RESUMEN
The technique of inversion-ligation appendectomy is used by some surgeons to eliminate the risk of peritoneal contamination as the result of incidental appendectomy during an otherwise clean surgical procedure. In most cases, the intussuscepted appendix necroses and sloughs into the cecum after several days. We present the first report of the ultrasonographic appearance of a retained, inflamed appendix, which occurred in a neutropenic pediatric patient 15 months after inversion appendectomy. Our case illustrates the importance of a complete surgical history for the interpretation of abnormal sonographic findings of the cecum.
Asunto(s)
Apendicitis/diagnóstico por imagen , Apéndice/diagnóstico por imagen , Neutropenia/complicaciones , Apendicitis/etiología , Apendicitis/cirugía , Neoplasias Óseas/complicaciones , Neoplasias Óseas/secundario , Neoplasias Óseas/terapia , Niño , Humanos , Masculino , Neuroblastoma/complicaciones , Neuroblastoma/patología , Neuroblastoma/terapia , Complicaciones Posoperatorias , UltrasonografíaRESUMEN
Recombinant haemopoietic growth factors (HGFs) are an attractive adjunct to reduce morbidity from chemotherapy regimens and their use has become widespread in paediatric oncology. Although patients receiving HGFs often have faster haematological recovery after intensive chemotherapy, this does not always translate into meaningful clinical benefits. This article reviews the clinical effectiveness of HGFs in a variety of different contexts. Most published studies have used granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) as prophylaxis to ameliorate the subsequent neutropenia following intensive chemotherapy. These 2 agents have also been used to mobilise peripheral blood stem cells for autologous transplantation. HGFs specific for anaemia and thrombocytopenia are currently in paediatric clinical trials and it is hoped that the proper context and administration strategy can be found to make their use clinically effective. This article also reviews data on toxicity, specifically focusing on differences between various formulations of growth factors. HGFs are expensive, and cost-benefit analyses reviewed in this article give an important perspective on the financial aspects of paediatric cancer care. Because HGFs do not benefit every child receiving chemotherapy and overuse increases costs and may result in unnecessary adverse effects, evidence-based guidelines for their rational use in paediatric oncology are proposed.
Asunto(s)
Factores Estimulantes de Colonias/uso terapéutico , Neutropenia/tratamiento farmacológico , Anemia/inducido químicamente , Anemia/tratamiento farmacológico , Antineoplásicos/efectos adversos , Trasplante de Médula Ósea , Quimioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/economía , Niño , Factores Estimulantes de Colonias/efectos adversos , Factores Estimulantes de Colonias/economía , Análisis Costo-Beneficio , Trasplante de Células Madre Hematopoyéticas , Humanos , Interleucina-11/uso terapéutico , Neoplasias/complicaciones , Neoplasias/terapia , Neutropenia/inducido químicamente , Neutropenia/prevención & control , Trombocitopenia/inducido químicamente , Trombocitopenia/tratamiento farmacológico , Trombopoyetina/uso terapéuticoRESUMEN
There is a paucity of radiologic literature addressing neurologic emergencies in children receiving therapy for non-CNS primary malignancies. In the acute setting, many of these children present to local community hospitals. This pictorial is from a single institutional experience describing the spectrum of neurologic emergencies seen in children with non-CNS cancers. We hope to familiarize pediatric radiologists with these entities in order to expedite diagnosis, facilitate treatment, and minimize morbidity and mortality that may be associated with these complications.
