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BACKGROUND: Combined use of inhibitors of mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF-2) receptors is a potential strategy to overcome resistance to either class of drugs when used alone. PATIENTS AND METHODS: We designed a phase 1 trial to test the drug combination of a multikinase VEGF receptor 2 inhibitor, vandetanib, and an mTOR inhibitor, everolimus, in a pediatric and young adult patient cohort with advanced cancers. Exceptional responders were probed for tumor mutational profile to explore possible molecular mechanisms of response. RESULTS: Among 21 enrolled patients, clinical benefit was observed in 38% (one patient with partial response and eight patients with stable disease) with a median progression-free survival of 3.3 months. The most common treatment-related adverse event was rash (n = 13). Other treatment-related toxicities included diarrhea, fatigue, hypertension, QT prolongation, hypertriglyceridemia/hypercholesterolemia, transaminitis, thrombocytopenia, and weight loss. None of the patients experienced dose-limiting toxicities. Three exceptional responders were analyzed and were found to harbor genetic alterations including kinase insert domain receptor (KDR) Q472H mutation, EWSR1-CREB3L1, CDKN2A/B loss, and ASPL/ASPSCR1-TFE3 fusion. CONCLUSIONS: The combination of vandetanib and everolimus showed early activity and tolerable toxicity profile in pediatric patients with advanced cancers.
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Everolimus , Neoplasias , Humanos , Adulto Joven , Adolescente , Niño , Everolimus/efectos adversos , Factor A de Crecimiento Endotelial Vascular , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Sirolimus/efectos adversos , Piperidinas/efectos adversos , Quinazolinas/efectos adversosRESUMEN
BACKGROUND: The purpose of this study was to assess the impact of bevacizumab alone and in combination with cytotoxic therapy on tumour vasculature in osteosarcoma (OS) using DCE-MRI. METHODS: Six DCE-MRI and three (18)F-FDG PET examinations were scheduled in 42 subjects with newly diagnosed OS to monitor the response to antiangiogenic therapy alone and in combination with cytotoxic therapy before definitive surgery (week 10). Serial DCE-MRI parameters (K(trans), v(p), and v(e)) were examined for correlation with FDG-PET (SUV(max)) and association with drug exposure, and evaluated with clinical outcome. RESULTS: K(trans) (P=0.041) and v(p) (P=0.001) significantly dropped from baseline at 24 h after the first dose of bevacizumab alone, but returned to baseline by 72 h. Greater exposure to bevacizumab was correlated with larger decreases in v(p) at day 5 (P=0.04) and week 10 (P=0.02). A lower K(trans) at week 10 was associated with greater percent necrosis (P=0.024) and longer event-free survival (P=0.034). CONCLUSIONS: This is the first study to demonstrate significant changes of the plasma volume fraction and vascular leakage in OS with bevacizumab alone. The combination of demonstrated associations between drug exposure and imaging metrics, and imaging metrics and patient survival during neoadjuvant therapy, provides a compelling rationale for larger studies using DCE-MRI to assess vascular effects of therapy in OS.
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Inhibidores de la Angiogénesis/uso terapéutico , Bevacizumab/uso terapéutico , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/terapia , Quimioterapia Adyuvante/métodos , Niño , Medios de Contraste/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Fluorodesoxiglucosa F18 , Gadolinio DTPA , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Terapia Neoadyuvante/métodos , Tomografía de Emisión de Positrones/métodosRESUMEN
BACKGROUND: Late relapse and solitary lesion are positive prognostic factors in recurrent osteosarcoma. METHODS: We reviewed the records of 39 patients treated at three major centres for recurrent osteosarcoma with a single pulmonary metastasis more than 1 year after diagnosis. We analysed their outcomes with respect to clinical factors and treatment with chemotherapy. RESULTS: Median age at diagnosis was 14.6 years. Relapse occurred at a median of 2.5 years (range, 1.2-8.2 years) after initial diagnosis. At relapse, all patients were treated by metastasectomy; 12 (31%) patients also received chemotherapy. There was no difference in time to recurrence or nodule size between the patients who received or did not receive chemotherapy at relapse. Sixteen patients had no subsequent recurrence, 13 of whom survive without evidence of disease. The 5-year and 10-year estimates of post-relapse event-free survival (PREFS) were 33.0±7.5% and 33.0±9.6%, respectively, and of post-relapse survival (PRS) 56.8±8.6% and 53.0±11.0%, respectively. There was a trend for nodules <1.5 cm to correlate positively with PREFS (P=0.070) but not PRS (P=0.49). Chemotherapy at first relapse was not associated with PREFS or PRS. CONCLUSION: Approximately half of the patients with recurrent osteosarcoma presenting as a single pulmonary metastasis more than 1 year after diagnosis were long-term survivors. Metastasectomy was the primary treatment; chemotherapy did not add benefit.
