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Introduction: The primary analysis (median follow-up 34.9 mo across all arms) of the phase 3 POSEIDON study revealed a statistically significant overall survival (OS) improvement with first-line tremelimumab plus durvalumab and chemotherapy (T+D+CT) versus CT in patients with EGFR and ALK wild-type metastatic NSCLC (mNSCLC). D+CT had a trend for OS improvement versus CT that did not reach statistical significance. This article reports prespecified OS analyses after long-term follow-up (median >5 y)., Methods: A total of 1013 patients were randomized (1:1:1) to T+D+CT, D+CT, or CT, stratified by tumor cell programmed cell death ligand-1 (PD-L1) expression (≥50% versus <50%), disease stage (IVA versus IVB), and tumor histologic type (squamous versus nonsquamous). Serious adverse events were collected during follow-up., Results: After a median follow-up of 63.4 months across all arms, T+D+CT had sustained OS benefit versus CT (hazard ratio [HR] = 0.76, 95% confidence interval [CI]: 0.64-0.89; 5-y OS: 15.7% versus 6.8%). OS improvement with D+CT versus CT (HR = 0.84, 95% CI: 0.72-1.00; 5-y OS: 13.0%) was consistent with the primary analysis. OS benefit with T+D+CT versus CT remained more pronounced in nonsquamous (HR = 0.69, 95% CI: 0.56-0.85) versus squamous (HR = 0.85, 95% CI: 0.65-1.10) mNSCLC. OS benefit with T+D+CT versus CT was still evident regardless of PD-L1 expression, including patients with PD-L1 tumor cell less than 1%, and remained evident in STK11-mutant (nonsquamous), KEAP1-mutant, and KRAS-mutant (nonsquamous) mNSCLC. No new safety signals were identified., Conclusions: After a median follow-up of more than 5 years, T+D+CT had durable long-term OS benefit versus CT, supporting its use as first-line treatment in mNSCLC, including in patient subgroups with harder-to-treat disease., Competing Interests: Disclosure Peters has received grants (paid to institution) from Amgen, Arcus, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, F. Hoffmann-La Roche/Genentech, GlaxoSmithKline, iTeos, Merck Sharp & Dohme, Merck Serono, Mirati, PharmaMar, Promontory Therapeutics, and Seattle Genetics; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events (paid to institution) from AiCME, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ecancer, Eli Lilly, F. Hoffmann-La Roche/Genentech, Foundation Medicine, GlaxoSmithKline, Illumina, Imedex, Ipsen, Medscape, Merck Sharp & Dohme, Mirati, MJH Life Sciences, Novartis, Peerview, Pfizer, RTP, and Takeda; and has participation on a data safety monitoring board or advisory board (payment to institution) for AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, BerGenBio, Biocartis, Bioinvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F. Hoffmann-La Roche/Genentech, Fishawack, Foundation Medicine, F-Star, Genzyme, Gilead, GlaxoSmithKline, Hutchmed, Illumina, Imedex, Incyte, Ipsen, IQVIA, iTeos, Janssen, Medscape, Medtoday, Merck Sharp & Dohme, Merck Serono, Merrimack, Mirati, MJH Life Sciences, Novartis, Novocure, Nykode Therapeutics, OncologyEducation, Peerview, Pharma Mar, Pfizer, Promontory Therapeutics, Regeneron, RMEI, RTP, Sanofi, Seattle Genetics, and Takeda. Cho reports receiving research funding from MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp., GIInnovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Oncology, CJ Bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Janssen, Lilly, Merck Sharp & Dohme, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, Bridgebio Therapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph Therapeutics, Therapex, JINTSbio, Hanmi, CHA Bundang Medical Center, and Vertical Bio AG; receiving royalties from Champions Oncology, Crown Bioscience, Imagen, and PearlRiver Bio GmbH; receiving consulting fees from Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, CJ, CureLogen, Cyrus Therapeutics, Ono, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI-Cell, Guardant, HK Inno-N, Imnewrun Biosciences Inc., Janssen, Takeda, Merck Sharp & Dohme, Janssen, Medpacto, Blueprint Medicines, RandBio, and Hanmi; receiving payment or honoraria for presentations from ASCO, AstraZeneca, Guardant, Roche, ESMO, International Association for the Study of Lung Cancer, Korean Cancer Association, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, Merck Sharp & Dohme, The Chinese Thoracic Oncology Society, and Pfizer; having scientific advisory board participation for Kanaph Therapeutics Inc., Bridgebio Therapeutics, Cyrus Therapeutics, Guardant Health, Oscotec Inc., J INTS Bio, Therapex Co., Ltd., Gilead, and Amgen; having membership of the board of directors for J INTS BIO; having stock ownership in TheraCanVac Inc., Gencurix Inc., Bridgebio Therapeutics, Kanaph Therapeutics Inc., Cyrus Therapeutics, Interpark Bio Convergence Corp., and J INTS BIO; having employment with Yonsei University Health System; and being a founder of DAAN Biotherapeutics. Alatorre-Alexander has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme, and Roche; received support for attending meetings and/or travel from AstraZeneca, Merck Sharp & Dohme, and Roche; and participated on a data safety monitoring board or advisory board for Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme, and Roche. Geater has received research funding (paid to institution) from AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, and