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BACKGROUND: Transverse (t)-tubules drive the rapid and synchronous Ca2+ rise in cardiac myocytes. The virtual complete atrial t-tubule loss in heart failure (HF) decreases Ca2+ release. It is unknown if or how atrial t-tubules can be restored and how this affects systolic Ca2+. METHODS: HF was induced in sheep by rapid ventricular pacing and recovered following termination of rapid pacing. Serial block-face scanning electron microscopy and confocal imaging were used to study t-tubule ultrastructure. Function was assessed using patchclamp, Ca2+, and confocal imaging. Candidate proteins involved in atrial t-tubule recovery were identified by western blot and expressed in rat neonatal ventricular myocytes to determine if they altered t-tubule structure. RESULTS: Atrial t-tubules were lost in HF but reappeared following recovery from HF. Recovered t-tubules were disordered, adopting distinct morphologies with increased t-tubule length and branching. T-tubule disorder was associated with mitochondrial disorder. Recovered t-tubules were functional, triggering Ca2+ release in the cell interior. Systolic Ca2+, ICa-L, sarcoplasmic reticulum Ca2+ content, and SERCA function were restored following recovery from HF. Confocal microscopy showed fragmentation of ryanodine receptor staining and movement away from the z-line in HF, which was reversed following recovery from HF. Acute detubulation, to remove recovered t-tubules, confirmed their key role in restoration of the systolic Ca2+ transient, the rate of Ca2+ removal, and the peak L-type Ca2+ current. The abundance of telethonin and myotubularin decreased during HF and increased during recovery. Transfection with these proteins altered the density and structure of tubules in neonatal myocytes. Myotubularin had a greater effect, increasing tubule length and branching, replicating that seen in the recovery atria. CONCLUSIONS: We show that recovery from HF restores atrial t-tubules, and this promotes recovery of ICa-L, sarcoplasmic reticulum Ca2+ content, and systolic Ca2+. We demonstrate an important role for myotubularin in t-tubule restoration. Our findings reveal a new and viable therapeutic strategy.
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Using hybridized [18F]-fluorodeoxyglucose positron emission tomography with cardiac magnetic resonance, we identify active myocardial inflammation and demonstrate its relationship with late gadolinium enhancement, in Fabry disease. We demonstrate that late gadolinium enhancement represents, at least in part, active myocardial inflammation and identify an early inflammatory phenotype that may represent a therapeutic window before irreversible tissue injury and adaptation occur. (Level of Difficulty: Intermediate.).
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INTRODUCTION: Understanding how the COVID-19 pandemic has impacted our health and safety is imperative. This study sought to examine the impact of COVID-19's stay-at-home order on daily vehicle miles travelled (VMT) and MVCs in Connecticut. METHODS: Using an interrupted time series design, we analysed daily VMT and MVCs stratified by crash severity and number of vehicles involved from 1 January to 30 April 2017, 2018, 2019 and 2020. MVC data were collected from the Connecticut Crash Data Repository; daily VMT estimates were obtained from StreetLight Insight's database. We used segmented Poisson regression models, controlling for daily temperature and daily precipitation. RESULTS: The mean daily VMT significantly decreased 43% in the post stay-at-home period in 2020. While the mean daily counts of crashes decreased in 2020 after the stay-at-home order was enacted, several types of crash rates increased after accounting for the VMT reductions. Single vehicle crash rates significantly increased 2.29 times, and specifically single vehicle fatal crash rates significantly increased 4.10 times when comparing the pre-stay-at-home and post-stay-at-home periods. DISCUSSION: Despite a decrease in the number of MVCs and VMT, the crash rate of single vehicles increased post stay-at-home order enactment in Connecticut after accounting for reductions in VMT.
