Paediatric Strategy Forum for medicinal product development of multi-targeted kinase inhibitors in bone sarcomas: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

The eighth Paediatric Strategy Forum focused on multi-targeted kinase inhibitors (mTKIs) in osteosarcoma and Ewing sarcoma. The development of curative, innovative products in these tumours is a high priority and addresses unmet needs in children, adolescents and adults. Despite clinical and investigational use of mTKIs, efficacy in patients with bone tumours has not been definitively demonstrated. Randomised studies, currently being planned or in progress, in front-line and relapse settings will inform the further development of this class of product. It is crucial that these are rapidly initiated to generate robust data to support international collaborative efforts. The experience to date has generally indicated that the safety profile of mTKIs as monotherapy, and in combination with chemotherapy or other targeted therapy, is consistent with that of adults and that toxicity is manageable. Increasing understanding of relevant predictive biomarkers and tumour biology is absolutely critical to further develop this class of products. Biospecimen samples for correlative studies and biomarker development should be shared, and a joint academic-industry consortium created. This would result in an integrated collection of serial tumour tissues and a systematic retrospective and prospective analyses of these samples to ensure robust assessment of biologic effect of mTKIs. To support access for children to benefit from these novel therapies, clinical trials should be designed with sufficient scientific rationale to support regulatory and payer requirements. To achieve this, early dialogue between academia, industry, regulators, and patient advocates is essential. Evaluating feasibility of combination strategies and then undertaking a randomised trial in the same protocol accelerates drug development. Where possible, clinical trials and development should include children, adolescents, and adults less than 40 years. To respond to emerging science, in approximately 12 months, a multi-stakeholder group will meet and review available data to determine future directions and priorities.

Ischaemic Preconditioning and Intermittent Clamping Does not Influence Mediators of Liver Regeneration in a Human Liver Sinusoidal Endothelial Cell Model of Ischaemia-Reperfusion Injury.

BACKGROUND: The role of surgical technique on liver regeneration following surgery remains inconclusive. The aim of the study was to assess the effect of ischaemic preconditioning (IPC) and intermittent clamping (IC) on mediators of regeneration produced by human liver sinusoidal endothelial cells (SECs), using an in vitro hypoxia-reoxygenation model to mimic ischaemia-reperfusion injury (IRI). METHODS: Following extraction from samples obtained from liver resection (n = 5), confluent culture flasks of SECs were subjected to IRI (1 hour hypoxia + 1 hour reoxygenation), IPC prior to IRI (10 minutes hypoxia + 10 minutes reoxygenation + 1 hour hypoxia + 1 hour reoxygenation), IC (15 minutes hypoxia + 5 minutes reoxygenation x 3 + 1 hour reoxygenation) and compared to controls. The production of various mediators was determined over 48 hours. RESULTS: Interleukin (IL)-6, IL-8, granulocyte-colony stimulating factor (G-CSF) and hepatocyte growth factor (HGF) were produced by SECs. Both IPC and IC did not significantly influence the profile of IL-6, IL-8, G-CSF and HGF by SECs compared to IRI over the study period. CONCLUSION: IPC and IC did not influence the production of pro-regenerative mediators in a SECs model of IRI. The role of surgical technique on liver regeneration remains to be determined.