Darbepoetin alfa for treating chemotherapy-induced anemia in patients with a baseline hemoglobin level < 10 g/dL versus ≥10 g/dL: an exploratory analysis from a randomized, double-blind, active-controlled trial

<p>Abstract</p> <p>Background</p> <p>Several studies have shown that darbepoetin alfa, an erythropoiesis-stimulating agent (ESA), can reduce transfusions and increase hemoglobin (Hb) levels in patients with chemotherapy-induced anemia (CIA). Recent safety concerns, however, have prompted changes to ESA product information. In the European Union and United States, ESA therapy initiation for CIA is now recommended at a Hb level ≤10 g/dL. The present exploratory analysis examined how ESA initiation at this Hb level may impact patient care.</p> <p>Methods</p> <p>Data from a phase 3 randomized trial were retrospectively reanalyzed. CIA patients with nonmyeloid malignancies were randomized 1:1 to 500 mcg darbepoetin alfa every three weeks (Q3W) or 2.25 mcg/kg darbepoetin alfa weekly (QW) for 15 weeks. A previously published report from this trial showed Q3W dosing was non-inferior to QW dosing for reducing transfusions from week 5 to end-of-the-treatment period (EOTP). In the present analysis, outcomes were reanalyzed by baseline Hb <10 g/dL and ≥10 g/dL. Endpoints included transfusion rates, Hb outcomes, and safety profiles.</p> <p>Results</p> <p>This study reanalyzed 351 and 354 patients who initiated ESA therapy at a baseline Hb of <10 g/dL or ≥10 g/dL, respectively. From week 5 to EOTP, the estimated Kaplan-Meier transfusion incidence (Q3W vs QW) was lower in the ≥10 g/dL baseline-Hb group (14% vs 21%) compared with the <10 g/dL baseline-Hb group (36% vs 41%). By week 5, the ≥10 g/dL baseline-Hb group, but not the <10 g/dL baseline-Hb group, achieved a mean Hb ≥11 g/dL. The Kaplan-Meier estimate of percentage of patients (Q3W vs QW) who achieved Hb ≥11 g/dL from week 1 to EOTP was 90% vs 85% in the ≥10 g/dL baseline-Hb group and 54% vs 57% in the <10 g/dL baseline-Hb group. Both baseline-Hb groups maintained mean Hb levels <12 g/dL and had similar safety profiles, though more patients in the ≥10 g/dL baseline-Hb group reached the threshold Hb of ≥13 g/dL.</p> <p>Conclusion</p> <p>In this exploratory analysis, darbepoetin alfa Q3W and QW raised Hb levels and maintained mean Hb at <12 g/dL in both baseline-Hb groups. The ≥10 g/dL baseline-Hb group had fewer transfusions and faster anemia correction. Additional studies should prospectively evaluate the relationship between Hb levels at ESA initiation and outcomes.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier NCT00118638.</p

Educational paper: Abusive Head Trauma Part I. Clinical aspects

Abusive Head Trauma (AHT) refers to the combination of findings formerly described as shaken baby syndrome. Although these findings can be caused by shaking, it has become clear that in many cases there may have been impact trauma as well. Therefore a less specific term has been adopted by the American Academy of Pediatrics. AHT is a relatively common cause of childhood neurotrauma with an estimated incidence of 14–40 cases per 100,000 children under the age of 1 year. About 15–23% of these children die within hours or days after the incident. Studies among AHT survivors demonstrate that approximately one-third of the children are severely disabled, one-third of them are moderately disabled and one-third have no or only mild symptoms. Other publications suggest that neurological problems can occur after a symptom-free interval and that half of these children have IQs below the 10th percentile. Clinical findings are depending on the definitions used, but AHT should be considered in all children with neurological signs and symptoms especially if no or only mild trauma is described. Subdural haematomas are the most reported finding. The only feature that has been identified discriminating AHT from accidental injury is apnoea. Conclusion: AHT should be approached with a structured approach, as in any other (potentially lethal) disease. The clinician can only establish this diagnosis if he/she has knowledge of the signs and symptoms of AHT, risk factors, the differential diagnosis and which additional investigations to perform, the more so since parents seldom will describe the true state of affairs spontaneously

Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes

BACKGROUND: Cancer patients often develop the potentially debilitating condition of anaemia. Numerous controlled studies indicate that erythropoiesis-stimulating agents (ESAs) can raise haemoglobin levels and reduce transfusion requirements in anaemic cancer patients receiving chemotherapy. To evaluate recent safety concerns regarding ESAs, we carried out a meta-analysis of controlled ESA oncology trials to examine whether ESA use affects survival, disease progression and risk of venous-thromboembolic events

Postulated Vasoactive Neuropeptide Autoimmunity in Fatigue-Related Conditions: A Brief Review and Hypothesis

Disorders such as chronic fatigue syndrome (CFS) and gulf war syndrome (GWS) are characterised by prolonged fatigue and a range of debilitating symptoms of pain, intellectual and emotional impairment, chemical sensitivities and immunological dysfunction. Sudden infant death syndrome (SIDS) surprisingly may have certain features in common with these conditions. Post-infection sequelae may be possible contributing factors although ongoing infection is unproven. Immunological aberration may prove to be associated with certain vasoactive neuropeptides (VN) in the context of molecular mimicry, inappropriate immunological memory and autoimmunity

The transcription factor ERG regulates a low shear stress-induced anti-thrombotic pathway in the microvasculature.

