Continuous infusion of factor concentrates in children with haemophilia A in comparison with bolus injections.

Although the concept of continuous infusion (CI) of factor concentrates is well known, prospective paediatric data are rare. We present a prospective open-labelled non-randomized study focusing on safety, efficacy and factor VIII (FVIII) usage compared with bolus injections (BI) in children. In 43 consecutive patients (0.5-17 years; median: 9.6) undergoing different operations, CI was started with an initial FVIII-bolus of 70 IU kg(-1) bodyweight, followed by a median infusion rate of 4.4 IU kg(-1) h(-1) (range: 2.8-9.5) dose adjusted for daily FVIII levels (target: 60-80%). No direct serious adverse events occurred; however, two out of 43 patients, both from the group of four patients with less than 20 exposure days (ED) before starting CI, developed a high-responding inhibitor. Two CI patients showed mild thrombophlebitis or rash. Infusion rates needed to achieve adequate FVIII levels were highly predictable and could be reduced because of decreasing FVIII clearance. Bleeding, requiring additional boli, was observed in eight out of 43 patients. Therapy duration and factor usage of CI were influenced by the procedure, but not by the product used or thrombophilia. Twelve of these CI patients were compared with 12 contemporary consecutive age- and procedure-matched BI patients. Compared with BI patients, CI patients saved 30% FVIII (812.9 vs. 563.2 IU kg(-1), P < 0.006). We conclude that CI forms a safe and effective method for perioperative care in children and reduces factor usage. Because of the unknown risk of inhibitor development, we will use CI only in patients beyond 20 ED.

Relationship between chemotherapy with paclitaxel, cisplatin, vinorelbine and titanocene dichloride and expression of proliferation markers and tumour suppressor gene p53 in human ovarian cancer xenografts in nude mice.

PURPOSE: In this study the relationship between therapy with paclitaxel, cisplatin, vinorelbine and titanocene dichloride and of the expression of proliferation markers (ki67 and S-phase fraction) and tumour suppressor gene p53 was analyzed using a human ovarian cancer xenograft model. METHODS: Biopsy material from one human ovarian cancer was expanded and transplanted into 102 nude mice. The mice were divided into six groups with different intraperitoneal treatments with paclitaxel, cisplatin, vinorelbine, titanocene dichloride and a control group treated with 0.9% saline solution. After the observation period the tumours were extracted and immunohistochemically stained with monoclonal antibodies against ki67 and p53. The S-phase-fraction was identified by flow cytometry. RESULTS: There where no statistically significant differences. Regarding the treatment groups, the vinorelbine-group showed the highest percentage (53.3%) and the titanocene dichloride-3x40 mg/kg-group the lowest percentage (7.1%) of ki67-positive specimens, whereas in the control group 35.7% of the specimens were positively stained for ki67. The results for the expression of p53 were similar. The vinorelbine-group had the highest percentage of p53-positive specimens (60%), in both titanocene-groups no specimen showed a positive staining for p53 and in the control group 7.1% of the specimens were positively stained for p53. The mean S-phase-fraction was 14.48% (SD +/- 3.98), no statistically significant relation between S-phase-fraction and expression of p53 (p = 0.883) or of ki67 (p = 0.351) could be shown. The change of tumour volume was independent of the results for ki67, p53 and the S-phase-fraction. CONCLUSION: Although, as previously published, a significant difference of tumour volume change occurred between the treatment groups, in this study we could not find a relation between this change of tumour volume and the expression of p53 or ki67. The absolute number of p53- and ki67-positive staining specimens was too small for statistical analysis, therefore the relevance of the differences between the different treatment groups and the control remains unclear. The results for the S-phase-fraction showed no correlation between the change of tumour volume, different treatment protocols or the expression of p53- and ki67. Our findings contribute to the controversy of the influence of chemotherapy on the expression of proliferation markers and p53.