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1.
Pediatr Blood Cancer ; 66(1): e27402, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30294914

RESUMEN

Treatment of Hodgkin lymphoma (HL) has advanced over time, rendering a fatal disease now largely curable. Multiagent chemotherapy regimens, hematopoietic stem cell transplantation, and radiotherapy are the mainstays of care. Surgical intervention is rarely indicated other than for biopsy at diagnosis. However, for patients with recurrent relapsed HL isolated to one anatomical location, refractory to all other therapy, there may be a beneficial role for surgical excision. Herein, we report the surgical management of three relapsed patients with stage IVB HL who were refractory to multiple other therapeutic approaches, who all achieved good event-free survival after operative management.


Asunto(s)
Enfermedad de Hodgkin/cirugía , Recurrencia Local de Neoplasia/cirugía , Terapia Recuperativa , Procedimientos Quirúrgicos Operativos/métodos , Adolescente , Niño , Femenino , Enfermedad de Hodgkin/patología , Humanos , Recurrencia Local de Neoplasia/patología , Pronóstico
2.
Br J Cancer ; 109(7): 1725-34, 2013 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-24022191

RESUMEN

BACKGROUND: This phase 1 clinical trial was conducted to determine the safety, maximum-tolerated dose (MTD), and pharmacokinetics of imatinib, bevacizumab, and metronomic cyclophosphamide in patients with advanced colorectal cancer (CRC). METHODS: Patients with refractory stage IV CRC were treated with bevacizumab 5 mg kg(-1) i.v. every 2 weeks (fixed dose) plus oral cyclophosphamide q.d. and imatinib q.d. or b.i.d. in 28-day cycles with 3+3 dose escalation. Response was assessed every two cycles. Pharmacokinetics of imatinib and cyclophosphamide and circulating tumour, endothelial, and immune cell subsets were measured. RESULTS: Thirty-five patients were enrolled. Maximum-tolerated doses were cyclophosphamide 50 mg q.d., imatinib 400 mg q.d., and bevacizumab 5 mg kg(-1) i.v. every 2 weeks. Dose-limiting toxicities (DLTs) included nausea/vomiting, neutropaenia, hyponatraemia, fistula, and haematuria. The DLT window required expansion to 42 days (1.5 cycles) to capture delayed toxicities. Imatinib exposure increased insignificantly after adding cyclophosphamide. Seven patients (20%) experienced stable disease for >6 months. Circulating tumour, endothelial, or immune cells were not associated with progression-free survival. CONCLUSION: The combination of metronomic cyclophosphamide, imatinib, and bevacizumab is safe and tolerable without significant drug interactions. A subset of patients experienced prolonged stable disease independent of dose level.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Ciclofosfamida/uso terapéutico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Anciano , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Bevacizumab , Ciclofosfamida/efectos adversos , Ciclofosfamida/farmacocinética , Esquema de Medicación , Femenino , Humanos , Mesilato de Imatinib , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Células Neoplásicas Circulantes/efectos de los fármacos , Piperazinas/efectos adversos , Piperazinas/farmacocinética , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Resultado del Tratamiento
3.
Curr Oncol ; 18(1): e19-24, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21331268

RESUMEN

OBJECTIVE: To describe the use of temozolomide (tmz) in Canadian children treated for brain tumours and to evaluate survival and predictors of survival for children treated with this agent. METHODS: A survey was conducted within the Canadian Paediatric Brain Tumour Consortium (cpbtc), a group of tertiary care centres in pediatric neuro-oncology (n = 16) in Canada that are involved in the treatment of children with central nervous system tumours. RESULTS: In 10 of the 16 participating pediatric oncology centres of the cpbtc, 137 children with brain tumours were treated with tmz between January 2000 and March 2006. Although 33% of the children were enrolled into a clinical trial, 67% were treated outside open studies. Most patients (72%) received tmz treatment on recurrence of their brain tumour (first or subsequent). The most commonly administered regimen was single-agent tmz 150-200 mg/m(2) administered on 5 consecutive days every 28 days. The median duration of tmz treatment was 141 days (range: 4-1102 days). Response data were provided for 127 of the 137 patients, of whom 6 showed a complete response. Sixteen patients experienced a minor or partial response, 53 had stable disease, and 52 had progressive disease. Of 32 patients alive at last follow-up, 19 had a diagnosis of low-grade glioma. CONCLUSIONS: Temozolomide is used in a variety of pediatric brain tumours, often at the time of recurrence. The lack of insight into clear indications for this agent in pediatric brain tumours-used either alone or in combination therapy-may be a result of suboptimal design of phase i and ii studies and a lack of phase iii trials in the pediatric brain tumour population.