Endothelial cells actively maintain an anti-thrombotic environment; loss of this protective function may lead to thrombosis and systemic coagulopathy. The transcription factor ERG is essential to maintain endothelial homeostasis. Here, we show that inducible endothelial ERG deletion (ErgiEC-KO) in mice is associated with spontaneous thrombosis, hemorrhages and systemic coagulopathy. We find that ERG drives transcription of the anticoagulant thrombomodulin (TM), as shown by reporter assays and chromatin immunoprecipitation. TM expression is regulated by shear stress (SS) via Krüppel-like factor 2 (KLF2). In vitro, ERG regulates TM expression under low SS conditions, by facilitating KLF2 binding to the TM promoter. However, ERG is dispensable for TM expression in high SS conditions. In ErgiEC-KO mice, TM expression is decreased in liver and lung microvasculature exposed to low SS but not in blood vessels exposed to high SS. Our study identifies an endogenous, vascular bed-specific anticoagulant pathway in microvasculature exposed to low SS

Consensus statement on abusive head trauma in infants and young children

Abusive head trauma (AHT) is the leading cause of fatal head injuries in children younger than 2 years. A multidisciplinary team bases this diagnosis on history, physical examination, imaging and laboratory findings. Because the etiology of the injury is multifactorial (shaking, shaking and impact, impact, etc.) the current best and inclusive term is AHT. There is no controversy concerning the medical validity of the existence of AHT, with multiple components including subdural hematoma, intracranial and spinal changes, complex retinal hemorrhages, and rib and other fractures that are inconsistent with the provided mechanism of trauma. The workup must exclude medical diseases that can mimic AHT. However, the courtroom has become a forum for speculative theories that cannot be reconciled with generally accepted medical literature. There is no reliable medical evidence that the following processes are causative in the constellation of injuries of AHT: cerebral sinovenous thrombosis, hypoxic-ischemic injury, lumbar puncture or dysphagic choking/vomiting. There is no substantiation, at a time remote from birth, that an asymptomatic birth-related subdural hemorrhage can result in rebleeding and sudden collapse. Further, a diagnosis of AHT is a medical conclusion, not a legal determination of the intent of the perpetrator or a diagnosis of murder. We hope that this consensus document reduces confusion by recommending to judges and jurors the tools necessary to distinguish genuine evidence-based opinions of the relevant medical community from legal arguments or etiological speculations that are unwarranted by the clinical findings, medical evidence and evidence-based literature

The requirement of zinc and calcium ions for functional MMP activity in demineralized dentin matrices.

The progressive degradation of resin-dentin bonds is due, in part, to the slow degradation of collagen fibrils in the hybrid layer by endogenous matrix metalloproteinases (MMPs) of the dentin matrix. In in vitro durability studies, the storage medium composition might be important because the optimum activity of MMPs requires both zinc and calcium. Objective. This study evaluated the effect of different storage media on changes in matrix stiffness, loss of dry weight or solubilization of collagen from demineralized dentin beams incubated in vitro for up to 60 days. Methods. Dentin beams (1 mm x 2 mm x 6 mm) were completely demineralized in 10% phosphoric acid. After baseline measurements of dry mass and elastic modulus (E) (3-point bending, 15% strain) the beams were divided into 5 groups (n = 11/group) and incubated at 37 degrees C in either media containing both zinc and calcium designated as complete medium (CM), calcium-free medium, zinc-free medium, a doubled-zinc medium or water. Beams were retested at 3, 7, 14, 30, and 60 days of incubation. The incubation media was hydrolyzed with HCl for the quantitation of hydroxyproline (HOP) as an index of solubilization of collagen by MMPs. Data were analyzed using repeated measures of ANOVA. Results. Both the storage medium and the storage time showed significant effects on E, mass loss and HOP release (p < 0.05). The incubation in CM resulted in relatively rapid and significant (p < 0.05) decreases in stiffness, and increasing amounts of mass loss. The HOP content of the experimental media also increased with incubation time but was significantly lower (p < 0.05) than in the control CM medium, the recommended storage medium. Conclusions. The storage solutions used to age resin-dentin bonds should be buffered solutions that contain both calcium and zinc. The common use of water as an aging medium may underestimate the hydrolytic activity of endogenous dentin MMPs. (c) 2010 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved

Chlorhexidine binding to mineralized versus demineralized dentin powder.

Objectives. The purposes of this work were to quantitate the affinity and binding capacity of chlorhexidine (CHX) digluconate to mineralized versus demineralized dentin powder and to determine how much debinding would result from rinsing with water, ethanol, hydroxyethylmethacrylate (HEMA) or 0.5 M NaCl in water. Methods. Dentin powder was made from coronal dentin of extracted human third molars. Standard amounts of dentin powder were tumbled with increasing concentrations of CHX (0-30 mM) for 30 min at 37 degrees C. After centrifuging the tubes, the supernatant was removed and the decrease in CHX concentration quantitated by UV-spectroscopy. CHX-treated dentin powder was resuspended in one of the four debinding solutions for 3 min. The amount of debound CHX in the solvents was also quantitated by UV-spectroscopy. Results. As the CHX concentration in the medium increased, the CHX binding to mineralized dentin powder also increased up to 6.8 mu mol/g of dry dentin powder. Demineralized dentin powder took up significantly (p < 0.01) more CHX, reaching 30.1 mu mol CHX/g of dry dentin powder. Debinding of CHX was in the order: HEMA < ethanol < 0.05 M NaCl < water. The highest CHX binding to demineralized dentin occurred at 30 mM (1.5 wt.%). Significance. As CHX is not debound by HEMA, it may remain bound to demineralized dentin during resin-dentin bonding. This may be responsible for the long-term efficacy of CHX as an MMP inhibitor in resin-dentin bonds. (C) 2010 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved