RESUMEN

In a native osteosarcoma specimen of a patient cured of a bilateral retinoblastoma eight years before we found a homozygous deletion of a 7.5 kb Hind III-fragment within the retinoblastoma gene and a hemizygous deletion of the same fragment in its constitutional cells. In a native osteosarcoma tissue of a lung metastasis of a patient with sporadic osteosarcoma the Rb-gene-analysis did not reveal any deletion within the gene. This might be due to the fact that the used c-DNA-probe did not detect point mutations. Nevertheless, the possibility of additional or alternative transforming events should be kept in mind.

Asunto(s)

Asunto(s)

RESUMEN

The risk of congestive heart failure restricts the clinical use of doxorubicin to cumulative doses of 450-550 mg/m2, when it is given using high-dose rapid intravenous application. As the high peak serum levels which follow rapid administration seem to be correlated with cardiotoxicity, application schedules leading to lower peak serum concentrations have been developed. This paper reviews the influence of those schedules on cardiotoxicity, non-cardiac toxicities, pharmacokinetic data and antineoplastic efficacy. While the reduction of cardiotoxicity by long-term application schedules is well documented, much less can be said about the antitumor effect of those schedules. Controlled studies dealing with this problem are needed. This review provides a base for that purpose.

Asunto(s)

RESUMEN

The in-vitro uptake of four anthracyclines into leukemic cells was investigated. The accumulation was found to be dependent on the extracellular anthracycline concentration in a linear fashion. The steady state intracellular drug level was reached very quickly and was found to be correlated to the extracellular pH-value in the range between 6.4 and 7.4. Intracellular anthracycline accumulation was restricted in a leukemic subline (F 4-6 R), which was found to be 86 times more resistant to doxorubicin compared with its wild tpye (F 4-6). The importance of the initial uptake phase of anthracyclines into leukemic cells raises the question whether long-term "cardioprotective" anthracycline application schedules will retain the same antileukemic effect as conventional bolus injection.

Asunto(s)

RESUMEN

Preoperative chemotherapy according to the COSS 86 protocol, including two courses of cisplatin, was used for high-risk osteosarcoma. Patients were randomised to receive either intraarterial (i.a.) or intravenous (i.v.) cisplatin infusions. As measured by flameless atomic absorption spectroscopy (FAAS), platinum (Pt) levels in serum, ultrafiltrate, and urine did not show a decrease in systemic drug availability with i.a. administration. Tumors were surgically removed 3 weeks after the last cisplatin dose and analysed for Pt content and response to chemotherapy. A correlation could not be demonstrated between Pt levels in tumor tissue samples and the mode of CDDP application or extent of tumor cell destruction.

Asunto(s)

RESUMEN

Cardiac performance was evaluated at least two years after doxorubicin treatment in childhood in 55 patients without overt congestive cardiomyopathy. None of the patients had received mediastinal irradiation. Computer-assisted analysis of digitised echocardiograms showed impaired rapid diastolic filling and an increased change of dimension between minimal cavity dimension and mitral valve opening. This impairment of diastolic function was related to the cumulative dose of doxorubicin. In contrast when angiotensin II was infused to increase the afterload the end systolic pressure-length and stress-shortening relation indicated normal left ventricular systolic function. But during baseline conditions the end systolic wall stress was significantly increased in patients in whom the cumulative dose of doxorubicin exceeded 360 mg/m2.

Asunto(s)

RESUMEN

11 patients with refractory acute leukemia of childhood were treated with idarubicin per os. Bone marrow toxicity which was observed at a dose level of 60 mg/m2 p.o. (3 x 20 mg q 24 hrs p.o.) per 3 weeks was found to be the dose limiting factor. In contrast to the first phase I study of Tan et al. (16) the maximal tolerated dose in the present study was found to be lower at a level of 90 mg/m2 p.o. (3 x 30 mg/m2 p.o. q 24 hrs) per 3 weeks. Therefore, we recommend a dosage of 60 mg/m2 p.o. (3 x 20 mg/m2 p.o. q 24 hrs) per 3 weeks as a starting dose for phase II/III studies. 2 out of the 11 anthracycline pretreated patients (91-880 mg/m2) with acute leukemia reached a complete remission undergoing idarubicin p.o. as a single therapy.

