SUMMARYDendritic cell (DC) development and function is critical in the initiation phase of any antigen-specific immune response against tumours. Impaired function of DC is one explanation as to how tumours escape immunosurveillance. In the presence of various soluble tumour-related factors DC precursors lose their ability to differentiate into mature DC and to activate T cells. Gangliosides are glycosphingolipids shed by tumours of neuroectodermal origin such as melanoma and neuroblastoma. In this investigation we address the question of whether gangliosides suppress the development and function of monocyte-derived DC in vitro . In the presence of gangliosides, the monocytic DC precursors showed increased adherence, cell spreading and a reduced number of dendrites. The expression of MHC class II molecules, co-stimulatory molecules and the GM-CSF receptor (CD116) on the ganglioside-treated DC was significantly reduced. Furthermore, the function of ganglioside-treated DC was impaired as observed in endocytosis, chemotactic and T cell proliferation assays. In contrast to monocytic DC precursors, mature DC were unaffected even when higher doses of gangliosides were added to the culture. With regard to their carbohydrate structure, five different gangliosides (GM2, GM3, GD2, GD3, GT1b), which are typically shed by melanoma and neuroblastoma, were tested for their ability to suppress DC development and function. Suppression was induced by GM2, but not by the other gangliosides. These data suggest that certain gangliosides impair DC precursors, implying a possible mechanism for tumour escape.

Metronomic chemotherapy, which is defined by the frequent, repetitive administration of chemotherapeutic drugs at relatively low doses, and without prolonged drug-free break, is an emerging strategy to fight cancer. Initially thought to act by targeting tumor angiogenesis, additional mechanisms have been recently unveiled, and metronomic chemotherapy is now considered to represent a form of multitargeted therapy. Despite representing a genuine alternative for advanced and/or high-risk cancer therapy, the development of metronomic approaches in pediatric oncology is still in the early stage. The few numbers of large-scale state-of-the-art clinical trials, issues regarding terminology and the limited understanding of the complex and intertwined mechanisms of action of metronomic treatments have limited progress in this important field of research. On March 18 and 19, 2010, the 2nd International Workshop on Metronomic and Anti-Angiogenic Chemotherapy in Paediatric Oncology was held in Marseille, France, and brought together clinicians, basic scientists, physician-scientists, trainees, and students from all around the world. The main aim of this international meeting was to provide a unique forum to 1) reflect on the major advances that have been made in this field of research since its creation, 2) communicate results from the most recent clinical trials and preclinical studies, 3) discuss the current and future challenges of the field, and 4) set forth a solid framework for future collaborative biologic and clinical studies. The present report documents the main preclinical and clinical data that were presented in the keynote and best abstract sessions and delivers the key messages from the meeting.

340 consecutive patients with neuroblastoma stage IV were analyzed for the possible impact of chemotherapy on general condition, remission status, event free survival and survival. The children entered the trials NB 79, NB 82 and NB 85 of the German Pediatric Oncology Society (GPO). The patients did benefit from chemotherapy by considerable improvement of the general condition, by achievement of 30-40% complete and 60-70% partial remissions. The event free survival (EFS) rate 5-8 years after diagnosis was 13% for all 299 protocol patients, the survival (S) rate 10%. The median/mean EFS time were 11.6/23.8 months, the median/mean S time 17.0/29.4 months. The use of response rates as early predictors for long term survival is challenged. Addition of PCVm (cisplatinum, cyclophosphamide, Vm 26) to ACVD (adriamycine, cyclophosphamide, vincristine, dacarbazine) in trial NB 82 resulted in an improvement of the long term EFS rate from 5% to 18% (S rates 7----21%). The introduction of IVp (ifosfamide, VP16) and increase of doses (cisplatinum, Vm 26) did not further improve the results. Maintenance therapy (NB 82) revealed a positive influence on the outcome. Shorter intervals for realization of chemotherapy were associated with a trend for better EFS (NB 85). Although the group of children with bone marrow transplantation showed better EFS and S data compared to the unselected chemotherapy group, the advantage was less clear if matched pairs (remission status at the time of BMT) were compared.(ABSTRACT TRUNCATED AT 250 WORDS)

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