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.
Long-term blood pressure variability, incidence of hypertension and changes in renal function in type 2 diabetes
JOURNAL OF HYPERTENSION
Authors: Viazzi, Francesca; Russo, Elisa; Mirijello, Antonio; Fioretto, Paola; Giorda, Carlo; Ceriello, Antonio; Copetti, Massimiliano; Russo, Giuseppina T.; Di Bartolo, Paolo; Manicardi, Valeria; Leoncini, Giovanna; De Cosmo, Salvatore; Pontremoli, Roberto
Abstract
Objectives: Long-term visit-to-visit SBP variability (VVV) predicts cerebro-cardiovascular and renal events in patients with hypertension. Whether VVV predicts hypertension and/or chronic kidney disease is currently unknown. We assessed the role of VVV on the development of hypertension and changes in renal function in patients with type 2 diabetes and normal blood pressure (NBP) in a real-life clinical setting. Methods: Clinical records from 8998 patients with type 2 diabetes, NBP, and normal estimated glomerular filtration rate (eGFR) were analyzed. VVV was measured by SD of the mean SBP recorded in at least four visits during 2 consecutive years before follow-up. Hypertension was defined as SBP at least 140 mmHg and DBP at least 90 mmHg or the presence of antihypertensive treatment. Renal function was defined as worsening of albuminuria status and/or a reduction in eGFR at least 30% from baseline. Results: After a mean follow-up time of 3.5 +/- 2.8 years, 3795 patients developed hypertension (12.1 per 100 person-years). An increase of 5 mmHg VVV was associated with a 19% (P < 0.0001) and a 5% (P = 0.008) independent increased risk of developing hypertension and worsening of albuminuria, respectively. We found no association between VVV and eGFR decrease from baseline. Patients with VVV in the upper quartile (>12.8 mmHg) showed a 50% increased risk of developing hypertension (P < 0.0001) and an almost 20% increased risk of worsening albuminuria (P = 0.004) as compared with those in the lower one (<6.9 mmHg). Conclusion: Increased VVV independently predicts incident hypertension and albuminuria worsening in type 2 diabetes and NBP.
COA
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