RESUMEN
In an attempt to maximize the therapeutic index and to overcome the large variations in 1-beta-D-arabinofuranosylcytosine (ara-C) plasma levels and host toxicities that have been documented with standard HDara-C regimens (3 g/m2 over 3 h every 12 h x 8 or x12 doses), pediatric patients with acute lymphocytic leukemia or lymphoma in relapse were treated with a regimen of loading bolus followed immediately by continuous infusion of ara-C. In addition, patients received a single dose of etoposide (VP-16, 1 g/m2) prior to the ara-C administration. In four patients, total body irradiation was administered as part of a bone marrow transplantation preparative regimen after the ara-C administration. The regimen was designed to attain and maintain plasma steady-state concentrations (Css) of ara-C three to four times the Km2 value of ara-C, which was determined with purified deoxycytidine kinase from the patients' tumor cells prior to treatment. Eight patients age 0.75 to 16 years with relapsed acute lymphocytic leukemia (three patients) or lymphoma (five patients, one with bone marrow involvement), received a test dose of 3 g/m2 ara-C injected over 1 h, and the plasma kinetics were determined. The peak plasma ara-C concentration of ara-C ranged from 57 to 199 microM with an average concentration of 103 +/- 49 microM; the half-lives of distribution (t1/2, alpha) and elimination (t1/2, beta) averaged 17 +/- 7 min and 4.04 +/- 3.1 h, respectively. The mean area under the plasma concentration time curve from 0 to 12 h (AUC0----12 h) of ara-C averaged 386.8 +/- 328.0 microMh (mean, +/- SD, n = 8). The peak concentration of uracil arabinoside averaged 501 +/- 123 microM, and it was eliminated with a t1/2, el of 2.3 +/- 0.6 h. The patients then received an individualized loading bolus (mean = 0.5 g/m2) followed by a continuous infusion regimen of ara-C (mean = 130 mg/m2/h), to achieve a Css in the range of 20 to 35 microM. The obtained plasma Css were similar to the desired ones, averaging in variation 10.7% +/- 8.2%. The percentage of variation of correlation of the AUC following the loading bolus plus the continuous infusion from 12 to 72 h was only 12.4% (mean = 2158 microMh, n = 8), whereas the percentage of variation of correlation of the AUC after the test dose of ara-C in the same patients was 84.8%.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Citarabina/farmacocinética , Leucemia/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Adolescente , Niño , Preescolar , Citarabina/administración & dosificación , Citarabina/efectos adversos , Desoxicitidina Quinasa/análisis , Humanos , LactanteRESUMEN
Because of the synergy seen in adult trials when 5-fluorouracil is combined with leucovorin, we initiated a Phase I trial of this combination in children's refractory cancer. Leucovorin, an equal mixture of the (6R,S)-diastereoisomers, was administered p.o. for 6 consecutive days as 4 equal doses at 0, 1, 2, and 3 h totaling 500 mg/m2/day. 5-Fluorouracil was given daily on days 2 to 6 as an i.v. bolus immediately following the last dose of leucovorin. The leucovorin dose was held constant while the 5-fluorouracil dose was escalated in cohorts of patients from 300 mg/m2/day to its maximally tolerated dose. Thirty-five patients (19 with acute leukemia and 16 with solid tumors) were evaluable for toxicity. The maximally tolerated dose of FUra was 450 mg/m2/day for 5 treatments for patients with solid tumors and 650 mg/m2/day for 5 treatments for the children with leukemia. The dose-limiting toxicities were myelosuppression and stomatitis. Other side effects included transient, mild elevations of serum transaminases, mild nausea, vomiting, and diarrhea. The pharmacokinetics of high-dose p.o. leucovorin was studied in 23 children. There was considerable interpatient variability in the plasma concentrations of total bioactive folates (TBAF), (6S)-leucovorin, and (6S)-5-methyltetrahydrofolic acid. The maximum plasma concentration (Cmax) of TBAF was 821 +/- 97 (SE) nM, occurring at a median of 8 h; the Cmax of (6S)-leucovorin was 77 +/- 11 nM, occurring at 4 h. The TBAF concentration fell to 146 +/- 42 nM by 24 h. (6S)-5-Methyltetrahydrofolic acid accounted for 90 +/- 7% of the TBAF at the Cmax. The plasma concentration of (6R)-leucovorin, the unnatural isomer, was equal to that of TBAF. Thus, p.o. leucovorin reduced the 5-fold excess of (6R)-leucovorin over TBAF seen after i.v. doses. The relative amounts of the three major plasma species were approximately the same as in adults, even though the Cmax of each compound was lower.
