How I Diagnose and Treat Acute Infection-associated Purpura Fulminans.

Purpura fulminans (PF) is a rare but devastating complication of sepsis characterized by a highly thrombotic subtype of disseminated intravascular coagulation (DIC). A medical emergency, PF cases often require the involvement of consultant hematologists to assist with diagnosis and management of patients who are in a highly dynamic and deteriorating clinical situation. Patients who survive past the first 24 to 72 hours often die from complications of unchecked thrombosis rather than from shock, and survivors are usually left with severe scarring and tissue loss.

Isocitrate Dehydrogenase Mutations in Cancer: Mechanisms of Transformation and Metabolic Liability.

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are metabolic enzymes that interconvert isocitrate and 2-oxoglutarate (2OG). Gain-of-function mutations in and occur in a number of cancers, including acute myeloid leukemia, glioma, cholangiocarcinoma, and chondrosarcoma. These mutations cripple the wild-type activity of IDH and cause the enzymes to catalyze a partial reverse reaction in which 2OG is reduced but not carboxylated, resulting in production of the ()-enantiomer of 2-hydroxyglutarate (()-2HG).

(R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers.

Unlabelled: Oncogenic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 occur in a wide range of cancers, including acute myeloid leukemia (AML) and glioma. Mutant IDH enzymes convert 2-oxoglutarate (2OG) to (R)-2-hydroxyglutarate [(R)-2HG], an oncometabolite that is hypothesized to promote cellular transformation by dysregulating 2OG-dependent enzymes. The only (R)-2HG target that has been convincingly shown to contribute to transformation by mutant IDH is the myeloid tumor suppressor TET2.

Secondary IDH1 resistance mutations and oncogenic IDH2 mutations cause acquired resistance to ivosidenib in cholangiocarcinoma.

The mutant IDH1 inhibitor ivosidenib improves outcomes for patients with IDH1-mutated cholangiocarcinoma, but resistance inevitably develops. Mechanisms of resistance and strategies to overcome resistance are poorly understood. Here we describe two patients with IDH1 R132C-mutated metastatic cholangiocarcinoma who developed acquired resistance to ivosidenib.