4.
Oncogene ; 28(19): 2024-33, 2009 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-19363520

RESUMEN

p73 encodes multiple functionally distinct isoforms. Proapoptotic TAp73 isoforms contain a transactivation (TA) domain, and like p53, have tumor suppressor properties and are activated by chemotherapies to induce cell death. In contrast, antiapoptotic DeltaNp73 isoforms lack the TA domain and are dominant-negative inhibitors of p53 and TAp73. DeltaNp73 proteins are overexpressed in a variety of tumors including neuroblastoma. Thus, identification of drugs that upregulate TAp73 and/or downregulate DeltaNp73 represents a potential therapeutic strategy. Here, we report that cyclooxygenase (COX) inhibitors induce apoptosis independent of p53, and differentially modulate endogenous p73 isoforms in neuroblastoma and other tumors. COX inhibitor-mediated apoptosis is associated with the induction of TAp73beta and its target genes. COX inhibitors also downregulate the alternative-spliced DeltaNp73(AS) isoforms, Deltaexon2 and Deltaexon2/3. Furthermore, forced expression of DeltaNp73(AS) results in diminished apoptosis in response to the selective COX-2 inhibitor celecoxib. Celecoxib-mediated downregulation of DeltaNp73(AS) is associated with decreased E2F1 levels and diminished E2F1 activation of the p73 promoter. These results provide the first evidence that COX inhibitors differentially modulate p73 isoforms leading to enhanced apoptosis, and support the potential use of COX inhibitors as novel regulators of p73 to enhance chemosensitivity in tumors with deregulated E2F1 and in those with wild-type (wt) or mutant p53.


Asunto(s)
Inhibidores de la Ciclooxigenasa/metabolismo , Proteínas de Unión al ADN/metabolismo , Neuroblastoma/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Apoptosis/efectos de los fármacos , Genes Supresores de Tumor , Humanos , Ratones , Trasplante de Neoplasias , Trasplante Heterólogo , Proteína Tumoral p73 , Proteínas Supresoras de Tumor/genética
5.
Oncogene ; 27(28): 3923-34, 2008 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-18332870

RESUMEN

The cellular and molecular mechanisms of tumor progression following chemotherapy are largely unknown. Here, we demonstrate that cisplatin (CDDP) treatment upregulates VEGF and Flt1 expression leading to the survival and expansion of a highly tumorigenic fraction of side-population (SP) cells in osteosarcoma (HOS), neuroblastoma (SK-N-BE2) and rhabdomyosarcoma (RH-4) cell lines. In all three lines, we show that CDDP treatment increases levels of VEGF and Flt1 expression, and induces enhanced clonogenic capacity and increased expression of the 'stemness'-associated genes Nanog, Bmi-1 and Oct-4 in the SP fraction. In HOS, these changes are associated with the transformation of a non-tumorigenic osteosarcoma SP fraction to a highly tumorigenic phenotype. Inhibition of Flt1 led to complete reduction of tumorigenicity in the HOS SP fraction, and reduction of clonogenic capacity and expression of stemness genes in the SK-N-BE(2) and RH-4 SP fractions. Treatment with U0126, a specific inhibitor of MAPK/ERK1,2 completely downregulates CDDP-induced VEGF and Flt1 expression and induction/expansion of SP fraction in all three cell lines, indicating that these effects are mediated through MAPK/ERK1,2 signaling. In conclusion, we report a novel mechanism of CDDP-induced tumor progression, whereby the activation of VEGF/Flt1 autocrine signaling leads to the survival and expansion of a highly tumorigenic SP fraction.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias Óseas/patología , Neoplasias Encefálicas/patología , Cisplatino/farmacología , Regulación Neoplásica de la Expresión Génica , Neuroblastoma/patología , Osteosarcoma/patología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Encefálicas/tratamiento farmacológico , Línea Celular Tumoral , Supervivencia Celular , Transformación Celular Neoplásica , Inhibidores Enzimáticos/farmacología , Humanos , Neuroblastoma/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Transducción de Señal
6.
Oncogene ; 26(13): 1920-31, 2007 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-16983334