Asunto(s)
Fluorouracilo/uso terapéutico , Leucovorina/uso terapéutico , Neoplasias/tratamiento farmacológico , Administración Oral , Adolescente , Adulto , Niño , Preescolar , Esquema de Medicación , Evaluación de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Fluorouracilo/toxicidad , Humanos , Lactante , Leucovorina/farmacocinética , Leucovorina/toxicidad , Masculino , Neoplasias/metabolismo , Estereoisomerismo , Tetrahidrofolatos/metabolismo , Tetrahidrofolatos/toxicidadRESUMEN
PURPOSE: The Children's Cancer Group (CCG) undertook a phase I study (CCG-0922) to determine a tolerable dose of idarubicin given with fludarabine and cytarabine in children with relapsed or refractory leukemia. The phase I study was extended to a limited phase II study to assess the activity of this combination in children with acute myelogenous leukemia (AML). PATIENTS AND METHODS: This was a multiinstitutional study within the CCG. Eleven patients were entered onto the phase I study: seven with AML, three with acute lymphoblastic leukemia (ALL), and one with chronic myelogenous leukemia (CML). The maximal-tolerated dose (MTD) of fludarabine and cytarabine determined in a previous study was a fludarabine loading dose (LD) of 10.5 mg/m2 followed by a continuous infusion (CI) of 30.5 mg/m2/24 hours for 48 hours, followed by cytarabine LD 390 mg/m2, then CI 101 mg/m2/h for 72 hours. Idarubicin was given at three dose levels: 6, 9, and 12 mg/m2 intravenously (I.V.) on days 0, 1, and 2. The phase II portion of the trial included 10 additional patients with relapsed or refractory AML. RESULTS: A dose of idarubicin 12 mg/m2/d for 3 days given in combination with fludarabine and cytarabine was tolerated. The major toxicity encountered was hematologic. Nonhematologic toxicities included transaminase elevations, hyperbilirubinemia, and infections. Eight of 10 patients with AML in the phase II portion (12 mg/m2 idarubicin) achieved a complete remission (CR). CONCLUSION: This combination is active in patients with relapsed or refractory AML. The major toxicity encountered is hematologic. This regimen may be useful therapy for AML and should be compared with standard induction therapy in children with newly diagnosed AML.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia/tratamiento farmacológico , Enfermedad Aguda , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Preescolar , Citarabina/administración & dosificación , Citarabina/efectos adversos , Femenino , Humanos , Idarrubicina/administración & dosificación , Idarrubicina/efectos adversos , Lactante , Infusiones Intravenosas , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/análogos & derivadosRESUMEN
The sequential administration of fludarabine followed by cytosine arabinoside (ara-C) has demonstrated significant synergistic effects against the CEM human leukemic cell line. This in vitro synergism was investigated in a Phase I trial in pediatric patients with relapsed acute leukemia. The optimum concentrations of 9-beta-D-arabinofuranosyl 2-fluoroadenine and ara-C necessary to achieve significant drug synergism from in vitro studies were between 10 and 20 microM. Fludarabine was infused at a dose to attain a target plasma concentration of 10 microM for 48 h, followed by a continuous infusion of escalated ara-C doses to maintain plasma ara-C concentrations of 10, 12.5, 15, or 17.5 microM for 72 h. Thirteen patients with acute lymphocytic leukemia and 18 with acute myelocytic leukemia were entered into the study, 30 of whom were clinically evaluable for toxicity. Pharmacokinetic and pharmacodynamic studies were performed on specimens from 20 patients. The optimal 9-beta-D-arabinofuranosyl 2-fluoroadenine and ara-C concentrations in plasma were easily achieved after continuous infusion regimens of both drugs. Cellular ara-CTP is augmented 5-8-fold in leukemic cells from patients receiving fludarabine phosphate treatment followed by ara-C. The maximum tolerated plasma concentrations for this combination regimen was 10 microM fludarabine for 48 h followed by 72 h of 15 microM ara-C, which were achieved at dose level 3. A significant number of responses were also seen. Nine of 18 evaluable patients (50%) with acute myelocytic leukemia achieved complete or partial responses, and 3 of 9 evaluable patients with acute lymphocytic leukemia achieved complete or partial responses. Fludarabine and ara-C successfully eradicated bone marrow disease in 16 of 27 patients (59%), 23 patients of which had been treated previously with high-dose ara-C. These results verified the synergistic effect fludarabine exhibited in augmenting ara-CTP concentrations in patients' leukemic blasts, thus improving the clinical response in relapsed pediatric leukemias.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Citarabina/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Vidarabina/análogos & derivados , Adolescente , Adulto , Trifosfato de Arabinofuranosil Citosina/farmacocinética , Niño , Preescolar , Citarabina/efectos adversos , Citarabina/farmacocinética , Humanos , Lactante , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/farmacocinéticaRESUMEN