Asunto(s)
Enfermedades del Sistema Nervioso Central/diagnóstico , Hemorragias Intracraneales/diagnóstico , Imagen por Resonancia Magnética , Neoplasias/complicaciones , Accidente Cerebrovascular/diagnóstico , Tomografía Computarizada por Rayos X , Adolescente , Adulto , Factores de Edad , Encefalopatías/diagnóstico , Encefalopatías/diagnóstico por imagen , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/secundario , Enfermedades del Sistema Nervioso Central/diagnóstico por imagen , Niño , Preescolar , Urgencias Médicas , Femenino , Hernia/diagnóstico , Hernia/diagnóstico por imagen , Humanos , Lactante , Hemorragias Intracraneales/diagnóstico por imagen , Hemorragias Intracraneales/etiología , Presión Intracraneal , Masculino , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/etiologíaRESUMEN
PURPOSE: To determine the frequency of CNS involvement at diagnosis of non-Hodgkin's lymphoma (NHL), to characterize its pattern of presentation, and to determine its prognostic significance. PATIENTS AND METHODS: We reviewed the records of 445 children (1975 through 1995) diagnosed with NHL (small noncleaved cell NHL/B-cell acute lymphoblastic leukemia [SNCC NHL/B-ALL], 201 patients; lymphoblastic, 113; large cell, 119; other, 12). Tumor burden was estimated by serum lactate dehydrogenase (LDH) measurement and reclassification of disease stage irrespective of CNS involvement (modified stage). RESULTS: Thirty-six of 445 children with newly diagnosed NHL had CNS involvement (lymphoma cells in the CSF [n = 23], cranial nerve palsy [n = 9], both features [n = 4]), representing 13%, 7%, and 1% of small noncleaved cell lymphoma, lymphoblastic lymphoma, and large-cell cases, respectively. By univariate analysis, CNS disease at diagnosis did not significantly impact event-free survival (P =. 095), whereas stage and LDH did; however, children with CNS disease at diagnosis were at 2.0 times greater risk of death than those without CNS disease at diagnosis. In a multivariate analysis, CNS disease was not significantly associated with either overall or event-free survival, whereas both serum LDH and stage influenced both overall and event-free survival. Among cases of SNCC NHL/B-ALL, CNS disease was significantly associated with event-free and overall survival (univariate analysis); however, in multivariate analysis, only LDH had independent prognostic significance. Elevated serum LDH or higher modified stage were associated with a trend toward poorer overall survival among children with CNS disease. CONCLUSION: A greater tumor burden at diagnosis adversely influences the treatment outcome of children with NHL and CNS disease at diagnosis, suggesting a need for ongoing improvement in both systemic and CNS-directed therapy.
Asunto(s)
Enfermedades del Sistema Nervioso Central/etiología , Enfermedades de los Nervios Craneales/etiología , Linfoma no Hodgkin/líquido cefalorraquídeo , Linfoma no Hodgkin/complicaciones , Adolescente , Antineoplásicos/administración & dosificación , Enfermedades del Sistema Nervioso Central/líquido cefalorraquídeo , Líquido Cefalorraquídeo/citología , Distribución de Chi-Cuadrado , Niño , Preescolar , Irradiación Craneana , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Inyecciones Intralesiones , L-Lactato Deshidrogenasa/sangre , Linfoma de Células B Grandes Difuso/líquido cefalorraquídeo , Linfoma de Células B Grandes Difuso/complicaciones , Linfoma de Células B Grandes Difuso/terapia , Linfoma no Hodgkin/terapia , Masculino , Análisis Multivariante , Oportunidad Relativa , Leucemia-Linfoma Linfoblástico de Células Precursoras/líquido cefalorraquídeo , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pronóstico , Recurrencia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Irinotecan (IRN), a topoisomerase I interactive agent, has significant antitumor activity in early Phase I studies in children with recurrent solid tumors. However, the disposition of IRN and its metabolites, SN-38 and APC, in children has not been reported. Children with solid tumors refractory to conventional therapy received IRN by a 1-h i.v. infusion at either 20, 24, or 29 mg/m2 daily for 5 consecutive days for 2 weeks. Serial blood samples were collected after doses 1 and 10 of the first course. IRN, SN-38, and APC lactone concentrations were determined by an isocratic high-performance liquid chromatography assay. A linear four-compartment model was fit simultaneously to the IRN, SN-38, and APC plasma concentration versus time data. Systemic clearance rate for IRN was 58.7 +/- 18.8 liters/h/m2 (mean +/- SD). The mean +/- SD ng/ml x h single-day lactone SN-38 area under the concentration-time curve (AUC(0-->6) was 90.9 +/- 96.4, 103.7 +/- 62.4, and 95.3 +/- 63.9 at IRN doses of 20, 24, and 29 mg/m2, respectively. The relative extent of IRN conversion to SN-38 and metabolism to APC measured after dose 1 were 0.49 +/- 0.33 and 0.29 +/- 0.17 (mean +/- SD). No statistically significant intrapatient difference was noted for SN-38 area under the concentration-time curve. Large interpatient variability in IRN and metabolite disposition was observed. The relative extent of conversion and the SN-38 systemic exposure achieved with this protracted schedule of administration were much greater than reported in adults or children receiving larger intermittent doses.
Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Camptotecina/análogos & derivados , Neoplasias/tratamiento farmacológico , Adolescente , Adulto , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/uso terapéutico , Área Bajo la Curva , Camptotecina/sangre , Camptotecina/farmacocinética , Camptotecina/uso terapéutico , Niño , Preescolar , Diarrea/inducido químicamente , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Humanos , Irinotecán , Recurrencia Local de Neoplasia , Neoplasias/patología , Neoplasias Complejas y Mixtas/tratamiento farmacológico , Neoplasias Complejas y Mixtas/patología , Neoplasias de los Tejidos Conjuntivo y Blando/tratamiento farmacológico , Neoplasias de los Tejidos Conjuntivo y Blando/patología , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/patología , Neutropenia/inducido químicamente , Factores de TiempoRESUMEN
We used contrast-enhanced three-dimensional magnetic resonance angiography (3D MRA) modified for pediatric use to evaluate the hepatic vasculature prior to partial hepatectomy in five consecutive children with hepatoblastoma. Modifications included non-breath-hold technique in four of the five children who were sedated. The single breath-hold technique was performed in only one awake child. Scan delay times were based on contrast infusion time rather than total infusion time. The hepatic artery, portal vein, and inferior vena cava were identified in all patients. MRA findings were confirmed by conventional angiography in one patient and by surgery in all. Contrast-enhanced 3D MRA is a useful and rapid technique prior to partial hepatectomy in patients with hepatoblastoma.
Asunto(s)
Hepatoblastoma/irrigación sanguínea , Neoplasias Hepáticas/irrigación sanguínea , Hígado/irrigación sanguínea , Angiografía por Resonancia Magnética/métodos , Niño , Preescolar , Femenino , Gadolinio , Hepatectomía , Hepatoblastoma/cirugía , Humanos , Aumento de la Imagen , Neoplasias Hepáticas/cirugía , MasculinoRESUMEN
PURPOSE: In a preclinical model of neuroblastoma, administration of irinotecan daily 5 days per week for 2 consecutive weeks ([qd x 5] x 2) resulted in greater antitumor activity than did a single 5-day course with the same total dose. We evaluated this protracted schedule in children. PATIENTS AND METHODS: Twenty-three children with refractory solid tumors were enrolled onto a phase I study. Cohorts received irinotecan by 1-hour intravenous infusion at 20, 24, or 29 mg/m(2) (qd x 5) x 2 every 21 days. RESULTS: The 23 children (median age, 14.1 years; median prior regimens, two) received 84 courses. Predominant diagnoses were neuroblastoma (n = 5), osteosarcoma (n = 5), and rhabdomyosarcoma (n = 4). The dose-limiting toxicity was grade 3/4 diarrhea and/or abdominal cramps in six of 12 patients treated at 24 mg/m(2), despite aggressive use of loperamide. The maximum-tolerated dose (MTD) on this schedule was 20 mg/m(2)/d. Five patients had partial responses and 16 had disease stabilization. On day 1, the median systemic exposure to SN-38 (the active metabolite of irinotecan) at the MTD was 106 ng-h/mL (range, 41 to 421 ng-h/mL). CONCLUSION: This protracted schedule is well tolerated in children. The absence of significant myelosuppression and encouraging clinical responses suggest compellingly that irinotecan be further evaluated in children using the (qd x 5) x 2 schedule, beginning at a dose of 20 mg/m(2). These results imply that data obtained from xenograft models can be effectively integrated into the design of clinical trials.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias/tratamiento farmacológico , Neuroblastoma/tratamiento farmacológico , Ensayo de Capsula Subrrenal , Adolescente , Adulto , Animales , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/farmacocinética , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/farmacocinética , Niño , Preescolar , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Evaluación de Medicamentos , Femenino , Humanos , Irinotecán , Masculino , Ratones , Resultado del TratamientoAsunto(s)
Abdomen Agudo/diagnóstico , Neoplasias/complicaciones , Abdomen Agudo/etiología , Adolescente , Niño , Preescolar , Diagnóstico por Imagen , Urgencias Médicas , Femenino , Enfermedades Urogenitales Femeninas/etiología , Enfermedades Gastrointestinales/etiología , Humanos , Masculino , Enfermedades Urogenitales Masculinas , PelvisRESUMEN
