{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T11:30:14Z","timestamp":1793791814461,"version":"4.6.1"},"reference-count":44,"publisher":"BMJ","issue":"5","license":[{"start":{"date-parts":[[2022,5,11]],"date-time":"2022-05-11T00:00:00Z","timestamp":1652227200000},"content-version":"unspecified","delay-in-days":10,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2022,3,31]]},"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Amino acid metabolism is essential for tumor cell proliferation and regulation of immune cell function. However, the clinical significance of free amino acids (plasma-free amino acids (PFAAs)) and tryptophan-related metabolites in plasma has not been fully understood in patients with non-small cell lung cancer (NSCLC) who receive immune checkpoint inhibitors.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We conducted a single cohort observational study. Peripheral blood samples were collected from 53 patients with NSCLC before treatment with PD-1 (Programmed cell death-1) inhibitors. The plasma concentrations of 21 PFAAs, 14 metabolites, and neopterin were measured by liquid chromatography\u2013mass spectrometry. Using Cox hazard analysis with these variables, a multivariate model was established to stratify patient overall survival (OS). Gene expression in peripheral blood mononuclear cells (PBMCs) was compared between the high-risk and low-risk patients by this multivariate model.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>On Cox proportional hazard analysis, higher concentrations of seven PFAAs (glycine, histidine, threonine, alanine, citrulline, arginine, and tryptophan) as well as lower concentrations of three metabolites (3h-kynurenine, anthranilic acid, and quinolinic acid) and neopterin in plasma were significantly correlated with better OS (p&lt;0.05). In particular, the multivariate model, composed of a combination of serine, glycine, arginine, and quinolinic acid, could most efficiently stratify patient OS (concordance index=0.775, HR=3.23, 95% CI 2.04 to 5.26). From the transcriptome analysis in PBMCs, this multivariate model was significantly correlated with the gene signatures related to immune responses, such as CD8 T-cell activation\/proliferation and proinflammatory immune responses, and 12 amino acid-related genes were differentially expressed between the high-risk and low-risk groups.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The multivariate model with PFAAs and metabolites in plasma might be useful for stratifying patients who will benefit from PD-1 inhibitors.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2021-004420","type":"journal-article","created":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T13:25:30Z","timestamp":1653312330000},"page":"e004420","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":44,"title":["Clinical significance of plasma-free amino acids and tryptophan metabolites in patients with non-small cell lung cancer receiving PD-1 inhibitor: a pilot cohort study for developing a prognostic multivariate model"],"prefix":"10.1136","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5040-5856","authenticated-orcid":false,"given":"Koichi","family":"Azuma","sequence":"first","affiliation":[{"name":"Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huihui","family":"Xiang","sequence":"additional","affiliation":[{"name":"Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Tagami","sequence":"additional","affiliation":[{"name":"Research Institute for Bioscience Products and Fine Chemicals, Ajinomoto Co Inc, Kawasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rika","family":"Kasajima","sequence":"additional","affiliation":[{"name":"Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumiko","family":"Kato","sequence":"additional","affiliation":[{"name":"Research Institute for Bioscience Products and Fine Chemicals, Ajinomoto Co Inc, Kawasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachise","family":"Karakawa","sequence":"additional","affiliation":[{"name":"Research Institute for Bioscience Products and Fine Chemicals, Ajinomoto Co Inc, Kawasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinya","family":"Kikuchi","sequence":"additional","affiliation":[{"name":"Research Institute for Bioscience Products and Fine Chemicals, Ajinomoto Co Inc, Kawasaki, 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Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Kawahara","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenta","family":"Murotani","sequence":"additional","affiliation":[{"name":"Biostatistics Center, Kurume University School of Medicine, Kurume, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2313-8833","authenticated-orcid":false,"given":"Tetsuro","family":"Sasada","sequence":"additional","affiliation":[{"name":"Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Miyagi","sequence":"additional","affiliation":[{"name":"Molecular Pathology and 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