No abstract

Key points Finding an inherited complement abnormality in HSCT-associated TMA provides a rationale for the use of a complement inhibitor. Alternative complement inhibitors such as Coversin should be considered in patients who are resistant to eculizumab.

Somatic mutations in ACVR1 are found in a quarter of children with diffuse intrinsic pontine glioma (DIPG), however there are no ACVR1 inhibitors licensed for the disease. Using an Artificial Intelligence-based platform to search for approved compounds for ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (Kd=150nM) and reduce DIPG cell viability in vitro, but has limited ability to cross the bloodbrain-barrier. In addition to mTOR, everolimus inhibits ABCG2 (BCRP) and ABCB1 (P-gp) transporters, and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination is well-tolerated in vivo, and significantly extended survival and reduced tumor burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Four patients with ACVR1-mutant DIPG were treated with vandetanib plus mTOR inhibitor, informing the dosing and toxicity profile of this combination for future clinical studies. STATEMENT OF SIGNIFICANCE25% patients with the incurable brainstem tumour DIPG harbour somatic activating mutations in ACVR1, however there are no approved drugs targeting the receptor. Using Artificial Intelligence, we identify and validate the novel combination of vandetanib and everolimus in these children based upon both signalling and pharmacokinetic synergies, experimentally and clinically.Research.

Postmortem blood and bile acylcarnitine profiles are influenced by several variables, and PMI can influence MS/MS acylcarnitine results. Metabolic disease may present as SUDI and may be identified from postmortem samples.

Fatal aspiration of a foreign body is rare in this population. The cases involve normal children who aspirate food, particularly grapes. There are typically minimal, non-specific findings at autopsy.