Citations

Abstract Gain-of-function mutations of the receptor tyrosine kinase KIT play a key role in the pathogenesis of systemic mastocytosis (SM), gastrointestinal stromal tumors (GISTs), and some cases of acute myeloid leukemia (AML). Whereas KIT juxtamembrane domain mutations seen in most patients with GIST are highly sensitive to imatinib, the kinase activation loop mutant D816V, frequently encountered in SM, hampers the binding ability of imatinib. We investigated the inhibitory activity of the novel tyrosine kinase inhibitor EXEL-0862 against 2 subclones of human mast cell line-1 (HMC-1)—HMC-1.1, harboring the juxtamembrane domain mutation V560G, and HMC-1.2, carrying V560G and the activation loop mutation D816V, found in more than 80% of patients with SM. EXEL-0862 inhibited the phosphorylation of KIT in a dose-dependent manner and decreased cell proliferation in both mast cell lines with higher activity against HMC-1.2 cells. The phosphorylation of KIT-dependent signal transducer and activator of transcription-3 (STAT3) and STAT5 was abrogated upon exposure to nanomolar concentrations of EXEL-0862. In addition, EXEL-0862 induced a time- and dose-dependent proapoptotic effect in both mast cell lines and caused a significant reduction in mast-cell content in bone marrow samples from patients with SM harboring D816V and from those without the D816V mutation. We conclude that EXEL-0862 is active against KIT activation loop mutants and is a promising candidate for the treatment of patients with SM and other KIT-driven malignancies harboring active site mutations.

Objective— We evaluated the role of lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ), an inflammatory biomarker, in defining risk after myocardial infarction (MI). Methods and Results— Olmsted County, Minn, residents who experienced an MI meeting standardized criteria between 2003 and 2005 (n=271) were prospectively identified and followed. Lp-PLA 2 levels were measured at baseline and evaluated along with traditional risk indicators. Lp-PLA 2 was modestly associated with total and low-density lipoprotein cholesterol, smoking, and age (inversely) but not with MI characteristics or severity, comorbidities, C-reactive protein, or the time from symptom onset to blood sampling. During the first year of follow-up, 42 deaths occurred. The survival estimates (95% confidence intervals [CI]) at 1 year were 92% (86% to 98%), 85% (78% to 93%), and 74% (65% to 84%) in the lowest, middle, and upper Lp-PLA 2 tertiles, respectively ( P =0.007). After adjustment for age and sex, the hazard ratios for death in the middle and upper Lp-PLA 2 tertiles were 2.20 (95% CI: 0.88 to 5.54) and 4.93 (95% CI: 2.10 to 11.60), compared with the lowest tertile, respectively ( P trend <0.001). Further adjustment for other risk indicators resulted in even stronger associations. Lp-PLA 2 also contributed to risk discrimination as indicated by the increases in the area under the receiver operating characteristic curves obtained in each of the models examined (all P ≤0.05). Conclusions— Among community subjects presenting with MI, increased Lp-PLA 2 levels measured early after MI are strongly and independently associated with mortality and provide incremental value in risk discrimination over traditional predictors.

ABSTRACT Tefibazumab (Aurexis), a humanized monoclonal antibody that binds to the surface-expressed adhesion protein clumping factor A, is under development as adjunctive therapy for serious Staphylococcus aureus infections. Sixty patients with documented S. aureus bacteremia (SAB) were randomized and received either tefibazumab at 20 mg/kg of body weight as a single infusion or a placebo in addition to an antibiotic(s). The primary objective of the study was determining safety and pharmacokinetics. An additional objective was to assess activity by a composite clinical end point (CCE). Baseline characteristics were evenly matched between groups. Seventy percent of infections were healthcare associated, and 57% had an SAB-related complication at baseline. There were no differences between the treatment groups in overall adverse clinical events or alterations in laboratory values. Two patients developed serious adverse events that were at least possibly related to tefibazumab; one hypersensitivity reaction was considered definitely related. The tefibazumab plasma half-life was 18 days. Mean plasma levels were <100 μg/ml by day 14. A CCE occurred in six patients (four placebo and two tefibazumab patients) and included five deaths (four placebo and one tefibazumab patient). Progression in the severity of sepsis occurred in four placebo and no tefibazumab patients. Tefibazumab was well tolerated, with a safety profile similar to those of other monoclonal antibodies. Additional trials are warranted to address the dosing range and efficacy of tefibazumab.

Abstract The proper treatment of synovial proliferative disorders depends on an accurate diagnosis and a knowledge of the natural history of these afflictions. A simple classification of the major synovial disorders with a brief general description of each, highlighting the prominent clinical features, is helpful. A thorough history and physical examination should enable the clinician to categorize the nature of the synovial disorder. Further evaluation and consultation can then be directed within the appropriate category. Radiologic, laboratory, and microscopic studies aid in arriving at a definitive diagnosis. Once a diagnosis has been established, therapy or further evaluation can be instituted.