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Accidentes de Tránsito/estadística & datos numéricos , Conducción de Automóvil/estadística & datos numéricos , COVID-19/epidemiología , Vehículos a Motor/estadística & datos numéricos , Connecticut/epidemiología , Humanos , Análisis de Series de Tiempo Interrumpido , SARS-CoV-2 , Transportes/estadística & datos numéricos , Viaje/estadística & datos numéricosRESUMEN
Autonomic dysregulation plays a key role in the development and progression of heart failure (HF). Vagal nerve stimulation (VNS) may be a promising therapeutic approach. However, the outcomes from clinical trials evaluating VNS in HF have been mixed, and the mechanisms underlying this treatment remain poorly understood. Intermittent high-frequency VNS (pulse width 300 µs, 30 Hz stimulation, 30 s on, and 300 s off) was used in healthy sheep and sheep in which established HF had been induced by 4 weeks rapid ventricular pacing to assess (a) the effects of VNS on intrinsic cardiac vagal tone, (b) whether VNS delays the progression of established HF, and (c) whether high-frequency VNS affects the regulation of cardiomyocyte calcium handling in health and disease. VNS had no effect on resting heart rate or intrinsic vagal tone in the healthy heart. Although fewer VNS-treated animals showed subjective signs of heart failure at 6 weeks, overall VNS did not slow the progression of clinical or echocardiographic signs of HF. Chronic VNS did not affect left ventricular cardiomyocyte calcium handling in healthy sheep. Rapid ventricular pacing decreased the L-type calcium current and calcium transient amplitude, but chronic VNS did not rescue dysfunctional calcium handling. Overall, high-frequency VNS did not prevent progression of established HF or influence cellular excitation-contraction coupling. However, a different model of HF or selection of different stimulation parameters may have yielded different results. These results highlight the need for greater insight into VNS dosing and parameter selection and a deeper understanding of its physiological effects.
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Acoplamiento Excitación-Contracción , Insuficiencia Cardíaca/fisiopatología , Taquicardia/fisiopatología , Estimulación del Nervio Vago/métodos , Animales , Señalización del Calcio , Células Cultivadas , Femenino , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/terapia , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/fisiología , Ovinos , Taquicardia/complicacionesRESUMEN
Background Atrial fibrillation ( AF ) is common in the elderly, but rare in the young; however, the changes that occur with age that promote AF are not fully understood. Action potential ( AP ) alternans may be involved in the initiation of AF . Using a translationally relevant model, we investigated whether age-associated atrial vulnerability to AF was associated with susceptibility to AP alternans. Methods and Results AF was induced in conscious young and old sheep using 50 Hz burst pacing. Old sheep were more vulnerable to AF . Monophasic and cellular AP s were recorded from the right atrium in vivo and from myocytes isolated from the left and right atrial appendages. AP alternans occurred at lower stimulation frequencies in old sheep than young in vivo (old, 3.0±0.1 Hz; young, 3.3±0.1 Hz; P<0.05) and in isolated myocytes (old, 1.6±0.1 Hz; young, 2.0±0.1 Hz; P<0.05). Simultaneous recordings of [Ca2+]i and membrane potential in myocytes showed that alternans of AP s and [Ca2+]i often occurred together. However, at low stimulation rates [Ca2+]i alternans could occur without AP alternans, whereas at high stimulation rates AP alternans could still be observed despite disabling Ca2+ cycling using thapsigargin. Conclusions We have shown, for the first time in a large mammalian model, that aging is associated with increased duration of AF and susceptibility to AP alternans. We suggest that instabilities in Ca2+ handling initiate alternans at low stimulation rates, but that AP restitution alone can sustain alternans at higher rates.
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Potenciales de Acción/fisiología , Fibrilación Atrial/etiología , Factores de Edad , Animales , Fibrilación Atrial/fisiopatología , Función Atrial/fisiología , Calcio/fisiología , Susceptibilidad a Enfermedades/etiología , Femenino , Atrios Cardíacos/fisiopatología , Potenciales de la Membrana/fisiología , Células Musculares/fisiología , OvinosRESUMEN
This prospective study tests the hypotheses that: 1) glaucoma is associated with evidence of cerebral small vessel disease; 2) that imaging biomarkers of cerebral small vessel disease in POAG and NTG will show different characteristics. 12 normal controls, 7 patients with primary open angle glaucoma (POAG) and 9 patients with normal tension glaucoma (NTG) were recruited. Ophthalmological clinical assessment and MR imaging of the brain were performed. MR imaging was used to quantify white matter lesion load, frequency of dilated perivascular spaces (PVS) and abnormalities in cerebral hydrodynamics. Patients with POAG had significantly greater white matter lesion load (p < 0.05), more PVS in the centrum semiovale (p < 0.05) and had higher overall PVS scores than controls (p < 0.05). In the POAG group, optic cup-to-disc ratio (CDR) was positively correlated with deep white matter hyperintensities (R(2) = 0.928, p < 0.01). Mean deviation on the Humphrey visual field assessment was negatively correlated with deep white matter lesion load (R(2) = -0.840, p < 0.01), total white matter lesion load (R(2) = -0.928, p < 0.01) and total PVS (R(2) = -0.820, p < 0.01). MR evidence of cerebral small vessel disease is strongly associated with a diagnosis of POAG and with the severity of abnormalities in CDR and visual field.
