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Purpose: MET amplification is a common resistance mechanism to EGFR inhibition in EGFR-mutant non-small cell lung cancer (NSCLC). Several trials showed encouraging results with combined EGFR and MET inhibition (EGFRi/METi). However, MET amplification has been inconsistently defined and frequently included both polysomy and true amplification., Methods: This is a multicenter, real-world analysis in patients with disease progression on EGFR inhibition and MET copy number gain (CNG), defined as either true amplification (MET to centromere of chromosome 7 ratio [MET-CEP7] ≥ 2) or polysomy (gene copy number ≥ 5, MET-CEP7 < 2)., Results: A total of 43 patients with MET CNG were included, 42 of whom were detected by FISH. Twenty-three, 7, and 14 received EGFRi/METi, METi, and SoC, respectively. Patients in the EGFRi/METi cohort exhibited a superior real-world clinical benefit rate, defined as stable disease or better, of 82% (95% confidence interval [CI], 60-95) compared to METi (29%, 4-71) and SoC (50%, 23-77). Median real-world progression-free survival was longer with EGFRi/METi with 9.8 vs. 4.3 months with METi (hazard ratio [HR], 0.19, 95% CI, 0.06-0.57) and 3.7 months with SoC (0.41, 0.18-0.91), respectively. Overall survival was numerically improved. Interaction analysis with treatment and type of CNG (amplification vs. polysomy) suggests that differences were exclusively driven by MET-amplified patients receiving EGFRi/METi (HR for OS, 0.09, 0.01-0.54)., Conclusion: In this real-world study, EGFRi/METi showed clinical benefit over METi and SoC. Future studies should focus on the differential impact of the type of MET CNG with a focus on true MET amplification as predictor of response., Competing Interests: Disclosure F. A. received support for attending meetings and speaker's honoraria from AstraZeneca, and consultant fees from IQVIA. P. C. received research funding from AstraZeneca, Amgen, Boehringer Ingelheim, Merck, Novartis, Roche, and Takeda, speaker's honoraria from AstraZeneca, Gilead, Janssen, Novartis, Roche, Pfizer, Thermo Fisher, and Takeda, support for attending meetings from AstraZeneca, Eli Lilly, Daiichi Sankyo, Janssen, Gilead, Novartis, Pfizer, Takeda, and personal fees for participating to advisory boards from AstraZeneca, Boehringer Ingelheim, Chugai, Pfizer, Novartis, MSD, Takeda and Roche, all outside the submitted work. H.-D. H. received personal fees for participating to advisory boards from Amgen, speaker's honoraria from Amgen, Boehringer Ingelheim, and Bristol-Myers Squibb. C. F. W. received personal fees for participating to advisory boards from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Lilly, Merck, MSD, Novartis, Pfizer, Roche, and Takeda, consultancy fees from Mylan/Viatris, Alvotech, Roche, support for attending meetings from Amgen, Bristol-Myers Squibb, Janssen, Lilly. A. Ri. received speaker's honoraria and consulting fees from Abbvie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Lilly, GSK, MSD, Novartis, Pfizer, Roche/Genentech. H. Z. received support for attending meetings from Janssen, speaker's honoraria from Pierre Fabre, and Roche. A. L. received support for attending meetings from Abbvie. D. K.-G. received consultant fees from AstraZeneca, Boehringer Ingelheim, Roche, MSD, Pfizer, Bristol-Myers Squibb, GSK, Novartis, Takeda, Sanofi, and Janssen, support for attending meetings from Takeda, Boehringer-Ingelheim, Janssen. R. B. received honoraries for lectures and advisory boards for AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Illumina, Janssen, Lilly, Merck-Serono, MSD, Novartis, Qiagen, Pfizer, Roche, Targos MP Inc. R.B. is a Co-Founder and Co-Owner of Targos Inc / Kassel (previous); Gnothis Inc / Stockholm (current); Timer Therapeutics Inc / Fulda & Freiburg (current). M. D. received personal fees for participating in advisory boards from AstraZeneca, Bayer, Diaceutics, Biocartis, Sophia Genetics, and ThermoFisher. F. C. A. has received research grants from Novartis, support for attending meetings and/or travel from Amgen, and consultant fees from IQVIA. S. H. has received