BackgroundHemophagocytic Lymphohistiocytosis (HLH), a rare but potentially fatal syndrome of immune hyperactivation, may be an under-recognized immune-related adverse event (irAE). Unlike other irAEs, HLH triggered by immune checkpoint blockade is not well described; no particular diagnostic guidelines and treatment regimens exist. The HLH-2004 criteria remain as the common diagnostic guide. For the treatment of HLH, various combinations of chemotherapeutic, immunosuppressive and glucocorticoid agents are used.Case presentationWe report a case of HLH in a 58-year-old metastatic melanoma patient who was undergoing immune checkpoint blockade with pembrolizumab, a programmed cell death-1 (PD-1) receptor inhibitor. The patient presented with fever, upper normal sized spleen, anemia, thrombocytopenia, hypertriglyceridemia, hyperferritinemia, reduced NK cell activity and elevated sCD163 levels, fulfilling the Histiocyte Society HLH-2004 diagnostic criteria. Our patient was successfully treated with oral prednisone (1 mg/kilogram/day), suggesting that HLH from immune checkpoint inhibitors may respond to steroids alone.ConclusionEarly diagnosis and treatment of HLH are critical to avoid progressive tissue damage, organ failure and possibly death. HLH should be suspected in clinical presentations with fever, cytopenias and hyperinflammatory markers. HLH in the setting of immune checkpoint blockade may be treated with steroids only but further evidence is required.
Fig 1. Complete response of squamous cell carcinoma to pembrolizumab in kidney allograft recipient (A) before initiation of pembrolizumab and (B) after four doses of treatment with pembrolizumab.
NEURO-ONCOLOGY • NOVEMBER 2017efit. Overall survival is variable but less than 10% of GBM patients survive 5 years, making it one of the most aggressive and clinically intractable cancers. The main cause of poor prognosis is the rapid emergence of recurrent disease, despite extensive removal of cancer cells from the primary site. Here, by using patient-derived xenografts we demonstrate that GBM is fueled by a mixture of fast-and slow-cycling cells. In vivo, treatment based on TMZ triggers a transient cell arrest in G2/M and DNA damage but does not promote cell death. In particular, by causing DNA double strand breaks, TMZ induces the autophosphorylation of ataxia telangiectasia mutated (ATM S1981) and the downstream phosphorylation of histone H2AX (YH2AX). In response to TMZ, GBM cells undergo a transient switch to a p53-driven mesenchymal phenotype with significant up-regulation of CD44, Vimentin and Gfap expression. The transient phenotype switch is followed by down-regulation of p53 and the emergence of treatment-resistant GBM. Illumina-based gene expression profiling and marker analysis reveal striking similarities between matched control and treatment-resistant tumors. ChIPseq experiments are currently ongoing to identify critical nodes of phenotype switch. We are also using genetically-engineered mouse models of gliomas to understand if wild-type p53 drives a mesenchymal phenotype in Nestin-, Gfap-, Glast-, ApoE-and Pla2-derived tumors. Altogether, these results contribute to increase our knowledge of the biology of GBM growth and treatment resistance and identify p53 as a driver of phenotypic plasticity.
TMOD-23. ESTABLISHMENT AND CHARACTERIZATION OF IDH1-
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