Roche; received honoraria from AstraZeneca and Boehringer Ingelheim; and performed an advisory role for Merck Sharp & Dohme and Pfizer. Laktionov has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for AstraZeneca, Biocad, Bristol-Myers Squibb, Merck Sharp & Dohme, and Roche AG, and has participated on a data safety monitoring board or advisory board for AstraZeneca, Biocad, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, and Roche AG. Kim has received grants (paid to institution) from Yuhan and support for attending an investigator meeting from AstraZeneca. Hussein has received consulting fees from IntegraConnect, Coherus Biosciences, Athenex, Karyopharm Therapeutics, Bristol-Myers Squibb, AstraZeneca, Mirati Therapeutics, Exelixis, Biopharma, Oncocyte, Aptitude Health, IntrinsiQ, GIntrinsiQ, National Community Oncology Dispensing Association, Integra PrescisionQ, AbbVie, and CTI BioPharma Corp. Araujo has received grants from Lilly, Boehringer, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, Pfizer, AstraZeneca, Novartis, and Merck; consulting fees from Merck Sharp & Dohme, Roche, AstraZeneca, Bristol-Myers Squibb, Lilly, Illumina, and Sanofi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Boehringer, Merck, Roche, Pfizer, and Lilly; and support for attending meetings and/or travel from Daiichi Sankyo, Bristol-Myers Squibb, and AstraZeneca. Saito has received grants from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, and ONO Pharmaceutical, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, ONO Pharmaceutical, and Pfizer. Reinmuth has received consulting fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck Sharp & Dohme, and Pfizer; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck Sharp & Dohme, Pfizer, Sanofi, and Takeda; received support for attending meetings and/or travel from Janssen, Sanofi, and Takeda; and participated on a data safety monitoring board or advisory board for Symphogen. Lowery, Mann, Stewart, and Jiang are employees of, and own stocks in, AstraZeneca. Garon has received grants paid to their institution from ABL-Bio, AstraZeneca, Bristol-Myers Squibb, Daiichi Sanko, Dynavax Technologies, Eli Lilly, EMD Serono, Genentech, Gilead, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon, and Novartis; consulting fees paid to their institution from AbbVie, ABL-Bio, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly, Gilead, GlaxoSmithKline, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, Xilio, and Zymeworks; and support for attending meetings and/or travel from A2 Bio and Novartis. Mok reports receiving grants paid to their institution from AstraZeneca, Bristol-Myers Squibb, G1 Therapeutics, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, and Xcovery; consulting fees from AbbVie Inc., ACEA Pharma, Adagene, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., AVEO Pharmaceuticals, Inc., Bayer Healthcare Pharmaceuticals Ltd., BeiGene, Berry Oncology, Boehringer Ingelheim, Blueprint Medicines Corporation, Bristol-Myers Squibb, Bowtie Life Insurance Company Limited, Bridge Biotherapeutics Inc., Covidien LP, C4 Therapeutics Inc., Cirina Ltd., CStone Pharmaceuticals, Curio Science, D3 Bio Ltd., Da Volterra, Daiichi Sankyo, Eisai, Elevation Oncology, F. Hoffmann-La Roche Ltd./Genentech, Fishawack Facilitate Ltd., G1 Therapeutics Inc., geneDecode Co., Ltd., Gilead Sciences, Inc., GLG’s Healthcare, Gritstone Oncology, Inc., Guardant Health, Hengrui Therapeutics Inc., HutchMed, Ignyta, Inc., Illumina Inc., Incyte Corporation, Inivata, IQVIA, Janssen, Lakeshore Biotech Ltd., Lilly, Lunit USA, Inc., Loxo-Oncology, Lucence Health Inc., Medscape LLC/WebMD, Medtronic, Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc., MiRXES, MoreHealth, Novartis, Novocure GmbH, Omega Therapeutics Inc., OrigiMed, OSE Immunotherapeutics, PeerVoice, Pfizer, PrIME Oncology, Prenetics, Puma Biotechnology Inc., Qiming Development (HK) Ltd., Regeneron Pharmaceuticals Inc., Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, SFJ Pharmaceutical Ltd., Simcere of America Inc., Synergy Research, Summit Therapeutics Sub, Inc., Takeda Pharmaceuticals HK Ltd., Tigermed, Vertex Pharmaceuticals, Virtus Medical Group, XENCOR, Inc., and Yuhan Corporation; receiving payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from ACEA Pharma, Alpha Biopharma Co. Ltd., Amgen, Amoy Diagnostics Co. Ltd., AstraZeneca (before January 1, 2019), BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Daz Group, Fishawack Facilitate Ltd., InMed Medical Communications, Janssen Pharmaceutica NV, Jiahui Holdings Co. Ltd., LiangYiHui Healthcare, Lilly, Lucence Health Inc., MD Health Brazil, Medscape LLC, Merck Pharmaceuticals HK Ltd., Merck Sharp & Dohme, MiRXES, Novartis, OrigiMed Co. Ltd., P. Permanyer SL, PeerVoice, Physicians’ Education Resource, Pfizer, PrIME Oncology, Research to Practice, Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting Co. Ltd., Taiho Pharmaceutical Co. Ltd., Takeda Oncology, and Touch Independent Medical Education Ltd.; receiving support for attending meetings and/or travel from Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Merck Sharp & Dohme (paid to institution), Novartis, Roche (paid to self and institution), AstraZeneca, Daiichi Sankyo, MiRXES, AbbVie, Zai Lab, and Liangyihui (paid to self); having participation on a data safety monitoring board or