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J Boos

Publications and source records attributed to J Boos.

86 records · Page 5Linked to original sources
PubMedDate not supplied

Asparagine concentration in plasma after 2,500 IU/m(2) PEG-asparaginase i.v. in children with acute lymphoblastic leukemia.

UNLABELLED: Polyethylene glycol conjugated asparaginase (PEG-ASNase) can be substituted in cases of hypersensitivity to native Escherichia coli asparaginase. We measured asparagine (asn) levels in plasma after a single dose of 2,500 IU/m(2) i.v. PEG-ASNase (Oncaspar) in consolidation treatment of ALL and compared those with data from the previous protocol COALL-05-92. This protocol was similar to COALL-06-97, except that children had been given 45,000 IU/m(2) C-ASNase instead of PEG-ASNase. PATIENTS AND METHODS: Between May 2000 and December 2001 seventy-one children (38 boys, 33 girls) with newly diagnosed ALL treated according to the multicenter protocol COALL-06-97 were investigated in this study. Four hundred and seventy-four plasma samples (71 patients) were analysed by ion exchange chromatography after column derivatization with o-phthaldialdehyde. For comparison data (350 plasma samples) from 51 patients treated according to the protocol COALL-05-92 were available. The same method for detection of asn in plasma was used. RESULTS: The median asparagine level in plasma after 2,500 IU/m(2) PEG-ASNase i.v. was below the limit of detection for at least 5 weeks in 81 % of the patients. When divided into high risk (HR) and low risk (LR) group, HR patients who had previously received one dose more of C-ASNase showed a markedly shorter depletion than the LR patients compatible with a higher risk of antibody formation and consequent silent inactivation after a higher number of exposures to ASNase. In the previous protocol COALL-05-92 median asn levels in plasma after 45,000 IU/m(2) native C-ASNase i.v. were below the limit of detection for at least 5 weeks in 65 % of the patients. CONCLUSIONS: 2,500 IU/m(2) PEG-ASNase led to an equally long depletion of asn in plasma as did 45,000 IU/m(2) native C-ASNase i.v. used in COALL-05-92.

Adolescent↗
PubMedDate not supplied

[Drug development in paediatric oncology].

Cure rates in children with cancer exceed 75 % today. Notwithstanding this high success rate, 60-90 % of drugs employed in Paediatric Oncology are used off label. Comprehensive pre-clinical screening of candidate substances may help to generate entity-specific priority lists and to be faster and more selective in feeding promising candidates into the development process of drugs for use in children. The upcoming EU regulation "Better medicine for children" offers professional societies and their trial groups the opportunity to upgrade existing structures and benefit from the expected increase in paediatric clinical trials. Networking joining more national and international institutions and boards may serve to expand the repertoire of clinical trials and to establish powerful structures. Such a network may be an attractive partner for the drug industry and may thus eventually lead to a reduction in off label use in paediatric oncology.

Antineoplastic Agents↗
PubMedDate not supplied

[Pharmacokinetics of etoposide short-term infusions within the scope of the GPOH therapy protocol].

Important interpatient variability of etoposide pharmacokinetics during continuous infusion has been reported and drug level targeting, therefore, been suggested. The current German therapeutic protocols are mainly based on short-term infusion. We determined pharmacokinetic parameters during short-term infusion in 18 children aged between 10/12 and 17 years on different therapeutic schedules in order to investigate interpatient variability. The dosages ranged from 66 to 200 mg/m2. In the subgroup of patients who received 150 mg/m2 (n = 10) the AUC was 106 +/- 15 micrograms.h/ml (range 82-139), clearance 24 +/- 3 ml/min/m2 (18-31), t1/2 3.5 +/- 0.4. To compare kinetic data of all 21 courses in 18 children, standard AUC was calculated (AUC/100 mg/m2). The AUC then was (68 +/- 17 micrograms.h/ml)/(100 mg/m2). Half-life was 3.3 +/- 0.7 h and total clearance 26 +/- 6 ml/min/m2, respectively. In 5 courses in children < 2 years (< 10 kg), pharmacokinetic parameters were within the normal range. In this group dosage was calculated per kg. Dose reduction of 31% (mean) resulted in 22% (mean) lower AUC's. In conclusion, interpatient variability of etoposide pharmacokinetics during short-term infusion is limited. Dose reduction in children < 2 years is not substantiated by our pharmacokinetic data.

