Citations

A 67-year-old male presented to the emergency department with concern for accidental aspiration of an aluminum beverage can pull tab. Neck and chest radiographs did not reveal an aspirated foreign body. Despite ongoing complaint of dysgeusia and adamancy of aspiration by the patient, he was discharged to home without recommendation for further follow-up. Seven months later, a computed tomography (CT) scan of the chest performed as part of an unrelated lung cancer work up confirmed the presence of a left mainstem bronchus metallic foreign body compatible with a pull tab. This case report illustrates the poor negative predictive value of radiographs for a suspected aluminum foreign body and demonstrates the superiority of CT for this purpose. In such presentations it is imperative to have a low threshold for performing further diagnostic evaluation with CT due to the relatively high radiolucency of aluminum.

Abstract Purpose: This first-in-human study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of single and multiple doses of TAK-441, an investigational inhibitor of the Hedgehog signaling pathway. Experimental Design: Patients with advanced, solid tumors received daily oral TAK-441 (50–1,600 mg/day); daily dose was doubled in each subsequent cohort until the maximum tolerated/feasible dose (MTD/MFD) was reached. Blood was collected to evaluate TAK-441 plasma concentrations. Skin biopsies were obtained to evaluate suppression of the Hedgehog-regulated gene Gli1. Results: Thirty-four patients were enrolled (median age 59). The most common diagnoses were colorectal cancer (26%), basal cell carcinoma (BCC, 21%), and pancreatic cancer (9%). The MFD of 1,600 mg/day (based on tablet size and strength) was considered the MTD. Dose-limiting toxicities included muscle spasms and fatigue. Grade ≥3 treatment-emergent adverse events, regardless of causality, occurred in 15 patients (44%), of which hyponatremia (n = 4) and fatigue (n = 3) were most common. Oral absorption was fairly rapid; median Tmax was 2.0 to 4.0 hours after a single dose. Mean elimination half-life was 13.5 to 22.6 hours. Systemic exposure of TAK-441 based on the area under the plasma concentration–time curve was linear across the dose range. Gli1 expression in skin biopsies was strongly inhibited at all dose levels. Best response was partial response (1 patient with BCC) and stable disease (7 patients with various solid tumors). Conclusions: TAK-441 was generally well tolerated up to MFD of 1,600 mg/day, with preliminary antitumor activity. Further study of TAK-441 may be appropriate in populations selected for tumors with ligand-dependent or independent Hedgehog signaling. Clin Cancer Res; 21(5); 1002–9. ©2014 AACR.

Background— Post-percutaneous coronary intervention (PCI) bleeding complications are an important quality metric. We sought to characterize site-level variation in post-PCI bleeding and explore the influence of patient and procedural factors on hospital bleeding performance. Methods and Results— Hospital-level bleeding performance was compared pre- and postadjustment using the newly revised CathPCI Registry ® bleeding risk model (c-index, 0.77) among 1292 National Cardiovascular Data Registry ® hospitals performing >50 PCIs from 7/2009 to 9/2012 (n=1 984 998 procedures). Using random effects models, outlier sites were identified based on 95% confidence intervals around the hospital’s random intercept. Bleeding 72 hours post-PCI was defined as: arterial access site, retroperitoneal, gastrointestinal, or genitourinary bleeding; intracranial hemorrhage; cardiac tamponade; nonbypass surgery–related blood transfusion with preprocedure hemoglobin ≥8 g/dL; or absolute decrease in hemoglobin value ≥3 g/dL with preprocedure hemoglobin ≤16 g/dL. Overall, the median unadjusted post-PCI bleeding rate was 5.2% and varied among hospitals from 2.6% to 10.4% (5th, 95th percentiles). Center-level bleeding variation persisted after case-mix adjustment (2.8%–9.5%; 5th, 95th percentiles). Although hospitals’ observed and risk-adjusted bleeding ranks were correlated (Spearman ρ: 0.88), individual rankings shifted after risk-adjustment (median Δ rank order: ±91.5; interquartile range: 37.0, 185.5). Outlier classification changed postadjustment for 29.3%, 16.1%, and 26.5% of low-, non-, and high-outlier sites, respectively. Hospital use of bleeding avoidance strategies (bivalirudin, radial access, or vascular closure device) was associated with risk-adjusted bleeding rates. Conclusions— Despite adjustment for patient case-mix, there is wide variation in rates of hospital PCI-related bleeding in the United States. Opportunities may exist for best performers to share practices with other sites.

It is recognized that individuals with mild cognitive impairment (MCI) already demonstrate difficulty in aspects of daily functioning, which predicts disease progression. This study examined the relationship between self‐ versus informant‐report of functional ability, and how those reports relate to objective disease measures across the disease spectrum (i.e. cognitively normal, MCI, Alzheimer's disease). A total of 1080 subjects with self‐ and/or informant‐rated Everyday Cognition questionnaires were included. Objective measures included cognitive functioning, structural brain atrophy, cerebrospinal fluid abnormalities, and a marker of amyloid deposition using positron emission tomography with [ 18 F]AV45 (florbetapir). Overall, informant‐report was consistently more associated with objective markers of disease than self‐report although self‐reported functional status may still have some utility in early disease.

AbstractBackgroundInexpensive, non‐invasive tools for assessing Alzheimer‐type pathophysiologies are needed. Computerized cognitive assessments are prime candidates.MethodsCognitively normal participants, aged 51–71, with magnetic resonance imaging, fluorodeoxyglucose‐positron emission tomography (FDG‐PET), amyloid PET, CogState computerized cognitive assessment, and standard neuropsychological tests were included. We first examined the association between the CogState battery and neuroimaging measures. We then compared that association to the one between standard neuropsychological z‐scores and neuroimaging.ResultsSlower reaction times for CogState Identification and One Back, and lower memory and attention z‐scores, were associated (P < .05) with FDG‐PET hypometabolism. Slower time on the Groton Maze Learning Task and worse One Card Learning accuracy were associated (P < .05) with smaller hippocampal volumes. There were no associations with amyloid PET. Associations of CogState and neuropsychological Z‐scores with neuroimaging were small and of a similar magnitude.ConclusionsCogState subtests were cross‐sectionally comparable to standard neuropsychological tests in their relatively weak associations with neurodegeneration imaging markers.

Despite successful treatment of the clonal plasma cell implicated in its pathogenesis, patients with AL amyloidosis (AL) experience significant morbidity related to underlying amyloid mediated organ dysfunction. While normalization of the serum free light chain measurements [normal ratio of involved and uninvolved free light chains (nFLCr)] is the goal of therapy and centerpiece of hematologic response criteria, achieving (or not achieving) meaningful organ response (OR) is clinically significant for its implications on long‐term symptomatology as well as overall survival (OS), and remains the ultimate goal of treatment. Expectations for organ recovery following successful therapy leading to nFLCr in AL remain poorly described. We evaluated the timeframe and predictive factors for OR, and long‐term outcome, in 313 AL patients who achieved nFLCr following therapy initiation. OR was seen in 80% of surviving AL patients within 1‐year of nFLCr. Patients achieving early OR within 1 year of nFLCr had superior OS compared with those who despite obtaining nFLCr did not achieve early OR. We further evaluated factors predicting OR and OS among patients achieving nFLCr. Higher values of dFLC (involved–uninvolved) at diagnosis predict OR, and early OR predicts improved OS following successful hematologic therapy in AL. Am. J. Hematol. 90:181–186, 2015. © 2014 Wiley Periodicals, Inc.