RESUMEN

Cyclooxygenase-2 (COX-2) is upregulated in many tumors including neuroblastoma, and its overexpression has been implicated in resistance to p53-dependent apoptosis. Although p53 is rarely mutated in neuroblastoma, the p53 protein is rendered inactive via several mechanisms including sequestration in the cytoplasm. Here, we show that COX inhibitors inhibit the growth of neuroblastoma and when combined with low doses of chemotherapy, exert synergistic effects on neuroblastoma cells. Following COX inhibitor treatment, HDM2, which targets p53 for ubiquitin-mediated degradation, is downregulated, resulting in an attenuation of p53 ubiquitination and an increase in p53 half-life. The level of HDM2 phosphorylation at ser166, which influences both HDM2 and p53 subcellular distribution, is markedly diminished in response to COX inhibitors and is associated with increased p53 nuclear localization. Combining COX inhibitors with low-dose chemotherapy potentiates apoptosis and p53 stability, nuclear localization, and activity. p53 knockdown by siRNA resulted in the rescue of COX-inhibitor-treated cells, indicating that COX inhibitor-induced apoptosis is, at least in part, p53-dependent. Taken together, these results provide the first evidence that COX inhibitors enhance chemosensitivity in neuroblastoma via downregulating HDM2 and augmenting p53 stability and nuclear accumulation.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Inhibidores de la Ciclooxigenasa/farmacología , Neuroblastoma/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Secuencia de Bases , Línea Celular Tumoral , Núcleo Celular/metabolismo , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Neuroblastoma/patología , Fosforilación , ARN Interferente Pequeño
7.
Eur J Cancer ; 42(14): 2335-42, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16899365

RESUMEN

The aims of this study were to determine the maximum tolerated dose (MTD), toxicity and pharmacokinetics of oral temozolomide administered over 42 d in children with recurrent/refractory brain tumours. Cohorts of 3-6 patients were treated for 42 d, followed by a 7-d rest period for a maximum of 6 cycles. Patients were stratified as heavily pre-treated (HPT) and non-heavily pre-treated (NHPT). Starting doses were 50 mg/m2 (HPT) or 75 mg/m2 (NHPT). Out of 28 patients enrolled, 20 were evaluable for toxicity and 19 for pharmacokinetics. Three patients in the NHPT group developed grade 3/4 haematological toxicity, 2 experienced dose-limiting toxicity (thrombocytopenia) at 100 mg/m2, and 9/20 developed grade 3 lymphopenia. MTD in both strata was 85 mg/m2. Responses were observed in 4 patients: 2 complete responses (CR) in medulloblastoma and supratentorial primitive neuroectodermal tumours (PNET), and 2 partial responses (PR) in high-grade glioma, respectively. Overall cumulative exposure was at least 1.5 times higher than in the 5-d administration schedule. In conclusion, the recommended dose of temozolomide is 85 mg/m2 x 42 d. Dose-limiting toxicities are thrombocytopenia and lymphopenia. The observed response rate warrants phase II studies.


Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Dacarbazina/análogos & derivados , Recurrencia Local de Neoplasia/tratamiento farmacológico , Administración Oral , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/farmacocinética , Neoplasias Encefálicas/patología , Niño , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Dacarbazina/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Estudios de Factibilidad , Femenino , Humanos , Masculino , Recurrencia Local de Neoplasia/patología , Temozolomida
8.
Eur J Cancer ; 39(17): 2556-65, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-14602142

RESUMEN

The development of a non-toxic selective cytoprotective agent that preferentially protects normal tissues from chemotherapy toxicity, without protecting malignant tissues, is a major challenge in cancer chemotherapy research. The available cytoprotective agents are either toxic or lack selective cytoprotective activity. Here, we report the in vitro selective cytoprotective activity of squalene, an isoprenoid molecule with antioxidant properties. Normal human bone marrow (BM) derived colony-forming unit (CFU) growth was increased by squalene in a dose-dependent manner. Squalene (12.5-25 microM) treatment significantly protected the CFUs from cisplatin-induced toxicity; the protective effect was equivalent to reduced glutathione (GSH), a known cytoprotective agent. Squalene also increased the long-term survival of cisplatin-treated 4-week-old CFUs. Cisplatin-induced apoptosis of CFUs as measured by the TUNEL assay was reduced by squalene. To examine the squalene-induced protection of tumours, several neuroblastoma cell lines, including five MYCN-amplified cell lines, were grown in monolayers, as well as in anchorage-independent cultures, in the presence of squalene and cisplatin. Squalene did not protect the neuroblastoma (NBL) cell lines from cisplatin-induced toxicity. In addition, squalene did not protect the NBL cells from carboplatin, cyclophosphamide, etoposide and doxorubicin-induced toxicity. In conclusion, our results suggest that squalene has a selective in vitro cytoprotective effect on BM-derived haematopoietic stem cells that is equipotent to GSH.