Clinical results with irinotecan (CPT-11 [Camptosar]) and other camptothecin derivatives in various cancers, although encouraging, have fallen short of the expectations predicted by preclinical models. One proposed explanation for this is that preclinical xenograft models do not predict for the sensitivity of human cancer. In this article, we describe the results of several studies suggesting that this explanation is incorrect. Instead, our results indicate that the discrepancy between clinical response rates and findings in preclinical models may be due to a failure to incorporate the principles learned from preclinical studies into the design of clinical trials. Our analysis suggests that if differences in host tolerance are taken into account, the xenograft models are quite accurate predictors of clinical response. Moreover, application of the principles derived from preclinical models to the design of clinical trials may significantly enhance clinical response rates. Thus, the camptothecin analogs provide a paradigm for better integrated, pharmacokinetically driven, preclinical and clinical development of new drugs.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Camptotecina/análogos & derivados , Ensayos Clínicos como Asunto , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Camptotecina/uso terapéutico , Niño , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Esquema de Medicación , Evaluación de Medicamentos , Femenino , Humanos , Irinotecán , Ratones , Ratones Endogámicos CBA , Modelos Biológicos , Proyectos de InvestigaciónRESUMEN
The predisposition to malignancy that is dominantly inherited in Li-Fraumeni syndrome is associated with germline mutations of the tumour suppressor gene p53. Although second malignant neoplasms have been described in children with p53 mutations, the synchronous occurrence of two embryologically different tumours in these children has not been reported. A 20 month old girl with failure to thrive and congenital heart defects was found to have unilateral adrenal masses which, at surgical removal, proved to be an adrenocortical carcinoma and a ganglioneuroblastoma. Further investigation showed a germline p53 mutation and Turner syndrome. It remains to be determined what effect the 45,X chromosomal complement may have on the expression of neoplasms seen in patients with p53 germline mutations.
Asunto(s)
Carcinoma Corticosuprarrenal/genética , Ganglioneuroblastoma/genética , Mutación de Línea Germinal , Proteína p53 Supresora de Tumor/genética , Síndrome de Turner/genética , Carcinoma Corticosuprarrenal/complicaciones , Carcinoma Corticosuprarrenal/patología , Femenino , Ganglioneuroblastoma/complicaciones , Ganglioneuroblastoma/patología , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Linaje , Tomografía Computarizada por Rayos X , Síndrome de Turner/complicacionesRESUMEN
PURPOSE: To examine the relationships among platelet counts, bone marrow megakaryocyte frequency, and circulating thrombopoietin (TPO) levels. PATIENTS AND METHODS: TPO levels in 17 children and one young adult with chronic or recurrent thrombocytopenia were measured by ELISA and megakaryocyte frequency was analyzed by light microscopy. Three groups of patients were studied: Group I patients had aplastic anemia and absent or decreased megakaryocytes; Group II patients had intermittent periods of chemotherapy-induced thrombocytopenia; and Group III patients had normal or increased megakaryocytes. Controls consisted of 77 healthy adults. RESULTS: Patients in Group I had markedly increased TPO levels compared to normal controls. Their levels were significantly different (p = 0.03) from those of patients in Group III. The latter had normal or only mildly increased TPO levels except for one patient with myelodysplastic syndrome. Patients in Group II had markedly elevated TPO levels. After their bone marrow and platelet counts recovered from chemotherapy, their TPO levels decreased. In all three groups, a transient increase in platelet count (e.g., after platelet transfusion or anti-D immune globulin therapy) was associated with a moderate decrease in TPO. CONCLUSIONS: From this study, three conclusions can be made: 1) TPO levels are inversely related to megakaryocyte frequency; 2) platelet counts have a modest influence on TPO level; and 3) TPO levels may have clinical utility in diagnosis and management and further our understanding of the pathobiology of the disorders that cause thrombocytopenia.