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Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico , Glaucoma de Ángulo Abierto/complicaciones , Glaucoma de Ángulo Abierto/diagnóstico , Imagen por Resonancia Magnética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Circulación Cerebrovascular , Femenino , Humanos , Presión Intraocular , Masculino , Persona de Mediana Edad , Pruebas del Campo Visual , Campos VisualesRESUMEN
The concept that fat cells could influence the circulation and indeed cardiac function has been in existence for ≥20 years and has gained a wide interest and no less excitement as evidence has accrued to suggest that such effects may be profound enough to explain disease states, such as hypertension and metabolic changes associated with obesity and type II diabetes mellitus. This ATVB in Focus intends to examine our current knowledge in this field, and suggests mechanisms that may be responsible for normal perivascular function and how they become disordered in obesity. There is the tantalizing prospect of developing new therapeutic approaches to keep obese individuals healthy and redesignating type II diabetes mellitus as a vascular disease.
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Adiponectina/metabolismo , Tejido Adiposo/metabolismo , Vasos Sanguíneos/metabolismo , Obesidad/metabolismo , Comunicación Paracrina , Transducción de Señal , Enfermedades Vasculares/metabolismo , Tejido Adiposo/fisiopatología , Animales , Vasos Sanguíneos/fisiopatología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Humanos , Síndrome Metabólico/metabolismo , Síndrome Metabólico/fisiopatología , Obesidad/epidemiología , Obesidad/fisiopatología , Obesidad/terapia , Factores de Riesgo , Enfermedades Vasculares/epidemiología , Enfermedades Vasculares/fisiopatología , Enfermedades Vasculares/terapia , Pérdida de PesoRESUMEN
To ensure succession planning within the ranks of nurse managers meet current and projected nursing management needs and organizational goals, we developed and implemented a nurse manager residency program at our hospital. By identifying, supporting, and mentoring clinical experts who express a desire and display an aptitude for nursing leadership, we are graduating individuals who can transition to a nurse manager position with greater ease and competence.
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Educación Continua en Enfermería/organización & administración , Enfermeras Administradoras , Personal de Enfermería en Hospital/educación , Movilidad Laboral , Curriculum , Hospitales Comunitarios , Humanos , Pennsylvania , Desarrollo de ProgramaRESUMEN
A new dual temporal resolution-based, high spatial resolution, pharmacokinetic parametric mapping method is described--improved coverage and spatial resolution using dual injection dynamic contrast-enhanced (ICE-DICE) MRI. In a dual-bolus dynamic contrast-enhanced-MRI acquisition protocol, a high temporal resolution prebolus is followed by a high spatial resolution main bolus to allow high spatial resolution parametric mapping for cerebral tumors. The measured plasma concentration curves from the dual-bolus data were used to reconstruct a high temporal resolution arterial input function. The new method reduces errors resulting from uncertainty in the temporal alignment of the arterial input function, tissue response function, and sampling grid. The technique provides high spatial resolution 3D pharmacokinetic maps (voxel size 1.0 × 1.0 × 2.0 mm(3)) with whole brain coverage and greater parameter accuracy than that was possible with the conventional single temporal resolution methods. High spatial resolution imaging of brain lesions is highly desirable for small lesions and to support investigation of heterogeneity within pathological tissue and peripheral invasion at the interface between diseased and normal brain. The new method has the potential to be used to improve dynamic contrast-enhanced-MRI techniques in general.
