Does the Combination of a Proteasome Inhibitor, Lenalidomide, and Dexamethasone Reduce Fatigue in Patients with Relapsed or Refractory Multiple Myeloma?

OBJECTIVE: The objective of this selective EBM review is to determine whether or not “the combination of a proteasome inhibitor, lenalidomide, and dexamethasone reduce fatigue in patients with relapsed or refractory multiple myeloma (RRMM)?” STUDY DESIGN: A systematic review of three English language open-label clinical trials with one published in 2013 and two published in 2016. DATA SOURCES: Two randomized open-label, phase 3 clinical trials and one open-label phase 2 cohort study found using PubMed and Cochrane Library. All sources were published in peer-reviewed journals. OUTCOME MEASURED: Fatigue was the outcome measured in all three studies utilizing Common Terminology Criteria for AEs (version 3.0) or European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire core 30 module (EORTC QLQ-C30) and myeloma-specific module (QLQ-MY20). RESULTS: In the cohort study conducted by Wang et al. (Blood. 2013;122(18):3122–3128. doi:10.1182/blood-2013-07-511170.), showed no reduction in fatigue in the maximum planned dose (MPD) of carfilzomib, lenalidomide, and dexamethasone group compared to the other cohorts. The MPD group reported fatigue 69.2% compared to 65.5% overall. The RCT performed by Stewart et al. (J Clin Oncol. 2016;34(32):3921–3930. doi:10.1200/JCO.2016.66.9648.) found no statistical significance in reduction of fatigue between the carfilzomib, lenalidomide, and dexamethasone (KRd) group and control group (-0.46 in favor of KRd, p=0.71); however, both groups had statistically significant mean change from baseline of worsening fatigue in multiple cycles (p\u3c0.05). Lastly, in a double-blind RCT by Moreau et al. (N Engl J Med. 2016;374(17):1621–1634. doi:10.1056/NEJMoa1516282.), there was no significant difference in fatigue reduction between the ixazomib group and placebo group. CONCLUSIONS: Based on analysis of these studies, the combination of a proteasome inhibitor, lenalidomide, and dexamethasone does not reduce fatigue in patients with relapsed or refractory multiple myeloma. Future studies need to be designed in order to evaluate the effectiveness in fatigue reduction in patient with relapsed or refractory multiple myeloma

A Soluble Form of the High Affinity IgE Receptor, Fc-Epsilon-RI, Circulates in Human Serum

Soluble IgE receptors are potential in vivo modulators of IgE-mediated immune responses and are thus important for our basic understanding of allergic responses. We here characterize a novel soluble version of the IgE-binding alpha-chain of Fc-epsilon-RI (sFcεRI), the high affinity receptor for IgE. sFcεRI immunoprecipitates as a protein of ∼40 kDa and contains an intact IgE-binding site. In human serum, sFcεRI is found as a soluble free IgE receptor as well as a complex with IgE. Using a newly established ELISA, we show that serum sFcεRI levels correlate with serum IgE in patients with elevated IgE. We also show that serum of individuals with normal IgE levels can be found to contain high levels of sFcεRI. After IgE-antigen-mediated crosslinking of surface FcεRI, we detect sFcεRI in the exosome-depleted, soluble fraction of cell culture supernatants. We further show that sFcεRI can block binding of IgE to FcεRI expressed at the cell surface. In summary, we here describe the alpha-chain of FcεRI as a circulating soluble IgE receptor isoform in human serum

Characterization of Genome-Wide Association-Identified Variants for Atrial Fibrillation in African Americans

Despite a greater burden of risk factors, atrial fibrillation (AF) is less common among African Americans than European-descent populations. Genome-wide association studies (GWAS) for AF in European-descent populations have identified three predominant genomic regions associated with increased risk (1q21, 4q25, and 16q22). The contribution of these loci to AF risk in African American is unknown.We studied 73 African Americans with AF from the Vanderbilt-Meharry AF registry and 71 African American controls, with no history of AF including after cardiac surgery. Tests of association were performed for 148 SNPs across the three regions associated with AF, and 22 SNPs were significantly associated with AF (P<0.05). The SNPs with the strongest associations in African Americans were both different from the index SNPs identified in European-descent populations and independent from the index European-descent population SNPs (r(2)<0.40 in HapMap CEU): 1q21 rs4845396 (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.13-0.67, P = 0.003), 4q25 rs4631108 (OR 3.43, 95% CI 1.59-7.42, P = 0.002), and 16q22 rs16971547 (OR 8.1, 95% CI 1.46-45.4, P = 0.016). Estimates of European ancestry were similar among cases (23.6%) and controls (23.8%). Accordingly, the probability of having two copies of the European derived chromosomes at each region did not differ between cases and controls.Variable European admixture at known AF loci does not explain decreased AF susceptibility in African Americans. These data support the role of 1q21, 4q25, and 16q22 variants in AF risk for African Americans, although the index SNPs differ from those identified in European-descent populations

The Impact of Parental Presence on Trainee Education During PICU Rounds: A Brief Report

OBJECTIVES: To determine the impact of parental presence on the number and types of educational questions asked of and by medical trainees during PICU rounds. METHODS: An investigator joined bedside rounds in a 14-bed medical-surgical PICU on 20 weekdays between December 2016 and June 2017. For each patient, the investigator recorded the time devoted to education. Educational questions were recorded verbatim. Questions were categorized as teaching (senior team member to a trainee) or learning (trainee to a more senior team member) and by content (eg, physiology, imaging, prognosis). Two blinded investigators independently assigned codes to each educational question; discrepancies were resolved to the satisfaction of both. RESULTS: Data include 151 patient-specific rounding events, involving 92 patients. At least 1 parent attended the entirety of 59/151 rounding events (39%). There were no significant differences between the duration of education or the number of educational questions asked when parents were present (1 minute; 2 questions) versus absent (2 minutes; 2 questions). When parents were present, 20% questions were learning versus 25% when parents were absent. Zero percent of rounding events included \u3e/=1 question about prognosis when parents were present versus 9% when absent (P = .02). There was no statistically significant difference in the frequency of questions related to complications of management or social factors. CONCLUSIONS: Parent participation in rounds did not impact the quantity of education during rounds but did impact the type of educational questions asked, specifically restricting the discussion of patient prognosis

Two novel α7 nicotinic acetylcholine receptor ligands: in vitro properties and their efficacy in collagen-induced arthritis in mice.

