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  • 1
    ISSN: 1432-0932
    Keywords: Key words Spinal fusion ; Autogenous bone graft ; Osteoblasts ; Prediction ; Culture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The capacity of the individual patient to initiate osteoblast proliferation as a predictor for successful lumbar spinal fusion has not yet been reported. The objectives of this study were, first, to analyze the relationship between in vitro osteoblast proliferation and clinical bony fusion in the individual patient in order to predict the fusion outcome and, second, to measure the effect of preoperative tobacco smoking on osteoblast proliferation. Sixty-one patients (mean age 46 years) underwent posterolateral lumbar fusion in the period 1994–1995. Thirty-eight patients received CD pedicle screw implants and 23 received posterolateral fusions alone. During surgery, autogenous iliac bone was harvested and 1 g of trabecular bone without blood or bone marrow was then isolated for cell culturing. The cultures were classified as excellent (confluence within 4 weeks), good (confluence between 4 and 6 weeks) and poor (no or poor growth). Spine fusion was evaluated by two independent observers from plain anterior-posterior, lateral, and flexion/extension radiographs taken 1 year postoperatively, and the functional outcome was measured by the Dallas Pain Questionnaire (DPQ). Twenty-three patients had excellent, 19 good, and 19 poor in vitro osteoblast proliferation. Bony fusion was obtained in 77% of patients: 83% in the CD instrumentation group and 70% in the non-instrumentation group (NS). There was no significant correlation between osteoblast proliferation and spinal fusion or functional outcomes when analyzing the CD instrumentation and non-instrumentation groups together or separately. Elderly patients had a significantly poorer osteoblast proliferation than younger patients (P 〈 0.008). Preoperative tobacco consumption had no discernible effect on osteoblast proliferation, and no correlation between smoking and fusion was found. Further refinement of autologous osteoblast culturing may provide a biological tool for selection of patients who require biological enhancement of their bone fusion capacity. The poorer osteoblast proliferation related to advanced age supports the important negative biological influence of age on bony fusion. However, with more sensitive testing and better discrimination, other results are possible – or can in any event not be excluded.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1569-8041
    Keywords: carboplatin ; drug-target interaction ; ovarian cancer ; pharmacokinetically based dosing ; pharmacokinetics ; platinum-DNA adducts
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Platinum based drugs are active agents in epithelial ovarian cancer and increased platinum drug dose intensity is thought to lead to improved survival, because of the largely untested assumption that increased dose intensity results in an increased interaction of the platinum drug with its target, DNA. In a previously reported phase I trial (Lind et al., J Clin Oncol 1996; 14: 800–5), carboplatin dose intensity was increased by the use of G-CSF to support the bone marrow and using pharmacokinetically-guided carboplatin dosing. The objectives of this study were to validate the carboplatin dosing formula during high dose intensity therapy and evaluate the relationship between systemic carboplatin exposure and Pt-DNA adduct levels in peripheral blood leucocytes. Patients and methods: A total of 17 patients were studied over four levels of dose intensification. The carboplatin dose was calculated using the ‘Calvert formula’. Levels of drug-target interaction in peripheral blood leukocytes were measured using an immunoassay based on a monoclonal antibody that recognises DNA-platinum adducts. Pharmacokinetic measurements were carried out using a previously validated single sample method. Results: The area under the curve of concentration of unbound carboplatin in plasma versus time (AUC) for target AUC values of 5, 7 and 9 mg/ml·min were: 5.6 ± 1.0, 7.3 ± 0.7 and 9.8 ± 0.5 mg/ml·min (mean ± S.D.). There was a good correlation between target and achieved dose intensities (r2 = 0.899) and the slope of the linear regression line was 0.95 (± 0.09 SD) not significantly different to 1.0 (P 〉 0.6). The levels of immunoreactive DNA adducts were not detectable at a target AUC of 5 mg/ml·min but increased progressively at the higher AUC levels. Accumulation of adducts between courses was not detected. Conclusions: Pharmacokinetically-based carboplatin dosing during high intensity therapy accurately predicted the dose required to achieve a target AUC and resulted in consistent patient exposure to active drug. During the dose escalation study, peripheral blood leucocyte DNA platinum-DNA adduct levels were positively related to drug dose and drug AUC.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1573-7373
    Keywords: glioma ; RMP-7 ; carboplatin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The selective bradykinin analogue, RMP-7, transiently increases the permeability of the blood brain barrier and the delivery of hydrophilic agents into brain tumours. In 87 recurrent glioma patients (WHO Grade III/IV, median age 46, Karnofsky 70%) clinical and Magnetic Resonance Imaging (MRI) responses to i.v. cycles (q 28 days) of RMP-7 (300 ng/kg given as a 10 min infusion) and carboplatin (AUC 4-9) were assessed. 45 of these patients were chemotherapy naive (CN-RMP) and 42 had received one prior course of chemotherapy (CP-RMP). Neurological impairment, performance status and steroid use were measured prior to dosing at each cycle and tumour volume by 3-D MRI at the end of cycles 2, 4, 6, 9 and 12. Clinical evaluation of response demonstrated that 61% of CN-RMP patients were either stable or improved whilst this was 39% for CP-RMP patients, of which 37% and 8% improved respectively. Radiological evaluation showed 79% of CN-RMP patients were either stable, partial or complete responses and 24% for CP-RMP patients, of which 32% and 5% were CR or PR respectively. The median duration of response was 30.3 weeks in CN-RMP patients and 19.6 weeks in the CP-RMP group. Lack of response was associated with substantial baseline tumour volume. Drug toxicity was as previously reported for carboplatin. 11 patients had treatment-associated transient focal seizures. These results indicate that RMP-7 and carboplatin have significant activity in recurrent malignant glioma following radiotherapy.
    Type of Medium: Electronic Resource
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