Purpose of Review Multiple myeloma is the second most common hematologic malignancy in the USA, with over 32,000 new cases and nearly 13,000 deaths expected in 2019. The past few decades in myeloma research have yielded significant advances, leading to the expansion of novel anti-myeloma agents. This review describes the incidence and mechanisms of cardiotoxicity for the FDA-approved proteasome inhibitors in myeloma and proposes strategies to assess and manage resultant cardiovascular adverse events. Recent Findings Proteasome inhibition precipitates protein aggregation and alters transcriptional activation of NF-κB targets which contributes to a pro-apoptotic signaling cascade in myeloma cells. Similar effects in cardiomyocytes and vascular smooth muscle endothelium, along with off-target downregulation of autophagy and signaling alterations of nitric oxide homeostasis, may be linked to observed cardiotoxic effects. There is preliminary evidence for cardioprotective potential for rutin, dexrazoxane, and apremilast that could have clinical applicability in the future. Summary Of the proteasome inhibitors used in clinical practice, carfilzomib is the most strongly associated with cardiotoxicity. Patients with anticipated carfilzomib treatment should undergo assessment and optimization of baseline cardiovascular risk, with close monitoring during treatment. Previous clinical trials were not specifically designed to assess proteasome inhibitor-related cardiotoxicity, creating a need for future studies to identify and risk stratify vulnerable individuals and to develop potential cardioprotective strategies in attenuating cardiac injury.
The experience with the use of monoclonal antibodies and Fc‐fusion proteins (mAb/Fc) in the pediatric population is limited. The objective of this study is to review those factors impacting the clinical efficacy and product safety of mAb/Fc products in pediatric patients during drug development. We reviewed the list of biologic products in the US Food and Drug Administration's Purple Book as of March 2018 with a focus on mAb/Fc products that are indicated for use in both adults and pediatric patients. Of 68 mAb/Fc products in the Purple Book (excluding biosimilars), 20 products have approved indications in both adults and children. Thirteen products had concurrent approval for both adult and pediatric populations. The sample size of pediatric studies generally ranged from approximately 2% to 70% of the sample size of adult studies with the same indication. In general, pediatric dosing regimens were found to be more based on body weight and weight tiered than the regimens for adults. Modeling and simulation techniques comprised mainly population pharmacokinetic and pharmacodynamic models. A review of the immunogenicity incidence did not reveal any notable difference in the 5 products having data on both pediatric and adult patients. In conclusion, most of the mAb/Fc products have a different weight‐based dosing regimen for pediatric patients versus adults. An understanding of the comparative experience in drug development for mAb/Fc products between adult and pediatric patients coupled with the application of advanced modeling and simulation methods should assist future development of new mAb/Fc products for pediatric patients.
Ventricular arrhythmias (VA) can range in presentation from asymptomatic to cardiac arrest and sudden cardiac death (SCD). Sustained ventricular tachycardias/ventricular fibrillation (VT/VF) are a common cause of SCD in the setting of myocardial infarction (MI) and heart failure. A particularly arrhythmogenic cardiac syncytia in these conditions can be attributed to both sympathetic activation and parasympathetic dysfunction, while appropriate neuromodulation has the potential to reduce occurrence of VT/VF. In this review, we outline the components of the autonomic nervous system that play an important role in normal cardiac electrophysiology and function. In addition, we discuss changes that occur in the setting of cardiac disease including adverse neural remodeling and neurohormonal activation which significantly contribute to propensity for VT/VF. Finally, we review neuromodulation strategies to mitigate VT/VF which predominantly rely on increasing parasympathetic drive and blockade of sympathetic neurotransmission.
Background Transcatheter aortic valve replacement (TAVR) is increasingly offered for aortic stenosis (AS) treatment in patients with a history of cancer. The impact of frailty on outcomes in this specific patient population is not well described. Hypothesis Frailty is associated with mortality and poorer quality of life (QOL) outcomes in patients undergoing TAVR with a history of cancer. Methods This retrospective single center cohort study included AS patients who underwent TAVR from August 1, 2012 to May 15, 2020. Frailty was measured using serum albumin, hemoglobin, gait speed, functional dependence, and cognitive impairment. The primary outcome was a composite of all‐cause mortality and QOL at 1 year. A poor primary outcome was defined as either all‐cause mortality, Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ‐OS) score <45 or a KCCQ‐OS score decline of ≥10 points from baseline. Regression analysis was used to determine the impact of frailty on the primary outcome. Results The study population was stratified into active/recent cancer ( n = 107), remote cancer ( n = 85), and non‐cancer ( n = 448). Univariate analysis of each cohort showed that frailty was associated with the primary outcome only in the non‐cancer cohort ( p = .004). Multivariate analysis showed that cancer history was not associated with a poor primary outcome, whereas frailty was (1.7 odds ratio, 95% confidence interval [CI]: 1.1–2.8; p = .028). Conclusions Frailty is associated with mortality and poor QOL in the overall and non‐cancer cohorts. Further investigation is warranted to understand frailty's effect on the cancer population. Frailty should be heavily considered during TAVR evaluation.
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