Adolescent↗
PubMedDate not supplied

[Is the pharmacokinetic profile of cytarabine clinically relevant?].

Cytarabine (Ara-C) is a cytotoxic agent which is rapidly metabolized and thus has a short half-life. Consequently, variations of infusion time influence directly the plasma level over time. Individual differences in plasma level courses with identical dosage are irrelevant regarding treatment response. Several studies, however, reported correlation of the leukemic cells' ability to build and retain the metabolite Ara-C-triphosphate (Ara-CTP) intracellularly with clinical response to therapy. The half-life of the intracellular Ara-CTP concentration in myelogenic blasts (AML) is lower than in blasts from children with acute lymphoblastic leukemia (common-ALL). The varying dosage recommendations of conventional (CD), intermediate (ID) and high-dose (HD) Ara-C therapy are based on considerations of cellular pharmacology. ID and HD Ara-C therapy schedules are designed to overcome well-known resistance phenomena thus providing high intracellular Ara-CTP concentrations.

Child↗
PubMedDate not supplied

[Ifosfamide and the metabolites of side chain oxidation--excretion in urine in various pediatric therapeutic protocols].

The precondition for the antineoplastic effect of ifosfamide (Ifo) is the oxydation of the oxazaphosphorine ring system. The 'ring oxidation' by several steps leads to the formation of alkylating mustard. A second metabolic pathway results in the cytostatically inactive metabolites 2- and 3-deschlorethyl-ifosfamide (2-, and 3-d-Ifo). This 'side chain oxidation' plays a quantitatively more important role with ifosfamide than with cyclophosphamide. The urinary excretion of unmetabolized Ifo and of 2- and 3-d-Ifo, which represents the amount of Ifo not activated, has been investigated by capillary gaschromatography in 18 treatment cycles of 14 children with various therapeutic schedules (800, 2000 and 3000 mg/m2 given as bolus, over 1 h or as continuous infusion for 2 respectively 5 days). The total cumulative excretion during 12 completely sampled cycles ranged from 27 to 50% of the given Ifo. Between 14 and 34% could be detected as IFO, 9 to 29% as 3-d-Ifo and 2 to 8% as 2-d-Ifo. In 4 children the amount of 'side chain oxidized' IFO exceeded the amount of unmetabolized Ifo. 24 hours after the end of therapy excretion is nearly complete. No relationship between the excreted amount of unmetabolized Ifo, 2-d-Ifo and 3-d-Ifo and the dose schedule could be determined. There was no clearcut dependency between cumulative dose, the children got in the past, and formation of 2- and 3-d-metabolites.

Adolescent↗
PubMedDate not supplied

[Effect of etamsylate on hemorrhagic diathesis of children with oncologic diseases. Retrospective matched-pair analysis of 64 patients in a study of 100 patients of the Münster University Pediatric Clinic].

The hemostatic efficacy of ethamsylate studied by a matched-pair analysis was not proved to be statistically significant. The appearance of bleeding signs as well as the frequency of platelet transfusions have been examined. An important side-effect was found in patients receiving ethamsylate: severe leucocytopenia (less than 1000 leucocytes/microliters) was noticed more frequently followed by an enhanced susceptibility to infections. The incidence of septic infections was proved to be significantly increased in an extended sample of 100 patients.

Blood Coagulation Tests↗
PubMedDate not supplied

[Antiinfectious prophylaxis in pediatric oncology. Work group "Quality Assurance" of Society for Pediatric Oncology and Hematology (GPOH)].