INTRODUCTION:The cholinergic anti-inflammatory pathway can downregulate inflammation via the release of acetylcholine (ACh) by the vagus nerve. This neurotransmitter binds to the α7 subunit of nicotinic acetylcholine receptors (α7nAChR), expressed on macrophages and other immune cells. We tested the pharmacological and functional profile of two novel compounds, PMP-311 and PMP-072 and investigated their role in modulating collagen-induced arthritis (CIA) in mice. METHODS:Both compounds were characterized with binding, electrophysiological, and pharmacokinetic studies. For in vivo efficacy studies in the CIA model the compounds were administered daily by oral gavage from day 20 till sacrifice at day 34. Disease progression was monitored by visual clinical scoring and measurement of paw swelling. Inflammation and joint destruction were examined by histology and radiology. RESULTS:Treatment with PMP-311 was effective in preventing disease onset, reducing clinical signs of arthritis, and reducing synovial inflammation and bone destruction. PMP-072 also showed a trend in arthritis reduction at all concentrations tested. The data showed that while both compounds bind to α7nAChR with high affinity, PMP-311 acts like a classical agonist of ion channel activity, and PMP-072 can actually act as an ion channel antagonist. Moreover, PMP-072 was clearly distinct from typical competitive antagonists, since it was able to act as a silent agonist. It synergizes with the allosteric modulator PNU-120596, and subsequently activates desensitized α7nAChR. However, PMP-072 was less efficacious than PMP-311 at both channel activation and desensitization, suggesting that both conducting and non-conducting states maybe of importance in driving an anti-inflammatory response. Finally, we found that the anti-arthritic effect can be observed despite limited penetration of the central nervous system. CONCLUSIONS:These data provide direct evidence that the α7nAChR in immune cells does not require typical ion channel activation to exert its antiinflammatory effects

Two novel α7 nicotinic acetylcholine receptor ligands: in vitro properties and their efficacy in collagen-induced arthritis in mice

The cholinergic anti-inflammatory pathway can downregulate inflammation via the release of acetylcholine (ACh) by the vagus nerve. This neurotransmitter binds to the α7 subunit of nicotinic acetylcholine receptors (α7nAChR), expressed on macrophages and other immune cells. We tested the pharmacological and functional profile of two novel compounds, PMP-311 and PMP-072 and investigated their role in modulating collagen-induced arthritis (CIA) in mice. Both compounds were characterized with binding, electrophysiological, and pharmacokinetic studies. For in vivo efficacy studies in the CIA model the compounds were administered daily by oral gavage from day 20 till sacrifice at day 34. Disease progression was monitored by visual clinical scoring and measurement of paw swelling. Inflammation and joint destruction were examined by histology and radiology. Treatment with PMP-311 was effective in preventing disease onset, reducing clinical signs of arthritis, and reducing synovial inflammation and bone destruction. PMP-072 also showed a trend in arthritis reduction at all concentrations tested. The data showed that while both compounds bind to α7nAChR with high affinity, PMP-311 acts like a classical agonist of ion channel activity, and PMP-072 can actually act as an ion channel antagonist. Moreover, PMP-072 was clearly distinct from typical competitive antagonists, since it was able to act as a silent agonist. It synergizes with the allosteric modulator PNU-120596, and subsequently activates desensitized α7nAChR. However, PMP-072 was less efficacious than PMP-311 at both channel activation and desensitization, suggesting that both conducting and non-conducting states maybe of importance in driving an anti-inflammatory response. Finally, we found that the anti-arthritic effect can be observed despite limited penetration of the central nervous system. These data provide direct evidence that the α7nAChR in immune cells does not require typical ion channel activation to exert its antiinflammatory effect

Inhibition of bone degradation and reduction of synovial inflammation in murine collagen-induced arthritis by PMP-311 (n = 15, 5 mg/kg).

<p><b>A</b>, Semiquantitative scores of joint destruction. Joint destruction was decreased in mice treated with PMP-311. ** <i>P</i> < 0.01 compared to saline-treated mice <b>B</b>, Semiquantitative scores for synovial inflammation, assessed by hematoxylin and eosin staining of the knee joints, showed a decrease of synovitis in PMP-311-treated mice. * <i>P</i> < 0.05 compared to the control group.</p

Inhibition of bone degradation and reduction of synovial inflammation in murine collagen-induced arthritis at different doses of PMP-311 (n = 15) and PMP-072 (n = 15) given by oral gavage from day 20 until day 34.

<p><b>A</b>, Semiquantitative scores for radiographic joint destruction of the knee joints. Joint destruction was significantly decreased in mice treated with PMP-311 2 mg/kg and 10 mg/kg compared to the control group. <b>B</b>, Semiquantitative scores for synovial inflammation, assessed by hematoxylin and eosin staining of the knee joints, showed a decrease of synovitis in mice treated with PMP-311 2 mg/kg and PMP-072 10 mg/kg. * <i>P</i> < 0.05 and ** <i>P</i> < 0.01 versus saline-treated mice.</p