Asunto(s)

RESUMEN

Doxorubicin serum elimination kinetics were measured by HPLC in three different patient groups. A dose of (a) 30 mg/m2; (b) 50 mg/m2, and (c) 4 x 15 mg/m2 every 10 h was administered by bolus injection to (a) 10, (b) 6, and (c) 8 patients. The results obtained provided strong evidence for a nonlinear dependence of doxorubicin serum elimination on the dose and administration schedule used. Comparing the 15 and 30 mg/m2 dose there was no significant increase in early drug levels but a marked increase in terminal half-life. At doses higher than 30 mg/m2, however, there was a steep increase in early drug levels, too. Moreover a marked cumulation of the anthracycline in the central compartment following short-term (4 x 15 mg/m2 every 10 h) consecutive administration was found. To obtain an optimal concentration x time product by single bolus injection a dose equal or higher than 30 mg/m2 should be used. However, in this dose range a steep dose-dependent rise in early drug levels is to be expected. As early high serum levels correlate with congestive heart failure, administration schedules reaching effective concentration x time products without high peak levels such as continuous infusion or consecutive administration of low doses seem to be necessary.

Asunto(s)

RESUMEN

Recently an amplification of NMYC oncogene was discovered in stage III and stage IV as well as in stage II neuroblastoma cells. The extent of NMYC amplification is of prognostic value. A high expression of NMYC on mRNA level is correlated to the NMYC gene-amplification. We utilized the in situ-hybridization technique for the detection of NMYC-mRNA expression on cellular level, and the Southern Blot method for analysing the total genomic DNA. In three stage IV patients with overt neuroblastoma in bone marrow cells, NMYC gene-amplification as well as NMYC-mRNA were detected. Seven control bone marrows of patients with different heamatological diseases in different stages did not contain positive cells in our in situ-hybridization assay.

Asunto(s)

RESUMEN

This is a case report of a 4 1/2-year-old boy who developed acute monoblastic leukemia 2 1/2 years after he had been treated successfully with combined chemotherapy for neuroblastoma. All analyzable bone marrow-derived metaphases had the karyotype 47,XY, + 8,t(9;11)(p21;q23). The rare occurrence of specific chromosomal translocations in leukemias following prior chemotherapy and/or radiotherapy and their possible clinical implications in such cases are discussed.

Asunto(s)

RESUMEN

Doxorubicin serum levels were measured with a highly specific reversed-phase HPLC-method in patients undergoing combination chemotherapy. Serum elimination kinetics of doxorubicin follow a bi- or triphasic first order pattern with a high interpatient variability. T 1/2 of the first distribution phase was 5.4 min. T 1/2 of the terminal steady-state elimination phase was 1273 min. After consecutive bolus application of 15 mg/m2 (4 times per 48 h) cumulation of doxorubicin was found in patient's serum. Serum levels 4 h after bolus injection of doxorubicin were found to be correlated with the area under the elimination curve. Therefore, 4 h serum levels after bolus injection can be used for clinical studies correlating pharmacokinetics with antineoplastic properties of doxorubicin.

Asunto(s)

RESUMEN

A rapid chromatographic procedure for the quantitative determination of the anthracycline antibiotics adriamycin and daunorubicin and their chief metabolites adriamycinol and daunorubicinol in plasma and urine is described. The extraction is performed using SEP-PAK silica cartridges. After filtration the eluate is chromatographed on a reversed-phase column.

Asunto(s)

RESUMEN

A rapid and sensitive reversed phase HPLC method was developed for the detection of 7-hydroxymethotrexate (7-OHMTX) which is the main metabolite in human plasma after high-dose methotrexate (MTX) therapy. The simple clean-up procedure of plasma samples described allows the measurement of 7-OHMTX during clinical management of MTX infusions. Elimination kinetics of 7-OHMTX are given from 53 drug cycles of 6 patients.