The antitumor activity of topotecan administered as a 72-h continuous i.v. infusion was evaluated in children with refractory neuroblastoma and sarcomas of soft tissue and bone. We also attempted to increase the dose intensity of topotecan by including an intrapatient dose escalation in the trial design. Ninety-three children (85 eligible and evaluable for response) with recurrent or refractory neuroblastoma, osteosarcoma, Ewing's sarcoma/peripheral neuroectodermal tumor, rhabdomyosarcoma, or other soft-tissue sarcomas received topotecan administered as a 72-h i.v. infusion every 21 days. The initial dose was 1.0 mg/m2/day, with subsequent intrapatient dose escalation to 1.3 mg/m2/day for those patients who did not experience dose-limiting toxicity after their first cycle of topotecan. There was one complete response in a patient with neuroblastoma (n = 26) and one partial response in a patient with Ewing's sarcoma/peripheral neuroectodermal tumor (n = 25). No complete or partial responses were observed in 17 patients with osteosarcoma, 15 patients with rhabdomyosarcoma, or 2 patients with other soft-tissue sarcomas; however, 8 patients had prolonged (15-48 weeks) stable disease while receiving topotecan. Topotecan was well tolerated. The most commonly observed toxicities were myelosuppression (dose-limiting) and nausea and vomiting. Intrapatient dose escalations were performed in 68% of the patients who received more than one cycle of topotecan, and 1.3 mg/m2/day was tolerated by 79% of the patients who received the higher dose and were evaluable for hematological toxicity. In conclusion, topotecan administered as a 72-h continuous infusion every 21 days is inactive (objective response rate, < 20%) in children with refractory or recurrent neuroblastoma and sarcomas of soft tissue or bone.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Topotecan/uso terapéutico , Adolescente , Adulto , Antineoplásicos/efectos adversos , Neoplasias Óseas/tratamiento farmacológico , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Lactante , Infusiones Intravenosas , Masculino , Neuroblastoma/tratamiento farmacológico , Tumores Neuroectodérmicos Periféricos Primitivos/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Rabdomiosarcoma/tratamiento farmacológico , Sarcoma de Ewing/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Topotecan/efectos adversosRESUMEN
Pleuropulmonary blastoma (PPB) is a rare and highly aggressive tumor in children and is distinct from ordinary pulmonary blastoma or carcinosarcoma of the lung. This report describes the phenotypical characteristics of seven PPB tumors. The patients were five females and two males, all diagnosed in their third year of life. Five tumors were located within the pulmonary parenchyma, one in the mediastinum, and one involved both lung and mediastinum. Two children are alive and five have died of disease. Histologically, PPB showed a diffuse proliferation of undifferentiated blastemal cells with additional areas of chondroblastic foci (six tumors), storiform pattern (three tumors), alveolar pattern (one tumor), and lipoblastic differentiation (one tumor). Immunohistochemically, tumor cells were positive for vimentin in five of five tumors, histiocytic markers (A1AT and A1ACT, four of six cases; lysozyme, two of six; KP1, three of five) and myogenic markers (desmin, four of six; HHF35, five of six). S-100 was expressed in the chondroblastic areas (in three of four cases). Epithelial membrane antigen and cytokeratin were positive only in epithelial or mesothelial cells entrapped in the tumor. Ultrastructural examination demonstrated a similarity between the proliferating cells in PPB and those seen in malignant fibrous histiocytoma; that is, PPB tumor was mainly composed of a mixture of primitive, fibroblastic, myofibroblastic, histiocytoid, and fibrohistiocytoid cells. Also identified were cells with rhabdomyoblastic differentiation (two tumors) showing thick and thin filaments with Z-discs. In conclusion, PPB showed phenotypical diversity and was composed of MFH-type cells and cells with more specific mesenchymal differentiation.
