Tyrosine kinase domains dynamically fluctuate between two main structural forms that are referred to as type I (DFG-in) or type II (DFG-out) conformations. Comprehensive data comparing type I and type II inhibitors are currently lacking for NTRK fusion-driven cancers. Here we used a type II NTRK inhibitor, altiratinib, as a model compound to investigate its inhibitory potential for larotrectinib (type I inhibitor)-resistant mutations in NTRK. Our study shows that a subset of larotrectinib-resistant NTRK1 mutations (V573M, F589L and G667C) retains sensitivity to altiratinib, while the NTRK1V573M and xDFG motif NTRK1G667C mutations are highly sensitive to type II inhibitors, including altiratinib, cabozantinib and foretinib. Moreover, molecular modeling suggests that the introduction of a sulfur moiety in the binding pocket, via methionine or cysteine substitutions, specifically renders the mutant kinase hypersensitive to type II inhibitors. Future precision treatment strategies may benefit from selective targeting of these kinase mutants based on our findings.

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Background Many urgent and elective surgeries were postponed to cope with the Coronavirus disease (COVID-19) pandemic, with latest data found a substantial postoperative mortality risk (25·6%, 18.9%) after emergency and elective surgery, respectively. Our institution was one of the first trust to offer essential elective surgery using a “COVID-free” designated site during the start of the pandemic. The aim of this study is to analyse the clinical outcomes of patients who underwent essential elective procedures during the virus outbreak in the UK. Method Retrospective analysis of outcomes all patients who had undergone urgent elective and cancer surgery, from 30th March 2020 to 21st May 2020, using an implemented “Super Green Pathway”. The primary endpoints were 30 days mortality and COVID related morbidities, and the secondary endpoints were surgical related complications and oncological outcomes. Results 92 patients (Male:45%; Female:55%) across 5 surgical specialties were identified. There was no record of mortality in our cohort. Only 1 patient was tested positive for SARS-CoV-2, 18 days after the initial operation without any pulmonary complications. Conclusions It is possible to mitigate the high mortality risk of postoperative complications associated with COVID-19, with no delay to essential surgeries for cancer patients, thus delivering safe practice during the pandemic.

Objective: To determine absolute and relative risks of either symptomatic or asymptomatic SARS-CoV-2 infection for late cardiovascular events and all-cause mortality. Methods: We conducted a retrospective double-cohort study of patients with either symptomatic or asymptomatic SARS-CoV-2 infection [COVID-19(+) cohort] and its documented absence [COVID-19(-) cohort]. The study investigators drew a simple random sample of records from all Oregon Health & Science University (OHSU) Healthcare patients (N=65,585) with available COVID-19 test results, performed 03.01.2020 - 09.13.2020. Exclusion criteria were age < 18y and no established OHSU care. The primary outcome was a composite of cardiovascular morbidity and mortality. All-cause mortality was the secondary outcome. Results: The study population included 1355 patients (mean age 48.7 ± 20.5 y; 770(57%) female, 977(72%) white non-Hispanic; 1072(79%) insured; 563(42%) with cardiovascular disease (CVD) history). During a median 6 months at risk, the primary composite outcome was observed in 38/319 (12%) COVID-19(+) and 65/1036 (6%) COVID-19(-) patients (p=0.001). In Cox regression adjusted for demographics, health insurance, and reason for COVID-19 testing, SARS-CoV-2 infection was associated with the risk of the primary composite outcome (HR 1.71; 95%CI 1.06-2.78; p=0.029). Inverse-probability-weighted estimation, conditioned for 31 covariates, showed that for every COVID-19(+) patient, the average time to all-cause death was 65.5 days less than when all these patients were COVID-19(-): average treatment effect on the treated -65.5 (95%CI -125.4 to -5.61) days; p=0.032. Conclusions: Either symptomatic or asymptomatic SARS-CoV-2 infection is associated with increased risk of late cardiovascular outcomes and has a causal effect on all-cause mortality in a late post-COVID-19 period.

BackgroundThe coronavirus disease (COVID-19) had so far claimed more than 600 000 lives worldwide. Many urgent and elective surgeries were postponed to cope with the pandemic, with the latest data found a substantial postoperative mortality risk (25.6%, 18.9%) after an emergency and elective surgery, respectively. Our institution was one of the first few in the country to offer essential elective surgery using a “COVID-free” designated site during the start of the pandemic. This study aims to analyze the clinical outcomes of patients who underwent essential elective procedures during the virus outbreak in the UK. MethodsRetrospective analysis of outcomes of all patients who had undergone urgent elective and cancer surgery, from 30th March 2020 to 21st May 2020, using an implemented “Super Green Pathway.”The primary endpoints were 30 days mortality and COVID-related morbidities, and the secondary end-points were surgically related complications and oncological outcomes. ResultsA total of 92 patients (Male: 45%; Female: 55%) across 5 surgical specialties were identified. There was no record of mortality in our cohort. Only 1 patient was tested positive for SARS-CoV-2, 18 days after the initial operation without any pulmonary complications. There were 7 postoperative surgical complications managed at the acute hospital site. The waiting time for surgery ranges from 6 to 191 days, mean of 30 days, and a median of 23 days. ConclusionIt is possible to mitigate the high mortality risk of post-operative complications associated with COVID-19, with no delay to essential surgeries for cancer patients, thus delivering safe practice during the pandemic.