Asunto(s)
Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Citoprotección , Células Madre Hematopoyéticas/citología , Neuroblastoma/tratamiento farmacológico , Escualeno/uso terapéutico , Apoptosis/efectos de los fármacos , Enfermedades de la Médula Ósea/inducido químicamente , Enfermedades de la Médula Ósea/prevención & control , División Celular/efectos de los fármacos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Glutatión/uso terapéutico , Humanos
10.
Ther Drug Monit ; 23(5): 542-9, 2001 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11591901

RESUMEN

High-performance liquid chromatography separation of reduced and oxidized glutathione (GSH and GSSG) in biologic samples using electrochemical detection offers the convenience of both simultaneous quantitation and simple sample preparation. Rapid acidification is required to prevent GSH autooxidation, GSH and GSSG degradation, and precipitate proteins that interfere with analysis. Currently, little consistency exists in the literature regarding acid selection or the feasibility of sample storage before analysis. The purpose of this work was to examine the effects of perchloric (PCA), trichloroacetic (TCA), metaphosphoric (MPA), and 5-sulfosalicylic (SSA) acids on the short-term stability of GSH and GSSG measurements in whole blood. Samples were collected from adult volunteers and treated with multiple concentrations of each acid. The samples were analyzed immediately and aliquots were stored at -80 degrees C for up to 28 days. The suitability of each acid was assessed by percentage change of GSH and GSSG from baseline, efficiency of protein removal, and alteration of chromatogram characteristics. In general, increasing the acid concentration improved sample stability. Nevertheless, SSA did not achieve acceptable sample stability at any concentration tested. MPA was found to leave substantial amounts of protein in the samples, and TCA may interfere with the peaks of interest. Based on these results, a final concentration of 15% PCA is suggested for analysis of glutathione in whole blood. Although immediate sample preparation is preferred, 15% PCA can maintain sample integrity for 4 weeks after storage at -80 degrees C.


Asunto(s)
Disulfuro de Glutatión/sangre , Glutatión/sangre , Adulto , Bencenosulfonatos , Proteínas Sanguíneas/metabolismo , Cromatografía Líquida de Alta Presión , Estabilidad de Medicamentos , Humanos , Oxidación-Reducción , Percloratos/farmacocinética , Ácidos Fosforosos/farmacocinética , Salicilatos/farmacocinética , Ácido Tricloroacético/farmacocinética
11.
Cancer ; 92(4): 914-23, 2001 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-11550166

RESUMEN

BACKGROUND: Amifostine protects normal tissues against chemotherapy and radiation-induced toxicity without loss of antitumor effects. Evidence suggests that multiple daily doses of amifostine may improve its cytoprotective effects. The purpose of this study was to assess the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of twice-daily doses of amifostine with ifosfamide, carboplatin, and etoposide (ICE) chemotherapy for children with refractory malignancies and to determine the pharmacokinetic properties of amifostine, WR-1065, and the disulfide metabolites of amifostine. METHODS: Patients with refractory malignancies were treated with amifostine 15 minutes before and 2 hours after chemotherapy with ifosfamide (3 g/m(2) per dose on Days 1 and 2) and carboplatin (635 mg/m(2) on Day 3). Etoposide was administered on Days 1 and 2 (150 mg/m(2)). The starting dose of amifostine was 740 mg/m(2). Pharmacokinetic studies were performed after the first dose of amifostine. RESULTS: Twelve patients received 23 courses of ICE and amifostine. Dose-limiting toxicities for amifostine at 740 mg/m(2) were somnolence and anxiety. The other Grade 3 and 4 toxicities included asymptomatic, reversible hypocalcemia, vomiting, and reversible hypotension. At a dose of 600 mg/m(2), amifostine was well tolerated. Hypocalcemia, due to rapid, transient suppression of parathyroid hormone production, required close monitoring and aggressive intravenous calcium supplementation. Pharmacokinetic studies revealed high interpatient variability with rapid plasma clearance of amifostine and WR-1065. The median elimination half-life of amifostine (9.3 minutes) and WR-1065 (15 minutes) was much shorter than the disulfide metabolites (74.4 minutes). CONCLUSIONS: The recommended pediatric dose of amifostine for a twice-daily regimen is 600 mg/m(2) per dose (1200 mg/m(2)/day) with DLTs of anxiety and somnolence, lower than the previously recommended single dose of 1650 mg/m(2).


Asunto(s)
Amifostina/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Adolescente , Amifostina/metabolismo , Amifostina/farmacocinética , Carboplatino/administración & dosificación , Niño , Preescolar , Esquema de Medicación , Etopósido/administración & dosificación , Femenino , Humanos , Ifosfamida/administración & dosificación , Masculino , Mercaptoetilaminas/farmacocinética , Insuficiencia del Tratamiento
12.
Eur J Haematol ; 66(5): 347-51, 2001 May.
Artículo en Inglés | MEDLINE | ID: mdl-11422416

RESUMEN

Patients with refractory autoimmune thrombocytopenia do not respond to standard therapy with high-dose corticosteroids, intravenous immunoglobulin, and splenectomy. We describe the cases of two patients with refractory autoimmune thrombocytopenia treated with oral cyclosporin A (CsA) to evaluate the efficacy of this alternative therapy. Blood pressure and hepatic and renal function were in the normal range before initiation of treatment. Induction therapy with pulses of high-dose methylprednisolone was used for 3 consecutive days to improve the initial immune suppression. Gradual dose reduction of CsA, according the platelet count, minimized the long-term adverse effects of CsA. Oral CsA with pulses of high-dose methylprednisolone induced remission of the thrombocytopenia. Gradual weaning of CsA over months, according the platelet count, produced no observable adverse effects of the CsA. Rapid dose reduction caused thrombocytopenia, which resolved with higher dosages of CsA. Our cases show the efficacy of CsA for refractory immune thrombocytopenia. This therapeutic option with oral CsA as an additional salvage option may avoid splenectomy and the adverse effects of long-term corticosteroids. Larger clinical investigations are necessary to establish the indications and therapeutic regimen for CsA in immune thrombocytopenia.


Asunto(s)
Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Adolescente , Ciclosporina/administración & dosificación , Ciclosporina/efectos adversos , Femenino , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Metilprednisolona/administración & dosificación , Metilprednisolona/uso terapéutico , Recuento de Plaquetas , Inducción de Remisión
13.
J Clin Invest ; 105(8): R15-24, 2000 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-10772661

RESUMEN

Various conventional chemotherapeutic drugs can block angiogenesis or even kill activated, dividing endothelial cells. Such effects may contribute to the antitumor efficacy of chemotherapy in vivo and may delay or prevent the acquisition of drug-resistance by cancer cells. We have implemented a treatment regimen that augments the potential antivascular effects of chemotherapy, that is devoid of obvious toxic side effects, and that obstructs the development of drug resistance by tumor cells. Xenografts of 2 independent neuroblastoma cell lines were subjected to either continuous treatment with low doses of vinblastine, a monoclonal neutralizing antibody (DC101) targeting the flk-1/KDR (type 2) receptor for VEGF, or both agents together. The rationale for this combination was that any antivascular effects of the low-dose chemotherapy would be selectively enhanced in cells of newly formed vessels when survival signals mediated by VEGF are blocked. Both DC101 and low-dose vinblastine treatment individually resulted in significant but transient xenograft regression, diminished tumor vascularity, and direct inhibition of angiogenesis. Remarkably, the combination therapy resulted in full and sustained regressions of large established tumors, without an ensuing increase in host toxicity or any signs of acquired drug resistance during the course of treatment, which lasted for >6 months. This article may have been published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Neuroblastoma/tratamiento farmacológico , Proteínas Tirosina Quinasas Receptoras/inmunología , Receptores de Factores de Crecimiento/inmunología , Vinblastina/uso terapéutico , Animales , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos Fitogénicos/efectos adversos , Células Cultivadas , Terapia Combinada , Relación Dosis-Respuesta a Droga , Fluorescencia , Humanos , Ratones , Ratones SCID , Trasplante de Neoplasias , Neovascularización Patológica , Neuroblastoma/irrigación sanguínea , Neuroblastoma/patología , Receptores de Factores de Crecimiento Endotelial Vascular , Células Tumorales Cultivadas , Vinblastina/efectos adversos
14.
J Pediatr Hematol Oncol ; 21(6): 494-500, 1999.
Artículo en Inglés | MEDLINE | ID: mdl-10598660