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Aumento de la Imagen/métodos , Imagen por Resonancia Magnética/métodos , Meglumina/farmacocinética , Modelos Biológicos , Neuroma Acústico/metabolismo , Neuroma Acústico/patología , Compuestos Organometálicos/farmacocinética , Anciano , Simulación por Computador , Medios de Contraste/administración & dosificación , Femenino , Humanos , Inyecciones Intraarteriales , Masculino , Meglumina/administración & dosificación , Persona de Mediana Edad , Compuestos Organometálicos/administración & dosificación , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
A single-input whispering gallery optical microbubble resonator is presented. Spherical microbubbles with diameters less than 100 µm, micrometer-sized wall thicknesses, and a single opening or input were fabricated by heating the tapered tip of a pressurized glass capillary using a CO(2) laser. Optical whispering gallery modes with Q factors of â¼10(5) were obtained. The bubbles were filled with water and mode shifts of â¼20 GHz were observed. Fano-type resonances were detected when the coupling optical fiber diameter was less than 1 µm, causing the microresonator to switch from being a band-stop filter to a bandpass filter. Larger bubbles with submicrometer wall thickness were also fabricated.
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BACKGROUND: Sorafenib is an inhibitor of multiple kinases (e.g., VEGF receptors, PDGFR, FLT3, RET, BRAF, KIT) and is approved by FDA for treatment of two adult cancers. The activity of sorafenib was evaluated against the PPTP's in vitro and in vivo panels. PROCEDURES: Sorafenib was evaluated against the PPTP in vitro panel using 96-hr exposure at concentrations ranging from 1.0 nM to 10.0 µM. It was tested against the PPTP in vivo panels at a dose of 60 mg/kg administered by oral gavage daily for 5 days per week, repeated for 6 weeks. RESULTS: In vitro sorafenib demonstrated cytotoxic activity, with a median IC(50) value of 4.3 µM. Twenty of 23 cell lines had IC(50) values between 1.0 and 10.0 µM. A single cell line (Kasumi-1) with an activating KIT mutation had an IC(50) value < 1.0 µM (IC(50) = 0.02 µM). In vivo sorafenib induced significant differences in event-free survival (EFS) distribution compared to control in 27 of 36 (75%) of the evaluable solid tumor xenografts and in 1 of 8 (12.5%) of the evaluable ALL xenografts. Sorafenib induced tumor growth inhibition meeting criteria for intermediate activity (EFS T/C) in 15 of 34 (44%) evaluable solid tumor xenografts. No xenografts achieved an objective response. CONCLUSIONS: The primary in vitro activity of sorafenib was noted at concentrations above 1 µM, with the exception of a more sensitive cell line with an activating KIT mutation. The primary in vivo effect for sorafenib was tumor growth inhibition, which was observed across multiple histotypes.
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Bencenosulfonatos/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Línea Celular Tumoral , Niño , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Neoplasias/enzimología , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , SorafenibRESUMEN
BACKGROUND: Carboplatin is the most effective drug in retinoblastoma but systemic clearance is variable in young patients. While most regimens use a flat dose, individualized targeting may provide a more adjusted systemic exposure. PATIENTS AND METHODS: We compared carboplatin doses between two groups of children with retinoblastoma that were treated using a flat dose of 560 mg/m(2) or a targeted AUC of 6.5 using a modified Calvert formula. RESULTS: Ninety-eight patients with retinoblastoma received a total of 576 cycles of carboplatin (median 8 cycles). Fifty patients (51%) received a fixed dose per m(2), 32 (33%) received a dose based on AUC, 1 patient received fixed dose per kilogram, and in 15 patients a combination AUC and fixed doses was used. The median cumulative carboplatin dose (mg/m(2)) for patients who received eight cycles using fixed per m(2) dosing was 2151.8 (range, 1414.2-2852.0), compared to 1104.1 for nine patients who received eight cycles using Calvert dosing (range, 779.0-1992.7) (P < 0.001). For cycles given using AUC, the median percentage of the hypothetical fixed per m(2) dose was 70% (range, 48-134%). Younger patients had larger differences. Patients receiving carboplatin based on fixed per m(2) dosing were 3.0 times more likely to have a platelet transfusion (95% confidence interval, 1.3-7.3). CONCLUSIONS: Carboplatin administration needs to consider the changes in renal function occurring during the first months of life. The use of a targeted AUC provides the most accurate method; however, mg per kg of body weight dosing is a very reliable alternative method.