Asunto(s)
Neoplasias Pulmonares/patología , Neoplasias Pleurales/patología , Preescolar , Femenino , Humanos , Inmunohistoquímica/métodos , Neoplasias Pulmonares/metabolismo , Masculino , Microscopía Electrónica , Neoplasias Pleurales/metabolismo , Coloración y EtiquetadoRESUMEN
Pathologic features of eight cases of undifferentiated (embryonal) sarcoma of the liver (USL) in childhood were studied. Light microscopic examination showed a diffuse growth of spindle cells with occasional polygonal cells and multinucleated giant cells and also revealed focal areas of storiform pattern in four tumors, cambium layer formation in one tumor, and alveolar arrangement in one tumor. Immunohistochemical study showed positive staining of proliferating cells for suggestive histiocytic markers (A1AT in 6/6, A1ACT in 5/6, lysozyme in 4/6, and KP1 in 4/6) and for muscle markers (desmin in 4/6 and HHF35 in 3/6). Ultrastructural examination demonstrated that the individual tumors were composed of a mixture of cells having fibroblastic, histiocytoid, fibrohistiocytoid, myofibroblastic, and undifferentiated (primitive mesenchymal) morphologies. Also identified were cells with definite myoblastic morphology in three tumors: leiomyoblastic in one and rhabdomyoblastic in two. In conclusion, the tumor cells in USL show phenotypical diversity comparable to those of malignant fibrous histiocytoma with or without additional rhabdomyosarcomatous or leiomyosarcomatous differentiation.
Asunto(s)
Transformación Celular Neoplásica/patología , Neoplasias Hepáticas/patología , Mesenquimoma/patología , Actinas/metabolismo , Desmina/metabolismo , Femenino , Humanos , Inmunohistoquímica , Queratinas/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/ultraestructura , Masculino , Glicoproteínas de Membrana/metabolismo , Mesenquimoma/metabolismo , Mesenquimoma/ultraestructura , Microscopía Electrónica , Mucina-1 , Muramidasa/metabolismo , Proteínas S100/metabolismo , Vimentina/metabolismo , alfa 1-Antiquimotripsina/metabolismo , alfa 1-Antitripsina/metabolismo , alfa-Fetoproteínas/metabolismoRESUMEN
OBJECTIVE: To describe platinum-based chemotherapy combined with local treatment modalities as an alternative to external beam radiotherapy for intraocular retinoblastoma. DESIGN: Platinum levels were measured by atomic absorption analysis in the tumors of 2 patients with retinoblastoma given carboplatin 5 or 2.5 hours before enucleation. Platinum levels in heated vs nonheated Greene melanoma tumors in rabbits were compared. A retrospective review of 172 affected eyes in 136 consecutive patients treated for retinoblastoma between January 1990 and December 1995 was performed. From 1990 to 1992, all treatable eyes initially received systemic carboplatin, 560 mg/m2, followed by 15 to 30 minutes of continuous diode laser hyperthermia (thermochemotherapy). Since 1992, larger tumors were treated initially with 3 monthly cycles of carboplatin, etoposide, and vincristine sulfate to reduce tumor volume (chemoreduction) followed by sequential aggressive local therapy (SALT) during examinations under anesthesia every 2 to 3 weeks. OUTCOME MEASURE: Treatment success was defined as eradication of tumor without enucleation or external beam radiotherapy. RESULTS: Significant therapeutic platinum levels were measured in the human tumors 2.5 and 5 hours after carboplatin administration. Increasing the