advisory board for AbbVie Inc., ACEA Pharma, Amgen, AstraZeneca, Berry Oncology, Blueprint Medicines Corporation, Boehringer Ingelheim, Bowtie Life Insurance Co., Ltd., Bristol-Myers Squibb, C4 Therapeutics Inc., Covidien LP, CStone Pharmaceuticals, Curio Science, D3 Bio Ltd., Daiichi Sankyo Inc., Eisai, Fishawack Facilitate Ltd., G1 Therapeutics Inc., Gilead Sciences Inc., Gritstone Oncology Inc., Guardant Health, geneDecode Co. Ltd. (uncompensated), Hengrui Therapeutics Inc., HutchMed, Ignyta Inc., Incyte Corporation, Imagene AI Ltd., Inivata, IQVIA, Janssen, Lakeshore Biotech, Lilly, Loxo-Oncology Inc., Lunit Inc., Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc., MiRXES Group, Novartis, OrigiMed, Pfizer, Puma Biotechnology Inc., Roche/Genentech, Regeneron Pharmaceuticals Inc., Sanofi-Aventis R&D, SFJ Pharmaceutical, Simcere of America Inc., Simcere Zaiming, Inc., Takeda, Vertex Pharmaceuticals, Virtus Medical Group, XENCOR, Inc., and Yuhan Corporation; having leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, with AstraZeneca PLC, HutchMed, and Aurora; and having stock or stock options in AstraZeneca, Aurora Tele-Oncology Ltd., Biolidics Ltd., HutchMed, Prenetics, D3 Bio, Lunit, Bowtie Life Insurance, Lakeshore Biotech Ltd., Loxo-oncology, Virtus Medical Group, and Phanes Therapeutics, Inc. Johnson has received research funding paid to their institution from AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Calithera Biosciences, Carisma Therapeutics, Corvus Pharmaceutical, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunitas Therapeutics, Immunocore, Incyte, Janssen, Kadmon Pharmaceuticals, Kartos Therapeutics, Loxo-Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, Y-mAbs Therapeutics, Bristol-Myers Squibb, Checkpoint Therapeutics, City of Hope National Medical Center, Jounce Therapeutics, Mythic Therapeutics, RasCal Therapeutics, WindMIL Therapeutics, ArriVent BioPharma, Bayer, LockBody Therapeutics, and Taiho Oncology; and receiving consulting fees paid to their institution from AbbVie, Amgen, Arrivent, Alentis Therapeutics, AstraZeneca, Bristol-Myers Squibb, D3 Bio Limited, Daiichi Sankyo, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Hookipa Biotech, Janssen, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Pyramid Biosciences, Revolution Medicines, Sanofi-Aventis, SeaGen, Takeda Pharmaceuticals, VBL Therapeutics, Arcus Biosciences, Immunocore, Jazz Pharmaceuticals, Synthekine, Boehringer Ingelheim, Gilead Sciences, Normunity, Lilly, Novocure, and Pfizer. The remaining authors delcare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Rising global temperatures can lead to heat waves, which in turn can pose health risks to the community. However, a notable gap remains in highlighting the primary contributing factors that amplify heat-health risk among vulnerable populations. This study aims to evaluate the precedence of heat stress contributing factors in urban and rural vulnerable populations living in hot and humid tropical regions. A comparative cross-sectional study was conducted, involving 108 respondents from urban and rural areas in Klang Valley, Malaysia, using a face-to-face interview and a validated questionnaire. Data was analyzed using the principal component analysis, categorizing factors into exposure, sensitivity, and adaptive capacity indicators. In urban areas, five principal components (PCs) explained 64.3% of variability, with primary factors being sensitivity (health morbidity, medicine intake, increased age), adaptive capacity (outdoor occupation type, lack of ceiling, longer residency duration), and exposure (lower ceiling height, increased building age). In rural, five PCs explained 71.5% of variability, with primary factors being exposure (lack of ceiling, high thermal conductivity roof material, increased building age, shorter residency duration), sensitivity (health morbidity, medicine intake, increased age), and adaptive capacity (female, non-smoking, higher BMI). The order of heat-health vulnerability indicators was sensitivity > adaptive capacity > exposure for urban areas, and exposure > sensitivity > adaptive capacity for rural areas. This study demonstrated a different pattern of leading contributors to heat stress between urban and rural vulnerable populations., (© 2024. The Author(s).)

Continued heat exposure can cause physiological and cellular responses. This study investigated the association between physiological responses and heat shock protein 70 (HSP70) expressions in Kuala Lumpur's urban vulnerable population. We conducted a cross-sectional study involving 54 participants from four areas classified as experiencing moderate to strong heat stress. Physiological measurements included core body temperature, heart rate, and diastolic and systolic blood pressure. RT-qPCR and ELISA were also performed on blood samples to assess HSP70 gene and protein expressions. Despite indoor heat stress, participants maintained normal physiological parameters while there were significant indications of HSP70 expression at both the gene and protein levels. However, our study found no significant correlation ( p  > 0.05) between physiological responses and HSP70 expressions. This study shows no interaction between physiological responses and HSP70 expressions in the study population, revealing the complex mechanisms of indoor heat stress in vulnerable individuals.

