/patologia , Prognóstico , Estudos Prospectivos , Neoplasias Supratentoriais/mortalidade , Neoplasias Supratentoriais/patologia , Taxa de Sobrevida , Vincristina/administração & dosagem , Adulto Jovem
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