temperature by 9 degrees C for 15 minutes doubled platinum levels in the rabbit model. Of the 38 eyes with Reese-Ellsworth group 1 through 5b tumors that were treated primarily with thermochemotherapy, all 24 eyes with group 1 and 2 tumors were treated successfully and two of the 4 eyes with group 3 tumors and all 10 eyes with group 5b tumors were treated unsuccessfully. Chemoreduction plus SALT was the primary treatment in 35 eyes and was successful in all 10 eyes with group 1 through 4 tumors and unsuccessful in all 7 eyes with extensive subretinal seeding and all 18 eyes with group 5b tumors with vitreous seeding. Seventy patients received carboplatin or carboplatin, vincristine, and etoposide, with myelosuppression, occasionally associated with bacteremia, being the main side effect. Transfusions were required in 15% of patients. Radiation retinopathy occurred in all 6 eyes treated with iodine 125 plaques. CONCLUSIONS: Thermochemotherapy is successful primary treatment for Reese-Ellsworth group 1 and 2 retinoblastomas. For larger tumors in the absence of vitreous or extensive subretinal seeding, 3 cycles of chemoreduction followed by SALT eradicates residual viable tumor. Chemoreduction plus SALT was not successful in eyes with diffuse vitreous or extensive subretinal seeding. Prior chemotherapy increases the risk for radiation retinopathy following 125I plaque therapy. External beam radiotherapy can safely be avoided in the primary treatment of Reese-Ellsworth groups 1 through 4 nondispersed retinoblastoma.
Asunto(s)
Antineoplásicos/uso terapéutico , Carboplatino/uso terapéutico , Neoplasias del Ojo/terapia , Hipertermia Inducida , Retinoblastoma/terapia , Animales , Cámara Anterior/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Braquiterapia , Carboplatino/análisis , Terapia Combinada , Crioterapia , Aductos de ADN/análisis , ADN de Neoplasias/análisis , Etopósido/administración & dosificación , Enucleación del Ojo , Neoplasias del Ojo/química , Humanos , Radioisótopos de Yodo/uso terapéutico , Coagulación con Láser , Melanoma/química , Melanoma/terapia , Conejos , Retinoblastoma/química , Vincristina/administración & dosificaciónRESUMEN
Dihydrofolate reductase, purified to homogeneity from a subline of L1210 murine leukemia cells resistant to 10(-6) M Methotrexate, was resolved into two principal forms (1 and 2) by isoelectric focusing. These forms had pI values of 7.4 and 8.2, respectively; both stained for protein and catalytic activity. Form 1 was a single component, comprising ca. 10% of the total protein, but multiple components of 2 were observed by narrowing the pH range in the electrophoretic procedure. Urea-denatured enzyme exhibited two bands of approximately equal intensity upon isoelectric focusing. These results were interpreted to mean that the enzyme consists of a set of conformationally different forms, arising from two primary structures. Inhibition of the native enzyme by Methotrexate was polyphasic, and appreciable activity remained when the drug was present at an equimolar concentration. Various agents (KCl, H+, urea, and SH-modifiers), known to "activate" dihydrofolate reductases, produced a monophasic, stoichiometric inhibition. Activating agents appear to induce a more open (and labile) conformation of the enzyme. This leads to increased affinity for MTX accompanied, in some instances, by increased catalytic activity.