Introduction: We evaluated efficacy and safety of cabozantinib plus atezolizumab or cabozantinib alone in advanced NSCLC previously treated with an immune checkpoint inhibitor (ICI)., Methods: COSMIC-021 (NCT03170960) is a phase 1b, multicenter study in advanced solid tumors. This analysis included patients with stage IV non-squamous NSCLC without actionable genomic aberrations in EGFR, ALK, ROS1 , or BRAF - V600E who progressed on one prior ICI and less than or equal to two prior lines of systemic anticancer therapy. Patients received cabozantinib 40 mg orally/day plus atezolizumab 1200 mg intravenously every three weeks (combination cohort) or cabozantinib 60 mg orally/day (single-agent cabozantinib cohort). Primary end point of the combination cohort was objective response rate per Response Evaluation Criteria in Solid Tumors v1.1 by investigator. Outcomes in the single-agent cabozantinib cohort were exploratory., Results: Eighty-one patients assigned to combination therapy and 31 assigned to single-agent cabozantinib received greater than or equal to one dose of study treatment. Median (range) follow-up was 26.1 months (12.1-44.2) and 22.4 months (1.5-29.0), respectively. Objective response rate was 20% (95% confidence interval: 11.7%-30.1%) in combination cohort and 6% (95% confidence interval: 0.8%-21.4%) in single-agent cabozantinib cohort. Treatment-related adverse events (TRAEs) occurred in 86% of patients in the combination cohort and 90% in the single-agent cabozantinib cohort; grade 3/4 TRAEs were 44% and 48%, respectively. There were two grade 5 TRAEs: pneumonitis (n = 1, combination) and gastric ulcer hemorrhage (n = 1, single-agent). Neither PD-L1 expression in tumor cells nor tumor mutation burden correlated with outcomes., Conclusions: Cabozantinib plus atezolizumab demonstrated modest clinical activity and manageable toxicity in advanced NSCLC after progression on prior ICI., Competing Interests: Dr. Neal reported receiving honoraria from Biomedical Learning Institute CME, Clinical Care Options, CME Matter, Medscape CME, MJH Life Sciences CME, MLI Peerview CME, Prime Oncology CME, Projects in Knowledge CME, Research to Practice CME, Rockpointe CME, Medical Educator Consortium, HMP Education, a consulting or advisory role with AstraZeneca, Blueprint Pharmaceuticals, Calithera Biosciences, D2G Oncology, Exelixis, Genentech, Roche, Jounce Therapeutics, Eli Lilly and Company, Natera, Regeneron, Sanofi, Surface Oncology, Takeda Pharmaceuticals, Turning Point Therapeutics, and receiving institutional research funding from 10.13039/100006483AbbVie, Adaptimmune, Boehringer Ingelheim, 10.13039/100010544Exelixis, 10.13039/100004328Genentech, 10.13039/100004337Roche, GSK, 10.13039/100005565Janssen, 10.13039/100004334Merck, Nektar Therapeutics, 10.13039/100004336Novartis, Takeda Pharmaceuticals. Dr. Armando Santoro reported having a consulting or advisory role with Sanofi, Incyte, receiving honoraria from AbbVie, Amgen, ArQule, AstraZeneca, Bayer, BMS, Celgene, Eisai, Gilead Sciences, Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, Servier, Takeda, and participating in a data safety or advisory board with BMS, Servier, Gilead, Pfizer, Eisai, Bayer, MSD. Dr. Maria Gonzalez-Cao reported receiving grants or contracts from Roche, AstraZeneca, and Novartis, honoraria from Bristol Myers Squibb, MSD, AstraZeneca, Novartis, and Pierre Fabre, support for travel, accommodations, and expenses from MSD, AstraZeneca, and Pierre Fabre, and having a leadership or fiduciary role with the Spanish Melanoma Group. Dr. Ryan D. Gentzler reported receiving honoraria from Targeted Oncology, OncLive, Clinical Care Options, Society for Immunotherapy of Cancer, American Society of Clinical Oncology, MedStar Health, Aptitude Health, support for attending meetings from International Association for the Study of Lung Cancer, American Society of Clinical Oncology, Dava Oncology, Tempus, having a consulting or advisory role with AstraZeneca, Daiichi Sankyo, Gilead, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, OncoCyte, Sanofi, Takeda, Merus, Regeneron, receiving institutional research funding from 10.13039/100002429Amgen, Alliance Foundation, 10.13039/100004325AstraZeneca, Big Ten Research Consortium, 10.13039/100002491Bristol Myers Squibb, 10.13039/100010795Chugai, 10.13039/501100022274Daiichi Sankyo, 10.13039/100008130Helsinn Therapeutics, Hoosier Cancer Research Network, 10.13039/100005565Janssen, 10.13039/100016765Jounce Therapeutics, Merck, 10.13039/100016957Mirati Therapeutics, 10.13039/100004319Pfizer, 10.13039/100008199RTI International, Takeda, Dizal, Puma, and having leadership or committee roles with Hoosier Cancer Research Network, ASCO, Journal of Clinical Oncology, NCI Investigational Drug Steering Committee, and International Association for the Study of Lung Cancer. Dr. Jerome Goldschmidt reported receiving honoraria from G1 Therapeutics, and support for travel, accommodations, and expenses from Sara Cannon Research Institute. Dr. Claudia Proto reports receiving honoraria from AstraZeneca, Bristol Myers Squibb, MSD, Roche, Sanofi, having a consulting or advisory role with AstraZeneca, MSD and Roche, institutional research funding from MSD, Lilly, Pfizer, support for travel, accommodations, expenses from AstraZeneca, MSD, and Roche, and is the principal investigator in clinical trials for Janssen, Pfizer, Lilly, Spectrum Pharmaceuticals, Roche, MSD, BMS, and AstraZeneca. Dr. Shiven Patel reported receiving a consulting or advisory role with AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Regeneron, Sanofi, TerSera Therapeutics LLC, Total Health Conferencing, Natera, Takeda, Merck, BMS, and receiving institutional research funding from AstraZeneca, Janssen, Merck, and Takeda. Dr. Sonam Puri reported having an institutional consulting or advisory role with Jazz Pharma, receiving consulting fees from G1 Therapeutics, Pfizer, Bristol-Myers Squibb, receiving honoraria from Aptitude Health, and support for travel, accommodations, and expenses from Dava Oncology. Dr. Stephen V. Liu reported having a consulting or advisory role with AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Catalyst, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech, Roche, Gilead Sciences, Guardant Health, Janssen Oncology, Jazz Pharmaceuticals, Merck, Merus, Mirati, Novartis, Regeneron, Sanofi, Takeda, and Turning Point Therapeutics, receiving institutional research funding from AbbVie, 10.13039/100018529Alkermes, Elevation Oncology, Ellipses, Genentech, Roche, 10.13039/100005564Gilead Sciences, Merck, Merus, Nuvalent, Inc., RAPT Therapeutics, and Turning Point Therapeutics, and participation in a data safety monitoring board or advisory board with Candel Therapeutics. Dr. Erminia Massarelli reported receiving honoraria from AstraZeneca, Merck, Eli Lilly and Company, Takeda Pharmaceuticals, Mirati, and having a consulting or advisory role with Bristol Myers Squibb, Daiichi Sankyo Co., Fusion Therapeutics, Janssen, Eli Lilly and Company, Sanofi, AbbVie, Iovance Therapeutics, and Mirati. Ms. Denise Williamson, Drs. Martin Schwickart, Christian Scheffold, and Svetlana Adrianova are employees of and reported having stock with Exelixis. In addition, Dr. Christian Scheffold reported a patent: Combinations of Cabozantinib and Atezolizumab to Treat Cancer; patent number 11198731. Dr. Enriqueta Felip reported having a consulting or advisory role with AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GlaxoSmithKline, Janssen, Merck Serono, MSD, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point, Daiichi Sankyo, honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, MSD, Peervoice, Pfizer, Sanofi, Takeda, Touch Oncology, and receiving support for travel, accommodations, and expenses from AstraZeneca, Janssen, Roche. The remaining authors declare no conflict of interest., (© 2024 The Authors.)