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Neoplasias Óseas/terapia , Neoplasias Pulmonares/terapia , Recurrencia Local de Neoplasia/prevención & control , Osteosarcoma/terapia , Adolescente , Neoplasias Óseas/epidemiología , Neoplasias Óseas/patología , Niño , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/secundario , Masculino , Recurrencia Local de Neoplasia/epidemiología , Osteosarcoma/epidemiología , Osteosarcoma/secundario , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Little information is available about the diagnosis and management of acute methotrexate (MTX)-induced encephalopathy. METHODS: We reviewed clinical and magnetic resonance imaging (MRI) [including diffusion-weighted imaging (DWI)] characteristics of this complication in pediatric cancer patients treated from 2000 to 2006. RESULTS: Six of 754 (0.8%) patients with leukemia or lymphoma and 2 of 44 (4.5%) with bone sarcoma experienced acute encephalopathy within 2 weeks (median, 7.5 days) after receiving high-dose i.v. and/or intrathecal MTX. The signs and symptoms varied at presentation and during episodes: hemiparesis (eight patients, alternating from side to side in four), dysphasia (six), confusion/emotionality (six), headache (three), choreoathetosis (two), and seizure (two). All patients recovered after 1-7 days (median, 5.5 days). DWI revealed restricted diffusion in anatomic brain regions associated with the symptoms; changes on T2-weighted and fluid-attenuated inversion recovery (FLAIR) imaging were consistently less marked. After recovery, DWI findings were normal but T2 and/or FLAIR imaging usually showed residual abnormalities. CONCLUSIONS: Acute MTX toxicity often manifests as fluctuating neurologic symptoms with alternating hemispheric involvement. Restricted diffusion on DWI is a reliable early sign of acute MTX encephalopathy and resolves as clinical status improves, despite the persistence of subtle abnormalities on MRI.
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Antimetabolitos Antineoplásicos/efectos adversos , Encéfalo/patología , Metotrexato/efectos adversos , Síndromes de Neurotoxicidad/etiología , Enfermedad Aguda , Adolescente , Aminofilina/uso terapéutico , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Niño , Imagen de Difusión por Resonancia Magnética , Femenino , Histiocitoma Fibroso Maligno/tratamiento farmacológico , Humanos , Inyecciones Intravenosas , Inyecciones Espinales , Leucemia/tratamiento farmacológico , Masculino , Tasa de Depuración Metabólica , Metotrexato/administración & dosificación , Metotrexato/sangre , Metotrexato/uso terapéutico , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/patología , Osteosarcoma/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
Canonical Wnt signalling is an osteoinductive signal that promotes bone repair through acceleration of osteogenic differentiation by progenitors. Dkk-1 is a secreted inhibitor of canonical Wnt signalling and thus inhibits osteogenesis. To examine a potential osteoinhibitory role of Dkk-1 in osteosarcoma (OS), we measured serum Dkk-1 in paediatric patients with OS (median age, 13.4 years) and found it to be significantly elevated. We also found that Dkk-1 was maximally expressed by the OS cells at the tumour periphery and in vitro, Dkk-1 and RANKL are coexpressed by rapidly proliferating OS cells. Both Dkk-1 and conditioned media from OS cells reduce osteogenesis by human mesenchymal cells and by immunodepletion of Dkk-1, or by adding a GSK3beta inhibitor, the effects of Dkk-1 were attenuated. In mice, we found that the expression of Dkk-1 from implanted tumours was similar to the human tumour biopsies in that human Dkk-1 was present in the serum of recipient animals. These data demonstrate that systemic levels of Dkk-1 are elevated in OS. Furthermore, the expression of Dkk-1 by the OS cells at the periphery of the tumour probably contributes to its expansion by inhibiting repair of the surrounding bone. These data demonstrate that Dkk-1 may serve as a prognostic or diagnostic marker for evaluation of OS and furthermore, immunodepletion of Dkk-1 or administration of GSK3beta inhibitors could represent an adjunct therapy for this disease.