Asunto(s)
Leucemia L1210/enzimología , Metotrexato/farmacología , Tetrahidrofolato Deshidrogenasa/metabolismo , Animales , Ácido Ditionitrobenzoico/farmacología , Electroforesis en Gel de Agar , Activación Enzimática/efectos de los fármacos , Antagonistas del Ácido Fólico , Yodoacetamida/farmacología , Isoenzimas/metabolismo , Ratones , Cloruro de Potasio/farmacología , Conformación Proteica , Ácido Tetratiónico/farmacologíaRESUMEN
Dihydrofolate reductase, purified to homogeneity (as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis), from a subline of L1210 murine leukemia cells resistant to 10(-6) M methotrexate, was resolved into two principal forms (1 and 2) by polyacrylamide gel electrophoresis at pH 8.3 or isoelectric focusing. In the latter procedure, these forms had pI values of 7.4 and 8.2, respectively; both stained for protein and catalytic activity. Form 1 appears to be a single component, comprising ca. 10% of the total protein and at least 20% of the total catalytic activity. It is also more sensitive to inhibition by MTX, more heat-stable, and less susceptible to activation than form 2. Multiple components of 2 were observed by narrowing the pH range in isoelectric focusing, and further resolution was achieved by urea denaturation. Substrate and inhibitor complexes of 1 and 2, differentiated by polyacrylamide gel electrophoresis or isoelectric focusing, provided information about the ability of the enzyme to undergo conformational changes. Interconversion of 1 with one of the components of 2 may also involve conformational isomerism. These conclusions are consistent with the well-known ability of eukaryotic dihydrofolate reductases to exhibit increased catalytic activity (attributed to transformations to more open conformations) when treated with salts, chaotropes, or cysteine-modifying agents. Treatment of the L1210/R6 enzyme preparation with one of these activating agents, 5,5'-dithiobis(2-nitrobenzoic acid), derivatized both 1 and 2 (changing their pI values to 7.3 and 6.9, respectively) and altered the enzyme such that stoichiometric inhibition for MTX was observed.
Asunto(s)
Isoenzimas/metabolismo , Leucemia L1210/enzimología , Metotrexato/farmacología , Tetrahidrofolato Deshidrogenasa/metabolismo , Animales , Línea Celular , Ácido Ditionitrobenzoico/farmacología , Resistencia a Medicamentos , Electroforesis en Gel de Poliacrilamida , Activación Enzimática/efectos de los fármacos , Focalización Isoeléctrica , Leucemia L1210/patología , Sustancias Macromoleculares , Ratones , Conformación ProteicaRESUMEN
Splenic abscess is an infrequent complication in the immunocompromised patient. Six patients underwent splenectomy for presumed splenic abscess from 1987 to 1991. Chemotherapy altered the immune system of four patients; the human immunodeficiency virus (HIV) rendered the other two vulnerable to infection. Five presented with fever but none had leukocytosis; only one exhibited palpable splenomegaly; three had abdominal pain. Cultures documented systemic infection in all but one, an HIV-positive individual. Respiratory embarrassment was the indication for surgery in one patient. In five cases the decision for surgical intervention was made after computed tomography (CT) indicated the presence of multiple splenic lesions and systemic antibiotics failed to resolve the fevers. CT additionally showed hepatic and/or renal microabscesses in four patients. Signs and symptoms experienced preoperatively resolved with splenectomy in all six patients. No additional surgery was required for the patients with extrasplenic abscesses. Surgical pathology determined that three spleens had fungal and two had mycobacterial abscesses. The other was shown to be a spindle cell sarcoma; no abscess was present. This patient had preoperative blood cultures positive for mycobacteria, and the same organism was recovered from retroperitoneal nodes sampled at the time of splenectomy for the sarcoma. Follow-up indicates that no patients experienced surgical complications or sequelae related to their splenic pathology. Splenectomy is necessary and effective in treating splenic abscesses in immunocompromised patients and is appropriate for diagnosis as well as therapy.
