Zongertinib (BI 1810631), an irreversible HER2 TKI, spares EGFR signaling and improves therapeutic response in preclinical models and patients with HER2-driven cancers.

Mutations in HER2 occur in 2-4% of non-small cell lung cancer (NSCLC) and confer poor prognosis. ERBB-targeting tyrosine kinase inhibitors, approved for treating other HER2-dependent cancers, are ineffective in HER2 mutant NSCLC due to dose-limiting toxicities or suboptimal potency. We report the discovery of zongertinib (BI 1810631), a covalent HER2 inhibitor.

Discovery of potent and selective HER2 inhibitors with efficacy against HER2 exon 20 insertion-driven tumors, which preserve wild-type EGFR signaling.

Oncogenic alterations in human epidermal growth factor receptor 2 (HER2) occur in approximately 2% of patients with non-small cell lung cancer and predominantly affect the tyrosine kinase domain and cluster in exon 20 of the ERBB2 gene. Most clinical-grade tyrosine kinase inhibitors are limited by either insufficient selectivity against wild-type (WT) epidermal growth factor receptor (EGFR), which is a major cause of dose-limiting toxicity or by potency against HER2 exon 20 mutant variants. Here we report the discovery of covalent tyrosine kinase inhibitors that potently inhibit HER2 exon 20 mutants while sparing WT EGFR, which reduce tumor cell survival and proliferation in vitro and result in regressions in preclinical xenograft models of HER2 exon 20 mutant non-small cell lung cancer, concomitant with inhibition of downstream HER2 signaling.

Improving Shared Decision Making in Vascular Surgery: A Stepped Wedge Cluster Randomised Trial.

Objective: Different treatment options are available and feasible for various vascular surgical disorders. Hence, vascular surgery seems an area par excellence for shared decision making (SDM), in which clinicians incorporate the patient's preferences into the final treatment decision. However, current SDM levels in vascular surgical outpatient clinics are below expectations.

Surgical Treatment of Diabetic Foot Ulcers Complicated by Osteomyelitis with Gentamicin-Loaded Calcium Sulphate-Hydroxyapatite Biocomposite.

Diabetic foot ulcers, complicated by osteomyelitis, can be treated by surgical resection, dead space filling with gentamicin-loaded calcium sulphate-hydroxyapatite (CaS-HA) biocomposite, and closure of soft tissues and skin. To assess the feasibility of this treatment regimen, we conducted a multicenter retrospective cohort study of patients after failed conventional treatments. From 13 hospitals we included 64 patients with forefoot ( = 41 (64%)), midfoot ( = 14 (22%)), or hindfoot ( = 9 (14%)) ulcers complicated by osteomyelitis.

Editor's Choice - Nationwide Analysis of Patients Undergoing Iliac Artery Aneurysm Repair in the Netherlands.

Objective: The new 2019 guideline of the European Society for Vascular Surgery (ESVS) recommends consideration for elective iliac artery aneurysm (eIAA) repair when the iliac diameter exceeds 3.5 cm, as opposed to 3.0 cm previously.