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  • 1
    ISSN: 1433-0350
    Keywords: Key words Medulloblastoma ; Primitive neuroectodermal tumour ; Germ cell tumour ; High-grade glioma ; Ependymoma ; Stem cell transplantation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  New therapeutic strategies are required to improve the prognosis of malignant brain tumours in children, in terms of survival and quality of life. During the last 10 years, high-dose chemotherapy (HDCT) with autologous haematopoietic stem cell rescue has been studied in different types of paediatric brain tumours. The most frequently used combined regimens were busulfan-thiotepa and etoposide-thiotepa along with carboplatin or BCNU. High response rates have been reported in medulloblastoma and germ cell tumours, and HDCT has been further developed as salvage therapy or for consolidation in these diseases. Interesting objective tumour responses have been obtained in supratentorial high-grade glioma, but HDCT has not so far been effective either in ependymoma or in diffuse pontine brain stem tumours. This article reviews the rationale for HDCT in brain tumours and the current clinical results obtained in each tumour type. The place of HDCT in the therapeutic strategy for paediatric brain tumours, especially in young children, is discussed.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0843
    Keywords: Key words Mitoxantrone ; Intratumoral injections ; Experimental liver tumors ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The intratumoral (i.t.) delivery of anticancer drugs aims at controlling tumor growth and thereby provides palliative treatment for liver neoplasms. Mitoxantrone is a good candidate for local or regional administration because (1) its metabolism is mainly hepatic, (2) it has a steep dose-response curve for multiple solid tumors, and (3) its fixation in tissues is sustained without vesicant effects after extravasation. We compared the tolerance, pharmacokinetics, and antitumor effects of mitoxantrone on hepatic VX2 tumors in rabbits treated with i.t. intraarterial hepatic (i.a.h.) or i.v. mitoxantrone, i.t. ethanol; or i.t. 0.9% NaCl and in control animals. Tumor growth rates (TGRs) were evaluated at 9 days after treatment. Myelosuppression was the limiting toxicity of i.v. mitoxantrone at 1.5 mg/kg (maximal tolerated dose, MTD), but neither i.t. nor i.a.h. administration led to hematologic toxicity at the same dose. The mitoxantrone retained in tumors after i.t. administration was seen as blue-stained areas of complete necrosis according to histologic analysis. Pharmacokinetic parameters showed a significantly decreased systemic exposure to the drug after both regional treatments, although the i.a.h. route appeared to have an edge over the i.t. route. TGRs were significantly reduced after i.t. mitoxantrone (81±62%), i.a.h. mitoxantrone (337±110%), and i.t. ethanol treatments (287±117%) as compared with control values (886±223%; p〈0.01). Treatment with i.v. mitoxantrone (816±132%) had no antitumor effect, nor did NaCl injections (868±116%). Mitoxantrone given i.t. induced the highest antitumor effects, resulting in a 3.5-fold reduction in TGRs as compared with i.a.h. mitoxantrone and i.t. ethanol treatments (p〈0.02). Treatment with i.t. mitoxantrone provided efficient antitumor therapy without producing major side effects. This method should be considered as palliative treatment for nonresectable liver tumors and other localized malignancies.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1573-7373
    Keywords: medulloblastoma ; loss of heterozygosity ; chromosomes 11 and 22 ; instability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Medulloblastomas are primitive neuroectodermal tumors (PNETs) of the cerebellum with poorly understood pathogenesis. Previous molecular studies suggested a role for loci on chromosome 11 in the development of medulloblastomas-PNETs. In order to identify the frequency of loss and eventually the extent of allelic loss on chromosome 11, we have examined 23 pediatric medulloblastomas for loss of heterozygosity (LOH) with 16 polymorphic microsatellites. Our data reveal that LOH on 11p or 11q occurs rarely (13%) suggesting the unlikely involvement of chromosome 11 in most cases of medulloblastomas. The same frequency of LOH in medulloblastomas was detected using 8 microsatellites on 22q. Alterations of microsatellite length were found in only 4/594 PCR analyses using 28 markers located on chromosomes 2, 9, 11, 18, and 22, demonstrating that genomic instability is uncommon in medulloblastomas.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0843
    Keywords: Busulfan ; Pharmacodynamics ; Hepatic veno-occlusive disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Hepatic veno-occlusive disease (HVOD) is a frequent life-threatening toxicity in patients undergoing bone marrow transplantation (BMT) after the administration of a high-dose busulfan-containing regimen. Recent studies have shown that the morbidity and mortality of HVOD may be reduced in adults by pharmacologically guided dose adjustment of busulfan. We analyzed the pharmacodynamic relationship between busulfan disposition and HVOD in 61 children (median age, 5.9 years) with malignant disease. Busulfan, given at a dose ranging from 16 mg/kg to 600 mg/m2, was combined with one or two other alkylating agents (cyclophosphamide, melphalan, thiotepa). Only 3 patients received the standard busulfan/cyclophosphamide (BUCY) regimen. A total of 24 patients (40%) developed HVOD, which resolved in all cases. A pharmacokinetics study confirmed the previously reported wide interpatient variability in busulfan disposition but did not reveal any significant alteration in children with HVOD. The mean area under the concentration-time curve (AUC) after the first dose of busulfan was higher in patients with HVOD (6,811±2,943 ng h ml−1) than in patients without HVOD (5,760±1,891 ng h ml−1;P=0.10). This difference reflects the higher dose of busulfan given to patients with HVOD. No toxic level could be defined and, moreover, none of the toxic levels identified in adults were relevant. The high incidence of HVOD in children given 600 mg/m2 busulfan may be linked to the use of more intensive than usual high-dose chemotherapy regimens and/or drug interactions. Before the prospective evaluation of busulfan dose adjustment in children, further studies are required to demonstrate firmly the existence of a pharmacodynamic relationship in terms of toxicity and allogeneic engraftment, especially when busulfan is combined with cyclophosphamide. The maximal tolerated and minimal effective AUCs in children undergoing BMT are likely to depend mainly upon the disease, the nature of the combined high-dose regimen, and the type of bone marrow transplant.
    Type of Medium: Electronic Resource
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