Asunto(s)
Absceso/diagnóstico , Absceso/terapia , Huésped Inmunocomprometido , Enfermedades del Bazo/diagnóstico , Enfermedades del Bazo/terapia , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Bazo/patología , Esplenectomía , Resultado del TratamientoRESUMEN
PURPOSE: The activity of the drug combination ifosfamide and etoposide (VP16) in refractory and relapsed childhood acute lymphoblastic leukemia (ALL) was assessed in a phase II study. PATIENTS AND METHODS: Twenty children with ALL, all heavily pretreated and in bone marrow relapse, were entered on the study. Drugs were given i.v. each day for 5 days at the following doses: ifosfamide 1.8 g/m2/day, VP16 100 mg/m2/day, and MESNA 2,880 mg/m2/day (as a uroprotectant); cycles were repeated every 28 days. At study entry, eight patients were in first relapse (five of whom had failed intensive reinduction regimens), seven were in second relapse, and five were in third relapse. All patients had received cyclophosphamide in regimens before relapse. RESULTS: Eight patients (40%; 95% confidence interval 19-64%) achieved complete bone marrow remission with ifosfamide/VP16. Three patients subsequently relapsed in the bone marrow while on ifosfamide/VP16 therapy. Duration of remission ranged from 21 to 247 days. Treatment was generally well tolerated, with myelosuppression the most common toxicity; fever and neutropenia occurred in 18 of 31 evaluable cycles. CONCLUSION: The combination of ifosfamide/VP16 has significant activity in recurrent and refractory childhood ALL with tolerable toxicity.
Asunto(s)
Etopósido/administración & dosificación , Ifosfamida/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica , Niño , Preescolar , Citarabina/administración & dosificación , Femenino , Humanos , Lactante , Masculino , Mesna/administración & dosificación , RecurrenciaRESUMEN
Commercially available 5-formyltetrahydrofolate (5-CHO-H4PteGlu) is chemically prepared in a reaction that introduces an asymmetric center at the 6 carbon, and hence is the mixture of diastereomers differing in chirality about this position. (6R)-5-CHO-H4PteGlu, the diastereomer that is not normally found in vivo, was prepared from folic acid. Folic acid was chemically reduced and (6R)-tetrahydrofolate (H4PteGlu) was obtained from the resultant (6R,S)-H4PteGlu by enzymatic consumption of the natural diastereomer of (6R,S)-5,10-CH2-H4PteGlu (reversibly formed from (6R,S)-H4PteGlu in the presence of formaldehyde) with Lactobacillus casei thymidylate synthase. The 5 position of purified (6R)-H4PteGlu was directly formylated in a carbodiimide-catalyzed reaction. The level of contamination of these preparations with the corresponding 6S diastereomers was estimated using the binding of fluorodeoxyuridylate to thymidylate synthase promoted by folate cofactor (for H4PteGlu) and by the growth of folate requiring bacteria (for 5-CHO-H4PteGlu). Purified preparations of (6R)-H4PteGlu promoted the binding of fluorodeoxyuridylate to L. casei thymidylate synthase (in the presence of formaldehyde) only at concentrations greater than 1000-fold higher than equiactive levels of (6S)-H4PteGlu. Likewise, the (6R)-5-CHO-H4PteGlu made by this method was 600 times less active as a growth factor for Pediococcus cerevisiae than was authentic (6S)-5-CHO-H4PteGlu. Hence, the minimum stereochemical purity of these preparations was 99.9% for (6R)-H4PteGlu and 99.8% for (6R)-5-CHO-H4PteGlu.
Asunto(s)
Leucovorina/síntesis química , Tetrahidrofolatos/síntesis química , Fluorodesoxiuridilato/metabolismo , Lacticaseibacillus casei/efectos de los fármacos , Lacticaseibacillus casei/enzimología , Lacticaseibacillus casei/crecimiento & desarrollo , Leucovorina/farmacología , Oxidación-Reducción , Pediococcus/efectos de los fármacos , Pediococcus/crecimiento & desarrollo , Unión Proteica/efectos de los fármacos , Estereoisomerismo , Tetrahidrofolatos/farmacología , Timidilato Sintasa/metabolismoRESUMEN
A young girl with a history of chondroblastic osteosarcoma of the tibia developed a pulmonary metastasis which was treated by metastasectomy, chemotherapy and lung irradiation. There years later, at the age of 15, she developed a breast mass which was excised and which proved to be a poorly differentiated sarcoma. This was almost certainly a metastasis rather than a radiation-induced second primary tumour, in view of the short interval since radiotherapy. The ultrasonographic features of this lesion are presented here and the differential diagnosis is discussed in this context.
