Summary. The standard therapy for patients with fever and chemotherapy-related neutropenia is hospitalization and infusion of broad-spectrum antibiotics. Early discharge of a de®ned group of patients at low risk for septicaemia would be of great advantage for these patients. In this study plasma interleukin-8 (IL-8) and interleukin-6 (IL-6) levels measured at start of fever (n 72) could de®ne a low-risk group of febrile patients with neutropenia due to chemotherapy. For this purpose we collected and analysed data on 72 fever episodes from 53 patients with chemotherapy-related neutropenia, aged between 1 and 66 years. Of the 72 episodes, 18 were classi®ed as bacteraemia and/or clinical sepsis (sepsis group). The IL-6 and IL-8 plasma concentration were signi®cantly increased in patients with chemotherapy-related neutropenia and fever due to bacteraemia versus fever of non-bacterial origin (P 0´043 and P 0´022 respectively). Logistic regression analysis, with sepsis as the outcome variable, revealed signi®cant effects of age combined with either IL-6 or IL-8. Sepsis occurrence was lowest for patients <16 years and highest in patients between 16 and 50 years, and was higher in patients with increased IL-6 (P 0´032) or IL-8 (P 0´049). No signi®cant effect of leucocyte count, C-reactive protein, sex or underlying malignancy at presentation was detected. The plasma IL-6 and IL-8 levels were fairly strongly correlated (Pearson r 0´62). Using a cut-off value with 100% sensitivity, both IL-8 and IL-6 could de®ne a low-risk group of neutropenic patients of 28% (CI 15±40%) at the start of the febrile period. Intervention studies are warranted to con®rm this result and to investigate whether an early discharge based on IL-8 or IL-6 measurement is safe, increases the quality of life, and results in cost savings.

No abstract

Animal experiments suggest that the response of acute-phase proteins (APPs) modulates the inflammatory reaction following tissue injury. To study this in man we investigated the relation between a number of APPs, including fibrinogen and alpha 2-macroglobulin, and the inflammatory edema induced by a primary immunization against cholera, typhoid, and yellow fever. Vaccination induces a significant APP response; however, only alpha 2-macroglobulin and fibrinogen were of importance to the amount of edema, measured 24 h after vaccination. High plasma levels of alpha 2-macroglobulin strongly inhibit the amount of edema, whereas a high level of fibrinogen proved to be a stimulating factor. This holds both for the basal prevaccination levels and the postvaccination levels. The normal variation of the plasma concentration of these proteins in healthy subjects seems to be a determining factor to the amount of edema in this kind of injury.

Prof. dr. F.G.M. RusselThe research described in this thesis was financially supported by Stichting Kinderen Kankervrij (KiKa). 7 Contents CONTENTS Chapter 1 IntroductionChapter 2 Age as prognostic factor in patients with osteosarcoma Bone. 2011;49:1173-1177 Chapter 3 Survival trends and long term toxicity in pediatric patients with osteosarcoma Sarcoma. 2012;636405Chapter 4 Taqman genotyping assays can be used on decalcified and paraffin embedded tissue from patients with osteosarcomaPediatr Blood Cancer. 2011;56:35-38 Chapter 5 A pilot study: Genetic variants may influence methotrexate plasma concentrations in pediatric malignancies Chapter 6The role of the MTHFR 677C>T polymorphism in methotrexate -induced liver toxicity: a meta-analysis in patients with cancer J. 2014;14:115-119 Chapter 6B Is there a role for the MTHFR 677C>T and the 1298 A>C polymorphism methotrexate induced liver toxicity? . 2014;15:1401-1403 . Treatment with bisphosphonates such as pamidronate or zoledronic acid in addition to chemotherapy is only applied to a hand full of patients and the clinical benefit of these agents need to be studied in a prospective randomized trial 21,22 . As the incidence of osteosarcoma is between 3 and 4.5 cases per million, it will take several years to include a large number of patients in a prospective trial to study the efficacy of these new agents. Furthermore, the a priori knowledge of which patients will benefit from new agents will help to define new strategies in order to improve outcome and decrease the burden of late effects. We hypothesized that pharmacogenetics may help to stratify patient into good responders and bad responders. More insight in the genetic determinants involved in drug response may help in designing more effective therapeutic approaches, e.g. targeted cancer therapy for patients not responding on standard therapy ( Figure I). Pharmacogenomics Pharmacogenomics O s t e o s a r c o m aOsteosarcoma is the most common primary tumor of the bone, which may occur at all ages but is seen predominantly in adolescents. Nevertheless, it is still a rare disease with a worldwide incidence rate of 3-4 cases per million per year 1 . Untreated, osteosarcoma is fatal. Aggressive local growth and the tendency to metastasize mark its course. In the 1970s when surgery was the only treatment option, the prognosis for patients with osteosarcoma was poor, with long-term survival rates of less than 20% 2 . Today, therapy is changed to a multi-disciplinary approach, focusing on both local and systemic manifestations of osteosarcoma, incorporating surgery and chemotherapy. The use of this multi-disciplinary approach has resulted in survival rates of 60-65% since the late 1980s Drug related phenotypeThe candidate gene approach is a hypothesis driven method that investigates genetic variants in genes known to be associated with the trait of interest e.g. metabolism of the used medication. However, replication studies often show inconsistent results making it difficult to interpret the clinical v...