{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T18:47:50Z","timestamp":1782067670342,"version":"3.54.5"},"reference-count":68,"publisher":"American Society for Clinical Investigation","issue":"12","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":55,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011725","name":"Servier","doi-asserted-by":"crossref","award":["IIT-95014-027-USA"],"award-info":[{"award-number":["IIT-95014-027-USA"]}],"id":[{"id":"10.13039\/501100011725","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,22]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Asparaginase is essential for curing acute lymphoblastic leukemia (ALL), but its use is limited by asparaginase-associated pancreatitis (AAP), a severe and unpredictable toxicity lacking validated prospective biomarkers. We sought to define early systemic molecular features of susceptibility to AAP.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We performed longitudinal lipidomic and proteomic profiling in two independent pediatric ALL cohorts (\n                      <jats:italic>n<\/jats:italic>\n                      = 161; 79 AAP cases, 82 controls) using paired blood samples collected before asparaginase exposure and at the end of induction therapy (including a single dose of asparaginase), thereby capturing pre-injury biology rather than consequences of pancreatitis. We applied differential abundance and network-based analyses and integrated lipid-cytokine associations using proteomics.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Across cohorts, we identified a reproducible lysophosphatidylcholine-centered (LPC-centered) signature characterized by attenuated induction therapy\u2013associated LPC responses and disruption of LPC coregulation at the network level. Proteomic profiling revealed enrichment of cytokine signaling pathways, and integrative analyses demonstrated altered lipid-cytokine coupling, including a flip in association direction for LPC species and IL-18 between cases and controls. Although IL-18\/LPC ratios did not differ globally, elevated postinduction IL-18\/LPC ratios identified AAP risk within a protocol-defined very high-risk ALL subgroup (AUC = 0.81).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>These findings support a systems-level model in which failure of coordinated lipid-immune responses under therapeutic stress confers vulnerability to AAP, providing a framework for validation and mitigation strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>TRIAL REGISTRATION<\/jats:title>\n                    <jats:p>NCT00400946; NCT01574274; NCT03020030 (parent trials).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUNDING<\/jats:title>\n                    <jats:p>Servier Pharmaceuticals (IIT-95014-027-USA); SDRC (P30DK116074); Stanford SPARK; Fonds de Recherche du Qu\u00e9bec \u2013 Sant\u00e9; Fondation Charles-Bruneau; Leukemia &amp; Lymphoma Society of Canada.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1172\/jci.insight.202662","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T14:44:41Z","timestamp":1777646681000},"source":"Crossref","is-referenced-by-count":0,"title":["A lipid-immune network signature defines susceptibility to asparaginase-associated pancreatitis"],"prefix":"10.1172","volume":"11","author":[{"given":"Cheng-Yu","family":"Tsai","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Stanford University, Palo Alto, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Bo","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thai Hoa","family":"Tran","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology Oncology, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maisam","family":"Abu-El-Haija","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA."},{"name":"Division of Pediatric Gastroenterology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gayathri","family":"Swaminathan","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Stanford University, Palo Alto, California, 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China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Th\u00e9or\u00eat","sequence":"additional","affiliation":[{"name":"D\u00e9partement Clinique de M\u00e9decine de Laboratoire, Secteur Pharmacologie Clinique, Optilab Montr\u00e9al, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2867-1298","authenticated-orcid":true,"given":"Steven D.","family":"Mittelman","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology, University of California, Los Angeles, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena J.","family":"Ladas","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology, Oncology, and Stem Cell Transplant, Columbia University Irving Medical Center, New York, New York, USA."},{"name":"Institute of Human Nutrition, Columbia University, New 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