Objectives: In the phase 3 POSEIDON study, first-line tremelimumab plus durvalumab and chemotherapy significantly improved overall survival and progression-free survival versus chemotherapy in metastatic non-small-cell lung cancer (NSCLC). We present patient-reported outcomes (PROs)., Patients and Methods: Treatment-naïve patients were randomized 1:1:1 to tremelimumab plus durvalumab and chemotherapy, durvalumab plus chemotherapy, or chemotherapy. PROs (prespecified secondary endpoints) were assessed using the European Organisation for Research and Treatment of Cancer 30-item core quality of life questionnaire version 3 (QLQ-C30) and its 13-item lung cancer module (QLQ-LC13). We analyzed time to deterioration (TTD) of symptoms, functioning, and global health status/quality of life (QoL) from randomization by log-rank test and improvement rates by logistic regression., Results: 972/1013 (96 %) patients randomized completed baseline QLQ-C30 and QLQ-LC13 questionnaires, with scores comparable between treatment arms. Patients receiving tremelimumab plus durvalumab and chemotherapy versus chemotherapy had longer median TTD for all PRO items. Hazard ratios for TTD favored tremelimumab plus durvalumab and chemotherapy for all items except diarrhea; 95 % confidence intervals did not cross 1.0 for global health status/QoL, physical functioning, cognitive functioning, pain, nausea/vomiting, insomnia, constipation, hemoptysis, dyspnea, and pain in other parts. For durvalumab plus chemotherapy, median TTD was longer versus chemotherapy for all items except nausea/vomiting and diarrhea. Hazard ratios favored durvalumab plus chemotherapy for all items except appetite loss; 95 % confidence intervals did not cross 1.0 for global health status/QoL, physical functioning, role functioning, dyspnea, and pain in other parts. For both immunotherapy plus chemotherapy arms, improvement rates in all PRO items were numerically higher versus chemotherapy, with odds ratios > 1., Conclusions: Tremelimumab plus durvalumab and chemotherapy delayed deterioration in symptoms, functioning, and global health status/QoL compared with chemotherapy. Together with significant improvements in survival, these results support tremelimumab plus durvalumab and chemotherapy as a first-line treatment option in metastatic NSCLC., Competing Interests: Declaration of Competing Interest Edward B. Garon reports grants or contracts from ABL Bio, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Dynavax Technologies, Eli Lilly, EMD Serono, Genentech, Gilead, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon, and Novartis; consulting fees from AbbVie, ABL Bio, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly, Gilead, GlaxoSmithKline, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, Xilio, and Zymeworks; and travel support from A2 Bio and Novartis. Byoung Chul Cho reports consulting fees from Abion, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Bridgebio Therapeutics, Bristol-Myers Squibb, CJ, CureLogen, Cyrus Therapeutics, Eli Lilly, GI-Cell, Hanmi, HK Inno-N, Imnewrun Biosciences, Janssen, KANAPH Therapeutic, Medpacto, MSD, Novartis, Ono Pharmaceutical, Onegene Biotechnology, Oscotec, Pfizer, RandBio, Roche, Takeda, and Yuhan; advisory board participation for Bridgebio Therapeutics, Cyrus Therapeutics, Guardant Health, Kanaph Therapeutics, and Oscotec; honoraria from ASCO, AstraZeneca, ESMO, Guardant Health, IASLC, Korean Cancer Association, Korean Cancer Study Group, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, MSD, Novartis, Pfizer, Roche, and The Chinese Thoracic Oncology Society; research funding from AbbVie, Abion, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bridgebio Therapeutics, CHA Bundang Medical Center, Champions Oncology, CJ Bioscience, CJ Blossom Park, Cyrus Therapeutics, Dizal Pharma, Dong-A ST, Eli Lilly, Genexine, GI-Cell, GIInnovation, Hanmi, Illumina, ImmuneOncia, Interpark Bio, Janssen, J Ints Bio, Kanaph Therapeutics, LG Chem, Medpacto, MOGAM Institute, MSD, Novartis, Nuvalent, Oncternal, Ono Pharmaceutical, Oscotec, Regeneron, Therapex, and Yuhan; royalties from Champions Oncology, Crown Bioscience, and Imagen; board membership for Interpark Bio and J Ints Bio; stock ownership in Bridgebio Therapeutics, Cyrus Therapeutics, Gencurix, Interpark Bio, Kanaph Therapeutics, J Ints Bio, and TheraCanVac; and other relationships for DAAN Biotherapeutics (Founder) and Korean University Health System (Employment). Alexander Luft has nothing to disclose. Jorge Alatorre-Alexander reports advisory board participation for Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, and Roche; travel support from AstraZeneca, MSD, and Roche; and honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, and Roche. Sarayut Lucien Geater reports research funding (to institution) from AstraZeneca, Boehringer Ingelheim, MSD, Novartis and Roche; honoraria from AstraZeneca, and Boehringer Ingelheim; and advisory board participation for Pfizer. Sang-We Kim reports research funding (to institution) from Yuhan; and travel support from AstraZeneca. Grygorii Ursol has nothing to disclose. Maen Hussein reports consulting fees from AbbVie, Aptitude Health, AstraZeneca, Athenex, Biopharma, Bristol-Myers Squibb, Coherus Biosciences, CTI BioPharma, Exelixis, GIntrinsiQ, IntegraConnect, Integra PrecisionQ, IntrinsiQ, Karyopharm Therapeutics, Mirati Therapeutics, National Community Oncology Dispensing Association, and Oncocyte. Farah Louise Lim has nothing to disclose. Cheng-Ta Yang has nothing to disclose. Luiz Henrique Araujo reports consulting fees from AstraZeneca, Bristol-Myers Squibb, Illumina, Lilly, MSD, Roche, and