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Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Adolescente , Antineoplásicos/efectos adversos , Carboplatino/efectos adversos , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
PURPOSE: The purpose of the study was to compare outcomes of pediatric patients with high-risk metastatic neuroblastoma who received radiotherapy (RT) with those of patients who did not. PATIENTS AND METHODS: We reviewed the records of 63 patients with newly diagnosed metastatic neuroblastoma treated at our institution (1989-2001) to investigate their characteristics at presentation, dose and field of RT, treatment response, and failure patterns. RESULTS: Seventeen patients received RT, and 46 did not. In the RT group, a greater percentage of patients had residual disease before consolidation than did those in the no-RT group (88.2% vs 69.6%, P = .008). Gross total resection was achieved less often in the RT group (65% vs 89%, P = .055), but the 5-year cumulative incidences of local failure were similar (35.3% +/- 12.4% vs 32.6% +/- 7.1%). Although there was no difference in 5-year event-free survival, overall survival was better in the no-RT group (47.8% +/- 7.2% vs 23.5% +/- 9.2%, P = .026). CONCLUSION: The addition of RT to the therapy of a group of patients with more residual locoregional disease appeared to improve the local failure rate to approximately that of patients with less residual disease. Radiotherapy may provide even greater benefit to those with less residual disease before consolidation.
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Neuroblastoma/radioterapia , Neuroblastoma/secundario , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Recurrencia Local de Neoplasia/prevención & control , Neuroblastoma/patología , Neuroblastoma/terapia , Radioterapia/efectos adversos , Dosificación Radioterapéutica , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
BACKGROUND: Topotecan is a small molecule DNA topoisomerase I poison, that has been successful in clinical trials against pediatric solid tumors and leukemias. Topotecan was evaluated against the Pediatric Preclinical Testing Program (PPTP) tumor panels as part of a validation process for these preclinical models. PROCEDURES: In vivo three measures of antitumor activity were used: (1) an objective response measure modeled after the clinical setting; (2) a treated to control (T/C) tumor volume measure; and (3) a time to event (fourfold increase in tumor volume for solid tumor models, or > or =25% human CD45+ cells in the peripheral blood for acute lymphoblastic leukemia, ALL models) measure based on the median event-free survival (EFS) of treated and control animals for each xenograft. RESULTS: Topotecan inhibited cell growth in vitro with IC(50) values between 0.71 and 489 nM. Topotecan significantly increased EFS in 32 of 37 (87%) solid tumor xenografts and in all 8 of the ALL xenografts. Seventy-five percent of solid tumors met EFS T/C activity criteria for intermediate (n = 17) or high activity (n = 7). Objective responses were noted in eight solid tumor xenografts (Wilms, rhabdomyosarcoma, Ewing sarcoma, neuroblastoma). Among the six neuroblastomas, three achieved a PR. For the ALL panel, two maintained CRs, three CRs, and two PRs were observed. CONCLUSIONS: Topotecan demonstrated broad activity in vitro and in vivo against both the solid tumor and ALL panels, with significant tumor growth delay generated in all the panels. These results further demonstrate the validity of the PPTP panel for preclinical testing of new drugs.
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Antineoplásicos/farmacología , Evaluación Preclínica de Medicamentos , Neoplasias/tratamiento farmacológico , Topotecan/farmacología , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Niño , Relación Dosis-Respuesta a Droga , Humanos , Modelos Teóricos , Topotecan/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Mapatumumab (HGS-ETR1) is a fully human IgG1 agonistic monoclonal antibody that exclusively targets and activates tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1). It was tested in vitro at concentrations from 0.01 to 100 microg/ml and in vivo at a dose of 10 mg/kg administered intraperitoneally using a twice-weekly schedule. Mapatumumab demonstrated limited activity against the 23 cell lines of the PPTP in vitro panel with no lines achieving 50% growth inhibition. Mapatumumab induced significant differences in event-free survival distribution compared to controls in 9 of 37 evaluable solid tumor xenografts tested, but in none of the 8 ALL xenografts.