Asunto(s)
Megacariocitos , Trombocitopenia/sangre , Trombopoyetina/sangre , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Recuento de PlaquetasRESUMEN
PURPOSE: To compare the relative hematopoietic protective effects of recombinant human interleukin-1alpha (rhuIL-1alpha), recombinant human granulocyte macrophage colony-stimulating factor (rhuGM-CSF), and PIXY321, a genetically engineered fusion protein combining interleukin-3 and rhuGM-CSF, in children with refractory solid tumors after treatment with ifosfamide, carboplatin, and etoposide (ICE). PATIENTS AND METHODS: A total of 53 children who had not responded to at least one earlier chemotherapy regimen were enrolled on consecutive trials of ICE chemotherapy alone (n = 14) or with rhuGM-CSF (n = 8), rhuIL-1alpha (n = 10), or PIXY321 (n = 21). The relative hematopoietic effects of these three cytokines were compared retrospectively to each other and to values for patients who received ICE alone. Because one cannot assume that hematopoietic toxicity and response to a given cytokine are independent of the course of chemotherapy, the analysis was restricted to the first treatment course. RESULTS: In this retrospective comparison, 1000 microg/m2/day of rhuGM-CSF reduced the median duration of grade 4 neutropenia (<500/microL) from a median of 17 days (range 3 to 34) in children who received ICE alone to 9 days (range 5 to 11, p = 0.003); it appeared to have a beneficial effect on severe thrombocytopenia (<20,000/microL), reducing the median duration from 4.5 days with ICE alone to 3 days (p = 0.08) and the number of platelet transfusions from a median of 5.75 transfusions (range 0 to 13) to 0 in these two cohorts. No significant improvement in these measures was seen with rhuIL-1alpha or PIXY321. CONCLUSIONS: This analysis suggests that 1000 microg/m2/day of rhuGM-CSF has clinically significant effects on platelet recovery and more effectively ameliorates thrombocytopenia and neutropenia than either rhuIL-1alpha or PIXY321 in the context of ICE chemotherapy. Further dose-intensification will require a combination of cytokines; the optimal dose and combination of these agents awaits further study.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Citocinas/uso terapéutico , Neoplasias/tratamiento farmacológico , Adolescente , Adulto , Plaquetas/efectos de los fármacos , Niño , Preescolar , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Granulocitos/efectos de los fármacos , Humanos , Lactante , Recién Nacido , Interleucina-1/uso terapéutico , Masculino , Neoplasias/inmunología , Proteínas Recombinantes , Recurrencia , Estudios RetrospectivosRESUMEN
BACKGROUND: Standard therapy for pediatric nonrhabdomyosarcoma soft tissue sarcomas (PNRSTS) consists of surgical resection with or without radiotherapy. The role of chemotherapy in the treatment of these tumors has not yet been defined. We investigated the efficacy and toxicity of an ifosfamide-based regimen in controlling disease in children with high-risk PNRSTS. PATIENTS AND METHODS: Between January 1992 and June 1994 at St. Jude Children's Research Hospital, we treated 11 children and young adults with PNRSTS who were at high risk for treatment failure by using a combined modality regimen that comprised aggressive surgery, radiotherapy, and chemotherapy including vincristine, ifosfamide, and doxorubicin (VID). Nine of these patients had grade 3 disease and one had grade 2 tumor; due to insufficient tissue, the disease grade of the remaining patient could not be established. Metastases were present at diagnosis in 2 children. RESULTS: Therapy was generally well tolerated, with minimal morbidity and no mortality. The most common toxicity was grade 4 neutropenia, which occurred in 51% of evaluable courses. Among 4 patients evaluable for response to chemotherapy alone, 1 child attained a partial response and 3 had stable disease. One child had a response to chemotherapy and concurrent irradiation. At a median follow-up of 30 months, 10 of 11 patients are alive; 8 of 11 patients are alive without evidence of disease. CONCLUSION: Aggressive multimodality therapy for PNRSTS is well tolerated, despite frequent and profound neutropenia. Although adjuvant chemotherapy for this group of cancers remains unproved, the rate of tumor control achieved in this pilot study encourages further investigation in a multi-institutional setting.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia Adyuvante , Niño , Preescolar , Terapia Combinada , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Humanos , Ifosfamida/administración & dosificación , Masculino , Neutropenia/inducido químicamente , Proyectos Piloto , Factores de Riesgo , Sarcoma/patología , Sarcoma/radioterapia , Sarcoma/cirugía , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/radioterapia , Neoplasias de los Tejidos Blandos/cirugía , Vincristina/administración & dosificaciónRESUMEN
UNLABELLED: A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor and interleukin-3 (PIXY321), showed some promise in early adult trials. However, studies for pediatric patients are limited, and there are no systematic data on the pharmacokinetics of PIXY321 given over prolonged periods at current dosage levels. PURPOSE: To determine the safety, clinical effects and plasma concentrations of increasing doses of PIXY321 in children treated with myelosuppressive chemotherapy. METHODS: A total of 39 children with relapsed or high-risk solid tumors were enrolled in this phase I/II study. PIXY321 was administered once or twice daily by subcutaneous injection in total doses of 500 to 1000 microg/m2 per day for 14 days after each course of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Pharmacokinetic studies were performed on day 1 of the first course in 33 patients and repeated on day 14 in 13 patients (once-daily schedule only). RESULTS: Although mild local skin reactions and fever were frequent, no dose-limiting toxicity was identified at the maximum dose studied (1000 microg/m2 per day). There were no statistically significant differences in chemotherapy-induced hematologic toxicity with increasing doses of PIXY321 or with twice-daily vs once-daily dosing. On day 1, the median PIXY321 clearance was 657 ml/min per m2 (range 77 1804 ml/min per m2) and the median half-life was 3.7 h (range 2.1-20.8 h). On day 14, clearance increased in all patients studied (median increase 63%), with a corresponding decrease in the median 12-h concentration (from 1.2 to 0.25 ng/ml). Maximum concentrations were < 1 ng/ml in 81% of patients, and only two patients had maximum plasma concentrations equivalent to those required for consistent activity in vitro. CONCLUSIONS: The recombinant fusion protein PIXY321 proved safe in children treated with myelosuppressive ICE chemotherapy but had no demonstrable clinical benefits. The pharmacokinetic studies suggest that the observed lack of hematologic benefit may be explained by low plasma concentrations resulting from increased clearance with prolonged administration. Moreover, the significant increase in PIXY321 systemic clearance in the absence of increased circulating myeloid cells suggests that the upregulation of either extravascular compartment hematopoietic progenitor cells or nonhematopoietic cells may play an important role in controlling circulating concentrations of this unique cytokine. These findings highlight the importance of a thorough assessment of the systemic disposition of cytokines when determining the dose and schedule necessary to achieve clinical activity in patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacocinética , Interleucina-3/administración & dosificación , Interleucina-3/farmacocinética , Neoplasias/tratamiento farmacológico , Adolescente , Adulto , Niño , Preescolar , Cisplatino/administración & dosificación , Esquema de Medicación , Etopósido/administración & dosificación , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/efectos adversos , Semivida , Humanos , Ifosfamida/administración & dosificación , Lactante , Interleucina-3/efectos adversos , Masculino , Tasa de Depuración Metabólica , Neoplasias/metabolismo , Neutropenia/inducido químicamente , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacocinéticaRESUMEN
PURPOSE: The outcome for children with advanced-stage rhabdomyosarcoma remains poor with contemporary treatment regimens. Evaluation of new drugs is important to improve clinical outcome. Because methotrexate has shown promising activity in the treatment of patients with recurrent rhabdomyosarcoma, we conducted a phase II trial in untreated children with advanced-stage disease to evaluate the efficacy and safety of this agent. PATIENTS AND METHODS: Fifteen patients received 1 to 4 courses of high-dose methotrexate (HDMTX, 12 g/m2). Patients then received standard multiagent chemotherapy (vincristine, dactinomycin, cyclophosphamide, ifosfamide, mesna) with cytokine support and local radiotherapy. Patients who responded to HDMTX received four additional courses of this drug during continuation therapy. RESULTS: Twelve patients were evaluable for response after 2 or more courses of HDMTX; 4 achieved a partial response (33.3%). After administration of standard chemotherapy and radiation, the estimated 2-year progression-free survival for all patients was 56% (SD 15%). The drug was well-tolerated and the most common side effects included mucositis, transient elevation of transaminases, and neutropenia. The four patients who received additional courses of HDMTX during continuation therapy had limited toxicity which included mucositis, anemia, and thrombocytopenia. CONCLUSIONS: About one-third of children with previously untreated advanced-stage rhabdomyosarcoma responded to HDMTX. Its different mechanism of action and non-overlapping toxicity with other agents make HDMTX an attractive candidate for incorporation into front-line treatment regimens for rhabdomyosarcoma.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Metotrexato/uso terapéutico , Rabdomiosarcoma/tratamiento farmacológico , Adolescente , Antimetabolitos Antineoplásicos/efectos adversos , Niño , Preescolar , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Metotrexato/efectos adversos , Estadificación de Neoplasias , Radiografía , Rabdomiosarcoma/diagnóstico por imagen , Rabdomiosarcoma/mortalidad , Rabdomiosarcoma/patología , Medición de Riesgo , Tasa de SupervivenciaRESUMEN
BACKGROUND: Neuroblastoma is the most common extracranial solid tumor among pediatric patients, and orbital metastatic disease is not uncommon in these children. Physical signs as a consequence of orbital metastases, such as proptosis and periorbital ecchymosis, frequently are encountered. However, subsequent blindness is rare. METHODS: A retrospective study was conducted to determine the incidence, related physical findings, treatment, and outcome of children who developed visual loss during treatment for neuroblastoma. Medical records for a 24-year period (1971-1994) were reviewed to identify these patients. The charts, diagnostic imaging studies, and autopsy material of these patients were reviewed. RESULTS: Of the 450 patients treated for neuroblastoma at the study institution during this period, 47 presented with abnormalities in physical examination of the eye. Eight of these 47 patients and 7 others developed visual loss in at least 1 eye during the first week after diagnosis (n = 5), during primary therapy (n = 6), at recurrence (n 2), or after completion of therapy (n = 2). In ten patients the visual loss was a direct consequence of the primary disease process, whereas a direct relationship between loss of vision and neuroblastoma could not be identified in the remaining five patients. Proptosis and periorbital ecchymosis were the most common associated physical findings. Although ten patients received steroids and eight received radiation, visual loss could not be prevented or reversed in these patients. CONCLUSIONS: Early initiation of effective, multiagent chemotherapy remains the primary approach for the treatment of neuroblastoma and its ophthalmologic complications. Radiation therapy and steroids may have benefit but failed to show good effect in this series. The prevention and treatment of blindness is probably most relevant in infants and children age < 2 years because they have the best chance for cure.