RESUMEN

To establish the maximum tolerated dosage (MTD), the dose-limiting toxicities (DLTs), and pharmacokinetic parameters of CI-980, a novel tubulin binder, in children with solid tumors refractory to standard therapy. Patients 21 years of age or younger with adequate nutritional, hematopoietic, renal, and hepatic function were eligible. The patient must not have been pregnant. Patients with brain tumors were not eligible for any dosage level until it was demonstrated the level did not produce DLT in patients with extracranial solid tumors. The starting dosage level was 3.5 mg/m2/day, for 3 days, administered as a continuous intravenous infusion (80% of the adult MTD). If a dosage level was associated with dose-limiting myelotoxicity, growth factors were to be added. Thirty-three patients received CI-980. Twenty-four had solid tumor; 9 had brain tumor. The MTD achieved without granulocyte colony stimulating factor (G-CSF) was 3.5 mg/m2/day (DLT: neutropenia) and with G-CSF, it was as follows: patients with brain tumor, 4.2 mg/m2/day (DLT: myelosupression); and patients with solid tumor, 5 mg/m2/day (DLT: cortical toxicity). Several responses were seen, most notably prolonged stable disease in two of five patients with medulloblastoma. Pharmacokinetic data showed a mean steady state level of 1.74 ng/mL for two patients treated with the 5 mg/m2/day regimen, with rapid decay after the termination of the infusion. CI-980 showed preliminary evidence of activity in recurrent pediatric malignancies, with tolerable, reversible toxicities.


Asunto(s)
Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Carbamatos/efectos adversos , Carbamatos/farmacocinética , Neoplasias/tratamiento farmacológico , Pirazinas/efectos adversos , Pirazinas/farmacocinética , Piridinas/efectos adversos , Piridinas/farmacocinética , Adolescente , Adulto , Niño , Relación Dosis-Respuesta a Droga , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Semivida , Humanos , Tasa de Depuración Metabólica , Neoplasias/patología , Selección de Paciente , Recurrencia
15.
J Clin Pharmacol ; 39(5): 454-61, 1999 May.
Artículo en Inglés | MEDLINE | ID: mdl-10234592

RESUMEN

Ifosfamide is widely used in the treatment of pediatric solid tumors. Its main adverse effects are various forms of renal tubular and glomerular damage. The authors sought to determine factors that predict the risk for the development and severity of ifosfamide-induced nephrotoxicity in children and to examine the long-term outcome of this complication. A total of 174 children who had received ifosfamide for various cancers were studied. Nephrotoxicity was assessed by laboratory markers of glomerular and tubular function and a grading score (none, mild, moderate, severe). Patients were assessed 4 to 12 weeks after each ifosfamide course, 3 months after completion of chemotherapy, and 5 years later. Of 174 children, 72 (41.4%) developed tubular dysfunction, whereas only 11 (6.3%) demonstrated glomerular dysfunction; 40 (23.0%) demonstrated mild toxicity, 16 (9.2%) demonstrated moderate toxicity, and 16 (9.2%) developed severe nephrotoxicity. The four severity subgroups (none, mild, moderate, severe) received comparable doses/m2/cycle of ifosfamide and mesna. Children exhibiting severe toxicity were significantly younger compared to those with moderate, mild, or no nephrotoxicity (median age: 2.2, 7.0, 8.2, and 10.5 years, respectively; p < 0.001) and received significantly higher cumulative doses of ifosfamide (49.6 +/- 12.3, 46.0 +/- 13.1, 36.2 +/- 9.7, and 33.8 +/- 7.6 g/m2, respectively; p < 0.001). Cumulative doses of cisplatin were higher among children with severe nephrotoxicity compared to those with moderate, mild, or no toxicity, although this difference did not reach statistical significance. Of all risk factors analyzed by multiple regression analysis, age was the most significant predictor for the grade of nephrotoxicity (p < 0.001), followed by the cumulative dose of ifosfamide (p = 0.005). Seven out of 16 children (44.0%) with severe nephrotoxicity and 4 out of 16 children (25.0%) with moderate nephrotoxicity demonstrated severe chronic tubular toxicity over a follow-up period of 5 years. Since severe ifosfamide-induced renal toxicity tends to be chronic in a substantial number of treated children, it should be balanced carefully against efficacy. Cumulative ifosfamide doses of 45 g/m2 and above should be carefully considered, especially in children younger than age 3.


Asunto(s)
Antineoplásicos Alquilantes/efectos adversos , Ifosfamida/efectos adversos , Enfermedades Renales/inducido químicamente , Adolescente , Adulto , Factores de Edad , Antineoplásicos Alquilantes/administración & dosificación , Niño , Preescolar , Esquema de Medicación , Humanos , Ifosfamida/administración & dosificación , Pruebas de Función Renal , Estudios Retrospectivos , Factores de Riesgo , Estadística como Asunto
16.
Childs Nerv Syst ; 14(10): 590-5, 1998 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-9840385

RESUMEN

Despite the improved outcome for patients with ependymoma treated by surgery and radiotherapy, their prognosis remains relatively poor. To assess the impact of adjuvant chemotherapy, we reviewed the overall survival of consecutive patients with anaplastic ependymoma treated over a 10-year period with surgery and ICE (ifosfamide+ VP 16+carboplatin) chemotherapy with or without radiation at our institution. There were 11 patients (6 male, 5 female), with a median age of 3.4 years (range 1.2-1 1.1): 4 under 2 years and 7 were over 2 years old. Overall, 5 had gross total resections: 4 are alive, 2 in continuous complete remission and 2 in second complete remission. One patient who was less than 2 years old died. Among the 6 with subtotal resection, 2 achieved a complete remission after chemotherapy. However, 5 of the 6 patients have since died of progressive disease, with a median overall survival of 75 months. Overall survival was 24% and progression-free survival was 39%. In 2 of 6 patients with residual postoperative disease a temporary objective response was noted with adjuvant ICE chemotherapy. This regimen did not confer an overall survival advantage.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Cerebelosas/tratamiento farmacológico , Ependimoma/tratamiento farmacológico , Envejecimiento/fisiología , Carboplatino/uso terapéutico , Neoplasias Cerebelosas/mortalidad , Neoplasias Cerebelosas/radioterapia , Neoplasias Cerebelosas/cirugía , Niño , Preescolar , Terapia Combinada , Ependimoma/mortalidad , Ependimoma/radioterapia , Ependimoma/cirugía , Etopósido/uso terapéutico , Femenino , Humanos , Ifosfamida/uso terapéutico , Lactante , Masculino , Análisis de Supervivencia
17.
Childs Nerv Syst ; 14(10): 596-601, 1998 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-9840386

RESUMEN

Concern about long-term sequelae of irradiation has led to the use of adjuvant chemotherapy with lower dose irradiation in the treatment of intracranial germinomas. To assess the feasibility of this approach versus radiation only, the survival of 16 evaluable patients (13 boys, 3 girls) with biopsy-proven intracranial germinomas treated at the Hospital for Sick Children was assessed. Between 1977 and 1988, 8 patients were treated with radiation only: 7 received tumour doses between 4000 and 5100 cGy and spinal prophylaxis; 1 received 3060 cGy to the tumour with no prophylaxis. After a median follow-up of 84 months, 7 are in continuous first CR and 1 is in second CR. Between 1988 and 1996, 8 patients received adjuvant platinum- and etoposide-based chemotherapy for two or three cycles followed by local irradiation to the tumour (2500-3500 cGy). After a median follow-up of 40 months, 6 are in continuous first CR and 1 in second CR; 1 has died of progression. Survival outcomes in the two groups are similar. Prospective trials to assess event-free survivals, neurocognitive and neuroendocrine outcomes are needed before definitive treatment recommendations can be made.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Germinoma/tratamiento farmacológico , Germinoma/radioterapia , Adolescente , Neoplasias Encefálicas/fisiopatología , Niño , Preescolar , Terapia Combinada , Relación Dosis-Respuesta en la Radiación , Glándulas Endocrinas/fisiopatología , Femenino , Germinoma/fisiopatología , Humanos , Masculino , Análisis de Supervivencia , Resultado del Tratamiento
18.
Med Pediatr Oncol ; 31(3): 153-8, 1998 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-9722897

RESUMEN

BACKGROUND: Renal-cell carcinoma (RCC) is a rare tumor in children. To address whether RCC in children differs from its adult counterpart, we report a series of 16 children with RCC (5 boys, 11 girls, mean age 9.6 years, range 3-19 years) presenting between 1979 and 1996 at three pediatric centers. PROCEDURE: Pathology showed papillary RCC in five patients (31%). Nonpapillary tumors were present in 11 (69%), of which nine were clear-cell type (56%), one was chromophobe-cell type (6%), and one was granular-cell type (6%). Cytogenetic studies were performed on four. RESULTS: In two tumors, normal karyotypes (45,XX or 45,XY) were found. In another, there were translocations: t(X;1), t(X;2) and t(6;14). In the fourth, analysis revealed 46,XX/46,X,t(X;17)(p11.2;q25),t(1;12). Several features in this series differ from those reported in adults. In adults, RCC is more frequent in males, is usually nonpapillary, and is characterized cytogenetically by deletions or rearrangements in the short arm of chromosome 3. In contrast, in our series there was no male predominance and a higher proportion of papillary tumors. In addition, two of four cytogenetically analyzed tumors had translocations involving the X chromosome. Translocations involving the Xp11.2 locus have been infrequently reported in both adults and children with papillary RCC. CONCLUSIONS: The higher frequency of papillary histology and the presence of translocations involving Xp.11.2 in two cases raise the possibility of a unique subtype of RCC in children.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Adolescente , Adulto , Carcinoma de Células Renales/complicaciones , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/terapia , Niño , Preescolar , Terapia Combinada , Femenino , Humanos , Cariotipificación , Neoplasias Renales/complicaciones , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/terapia , Masculino , Nefrectomía , Estudios Retrospectivos
19.
Oncogene ; 14(25): 3099-102, 1997 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-9223674

