Purpose: The impact of EGFR tyrosine kinase inhibitors (TKI) on the tumor immune microenvironment (TME) in non-small cell lung cancer (NSCLC) is unclear.Experimental Design: We retrospectively identified 138 patients with EGFR-mutated NSCLC who underwent rebiopsy after progression during EGFR-TKI treatment. PD-L1 and CD73 expression in tumor cells and tumor-infiltrating lymphocyte (TIL) density at baseline and after progression were determined by IHC. Tumor mutation burden (TMB) was determined by next-generation sequencing.Results: The proportion of patients with a PD-L1 expression level of ≥50% (high) increased from 14% before to 28% after EGFR-TKI (P ¼ 0.0010). Whereas CD8 þ and FOXP3 þ TIL densities were significantly lower after EGFR-TKI treatment than before, CD8 þ TIL density was maintained in tumors with a high PD-L1 expression level. Expression of CD73 in tumor cells after EGFR-TKI treatment was higher than that before in patients with a high PD-L1 expression level. TMB tended to be higher after EGFR-TKI treatment than before (3.3!4.1 mutations/Mbp, P ¼ 0.0508). Median progressionfree survival for subsequent treatment with antibodies to PD-1 was longer for patients with a high than for those with a low PD-L1 expression after EGFR-TKI (7.1 vs. 1.7 months, P ¼ 0.0033), and two of five patients whose PD-L1 expression level changed from low to high after EGFR-TKI treatment achieved a PFS of >6 months.Conclusions: EGFR-TKI treatment was associated with changes in the TME of EGFR-mutated NSCLC, and such changes may provide clues for optimization of subsequent PD-1 inhibitor treatment.

BackgroundAntimicrobial stewardship has not always prevailed in a wide variety of medical institutions in Japan.MethodsThe infection control team was involved in the review of individual use of antibiotics in all inpatients (6348 and 6507 patients/year during the first and second annual interventions, respectively) receiving intravenous antibiotics, according to the published guidelines, consultation with physicians before prescription of antimicrobial agents and organisation of education programme on infection control for all medical staff. The outcomes of extensive implementation of antimicrobial stewardship were evaluated from the standpoint of antimicrobial use density, treatment duration, duration of hospital stay, occurrence of antimicrobial-resistant bacteria and medical expenses.ResultsProlonged use of antibiotics over 2 weeks was significantly reduced after active implementation of antimicrobial stewardship (2.9% vs. 5.2%, p < 0.001). Significant reduction in the antimicrobial consumption was observed in the second-generation cephalosporins (p = 0.03), carbapenems (p = 0.003), aminoglycosides (p < 0.001), leading to a reduction in the cost of antibiotics by 11.7%. The appearance of methicillin-resistant Staphylococcus aureus and the proportion of Serratia marcescens to Gram-negative bacteria decreased significantly from 47.6% to 39.5% (p = 0.026) and from 3.7% to 2.0% (p = 0.026), respectively. Moreover, the mean hospital stay was shortened by 2.9 days after active implementation of antimicrobial stewardship.ConclusionExtensive implementation of antimicrobial stewardship led to a decrease in the inappropriate use of antibiotics, saving in medical expenses, reduction in the development of antimicrobial resistance and shortening of hospital stay.

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