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Neoplasias Óseas/patología , Neoplasias de la Mama/secundario , Condroblastoma/patología , Osteosarcoma/patología , Tibia , Neoplasias de la Mama/diagnóstico por imagen , Niño , Diagnóstico Diferencial , Resultado Fatal , Femenino , Humanos , Radiografía , UltrasonografíaRESUMEN
A Phase II study of thioTEPA was performed by the Children's Cancer Group. ThioTEPA was administered intravenously every three weeks, at a dose of 65 mg/m2. Pediatric patients with recurrent sarcomas were targeted, but patients with other tumor diagnoses were also eligible. Toxicity was primarily hematopoietic, with thrombocytopenia being predominant. ThioTEPA did not demonstrate significant activity in the target tumor groups evaluated.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Neoplasias/tratamiento farmacológico , Tiotepa/uso terapéutico , Adolescente , Neoplasias Óseas/tratamiento farmacológico , Niño , Humanos , Tumores Neuroectodérmicos Periféricos Primitivos/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Rabdomiosarcoma/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Sarcoma de Ewing/tratamiento farmacológicoRESUMEN
PURPOSE: The objectives of this study were: 1) to compare the time to hematologic recovery (absolute neutrophil count [ANC] > or = 1,000/mm3 and platelet count > or = 100,000/mm3) in a randomized prospective study of two doses of granulocyte colony-stimulating factor (G-CSF) (5.0 vs. 10.0 microg/kg per day) after ifosfamide, carboplatin, and etoposide (ICE) chemotherapy; and 2) to determine the response rate (complete response [CR] + partial response [PR]) of ICE in children with refractory or recurrent solid tumors. PATIENTS AND METHODS: From June 1992 until November 1994, 123 patients with recurrent or refractory pediatric solid tumors were treated with ifosfamide (1,800 mg/m2 per day x 5), carboplatin (400 mg/m2 per day x 2), and etoposide (100 mg/m2 per day x 5) and randomized to receive either 5.0 microg/kg per day or 10.0 microg/kg per day of G-CSF subcutaneously until recovery of ANC to > or = 1,000/mm3. RESULTS: The incidence of grade 4 neutropenia during the first course was 88%. Median time from the start of chemotherapy to ANC > or = 1,000/mm(-3) for all patients during courses 1 and 2 was 21 and 19 days, respectively. The incidence of developing platelet count < or = 20,000/mm3 during course 1 was 82%. The median time from the start of the course of chemotherapy to platelet recovery > or =100,000/mm3 for all patients during courses 1 and 2 was 27 days. There was no significant difference in the median time of ANC recovery, platelet recovery, or incidence of grade 4 neutropenia; and in the median days of fever and the incidence of infections requiring hospitalization and intravenous antibiotics during courses 1 and 2, there was no significant difference between the two doses of G-CSF. One hundred eighteen patients were evaluated for response to ICE. The overall response rate (CR + PR) in this study was 51% (90% confidence interval, 43%-59%). The CR rate for all diagnostic categories was 27%. The Kaplan-Meier estimates of 1-year and 2-year survival probabilities for all patients were 52% and 30%, respectively. CONCLUSION: In summary, this combination of chemotherapy (ICE) was associated with a high CR rate (27%) in children with recurrent or refractory solid tumors, but also with a high incidence of grade 4 neutropenia and thrombocytopenia. Doubling the dose of G-CSF from 5.0 to 10.0 microg/kg per day after ICE chemotherapy did not result in an enhancement of neutrophil or platelet recovery or the incidence of grade 4 neutropenia developing.