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Reoccurring/high-risk neuroblastoma (NB) tumors have the enrichment of non-RAS/RAF mutations along the mitogen-activated protein kinase (MAPK) signaling pathway, suggesting that activation of MEK/ERK is critical for their survival. However, based on preclinical data, MEK inhibitors are unlikely to be active in NB and have demonstrated dose-limiting toxicities that limit their use. Here, we explore an alternative way to target the MAPK pathway in high-risk NB. We find that NB models are among the most sensitive among over 900 tumor-derived cell lines to the allosteric SHP2 inhibitor SHP099. Sensitivity to SHP099 in NB is greater in models with loss or low expression of the RAS GTPase activation protein (GAP) neurofibromin 1 (NF1). Furthermore, NF1 is lower in advanced and relapsed NB and NF1 loss is enriched in high-risk NB tumors regardless of MYCN status. SHP2 inhibition consistently blocks tumor growth in high-risk NB mouse models, revealing a new drug target in relapsed NB. [Display omitted] • We identify neuroblastoma models as sensitive to SHP2 inhibition • SHP099 sensitivity is correlated with low expression of neurofibromin (NF1) • SHP2 inhibitors inhibit pERK in neuroblastoma cells better than in normal cells • NF1 mutation/expression may predict SHP2 inhibitor response in neuroblastoma In this paper, Cai et al. demonstrate that high-risk neuroblastomas with low NF1 expression are sensitive to SHP2 inhibitors, which may have treatment advantages over MEK inhibitors. Targeting SHP2 blocks neuroblastoma tumor growth. As several SHP2 inhibitors are in clinical trials, SHP2 inhibitors may benefit high-risk NB patients. [ABSTRACT FROM AUTHOR]

Background Various kinds of immune-related adverse events (irAEs) are caused by the usage of immune checkpoint inhibitors (ICI), which occasionally develop to severe conditions such as colitis and adrenal gland insufficiency. Since we are unable to anticipate when irAEs may occur, it is crucial to be informed of administration history of ICI on urgent visit. Methods We have utilized PDCA cycle Method to improve the quality of countermeasures for irAEs at the emergency room (ER). First, we invented an icon showing the patients treated with ICI on electronic medical records. Second, ICI-specified urgent sets of clinical examination were made to cover the spectrum of irAEs. Third, direct call system to either attending physician or chemotherapy team was established. And then a flow chart to manage irAEs has been prepared since September 2018. Retrospective examination was conducted to check whether the invented system work properly.[Results] Among 19 patients on ICI, four visited ER during these 4 months.Three cases were seen according to the flow chart, while one with grade 2 diarrhea was found not to undertake any examinations at ER, due to the complete lack of knowledge concerning ICI and irAEs.We informed all of the doctors of this flow chart at doctors' office committee and gave a lecture for the residents about the significance of irAEs and how to manage these patients at ER. Conclusions We are monitoring patients on ICI to check whether their management be performed in safety on urgent visit. [ABSTRACT FROM AUTHOR]