The next tier of EGFR resistance mutations in lung cancer
ONCOGENE
Authors: Tumbrink, Hannah L.; Heimsoeth, Alena; Sos, Martin L.
Abstract
EGFRmutations account for the majority of druggable targets in lung adenocarcinoma. Over the past decades the optimization of EGFR inhibitors revolutionized the treatment options for patients suffering from this disease. The pace of this development was largely dictated by the inevitable emergence of resistance mutations during drug treatment. As a result, a rapid understanding of the structural and molecular biology of the individual mutations is the key for the development of next-generation inhibitors. Currently, the field faces an unprecedented number of combinations of activating mutations with distinct resistance mutations in parallel to the approval of osimertinib as a first-line drug forEGFR-mutant lung cancer. In this review, we present a survey of the diverse landscape of EGFR resistance mechanisms with a focus on new insights into on-targetEGFRkinase mutations. We discuss array of mutations, their structural effects on the EGFR kinase domain as well as the most promising strategies to overcome the individual resistance profiles found in lung cancer patients.
Risk of mortality following transcatheter aortic valve replacement for low-flow low-gradient aortic stenosis
CLINICAL RESEARCH IN CARDIOLOGY
Authors: Wilde, Nihal; Sugiura, Atsushi; Sedaghat, Alexander; Becher, Marc Ulrich; Kelm, Malte; Baldus, Stephan; Nickenig, Georg; Veulemans, Verena; Tiyerili, Vedat
Abstract
Background Low-flow low-gradient (LF-LG) aortic stenosis (AS) is associated with high mortality, even after transcatheter aortic valve replacement (TAVR). Further knowledge of risk indicators is needed and a clinical risk score would be desirable for optimizing patient selection and therapeutic strategy. Methods The study cohort comprised of 219 consecutive LF-LG AS patients undergoing TAVR from 2008 to 2018 in two high-volume German centers. Predictive factors for one-year all-cause mortality were defined according to a Cox proportional hazard model. Results At one-year follow-up after TAVR, 28% of patients had died. A multivariate model revealed six independent predictors of one-year mortality: history of myocardial infarction (HR 2.05, 95%CI 1.13-3.72), eGFR < 30 ml/min/1.73m(2)(HR 2.75, 95%CI 1.48-5.11), tricuspid regurgitation moderate or more (HR 2.06, 95%CI 1.14-3.72), stroke volume index < 25 mL/m(2)(HR 2.03, 95%CI 1.14-3.62), self-expandable device (HR 2.72, 95%CI 1.17-6.27), and non-transfemoral approach (HR 3.42, 95%CI 1.28-9.14). The Rhineland Risk Score (RRS) consisting of these variables (c statistic 0.75, 95%CI 0.68-0.82,p < 0.001) was superior to the EuroSCORE II (c statistic 0.63) and STS-PROM score (c statistic 0.69) at predicting one-year mortality. Patients with a RRS >= 8 had a prohibitive risk of one-year mortality of 67.6% (95%CI 52.0-82.4%). Conclusion In patients with LF-LG AS, history of myocardial infarction, renal dysfunction, tricuspid regurgitation, a low stroke volume index, self-expandable device, and non-femoral approach were associated with increased 1-year mortality after TAVR. The RRS might serve as a helpful tool for risk prediction and patient selection for TAVR in patients with LF-LG AS.
COA
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