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.

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Introduction: Nivolumab is effective in the treatment of previously treated patients with advanced NSCLC. However, its radiological evaluation is challenging because of atypical patterns of response such as pseudoprogression. We examined the characteristics and outcomes of previously treated patients with NSCLC who were treated with nivolumab and experienced development of pseudoprogression. Methods: We conducted a 15-center retrospective cohort study of previously treated patients with advanced NSCLC who received nivolumab monotherapy. For the patients who showed pseudoprogression, we defined progression-free survival 1 (PFS1) as the time to Response Evaluation Criteria in Solid Tumors-defined first progressive disease and progression-free survival 2 (PFS2) as the time to Response Evaluation Criteria in Solid Tumors-defined second progressive disease or death.

The position of meroplanktonic larvae in the water column with depth-dependent current velocities determines horizontal transport trajectories. For those larvae occurring in inner shelf waters, little is known about how combined diel and tidally-synchronized vertical migration patterns shift ontogenetically.

BackgroundAlthough the cause of acute eosinophilic pneumonia (AEP) has not yet been fully clarified, cigarette smoking is reported to be a risk factor for developing AEP. The heat-not-burn cigarette (HNBC) was developed to reduce the adverse effects of smoke on the user's surroundings. However, the health risks associated with HNBCs have not yet been clarified. We report a successfully treated case of fatal AEP presumably induced by HNBC use.Presentation of caseA 16-year-old man commenced HNBC smoking two weeks before admission and subsequently suffered from shortness of breath that gradually worsened. The patient was transferred to emergency department and immediately intubated because of respiratory failure. Computed tomography showed mosaic ground-glass shadows on the distal side of both lungs with a PaO2/FIO2 ratio of 76. The patient required veno-venous extracorporeal membrane oxygenation (ECMO) for severe respiratory failure. He was diagnosed with AEP by clinical course and detection of eosinophils in sputum; thus, methylprednisolone was administrated. The patient was weaned off ECMO four days after initiation and extubated the day after. He fully recovered without sequelae.ConclusionAs far as we know, our patient is the first case of AEP induced by HNBC use successfully treated with ECMO. Emergency physicians must be aware that HNBCs can induce fatal AEP.