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Neoplasias Óseas/patología , Péptidos y Proteínas de Señalización Intercelular/fisiología , Osteosarcoma/patología , Adolescente , Fosfatasa Alcalina/metabolismo , Animales , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/terapia , Diferenciación Celular/efectos de los fármacos , Niño , Medios de Cultivo Condicionados/farmacología , Inhibidores Enzimáticos/farmacología , Ensayo de Inmunoadsorción Enzimática , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta , Humanos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intercelular/sangre , Péptidos y Proteínas de Señalización Intercelular/farmacología , Ratones , Ratones Desnudos , Neoplasias Experimentales/sangre , Neoplasias Experimentales/patología , Osteogénesis/efectos de los fármacos , Osteosarcoma/diagnóstico , Osteosarcoma/terapia , Valor Predictivo de las Pruebas , Ligando RANK/metabolismo , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
BACKGROUND: Better predictors of outcome would allow improved risk-adapted therapy for pediatric nonmetastatic osteosarcoma of the extremity. We investigated the predictive value of MR imaging-based measures of absolute and relative tumor size and volume at the time of diagnosis. We also assessed the relation of tumor size to age and histologic response. METHODS: We retrospectively abstracted demographic, treatment history, and outcome information of patients treated on a single institutional protocol. A single pediatric oncologic radiologist manually measured each primary lesion and the affected native bone in three dimensions on MR images obtained at the time of diagnosis. Eight parameters of tumor size were analyzed for their value in predicting overall survival (OS) and event-free survival (EFS). RESULTS: The median age of the 42 patients was 13.5 years (range: 5.9-18.7 years); 50% were female and 74% were Caucasian. Absolute tumor volume was an important predictor of OS (P < 0.05); absolute tumor depth (analyzed as a continuous variable) was a significant predictor of OS (P = 0.018) and EFS (P = 0.036). Relative measures of tumor size were not found to predict outcome. No relation was seen between tumor size and histologic response. CONCLUSIONS: Absolute tumor size at the time of diagnosis is significantly predictive of OS and EFS. If validated in a larger study, this indicator should be used in the design of risk-adapted treatment protocols for osteosarcoma.
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Osteosarcoma/diagnóstico , Carga Tumoral , Adolescente , Niño , Supervivencia sin Enfermedad , Femenino , Humanos , Imagenología Tridimensional , Imagen por Resonancia Magnética , Masculino , Osteosarcoma/mortalidad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVE: To determine a thrombopoietin schedule that would effectively enhance hematopoiesis and prevent death in mice after lethal myelosuppression. METHODS: First, we determined whether recombinant Mpl ligand (Mpl-L) has a priming effect on thrombopoiesis in normal mice. Mice were given pegylated recombinant murine Megakaryocyte Growth and Development Factor (PEG-rmMGDF) intravenously as a single injection or as two injections separated by intervals of 1 to 10 days. Second, we examined the scheduling of PEG-rmMGDF that would most effectively reduce thrombocytopenia in mice given a lethal myelosuppressive regimen (80 mg/kg carboplatin + 750 R Cs-137 total-body irradiation). RESULTS: In normal mice, peak platelet count with a 4-day to 8-day interval between PEG-rmMGDF injections was significantly higher than that with single injection. This priming effect was optimal with a 4-day interval between injections. In the lethal myelosuppression model, all mice given intravenous PEG-rmMGDF as a single injection on day 0 or as two injections (on days -4 and 0 or on days 0 and 4) survived; PEG-rmMGDF on day 0 was given immediately after the myelosuppressive regimen. In contrast, all mice given a single intravenous PEG-rmMGDF injection on day -4 or day 4 died. Two PEG-rmMGDF injections given on days -4 and 0 enhanced hematopoietic recovery more than did a single injection on day 0 or two injections on days 0 and 4. CONCLUSION: Mpl-L administration immediately after lethal carboplatin and radiation prevents death and enhances hematopoietic recovery in mice; this protective effect is further enhanced by a priming Mpl-L dose given 4 days before the myelosuppressive regimen.
