Despite the worldwide approval of three generations of EGFR tyrosine kinase inhibitors (TKI) for advanced nonsmall cell lung cancers with EGFR mutations, no TKI with a broad spectrum of activity against all clinically relevant mutations is currently available. In this study, we sought to evaluate a covalent mutation-specific EGFR TKI, TAS6417 (also named CLN-081), with the broadest level of activity against EGFR mutations with a prevalence of !1%. Lung cancer and genetically engineered cell lines, as well as murine xenograft models were used to evaluate the efficacy of TAS6417 and other approved/in-development EGFR TKIs (erlotinib, afatinib, osimertinib, and poziotinib). We demonstrate that TAS6417 is a robust inhibitor against the most common EGFR mutations (exon 19 deletions and L858R) and the most potent against cells harboring EGFR-T790M (first/second-generation TKI resistance mutation). In addition, TAS6417 has activity in cells driven by less common EGFR-G719X, L861Q, and S768I mutations. For recalcitrant EGFR exon 20 insertion mutations, selectivity indexes (wildtype EGFR/mutant EGFR ratio of inhibition) favored TAS6417 in comparison with poziotinib and osimertinib, indicating a wider therapeutic window. Taken together, we demonstrate that TAS6417 is a potent EGFR TKI with a broad spectrum of activity and a wider therapeutic window than most approved/in-development generations of EGFR inhibitors.Implications: TAS6417/CLN-081 is a potent EGFR TKI with a wide therapeutic window and may be effective in lung cancer patients with clinically relevant EGFR mutations.

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Purpose: There is a pressing need for safe venous thromboembolism (VTE) prophylaxis in orthopedic patients with the highest risks of both venous thrombosis and bleeding. Portable intermittent pneumatic compression device (IPCD) has proven to be effective and safe in patients with a high risk of venous thrombosis and low bleeding risk. Therefore, this study examined the effectiveness, safety, and wearing compliance of portable IPCD for postoperative VTE prophylaxis in patients with the highest risks of both venous thrombosis and bleeding. Methods: The cases consisted of 38 patients who had used a portable IPCD and had the highest risks of both venous thrombosis and bleeding. We examined the incidence of VTE to assess the effectiveness of the portable IPCD, the presence of hemorrhagic adverse events to assess safety, and the wearing rate to assess wearing compliance. Results: The incidences of asymptomatic and symptomatic deep vein thrombosis were 5.3% and 2.6%, respectively. The incidence of hemorrhagic adverse events was 21.1% in patients who received anticoagulants and wore an IPCD simultaneously and 0% in patients who wore an IPCD but did not receive anticoagulants. The wearing rate (i.e. ≥18 h/day) was 100%. Conclusion: Portable IPCD has the potential for safe VTE prophylaxis in patients at high risks for both venous thrombosis and bleeding. Therefore, we suggest that such patients use a portable IPCD for VTE prophylaxis.

Purpose: The present study aimed to compare the capabilities of preoperative usual and maximal gait speeds in predicting functional recovery in patients who have undergone total hip arthroplasty (THA). Methods: Primary and unilateral THAs were performed in 317 patients, and the proportion of patients who achieved unassisted walking (functional recovery) 5 days postoperatively was recorded as an outcome measure. Preoperative functional assessment included hip pain, leg muscle strength, range of motion (ROM), and gait speed evaluations. The capabilities of preoperative usual and maximal gait speeds in predicting functional recovery were compared based on the areas under the curves (AUCs) of receiver operating characteristic (ROC) curves. Further, ROC curves were constructed using two models: 1. a model of gait speed only and 2. a clinical model including age, sex, leg muscle strength, and ROM. Results: On the AUCs for predictive ability of functional recovery, maximal gait speed was greater than usual gait speed (0.66 and 0.70, respectively). The AUC for maximal gait speed was as large as that of the clinical model (0.70 and 0.70, respectively). Conclusion: Our results suggest that maximal gait speed is a simple and useful prognostic indicator of functional recovery in patients who have undergone THA.