Sanofi; honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, Merck, MSD, Pfizer, and Roche; travel support from AstraZeneca, Bristol-Myers Squibb, and Daiichi-Sankyo; and grants or contracts from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, Merck, MSD, Novartis, Pfizer, and Roche. Haruhiro Saito reports honoraria from AstraZeneca and ONO Pharmaceutical; and grants or contracts from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, and ONO Pharmaceutical. Niels Reinmuth reports honoraria from AstraZeneca, Bristol-Myers Squibb, Lilly, MSD, and Roche; and consulting fees from AstraZeneca, Bristol-Myers Squibb, MSD, and Roche. Nenad Medic, Helen Mann and Xiaojin Shi are full time employees of and own stock in AstraZeneca. Solange Peters reports honoraria (to institution) from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, ecancer, Eli Lilly, Fishawack, Imedex, IQVIA, Medscape, MSD, Novartis, Oncology Education, PER, Pfizer, Prime Oncology, RMEI Medical Education, Research to Practice, Roche/Genentech, and Takeda; advisory board participation for AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Biocartis, Bioinvent, Bristol-Myers Squibb, Clovis Oncology, Daiichi-Sankyo, Debiopharm Group, Eli Lilly, Foundation Medicine, Illumina, Incyte, Janssen, Merck Serono, MSD, Merrimack, Novartis, Pfizer, PharmaMar, Phosplatin Therapeutics, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, and Takeda; and research funding (to institution) from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Illumina, Iovance Biotherapeutics, Lilly, Merck Serono, MSD, Novartis, Pharma Mar, Pfizer, Phosplatin Therapeutics, Takeda, Sanofi, Seattle Genetics, and Roche/Genentech. Tony Mok reports honoraria from ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca (before 1/1/19), BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Daz, Fishawack Facilitate, InMed Medical Communication, Janssen, Jiahui Holdings, LiangYiHui Healthcare, Lilly, Lucence Health, MD Health Brazil, Medscape, Merck, MiRXES, MSD, Novartis, OrigiMed, P. Permanyer SL, PeerVoice, PER, Pfizer, Prime Oncology, Research to Practice, Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting, Taiho Pharmaceutical, Takeda, and Touch Independent Medical Education; consulting fees from for AbbVie, ACEA Pharma, Adagene, Alpha Biopharma, Amgen, Amoy Diagnostics, Bayer, BeiGene, Berry Oncology, Boehringer Ingelheim, Blueprint Medicines, Bristol-Myers Squibb, Covidien, C4 Therapeutics, Cirina, CStone Pharmaceuticals, Curio Science, D3 Bio, Da Volterra, Daiichi-Sankyo, Eisai, Elevation Oncology, G1 Therapeutics, geneDecode, Gilead, Gritstone Oncology, Guardant Health, Hengrui Therapeutics, HutchMed, Ignyta, Inivata, IQVIA, Janssen, Lilly, Lunit USA, Loxo Oncology, Lucence Health, Medscape/WebMD, Merck Serono, MSD, Mirati Therapeutics, MiRXES, MoreHealth, Novartis, Omega Therapeutics, OrigiMed, OSE Immunotherapeutics, PeerVoice, Pfizer, Prime Oncology, Puma Biotechnology, Qiming Development, Roche/Genetech, Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, SFJ Pharmaceutical, Simcere of America, Synergy Research, Takeda, Tigermed, Vertex Pharmaceuticals, Virtus Medical Group, and Yuhan; advisory board participation for AbbVie, ACEA Pharma, Amgen, AstraZeneca, Berry Oncology, Blueprint Medicines, Boehringer Ingelheim, Bowtie Life Insurance, Bristol-Myers Squibb, C4 Therapeutics, Covidien, CStone Pharmaceuticals, Curio Science, D3 Bio, Daiichi-Sankyo, Eisai, Fishawack Facilitate, G1 Therapeutics, Gilead, Gritstone Oncology, Guardant Health, geneDecode (uncompensated), Hengrui Therapeutics, HutchMed, Ignyta, Incyte, Inivata, IQVIA, Janssen, Lakeshore Biotech, Lilly, Loxo Oncology, Lunit, Merck Serono, Mirati Therapeutics, MiRXES, MSD, Novartis, OrigiMed, Pfizer, Puma Biotechnology, Roche/Genentech, Sanofi-Aventis, SFJ Pharmaceutical, Simcere of America, Takeda, Vertex Pharmaceuticals, Virtus Medical Group, Yuhan; leadership roles for ACT Genomics-Sanomics, AstraZeneca, Aurora Tele-Oncology, HutchMed, and Lunit USA; stock/stock options in Act Genomics-Sanomics, AstraZeneca, Aurora Tele-Oncology, Biolidics, and HutchMed; research funding (to institution) from AstraZeneca, Bristol-Myers Squibb, G1 Therapeutics, MSD, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, and XCovery; and travel support (some to institution) from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, MiRXES, MSD, Novartis, Pfizer, Roche. Melissa Johnson reports research funding (paid to institution) from AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Carisma Therapeutics, Checkpoint Therapeutics, City of Hope National Medical Center, Corvus Pharmaceuticals, Curis, CytomX, Daiichi-Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, Erasca, EQRx, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunitas Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Kartos Therapeutics, Loxo Oncology, Lycera, Memorial-Sloan Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, StemCentRx, Syndax Pharmaceuticals, Takeda, Tarveda, TCR2 Therapeutics, Tempest, Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL, and Y-mAbs Therapeutics; and consulting fees (paid to institution) from AbbVie, Arcus Biosciences, Amgen, Arrivent, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Calithera, Daiichi-Sankyo, EcoR1, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Ideaya Biosciences, Immunocore, iTeos, Janssen, Jazz Pharmaceuticals, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Oncorus, Pyramid Biosciences, Regeneron Pharmaceuticals, Revolution Medicines, SeaGen, Sanofi-Aventis, Takeda, Turning Point Therapeutics, Synethekine, and