Therapy of Core Binding Factor Acute Myeloid Leukemia: Incremental Improvements Toward Better Long-Term Results

BackgroundDespite being considered as good prognostic acute myelogenous leukemia (AML), the long-term survival rate in core binding factor (CBF) AML leaves room for substantial improvement.Materials and MethodsWe reviewed relevant English language literature related to treatment of CBF AML available in PubMed. Review also included meeting abstracts.ResultsMulticycle high dose cytarabine in consolidation improves remission duration but larger groups report overall survival in the range of 40% to 50% at 5 years or longer.ConclusionsConcerted effort is needed toward improving outcomes in CBF AML through clinical trials and risk-adapted approach.     

The diagnostic value of the fibrinogen/fibrin fragment E antigen assay in clinically suspected deep vein thrombosis

We have evaluated the fibrinogen/fibrin fragment E antigen assay as a diagnostic test in patients with clinically suspected venous thrombosis by comparing the results of this assay with venography in 272 patients. The result of the fragment E antigen assay was elevated in 79 of 80 patients with positive venograms for recent venous thrombosis (sensitivity 99%) and within the normal range in 161 of 192 patients with normal venograms (specificity 84%). The fragment E assay was also evaluated in 130 medical and surgical controls without evidence of venous thrombosis by leg scanning and the test was found to be relatively nonspecific. However, in the patient group under study, a correct clinical diagnosis of no thrombosis, based on a normal fragment E result, was made in 161 of 162 cases (negative predictive value of 99%). Therefore, a normal test result effectively excludes a diagnosis of venous thrombosis in clinically symptomatic patients. The assay, as currently performed, is technically demanding and takes 24 hr to complete. Therefore, it will have to be simplified before it can be applied to clinical practice.     

Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin. CAPRIE investigators

BACKGROUND: Repeat hospitalizations of patients with atherosclerosis represent a considerable burden on the health care system. We sought to determine whether clopidogrel compared with aspirin decreases the need for rehospitalization for ischemia and bleeding. METHODS AND RESULTS: The Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial was a randomized, blinded, multicenter, trial of 19,185 patients with atherosclerotic disease manifested as recent ischemic stroke or myocardial infarction or symptomatic peripheral arterial disease. Without any double-counting of events, the number of rehospitalizations for ischemic events (defined as angina, transient ischemic attack, or limb ischemia) or bleeding events was determined for the entire cohort. There was a significant reduction in the total number of rehospitalizations for ischemic events or bleeding with clopidogrel use compared with aspirin (1502 vs 1673; P =.010) over an average of 1.6 years of treatment. This reduction in rehospitalization was consistent across individual outcomes of angina, transient ischemic attack, limb ischemia, and bleeding. Compared with aspirin, clopidogrel also resulted in a 7.9% relative risk reduction in a combined end point of vascular death, stroke, myocardial infarction, or rehospitalization for ischemic events or bleeding (15.1% to 13.7% at 1 year; P =.011). Adjusting for baseline prognostic variables, clopidogrel therapy was an independent predictor for reduction of vascular death, stroke, myocardial infarction, or rehospitalization for ischemic events or bleeding (P =.009). CONCLUSIONS: Treatment with clopidogrel results in a significant decrease in the need for rehospitalization for ischemic events or bleeding compared with aspirin. This meaningful end point tracks well with other, more traditional measures of outcome and has incremental value beyond such end points.     

Increased Prevalence of Myocardial Injury in Patients with SARS-CoV-2 Viremia

BackgroundPatients with coronavirus disease 2019 (COVID-19) have a high prevalence of detectable troponin and myocardial injury. In addition, a subset of patients with COVID-19 has detectable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral loads. The objective of this study was to understand the relationship among SARS-CoV-2 viremia, detectable troponin, and myocardial injury in hospitalized patients with COVID-19.MethodsSARS-CoV-2 plasma viral load was measured in plasma samples drawn from patients hospitalized for COVID-19 at 2 academic medical centers. Baseline characteristics and clinically obtained high-sensitivity cardiac troponin T (hs-cTnT) values were abstracted from the medical record. The main outcome was detectable hs-cTnT (≥6 ng/mL) and myocardial injury (hs-cTnT ≥14 ng/mL; >99th percentile for assay).ResultsA total of 70 hospitalized patients with COVID-19 were included in this study, with 39% females and median age 58 ± 17 years; 21 patients (30%) were found to have detectable SARS-CoV-2 viral load and were classified in the viremia group. Patients with viremia were significantly older than those without viremia. All of the patients with viremia (100%) had detectable troponin during hospitalization compared with 59% of patients without viremia (P = 0.0003). Myocardial injury was seen in 76% of patients with viremia and 38% of those patients without viremia (P = 0.004).ConclusionsHospitalized patients with COVID-19 with SARS-CoV-2 viremia have a significantly higher prevalence of detectable troponin and myocardial injury during their hospitalization compared with patients who did not. This first report of the relationship among SARS-CoV-2 viremia, detectable troponin, and myocardial injury in patients with COVID-19 points to additional mechanistic pathways that require deeper study to understand the complex interplay among these unique findings, cardiovascular outcomes, and mortality in COVID-19.     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

Comparative Effectiveness of Commercial Bowel Preparations in Ambulatory Patients Presenting for Screening or Surveillance Colonoscopy

Digestive Diseases and Sciences - Inadequate bowel preparation (IBP) is associated with reduced adenoma detection. However, limited research has examined the impact of different commercial bowel...     

The CD11b promoter directs high-level expression of reporter genes in macrophages in transgenic mice [published erratum appears in Blood 1995 Apr 1;85(7):1983]

CD11b is the alpha chain of the Mac-1 integrin and is preferentially expressed in myeloid cells (neutrophils, monocytes, and macrophages). We have previously shown that the CD11b promoter directs cell-type- specific expression in myeloid lines using transient transfection assays. To confirm that these promoter sequences contain the proper regulatory elements for correct myeloid expression of CD11b in vivo, we have used the -1.7-kb human CD11b promoter to direct reporter gene expression in transgenic mice. Stable founder lines were generated with two different reporter genes, a Thy 1.1 surface marker and the Escherichia coli lacZ (beta-galactosidase) gene. Analysis of founders generated with each reporter demonstrated that the CD11b promoter was capable of driving high levels of transgene expression in murine macrophages for the lifetime of the animals. Similar to the endogenous gene, transgene expression was preferentially found in mature monocytes, macrophages, and neutrophils and not in myeloid precursors. These experiments indicate that the -1.7 CD11b promoter contains the regulatory elements sufficient for high-level macrophage expression. This promoter should be useful for targeting heterologous gene expression to mature myeloid cells.     

Recurrent Massive Upper Gastrointestinal Hemorrhage Due to Strongyloides stercoralis Infection

A 29-yr-old black male immigrant from Africa presented with recurrent life-threatening upper gastrointestinal bleeding due to massive duodenal infection by Strongyloides stercoralis. The diagnosis was missed by repeated examinations of fresh stool specimens for ova and parasites and by an initial esophagogastroduodenoscopy. The diagnosis was made by pathologic examination of a duodenal biopsy and of a duodenal aspirate obtained at a second esophagogastroduodenoscopy. This has been previously reported as a cause of massive upper gastrointestinal hemorrhage in four cases. Patients with obscure gastrointestinal bleeding who have travelled or lived in an endemic area should have a duodenal aspiration performed at esophagogastroduodenoscopy.