Infections in disease- and/or chemotherapy-related neutropenia are major, often emergency-type problems in the treatment of pediatric oncology patients and explain the ongoing discussion about antiinfectious prophylaxis. The different aspects of prophylaxis and an overview on the literature are presented. Antiinfectious prophylaxis in pediatric oncology includes the following issues: 1. General aspects such as information for patients and parents on neutropenia and risk of infectious diseases and indication and management of reverse isolation and barrier isolation; 2. antibacterial prophylaxis with oral non-absorbable and oral absorbable antibiotics; 3. Pneumocystis carinii (Pc) prophylaxis; 4. antifungal prophylaxis to prevent disseminated candidiasis and aspergillosis; 5. antiviral prophylaxis, especially varicella-zoster-virus (VZV) post-exposure prophylaxis and cytomegalovirus (CMV) prophylaxis; 6. immunoglobulins and hematopoietic growth-factors (HGF); 7. active immunization. An evaluation of those measures leads to the following conclusions: A major controversy exists regarding antibacterial and antifungal prophylaxis. Probably not effective are the use of reverse isolation and of oral, non-absorbable antibiotics. Oral absorbable antibiotics, antifungal prophylaxis using fluconazole and amphotericin B and the use of hematopoietic growth factors are likely to be effective. Clearly effective are strict hand-washing procedures, Pc and CMV prophylaxis and passive vaccination against VZV in case of VZV exposure of a seronegative patient.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

[Pharmacokinetic aspects of oral administration of etoposide].

BACKGROUND: Etoposide is a cytotoxic agent which is frequently employed in paediatric oncology and which is available for intravenous as well as oral application. Many advantages of the formulation for oral use have been opposed by concerns about its interindividually varying bioavailability. The influence of the dosage of etoposide on its activity and toxicity ("schedule dependency") has also been discussed. The present paper deals with the pharmacokinetics of oral etoposide focusing on the interindividual variability. PATIENTS: Sixteen patients aged between 3 and 73 years received oral etoposide at a dosage of 28 mg/m2 to 149 mg/m2 in combination with oral trofosfamide for palliation. METHOD: HPLC was used to measure total and free serum etoposide in 16 patients, and the etoposide concentration in several urine samples from 8 patients. Pharmacokinetic parameters were normalized to a dosage of 100 mg/m2. RESULTS: The peak serum concentration, the time to peak concentration, the area under the concentration-time curve, the terminal half-life and the apparent clearance after oral application were calculated to be 6.7 micrograms/ml, 2.1 h, 51.8 (microgram.h/ml)/(100 mg/m2), 5.6 h, and 40.3 ml/min for total etoposide, and 0.23 microgram/ml, 1.9 h, 1.76 (microgram.h/ml)/ (100 mg/m2), 5.9 h, and 1172 ml/min for free serum etoposide, respectively. On an average, urinary recovery of etoposide was 21% of the oral dose. The fraction of free etoposide was calculated to be close to 4%. Regarding the systemic exposure to etoposide, a variation coefficient of 40% was determined. Additional studies showed that the interindividual variability mainly concerned the peak levels, while the duration for which intermediate etoposide levels were maintained varied less between individuals. On simulating different dosage schedules, it was seen that the duration of intermediate concentrations (0.5-2 micrograms/ml) may be extended significantly by dividing the daily dose of etoposide into two oral applications. CONCLUSION: The total systemic exposure under oral etoposide treatment varies considerably between individuals. Extended intervals of intermediate etoposide concentration and less variation are, however, possible with oral therapy. Dividing the daily dose into two applications seems advisable. Future studies are warranted to test hypotheses on pharmacokinetic-pharmacodynamic aspects by pharmacological drug monitoring.

Administration, Oral↗
PubMedDate not supplied

[Prognosis of children with acute myelocytic leukemia after first relapse].

UNLABELLED: Nearly 40% of children treated within the AML BFM studies experience recurrence of their disease after having achieved remission. In our retrospective analysis we tried to estimate prognosis after relapse in children treated with intensive relapse regimens and studied the impact of prognostic factors for second remission and survival. PATIENTS: 102 patients suffering from first relapse were treated intensively according to the relapse protocols BFM REZ91 and REZ93 or intensive salvage therapy consisting of double induction with high dose Ara-C, mitoxantrone and VP-16. Once in CR, patients continued to receive a 6-week consolidation and either allogeneic or autologous bone marrow transplantation (BMT). RESULTS: Time to relapse was in median 1.1 years, range 0-8 years. Fifty-two of 102 pts. (51%) achieved 2nd remission (CR), 10 (10%) partial remission, 37 (36%) were nonresponders, and 3(3%) died early during salvage therapy. Twenty-seven were still in CR, median 2.5 years, range 0.4-7.0 years, with an overall survival of 21%, SE 5% after 5 years. The response and survival rate was similar in all treatment groups. Fifty patients were transplanted, 43 being in 2nd CR, and 7 with residual blasts. Twenty-seven patients received an allograft: Twenty-one from a matched sibling (MSD), 1 from a haploid and 5 from a matched unrelated donor (MUD); 23 received an autograft. None of the patients transplanted in partial remission survived. Whereas 7 of 16 patients were alive after MSD in 2nd CR, 1 after haploid BMT. Four of 5 patients died after MUD BMT. Multivariate risk factor analysis revealed duration until relapse to be the most important factor for survival after relapse. The maximum risk-ratio was obtained at a threshold value of 1.5 years after diagnosis resulting in a 5-year survival of 10%, SE 5% for early relapse, and 40%, SE 10% for late relapse, p logrank 0.0001. CONCLUSION: Intensive relapse regimens can induce a 2nd CR in half of the patients. Children with late relapse (> 1.5 years after diagnosis) have a realistic chance for longtime survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

[Intracellular retention of cytarabine-triphosphate (Ara-CTP) in blasts of children with acute lymphoblastic leukemia. Correlation with clinical course parameters].

BACKGROUND: Cellular uptake and intracellular phosphorylation to the nucleotide cytosine arabinoside-triphosphate (Ara-CTP) is the precondition for the cytostatic effect of cytarabine. The pharmacokinetics of Ara-CTP in leukemic cells was reported to be of clinical importance in adult nonlymphoblastic leukemia. Therefore, the role of intracellular Ara-CTP formation and retention was investigated in blast cells from children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: At the time of diagnosis, peripheral or bone marrow blast cells from 41 children with ALL and 13 with relapsed ALL were incubated in Ara-C containing medium (1 hour, 1 or 3 micrograms/ml) followed by reincubation in Ara-C free medium (3 h). Intracellular Ara CTP formation and Ara-CTP retention were determined. MAIN RESULTS: Ara-CTP formation did not show marked differences between the different immunological subtypes. Ara-CTP retention, however, was significantly lower in T-ALL (37 +/- 15%, n = 8) compared to non-T-ALL (67 +/- 25%, n = 33; p < 0.003). Ara-CTP retention was also significantly different in children with and without persistence of peripheral blast cells after one week of prednison treatment (71 +/- 30%, n = 9 and 53 +/- 19%, n = 21; p = 0.031) as well as in children with and without complete bone marrow remission on day 15 of the ALL-BFM treatment protocol (66 +/- 17%, n = 19 and 43 +/- 18%, n = 11; p = 0.018). Ara-CTP retention was inversely correlated with the risk groups defined by the ALL-BFM treatment protocols (standard 79 +/- 29, intermediate 59 +/- 25, high risk 47 +/- 21%). A trend towards lower Ara-CTP retention was observed in relapsed leukemias (relapsed non-T-ALL 51 +/- 17%, p = 0.061). The difference in the probability of event free survival (following risk group adapted treatment according to ALL-BFM trials) between children with high (> or = 72%; 0.92 +/- 0.08) and low (< 72%: 0.58 +/- 0.15) Ara-CTP retention up to now did not reach statistical significance (p = 0.12). CONCLUSIONS: The more rapid decrease of cellular Ara-CTP in T-cell leukemia and children at higher clinical risk groups provide a pharmacokinetic rationale for prolonged infusion duration as an alternative to the intensification by dose escalation alone.