Asunto(s)

RESUMEN

Kinetics of 7-hydroxy-methotrexate (7-OH-MTX) excretion after high-dose methotrexate (MTX) (12 g/m2) therapy were monitored in 93 consecutive drug cycles of 19 adolescent patients with osteosarcoma. A reversed-phase HPLC method was used. Serum elimination was found to be monophasic with a mean half-life of 5.5 h. Shortly after the 4-h MTX infusion period 7-OH-MTX levels exceeded those of the parent compound. By 12 h after MTX infusion 7-OH-MTX levels were 16.5 times higher than those of MTX itself. Autostimulation of MTX metabolism leading to enhanced 7-OH-MTX production after repeated drug cycles was not observed. The production of 7-OH-MTX decreased significantly from the first to the last high-dose MTX cycle of the adjuvant chemotherapy protocol.

Asunto(s)

RESUMEN

7-Hydroxy-MTX production after consecutive high-dose MTX therapy (12 g/m2) was measured in 7 patients with osteosarcoma by HPLC. 7-Hydroxy-MTX serum values in the last cycle were found to be significantly lower compared with the first high-dose MTX treatment of the adjuvant chemotherapy protocol (COSS 80). Moreover, in another patient highly reduced 7-hydroxy-MTX production was correlated with severe clinical toxicity. As 7-hydroxy-MTX is a 200 fold less potent dihydrofolic acid reductase inhibitor compared with MTX decreased production of the metabolite may lead to enhanced clinical toxicity which may not be predictable monitoring MTX serum levels alone.

Asunto(s)

RESUMEN

The anion exchange resin cholestyramine binds methotrexate (MTX) effectively in vitro. The binding capacity exceeds that of activated charcoal by a factor of 5.4. On two patients undergoing high-dose MTX therapy it is also shown that cholestyramine binds MTX in vivo. This leads to an enhanced non-renal excretion of MTX. Therefore, cholestyramine may be of clinical value in patients who develop renal function impairment whilst undergoing MTX therapy.

Asunto(s)

RESUMEN

21 patients, aged 1 to 15 years, who developed manifest varicella/zoster-virus infection while on chemotherapy for malignant disease were treated with acyclovir. Drug dosage was 10 mg/kg every eight hours for 5 days as a one hour infusion. The clinical course of the infection in all patients was mild. 1 to 4 (median 2,2) days after beginning of acyclovir therapy the formation of new lesions stopped. Within 4 to 8 (median 5,9) days all vesicles were scabbed . In 13 patients with fever in the beginning the temperature fell within 2 to 6 (median 2,6) days of treatment. The development of visceral involvement was not observed during or after acyclovir therapy. Acyclovir was well tolerated. Tests of the hematopoietic, liver and renal functions before and after acyclovir therapy revealed no adverse effects of the drug. Also the immunologic response seemed not to be impaired. With one exception, all patients investigated had antibodies against varicella/zoster-virus after recovery. In order to prevent varicella infection after household exposure two immunocompetent patients were treated prophylactically with acyclovir tablets (400 mg 5 times a day for 5 days). Both children did not exhibit manifest varicella/zoster infection, but five weeks later they had antibodies against varicella/zoster-virus (KBR 1:10, resp. KBR 1:20).

Asunto(s)

RESUMEN

Computed tomography is the most useful diagnostic method to demonstrate the pathophysiological consequences of secondary craniocerebral neuroblastoma. Hyperostotic metastases with subperiostal epidural tumour plaques as well as tumour deposits displacing and compressing adjacent venous sinuses show up well. Moreover, post-contrast computed tomography is a sensitive method for controlling patients under cytostatic or radiation therapy. In general, cranial computed tomography should be a part of basic diagnostics in neuroblastoma.

Asunto(s)

RESUMEN

Current concepts of pathogenesis and therapy of Wiskott-Aldrich syndrome are discussed, along with demonstrating the case history of a patient with the clinical features of this rare disorder. In addition to the known symptoms there was an elevated blood monocyte count together with a decreased total number of lymphocytes. Immunological analysis of the mononuclear cell fraction revealed an imbalance between mature T-cells, "natural-killer"-cells and monocytes.

Asunto(s)

Asunto(s)