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Células de la Médula Ósea/efectos de los fármacos , Carboplatino/farmacología , Hematopoyesis/efectos de los fármacos , Recuento de Plaquetas , Trombopoyetina/farmacología , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de la radiación , Femenino , Hematopoyesis/efectos de la radiación , Cinética , Ratones , Ratones Endogámicos C57BL , Polietilenglicoles/farmacología , Proteínas Recombinantes/farmacología , Factores de Tiempo , Irradiación Corporal TotalRESUMEN
BACKGROUND: Preclinical studies suggest a role of insulin-like growth factor-1 (IGF-1) in the proliferation of osteosarcoma cells in vivo. The purpose of this study is to address the relationship between serum levels of IGF-1 and its binding protein (IGFBP-3), and the clinical behavior and outcome of osteosarcoma in children, and to compare those levels present in osteosarcoma patients with a normal population. PROCEDURE: Serum IGF-1 and IGFBP-3 levels were determined by ELISA in 37 patients with osteosarcoma treated on the same treatment regimen (OS-91 protocol), and who had available serum samples from diagnosis. IGF-1 and IGFBP-3 levels were compared with those previously established in the normal population, matched for age and gender, and were correlated with the presence of metastatic disease, histologic response to preoperative chemotherapy, and event-free survival. RESULTS: In osteosarcoma patients the median IGF-1 level was 275 ng/ml (range, 105-613) and the median IGFBP-3 level was 3.4 mg/L (range, 2.3-5.1). IGF-1 levels differed from those in the normal population (P = 0.029); although we anticipated higher IGF-1 levels than normal children, 68% of observed standardized scores were less than 0. Furthermore, IGF-1 or IGFBP-3 levels failed to correlate with the presence of metastatic disease (P = 0.12 and P = 0.12, respectively), histologic response (Rosen-Huvos grades 3/4 vs. grades 1/2) (P = 0.95 and P = 0.71, respectively), or event-free survival (P = 0.52 and P = 0.41, respectively). There was a strong association observed between IGF-1 and IGFBP-3 levels (P < 0.001). CONCLUSIONS: In this retrospective study of 37 patients, we found that circulating levels of IGF-1 and IGFBP-3 are not predictive of the development or clinical characteristics of pediatric osteosarcoma. However, further studies on a larger patient population should be performed in order to investigate this relationship.
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Neoplasias Óseas/diagnóstico , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Osteosarcoma/diagnóstico , Adolescente , Adulto , Biomarcadores de Tumor/sangre , Neoplasias Óseas/sangre , Neoplasias Óseas/patología , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Masculino , Metástasis de la Neoplasia , Osteosarcoma/sangre , Osteosarcoma/patología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Metastatic osteosarcoma most commonly affects the lungs and other bones. Hepatic metastasis at the time of diagnosis is extremely rare. A 14-year-old boy with synovial sarcoma of the left popliteal fossa was treated with surgical resection, radiotherapy for microscopic residual disease, and 1 year of chemotherapy (vincristine, cyclophosphamide, dactinomycin, and doxorubicin). Approximately 10 years after the initial diagnosis, a secondary osteosarcoma developed in the left proximal tibia. Computed tomography at presentation showed bilateral pulmonary metastases and large ossified nodules in the liver that demonstrated abnormal avidity on 99mTc MDP bone scan indicating hepatic metastasis. Despite chemotherapy (cisplatin, ifosfamide, high-dose methotrexate, and dacarbazine), the patient died of progressive disease 4 months after the diagnosis of the second cancer. Hepatic metastasis was found at the time of diagnosis of a secondary osteosarcoma and manifested as ossified nodules. The risk of radiation-induced osteosarcoma should always be considered in decisions about treatment for soft-tissue sarcoma.