VBL Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Approximately 10-15% of pediatric B-cell acute lymphoblastic leukemia (B-ALL) are high risk at diagnosis or relapsed/ refractory. Prior to the availability of chimeric antigen receptor T-cell (CAR-T) in Singapore and the region, the treatment options for these paediatric and young adults are conventional salvage chemotherapy or chemo-immunotherapy regimens as a bridge to allogeneic total body irradiation-based hematopoietic stem cell transplantation (allo-HSCT). This results in significant acute and long-term toxicities, with suboptimal survival outcomes. Finding a curative salvage therapy with fewer long-term toxicities would translate to improved quality-adjusted life years in these children and young adults. In this review, we focus on the burden of relapsed/refractory pediatric B-ALL, the limitations of current strategies, the emerging paradigms for the role of CAR-T in r/r B-ALL, our local perspectives on the health economics and future direction of CAR-T therapies in pediatric patients., Competing Interests: Professor William YK Hwang reports Honorarium for talk from Novartis, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2023 Seng et al.)

Background: Acute cutaneous inflammation causes microbiome alterations as well as ultrastructural changes in epidermis stratification. However, the interactions between keratinocyte proliferation and differentiation status and the skin microbiome have not been fully explored., Objectives: Hypothesizing that the skin microbiome contributes to regulation of keratinocyte differentiation and can modify antimicrobial responses, we examined the effect of exposure to commensal (Staphylococcus epidermidis, SE) or pathogenic (Staphylococcus aureus, SA) challenge on epidermal models., Methods: Explant biopsies were taken to investigate species-specific antimicrobial effects of host factors. Further investigations were performed in reconstituted epidermal models by bulk transcriptomic analysis alongside secreted protein profiling. Single-cell RNA sequencing analysis was performed to explore the keratinocyte populations responsible for SA inflammation. A dataset of 6391 keratinocytes from control (2044 cells), SE challenge (2028 cells) and SA challenge (2319 cells) was generated from reconstituted epidermal models., Results: Bacterial lawns of SA, not SE, were inhibited by human skin explant samples, and microarray analysis of three-dimensional epidermis models showed that host antimicrobial peptide expression was induced by SE but not SA. Protein analysis of bacterial cocultured models showed that SA exposure induced inflammatory mediator expression, indicating keratinocyte activation of other epidermal immune populations. Single-cell DropSeq analysis of unchallenged naive, SE-challenged and SA-challenged epidermis models was undertaken to distinguish cells from basal, spinous and granular layers, and to interrogate them in relation to model exposure. In contrast to SE, SA specifically induced a subpopulation of spinous cells that highly expressed transcripts related to epidermal inflammation and antimicrobial response. Furthermore, SA, but not SE, specifically induced a basal population that highly expressed interleukin-1 alarmins., Conclusions: These findings suggest that SA-associated remodelling of the epidermis is compartmentalized to different keratinocyte populations. Elucidating the mechanisms regulating bacterial sensing-triggered inflammatory responses within tissues will enable further understanding of microbiome dysbiosis and inflammatory skin diseases, such as atopic eczema., Competing Interests: Conflicts of interest The authors declare they have no conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Purpose: The open-label, phase III POSEIDON study evaluated tremelimumab plus durvalumab and chemotherapy (T + D + CT) and durvalumab plus chemotherapy (D + CT) versus chemotherapy alone (CT) in first-line metastatic non-small-cell lung cancer (mNSCLC)., Methods: Patients (n = 1,013) with EGFR / ALK wild-type mNSCLC were randomly assigned (1:1:1) to tremelimumab 75 mg plus durvalumab 1,500 mg and platinum-based chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression and one additional tremelimumab dose; durvalumab plus chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression; or chemotherapy for up to six 21-day cycles (with or without maintenance pemetrexed; all arms). Primary end points were progression-free survival (PFS) and overall survival (OS) for D + CT versus CT. Key alpha-controlled secondary end points were PFS and OS for T + D + CT versus CT., Results: PFS was significantly improved with D + CT versus CT (hazard ratio [HR], 0.74; 95% CI, 0.62 to 0.89; P = .0009; median, 5.5 v 4.8 months); a trend for improved OS did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.02; P = .0758; median, 13.3 v 11.7 months; 24-month OS, 29.6% v 22.1%). PFS (HR, 0.72; 95% CI, 0.60 to 0.86; P = .0003; median, 6.2 v 4.8 months) and OS (HR, 0.77; 95% CI, 0.65 to 0.92; P = .0030; median, 14.0 v 11.7 months; 24-month OS, 32.9% v 22.1%) were significantly improved with T + D + CT versus CT. Treatment-related adverse events were maximum grade 3/4 in 51.8%, 44.6%, and 44.4% of patients receiving T + D + CT, D + CT, and CT, respectively; 15.5%, 14.1%, and 9.9%, respectively, discontinued treatment because of treatment-related adverse events., Conclusion: D + CT significantly improved PFS versus CT. A limited course of tremelimumab added to durvalumab and chemotherapy significantly improved OS and PFS versus CT, without meaningful additional tolerability burden, representing a potential new option in first-line mNSCLC.