Adolescent↗
PubMedDate not supplied

[HIT-GBM: multicenter study of treatment of children with malignant glioma].

The German society for paediatric oncology and hematology starts a clinical study for the treatment of children with glioblastoma, multifocal astrocytoma grade 3, brain stem grade 3 astrocytoma and typical diffuse ponsglioma. Conventional fractionated radiotherapy (54 Gy) will follow surgery. Simultaneously an additional experimental treatment will be given. The experimental treatment study will change every second year and starts with oral trofosfamide 100 mg/m2/d and VP16 25 mg/m2/d.

Antineoplastic Agents, Alkylating↗
PubMedDate not supplied

Inhibition of hypercoagulation by antithrombin substitution in E. coli L-asparaginase-treated children.

Acquired deficiency of antithrombin (AT), which in some patients could lead to thrombosis, has been a serious side effect of protocols which incorporate E. coli L-asparaginase (ASP) for the treatment of acute lymphoblastic leukaemia (ALL). In a longitudinal, prospective, non-randomized study children with ALL (n=27) were treated according to the protocol ALL-BFM-90. During the induction phase using prednisone, vincristine, daunorubicin and ASP, AT substitution was performed in 15/27 patients, when their plasma concentration decreased below 60% of normal with a concomitant increase of D-dimer formation. After the administration of the AT concentrate the patients, plasma concentration of AT increased and remained elevated after 18, 48, and 72 h. In addition, the plasma concentration of enhanced thrombin generation, D-dimer formation and plasminogen activator inhibitor 1 decreased towards normal levels. Although the observed laboratory findings may serve as evidence for a possible clinical benefit of AT substitution during ASP treatment, further randomized studies are requested to evaluate whether the use of prophylactic AT administration could reduce the incidence of thromboembolic events in childhood acute leukaemia.

Antineoplastic Agents↗
PubMedDate not supplied

Influence of two different Escherichia coli asparaginase preparations on fibrinolytic proteins in childhood ALL.

BACKGROUND: Alterations in hemostasis have frequently been observed in patients with leukemia, and thrombotic events are well documented in patients receiving L-asparaginase (ASP) as a single agent or in combination with vincristine, prednisone (sometimes complemented by an anthracycline). The present study was designed to evaluate prospectively fibrinolytic parameters in leukemic children receiving different E. coli ASP preparations (Kyowa ASP, n = 20; Bayer ASP, n = 20), and to relate changes in the fibrinolytic system to serum ASP activity. MATERIALS AND METHODS: Blood samples for coagulation studies were obtained together with serum samples for pharmacokinetic monitoring in the same venipuncture (before the first and 6th-7th doses of ASP). RESULTS: Patients receiving Kyowa ASP showed significantly (0.0001) enhanced ASP-activity compared to children treated with the Bayer preparation. Significantly decreased values of fibrinogen (p < 0.001), plasminogen (p < 0.0002) and alpha 2-antiplasmin (p < 0.0003) were found in the Kyowa group, along with significantly enhanced thrombin generation (F1 + 2; p < 0.001), t-P (p < 0.01) and D-dimer levels (p < 0.05). In contrast, PAI 1 activity demonstrated no significant difference in the two E. coli ASP administered. CONCLUSIONS: Changes in fibrinogen, plasminogen, alpha 2-antiplasmin and D-dimer are clearly associated with ASP activity during the course of ASP administration in children with ALL.

Antineoplastic Agents↗