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Neoplasias Hepáticas/secundario , Osteosarcoma/patología , Sarcoma Sinovial/patología , Sarcoma Sinovial/radioterapia , Adolescente , Resultado Fatal , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/secundario , Masculino , Neoplasias Inducidas por Radiación/patología , Neoplasias Primarias Secundarias/etiología , Neoplasias Primarias Secundarias/patología , Osificación Heterotópica/diagnóstico por imagen , Osificación Heterotópica/etiología , Osteosarcoma/etiología , Radiofármacos , Radioterapia/efectos adversos , Sarcoma Sinovial/terapia , Medronato de Tecnecio Tc 99m , Tomografía Computarizada de Emisión/normasRESUMEN
BACKGROUND: Bone sarcomas of the head and neck are difficult to resect. The authors reviewed their institutional experience with these tumors to characterize patients' clinical findings and to assess the impact of surgical resection on outcome. METHODS: The records of the 28 patients with bone sarcomas originating in the head and neck treated at St. Jude Children's Research Hospital between March 1962 and January 1998 were reviewed. RESULTS: There were 10 males and 18 females (median age, 12.6 years) each with a single sarcoma: osteosarcoma (18), Ewing sarcoma (7), malignant fibrous histiocytoma (MFH) (2), and fibrosarcoma (1). Primary tumor sites included the maxilla (13), skull (10), mandible (2), and other sites (3). All but one patient with Ewing sarcoma had localized disease at the time of diagnosis. All patients underwent surgery: complete resection, 8; gross total resection, 4; incomplete resection, 14; and biopsy only, 2; 22 also received chemotherapy. Radiotherapy was given to all patients with Ewing sarcoma and to four patients with primary osteosarcoma. Twelve patients survived a median of 8.4 years after diagnosis, 14 died of disease, and 2 died of unrelated causes. Local disease progression was evident in 12 patients (9 with osteosarcoma, 2 with MFH, and 1 with Ewing sarcoma) who died of disease, 9 of whom had the initial treatment of biopsy alone or incomplete resection. Patients with osteosarcoma who had the initial treatment of incomplete resection or biopsy alone were more likely to experience local failure (P = 0.001) and had poorer survival (P = 0.014) than those who underwent complete or gross total resection. CONCLUSIONS: Bone sarcomas of the head and neck are rare among children and most often are localized at the time of diagnosis. Incomplete resection of osteosarcoma is associated with local failure and poor outcome. Although aggressive surgery is essential for the cure of osteosarcoma, its necessity in the treatment of Ewing sarcomas remains controversial.
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Sarcoma/cirugía , Neoplasias Craneales/cirugía , Adolescente , Adulto , Causas de Muerte , Quimioterapia Adyuvante , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Fibrosarcoma/cirugía , Histiocitoma Fibroso Benigno/cirugía , Hospitales Pediátricos , Humanos , Lactante , Masculino , Neoplasias Mandibulares/cirugía , Neoplasias Maxilares/cirugía , Recurrencia Local de Neoplasia/patología , Osteosarcoma/cirugía , Radioterapia Adyuvante , Estudios Retrospectivos , Sarcoma de Ewing/cirugía , Tasa de Supervivencia , Tennessee , Resultado del TratamientoRESUMEN
The thrombopoietic efficacy of recombinant forms of c-mpl ligand is being actively investigated in preclinical studies using daily dosing schedules. However, a comprehensive kinetic study of the thrombopoietic response to a single injection of recombinant c-mpl ligand has not been performed. Here, we present the results of a detailed kinetic analysis of the platelet response to a single intravenous administration of pegylated recombinant murine megakaryocyte growth and development factor (PEG-rmMGDF) in mice. In addition, we compare the efficacy of single versus daily dosing in stimulating platelet production. A single intravenous injection of PEG-rmMGDF produced a marked and dose-dependent elevation in platelet number and a moderate increase in mean platelet volume (MPV). After administration of 25 or 250 micrograms/kg of PEG-rmMGDF, platelet number was first increased on day 3 and peaked at 2.7-fold (25 micrograms/kg) and 5.7-fold of normal (250 micrograms/kg) on day 5. Thereafter, platelet number declined and returned to baseline by days 9 and 14, with the 25 and 250 micrograms/kg doses, respectively. MPV began to increase on day 2 after PEG-rmMGDF, reaching maximum values of 1.2-fold (25 micrograms/kg) and 1.5-fold of normal (250 micrograms/kg) on day 4. Subsequently, MPV declined and was downregulated on days 6 to 7 (25 micrograms/kg) and day 8 (250 micrograms/kg). Based on these results, we evaluated the platelet response to PEG-rmMGDF administered intravenously as a single dose versus daily for 5 days. A single administration of 100 micrograms/kg produced a higher platelet number on day 5 than daily administration of 100 or 20 micrograms/kg for 5 days. However, the thrombocytosis was less sustained after single versus daily dosing. The smaller platelet number increase on day 5 after daily dosing reflected the production of larger platelets, rather than suppression of thrombopoiesis. Our results indicate that PEG-rmMGDF administered as a single intravenous dose potently stimulates platelet production in mice, challenging the need for its daily administration. Adoption of an intermittent administration schedule of this cytokine could be more efficacious and is merited in future clinical trials.