Novel therapeutic options for cancer offer hope for patients and their families, particularly when the cancer has not responded to established treatment regimens. The CAR-T cell therapeutic approach has changed the treatment paradigm for relapsed or refractory lymphoma, extending the capacity of the patient's own T cells to detect and eliminate cancer cells through genetic modification of T-cell surface receptors. The process of establishing treatment centers and developing clinical expertize in this novel treatment strategy is complex. Time, resources, and a commitment to focusing health budgets on a new area are required. Currently, Singapore is the only country in southeast and south Asia with market authorization of the CAR-T product, tisagenlecleucel. Availability of CAR-T treatment across international borders provides patients in neighboring countries with choice in therapeutic options. This paper describes the unique hub-and-spoke cross-border collaboration developed between Singapore and its neighbors to provide access to CAR-T cell therapy for patients with relapsed or refractory lymphoma. To date in 2022, four patients have been included in the CAR-T treatment cross-border collaboration. Their stay in Singapore has been at least 2 months' duration, including the pre-treatment evaluation, apheresis, CAR-T cell infusion and post-treatment monitoring. Patient support from referring and treating physicians, critical to the success of the undertaking, is characterized by early communication, patient selection, multi-disciplinary care, post-treatment monitoring, and attention to detail. The patient journey and the development and implementation of this unique collaboration are discussed., (© 2022 John Wiley & Sons Ltd.)

Keratinocytes produce lipids that are critical for the skin barrier, however, little is known about the impact of age on fatty acid (FA) biosynthesis in these cells. We have examined the relationship between keratinocyte FA composition, lipid biosynthetic gene expression, gene promoter methylation and age. Expression of elongase (ELOVL6 and 7) and desaturase (FADS1 and 2) genes was lower in adult versus neonatal keratinocytes, and was associated with lower concentrations of n-7, n-9 and n-10 polyunsaturated FA in adult cells. Consistent with these findings, transient FADS2 knockdown in neonatal keratinocytes mimicked the adult keratinocyte FA profile in neonatal cells. Interrogation of methylation levels across the FADS2 locus (53 genomic sites) revealed differential methylation of 15 sites in neonatal versus adult keratinocytes, of which three hypermethylated sites in adult keratinocytes overlapped with a SMARCA4 protein binding site in the FADS2 promoter., Competing Interests: Declaration of competing interest Messenger D.J.(2), Barrett K.E.(2), Hyliands D.(2), Talbot D.(2), Fowler M.I.(2), Kawatra T.(2), Gunn D.A.(2), Lim FL.(2), Wainwright L.J.(2), Jenkins G.(2), are employed by Unilever R&D. Griffiths H.R.(1,3) received part funding from Unilever R&D and BBSRC to undertake this study., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The olfactory system combines input from multiple receptor types to represent odor information, but there are few explicit examples relating olfactory receptor (OR) activity patterns to odor perception. To uncover these relationships, we performed genome-wide scans on odor-perception phenotypes for ten odors in 1000 Han Chinese and validated results for six of these odors in an ethnically diverse population (n = 364). In both populations, consistent with previous studies, we replicated three previously reported associations (β-ionone/OR5A1, androstenone/OR7D4, cis-3-hexen-1-ol/OR2J3 LD-band), but not for odors containing aldehydes, suggesting that olfactory phenotype/genotype studies are robust across populations. Two novel associations between an OR and odor perception contribute to our understanding of olfactory coding. First, we found a SNP in OR51B2 that associated with trans-3-methyl-2-hexenoic acid, a key component of human underarm odor. Second, we found two linked SNPs associated with the musk Galaxolide in a novel musk receptor, OR4D6, which is also the first human OR shown to drive specific anosmia to a musk compound. We noticed that SNPs detected for odor intensity were enriched with amino acid substitutions, implying functional changes of odor receptors. Furthermore, we also found that the derived alleles of the SNPs tend to be associated with reduced odor intensity, supporting the hypothesis that the primate olfactory gene repertoire has degenerated over time. This study provides information about coding for human body odor, and gives us insight into broader mechanisms of olfactory coding, such as how differential OR activation can converge on a similar percept., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: The study was funded in part by Unilever R&D (the Netherlands). M.A.M.S. and F.-L.L. are employees of Unilever. The other authors declare that they have no competing interests.