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Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/agonistas , Animales , Anticuerpos Monoclonales/toxicidad , Anticuerpos Monoclonales Humanizados , Antineoplásicos/toxicidad , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Pediatría , Análisis de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The combination of a platinating agent and etoposide has induced responses in various pediatric tumors. The study estimated the maximum tolerated dose (MTD) of an oxaliplatin and etoposide regimen in children with recurrent solid tumors. METHODS: Oxaliplatin was administered on Day 1 and etoposide on Days 1 to 3 of each 21-day course. Cohorts of 3 to 6 patients were enrolled at 3 dose levels: 1) oxaliplatin at a dose of 130 mg/m(2) and etoposide at a dose of 75 mg/m(2), 2) oxaliplatin at a dose of 130 mg/m(2) and etoposide at a dose of 100 mg/m(2), and 3) oxaliplatin at a dose of 145 mg/m(2) and etoposide at a dose of 100 mg/m(2). Calcium and magnesium infusions were used at dose level 3 in an attempt to escalate the oxaliplatin dose past the single-agent MTD. RESULTS: The 16 patients received a total of 63 courses. At dose level 1, dose-limiting epistaxis, neuropathy, and neutropenia occurred in 1 of 6 patients. No dose-limiting toxicity (DLT) occurred at dose level 2 (n = 6). At dose level 3, 2 of 4 patients experienced dose-limiting neutropenia; none experienced grade 3 or 4 acute neuropathy. Six patients required prolongation of the oxaliplatin infusion because of acute sensory neuropathy. Responses were observed in patients with medulloblastoma (1 complete response) and pineoblastoma (1 partial response); 3 others with atypical teratoid rhabdoid tumor, ependymoma, and soft tissue sarcoma had prolonged disease stabilization. CONCLUSIONS: The MTD of this regimen was found to be oxaliplatin at a dose of 130 mg/m(2) given on Day 1 and etoposide at a dose of 100 mg/m(2)/d given on Days 1 to 3. Neutropenia was found to be the DLT. Calcium and magnesium infusions did not allow escalation of the oxaliplatin dose. The combination was well-tolerated and demonstrated antitumor activity.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Etopósido/administración & dosificación , Neoplasias/tratamiento farmacológico , Compuestos Organoplatinos/administración & dosificación , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Preescolar , Esquema de Medicación , Etopósido/efectos adversos , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Dosis Máxima Tolerada , Neoplasias/patología , Neutropenia/inducido químicamente , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , RecurrenciaRESUMEN
BACKGROUND: The combination of gemcitabine and docetaxel has demonstrated promise in sarcomas diagnosed in adults. In the current study, the toxicity and efficacy of this combination were evaluated in pediatric sarcomas. METHODS: A retrospective case review of 22 patients with recurrent or refractory bone or soft-tissue sarcomas who received gemcitabine (at a dose of 675 mg/m(2) intravenously on Days 1 and 8) and docetaxel (at a dose of 75-100 mg/m(2) intravenously on Day 8) was undertaken. RESULTS: The patients (ages 8-23 years) received a total of 109 courses of chemotherapy (median, 4 courses; range, 1-13 courses). Seventeen patients had osteosarcoma, 2 patients had Ewing sarcoma family of tumors (ESFT), 1 patient had a malignant fibrous histiocytoma (MFH), 1 patient had a chondrosarcoma, and 1 patient had an undifferentiated sarcoma. Of the 14 patients evaluable for response, the patient with an MFH achieved a complete response (CR), 3 patients with osteosarcoma achieved a partial response (PR), and 2 patients (1 with ESFT and 1 with osteosarcoma) had stable disease (SD). The overall objective response (CR + PR) rate was 29%. Median duration of response (CR + PR + SD) was 4.8 months (range, 1.6-13 months). The toxicity was manageable and consisted primarily of thrombocytopenia and neutropenia. CONCLUSIONS: In the current study, gemcitabine in combination with docetaxel was found to be well tolerated and demonstrated antitumor activity in children and adolescents with recurrent or refractory osteosarcoma and MFH. Further evaluation of this drug combination is warranted in these patients.