PurposeAcute myeloid leukemia (AML) is the most common acute leukemia in adults and is often resistant to conventional therapies. The MYC oncogene is commonly overexpressed in AML but has remained an elusive target. We aimed to examine the consequences of targeting MYC both directly and indirectly in AML overexpressing MYC/Myc due to trisomy 8/15 (human/mouse), FLT3-ITD mutation, or gene amplification.MethodsWe performed in vivo knockdown of Myc (shRNAs) and both in vitro and in vivo experiments using four drugs with indirect anti-MYC activity: VX-680, GDC-0941, artemisinin, and JQ1.ResultsshRNA knockdown of Myc in mice prolonged survival, regardless of the mechanism underlying MYC overexpression. VX-680, an aurora kinase inhibitor, demonstrated in vitro efficacy against human MYC-overexpressing AMLs regardless of the mechanism of MYC overexpression, but was weakest against a MYC-amplified cell line. GDC-0941, a PI3-kinase inhibitor, demonstrated efficacy against several MYC-overexpressing AMLs, although only in vitro. Artemisinin, an antimalarial, did not demonstrate consistent efficacy against any of the human AMLs tested. JQ1, a bromodomain and extra-terminal bromodomain inhibitor, demonstrated both in vitro and in vivo efficacy against several MYC-overexpressing AMLs. We also confirmed a decrease in MYC levels at growth inhibitory doses for JQ1, and importantly, sensitivity of AML cell lines to JQ1 appeared independent of the mechanism of MYC overexpression.ConclusionsOur data support growing evidence that JQ1 and related compounds may have clinical efficacy in AML treatment regardless of the genetic abnormalities underlying MYC deregulation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-015-2766-z) contains supplementary material, which is available to authorized users.

We report a case of vaccine-induced immune thrombotic thrombocytopenia (VITT) in a young man diagnosed 13 days after Ad26.COV2.S COVID-19 (Johnson & Johnson/Janssen) vaccination. He presented to us with five days of progressive left leg pain, thrombocytopenia, hypofibrinogenemia, and markedly elevated D-dimers, but without radiographically-demonstrable thrombosis. Despite negative imaging, we initiated treatment for presumptive VITT given the striking clinical picture that included the timing of his recent adenovirus-based COVID-19 vaccine, leg symptoms, marked thrombocytopenia, and consumptive coagulopathy. He received intravenous immune globulin (IVIG), prednisone, and argatroban and was discharged seven days later much improved. His positive Platelet Factor 4 (PF4) ELISA antibody test returned after treatment was initiated. To our knowledge, this is the first reported case of VITT following Ad26.COV2.S vaccination presenting without radiographically-demonstrable thrombosis. Our patient highlights the importance of knowing vaccine status and initiating treatment as soon as possible in the right clinical setting, even in the absence of radiographic evidence of thrombus. Early VITT recognition and treatment provides an opportunity to prevent serious thrombotic complications.

PurposeFellows and residents provide inpatient consultations. Though consults vary considerably, measuring the associated cognitive load (CL) is key to guiding faculty on how to optimize learning during consults. However, existing CL instruments, such as the unidimensional Paas scale, cannot separate the 3 components of CL and may miss the nuances of consult CL. Therefore, the authors developed the Consult Cognitive Load (CCL) instrument to measure the 3 CL components during consults. To provide a window into the vital yet underresearched consult learning environment and to improve training and patient care, we developed a multidimensional instrument to measure the mental effort associated with trainees completing inpatient consults.

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