RESUMEN

A familial Wilms' tumour susceptibility gene, known as FWT1, has recently been localised to chromosome 17q12-q21 by genetic linkage analysis. Four Wilms' tumours from a family showing strong evidence of linkage to FWT1 were examined for allele loss using polymorphic microsatellite markers on chromosome 17q. In three tumours no loss of heterozygosity was observed. In the remaining case, loss of heterozygosity was detected at all markers analysed. However, the alleles lost in this Wilms' tumour were those segregating with the disease in the family. This is in contrast to the usual pattern observed in familial cancer syndromes, where the allele lost in tumours arising in gene carriers is the wild type inherited from the non mutation carrying parent. Taken together with previous data indicating that LOH on chromosome 17q is rare in sporadic Wilms' tumour, the results suggest that FWT1 is not a tumour suppressor gene. Moreover, loss of alleles linked to the disease and the implied absence of the mutated susceptibility gene in one tumour, suggests that a mutation in FWT1 may be necessary for the initiation of some familial Wilms' tumours but subsequently the maintenance of the neoplastic phenotype becomes independent of the FWT1 mutation.


Asunto(s)
Genes Supresores de Tumor , Genes del Tumor de Wilms , Tumor de Wilms/genética , Alelos , Cromosomas Humanos Par 11 , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Mutación , Reacción en Cadena de la Polimerasa
20.
J Immunol ; 158(8): 3705-15, 1997 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-9103434

RESUMEN

B lymphocyte development is characterized by deletion, via apoptosis, of immature cells that are stimulated via the B cell receptor in the absence of a second signal. We have investigated whether platelet-activating factor (PAF), a potent B lymphocyte activator, can provide a complementary signal with B cell receptor ligation to abrogate apoptosis. Cross-linking of the surface IgM on Ramos B lymphoblastoid cells using anti-IgM Abs (2 microg/ml) caused programmed cell death in 34 +/- 5.4% of the cells. Coincubation of PAF (10(-7)M) with alphaIgM led to a significant decrease in apoptotic cells as measured by DNA laddering and TUNEL assay (13.8 +/- 3%). The effect of PAF was dose dependent (10(-7)-10(-9) M) and was inhibited by the specific PAF receptor antagonist, WEB 2170. PAF protected cells from the effect of alphaIgM for up to 1 h after it was added. alphaIgM-induced programmed cell death in Ramos cells was blocked by catalase and, therefore, is caused in part by the production of toxic hydroxyl radicals from hydrogen peroxide. We investigated the action of PAF on markers of intracellular oxidation. H2O2 in low doses induced apoptosis, via production of OH. radicals. PAF inhibited H2O2-induced apoptosis in Ramos cells; it also attenuated H2O2- and alphaIgM-mediated increases in hydroxyl radical (OH.) as measured by the oxidation of 2',7'-dichlorofluorescein diacetate to 2',7'-dichlorofluorescein and blocked the depletion of reduced glutathione induced by alphaIgM. PAF maintained IgM secretion, which was greatly inhibited by incubation with alphaIgM alone. These data indicate that PAF potentially provides an important cosignal to surface IgM-stimulated Ramos cells by inhibiting apoptosis. This is in part due to the activity of PAF in the oxidant/ antioxidant pathway.


Asunto(s)
Apoptosis/inmunología , Linfocitos B/patología , Factor de Activación Plaquetaria/inmunología , Receptores Fc/inmunología , Transducción de Señal/inmunología , Linfocitos B/inmunología , Supervivencia Celular , Reactivos de Enlaces Cruzados , Humanos , Células Tumorales Cultivadas
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