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Plaquetas/efectos de los fármacos , Trombopoyetina/administración & dosificación , Animales , Plaquetas/citología , División Celular/efectos de los fármacos , Inyecciones Intravenosas , Masculino , Ratones , Ratones Endogámicos C57BL , Recuento de Plaquetas/efectos de los fármacos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacocinética , Trombopoyetina/farmacocinéticaRESUMEN
OBJECTIVE: We studied the prevalence of nasopharyngeal (NP) carriage, antimicrobial susceptibilities, and serotypes of Streptococcus pneumoniae (SP) in children with sickle cell disease (SCD) in the Mid-South. In addition, we examined risk factors for NP carriage of penicillin-resistant SP (PRSP). STUDY DESIGN: Between July 1994 and December 1995, we obtained NP cultures from 312 children with SCD followed at the Mid-South Sickle Cell Center, 208 (67%) of whom were receiving penicillin prophylaxis. RESULTS: Among the 312 patients, colonization with SP occurred in 42 (13%), 30 (71%) of whom were receiving penicillin prophylaxis. Twenty-three of the 42 SP isolates (55%) were resistant to penicillin; 5 of the 23 (22%) were highly resistant. PRSP organisms were also resistant to cefotaxime (43%), trimethoprim-sulfamethoxazole (57%), and erythromycin (22%). Serotypes 6A, 6B, 14, 19A, and 23F accounted for 19 (90%) of 21 resistant strains. Children who were treated with antibiotics during the preceding month were more likely to carry PRSP than children who were not treated. CONCLUSIONS: There is a high prevalence of NP carriage of PRSP in children with SCD in the Mid-South, which raises concerns regarding the continued effectiveness of penicillin prophylaxis in these children. Further studies on the antimicrobial susceptibilities of resistant organisms and the relationship between NP carriage of SP and invasive disease are needed before developing new recommendations for prophylaxis and treatment.
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Anemia de Células Falciformes/microbiología , Nasofaringe/microbiología , Resistencia a las Penicilinas , Streptococcus pneumoniae/aislamiento & purificación , Adolescente , Anemia de Células Falciformes/tratamiento farmacológico , Profilaxis Antibiótica , Niño , Preescolar , Recuento de Colonia Microbiana , Farmacorresistencia Microbiana , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Penicilinas/uso terapéutico , Factores de Riesgo , Serotipificación , Streptococcus pneumoniae/clasificaciónRESUMEN
Despite numerous studies investigating the action of c-mpl ligand, no reports have defined the in vivo changes in megakaryocytopoiesis in response to a single injection of this cytokine. Here we compare the kinetics of the megakaryocytopoietic response in C57BI/6J mice administered 25 micrograms/ kg or 250 micrograms/kg of pegylated (PEG) murine megakaryocyte growth and development factor (MGDF) as a single intravenous injection. Megakaryocytes of mice treated with MGDF had normal ultrastructure, showing a typical distribution of the demarcation membrane system, alpha-granules, and other cytoplasmic organelles. Megakaryocyte ploidy, size, and frequency were markedly increased with both MGDF doses. Megakaryocyte ploidy was maximally increased from a modal value of 16N to 64N on day 3, with both doses of MGDF. Similarly, a comparable increase in megakaryocyte size occurred in the two MGDF groups. Increased megakaryocyte size was coupled to the increase in megakaryocyte ploidy, and no evidence for independent regulation of megakaryocyte size within individual ploidy classes was apparent. In contrast to megakaryocyte ploidy and size, the increase in megakaryocyte frequency was markedly different with the two doses of MGDF. The proportion of 2N and 4N cells was increased from a baseline of 0.035% to 0.430% by day 4 in mice treated with the higher dose of MGDF, but only to 0.175% in mice administered 25 micrograms/kg of MGDF. The marked increase in the pool of these immature megakaryocytes translated to a sustained elevation in the frequency of polyploid megakaryocytes (8N cells and greater). In contrast to the sustained increase in the frequency of polyploid cells, the level of polyploidization was downregulated on days 6 to 10, but normalized by day 14. We conclude that a single injection of MGDF is able to expand the megakaryocytic pool in a dose-dependent manner, which, with subsequent maturation, should lead to an increased rate of platelet production.