Asunto(s)
Ceguera/etiología , Neoplasias del Ojo/complicaciones , Neuroblastoma/complicaciones , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Preescolar , Neoplasias del Ojo/patología , Neoplasias del Ojo/terapia , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Neuroblastoma/patología , Neuroblastoma/terapia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Interleukin-1 alpha (IL-1 alpha) is myeloprotective in a variety of animal models of cancer chemotherapy and is similarly beneficial in adults treated with carboplatin, 5-fluorouracil, and after autologous bone marrow transplantation. There are no trials of this agent in children. Our purpose was to determine the toxicity and maximum tolerated dose (MTD) of recombinant human interleukin-1 alpha (rhuIL-1 alpha) in children with solid tumors receiving intensive cancer chemotherapy and to evaluate its myelo-protective effects. Cohorts of patients received rhuIL-1 alpha in doses of 0.1-10 micrograms/m2 for 4 days by subcutaneous injection prior to ICF chemotherapy (ifosfamide, 2 g/m2/day x 3, carboplatin targeted to an area under the curve of 8 mg/ml x min on day 1, and etoposide, 100 mg/m2 daily for 3 days). Patients were randomized to receive rhuIL-1 alpha before either the first or second course of therapy. After the MTD of rhuIL-1 alpha was determined an additional group of patients received rhuIL-1 alpha at the dose immediately following ICE chemotherapy. The dose-limiting toxicities of rhuIL-1 alpha in the 27 children tested comprised systemic symptoms of fever, chills, headache, and hypotension. The MTD was 3 micrograms/m2/day. There were no differences in chemotherapy-induced hematologic toxicity with increasing doses of rhuIL-1 alpha or in comparisons before or after ICE chemotherapy. Although rhuIL-1 alpha can be given safely to children receiving myelosuppressive chemotherapy, clinical usefulness would mandate a significant hematopoietic benefit in view of the trouble some side effects identified. We saw no evidence of a hematoprotective effect.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Enfermedades de la Médula Ósea/prevención & control , Médula Ósea/efectos de los fármacos , Interleucina-1/administración & dosificación , Interleucina-1/efectos adversos , Neoplasias/tratamiento farmacológico , Adolescente , Adulto , Plaquetas/efectos de los fármacos , Enfermedades de la Médula Ósea/inducido químicamente , Carboplatino/efectos adversos , Niño , Preescolar , Esquema de Medicación , Etopósido/efectos adversos , Femenino , Granulocitos/efectos de los fármacos , Humanos , Ifosfamida/efectos adversos , Lactante , Inyecciones Subcutáneas , Masculino , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversosRESUMEN
We report an unusual case of acute lymphoblastic leukemia (ALL) that presented as right lower quadrant pain in a 17-year-old boy. Ultrasonographic findings were consistent with typhlitis. The clinical and imaging symptoms resolved upon treatment with antibiotics and conservative care, only to recur after initiation of chemotherapy. Familiarity with the clinical presentation and imaging findings of typhlitis is important for its correct diagnosis and management.
Asunto(s)
Enfermedades del Ciego/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Adolescente , Enfermedades del Ciego/diagnóstico , Humanos , Inflamación , Masculino , Neutropenia/etiologíaRESUMEN
BACKGROUND: The impact of overt testicular disease on survival was assessed among patients treated at the study institution for childhood acute lymphoblastic leukemia (ALL) over a 15-year period. To the authors' knowledge, the frequency of overt testicular involvement at diagnosis of ALL and its impact on treatment outcome have not been reported previously. METHODS: The medical records of all 651 boys with ALL enrolled on St. Jude Total Therapy Studies X-XIIIA (May 1979 to December 1993) were reviewed to determine the frequency of overt testicular involvement at diagnosis. The log rank test and sequential Cox regression analyses, adjusted for known adverse features, were used to compare event free and overall survival for patients with and without testicular leukemia. A matched-pairs analysis was then conducted for both outcome measures. RESULTS: Thirteen of the 651 male patients (1.9%) presented with overt testicular leukemia. Compared with the other patients, these 13 boys had a significantly higher frequency of infant or adolescent age at diagnosis, hyperleukocytosis, splenomegaly, and mediastinal mass; a poorer 5-year event free survival (38% [95% confidence interval (CI), 15.4-61.4%] vs. 58% [95% CI, 53.6-61.7%], P = 0.06, log rank test); and a significantly poorer 5-year overall survival (37% [95% CI, 14-60.4%] vs. 75% [95% CI, 71.3-78.4%], P = 0.002). The difference in overall, but not event free, survival was supported by sequential Cox regression analyses and by the matched-pairs analysis (P = 0.04). CONCLUSIONS: Overt testicular involvement with leukemia at diagnosis was associated with an adverse survival in boys with ALL. Testicular irradiation may not be necessary in those patients who present with overt testicular involvement. This finding merits prospective evaluation in a larger sample of similarly treated patients.