research grants from Novartis and travel support from BeiGene. J. A. S. received personal fees from Boehringer Ingelheim, AstraZeneca, Roche, Bristol-Myers Squibb, Amgen, LEO pharma, Novartis, and Takeda. J. W. received speaker's honoraria and personal fees for participating in advisory boards from Amgen, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Ignyta, Janssen, Lilly, Loxo, Merck, Mirati, MSD, Novartis, Nuvalent, Pfizer, Roche, Seattle Genetics, Takeda, and Turning Point and received institutional research grants from Bristol-Myers Squibb, Janssen, Novartis, Pfizer, and AstraZeneca. M. S. received research grants from AstraZeneca, consulting fees from AstraZeneca, Bristol-Myers Squibb, MSD, Novartis, Lilly, Roche, Boehringer Ingelheim, Amgen, Takeda, Johnson, Merck-Serono, and GSK, and speaker's honoraria from AstraZeneca, Bristol-Myers Squibb, MSD, Novartis, Lilly, Roche, Boehringer Ingelheim, Amgen, Takeda, Johnson, CureVac, BioNTech, Merck-Serono, GSK, Daiichi, and Pfizer. S. M. has received research grants from Novartis and Pfizer, personal fees from Eli Lilly, Janssen, and Astra Zeneca as well as support for attending meetings and/or travel from Eli Lilly, and Janssen. A. S. has received speaker's honoraria from Agilent, Aignostics, Amgen, Astellas, Astra Zeneca, Bayer, BMS, Eli Lilly, Illumina, Incyte, Janssen, MSD, Novartis, Pfizer, Qlucore, Roche, Seagen, Servier, Takeda, and Thermo Fisher, and institutional research grants from Bayer, BMS, Chugai, and Incyte. All other authors declared no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Platelets have long been known as mediators of hemostasis and, more recently, as mediators of thromboinflammation, although their physiopathological role has mostly been investigated in the context of disease of internal organs, such as liver and kidney, or systemic disorders. Of late, exciting recent data suggest that platelets may also play a role in inflammation at distal sites such as the skin: recent studies show that platelets, by engaging polymorphonuclear neutrophils (PMNs), contribute to local inflammation in the frequent skin disorder, psoriasis. In an experimental model, systemic depletion of platelets drastically attenuated skin inflammation by preventing PMN infiltration of the skin. A broader role of platelets in different types of skin inflammation is therefore likely, and in this paper, we specifically review recent advances in psoriasis. Special emphasis is given to the crosstalk with systemic platelet effects, which may be of interest in psoriasis-related cardiovascular comorbidities. Furthermore, we discuss the potential for platelet-centered interventions in the therapy for psoriasis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Staphylococcus aureus is a facultative pathogen found on skin and nasal surfaces. It is usually absent from the skin of healthy humans but frequently colonizes the skin of patients with atopic dermatitis. Here, we investigate the functional role of neutrophils in the initial steps of S. aureus skin colonization and how skin commensals modulate the S. aureus-induced recruitment of neutrophils to the skin. Using an epicutaneous mouse skin colonization model, we show that skin inflammation induced by tape-stripping leads to a rapid recruitment of neutrophils, which correlates with enhanced S. aureus skin colonization. Interestingly, the depletion of neutrophils in vivo reduces S. aureus colonization, and in vitro coculture of primary human keratinocytes with neutrophils promotes S. aureus adherence. We demonstrate that the interaction of neutrophil extracellular traps with keratinocytes are responsible for the increased S. aureus skin colonization. Finally, we show that S. epidermidis as part of the skin microbiota can reduce the neutrophil recruitment induced by S. aureus infection. These data suggest that microbiota-mediated skin protection against S. aureus is dampened in an inflammatory environment in which neutrophil extracellular traps released by infiltrating neutrophils unexpectedly contribute to enhanced S. aureus skin colonization., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)