{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:04:12Z","timestamp":1779926652312,"version":"3.53.1"},"posted":{"date-parts":[[2026,5,5]]},"group-title":"Cancer Biology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T00:00:00Z","timestamp":1777939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIA","award":["R01AG091760"],"award-info":[{"award-number":["R01AG091760"]}]},{"name":"NIA","award":["RF1AG08730"],"award-info":[{"award-number":["RF1AG08730"]}]},{"DOI":"10.13039\/100000070","name":"NIBIB","doi-asserted-by":"crossref","award":["P41EB029460"],"award-info":[{"award-number":["P41EB029460"]}],"id":[{"id":"10.13039\/100000070","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Tumor pseudo-progression (PsP) refers to an initial increase in tumor size or the appearance of new lesions. These pseudo-progressive lesions are predominantly composed of infiltrative inflammatory cells, such as macrophages. This phenomenon commonly occurs in patients undergoing radiation therapy or immunotherapy and typically indicates a positive treatment response. However, it often leads to premature treatment cessation due to misinterpretation as disease progression. Non-invasive imaging biomarkers capable of distinguishing pseudo-progression from true progression would greatly aid in treatment decision-making. In our preliminary study, we explored the potential of gadoterate meglumine (Gd-DOTA, a macrocyclic Gd-contrast) in combination with amine chemical-exchange saturation transfer (amine-CEST) imaging to differentiate tumor from radiation necrosis by assessing Gd-DOTA uptake by infiltrating immune cells, such as macrophages. To evaluate whether amine-CEST, in combination with Gd-DOTA, can differentiate macrophages from cancer cells, we incubated them with Gd-DOTA for 30 minutes. Subsequently, the cells were processed, and amine-CEST imaging was performed on a 9.4 Tesla preclinical scanner. Upon treatment with Gd-DOTA, we did not observe a significant change in amine-CEST contrast in F98 cells compared with untreated cells, whereas treated macrophages exhibited a marked decrease (\u223c40%) in amine-CEST signal compared with untreated macrophages. This reduction in signal was attributed to the uptake of Gd-DOTA by macrophages, which notably shortened water T\n                  <jats:sub>1<\/jats:sub>\n                  relaxation, thereby quenching the amine-CEST signal. Conversely, cancer cells showed no appreciable change in the amine-CEST signal, indicating no Gd-DOTA uptake. Furthermore, to validate that T\n                  <jats:sub>1<\/jats:sub>\n                  shortening influences amine-CEST signal, cancer cells were also treated with manganese chloride (MnCl\n                  <jats:sub>2<\/jats:sub>\n                  ) for 30 minutes. The uptake of MnCl\n                  <jats:sub>2<\/jats:sub>\n                  by cancer cells similarly induced T\n                  <jats:sub>1<\/jats:sub>\n                  shortening, as observed in macrophages, resulting in a decrease in the amine-CEST signal from these cells. Next, we performed the amin-CEST imaging on F98 tumor-bearing rats and radiation necrotic rats. Post-injection with Gd-DOTA showed no appreciable change in the amine-CEST contrast in the tumor-bearing rat, whereas a significant decrease in contrast was observed in the radiation necrotic rat. This further demonstrates that no change in the amine-CEST contrast in tumor-bearing rats is due to cancer cells failing to take up Gd-DOTA. The decrease in amine-CEST contrast in radiation-treated rats reflects the uptake of Gd-DOTA by macrophages infiltrating the radiation-necrotic regions. This straightforward imaging approach holds promise for clinical translation. It offers a novel method for characterizing pseudo-progressive lesions and monitoring diverse treatment responses in cancer patients using standard clinical scanners.\n                <\/jats:p>","DOI":"10.64898\/2026.05.01.722099","type":"posted-content","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T05:05:17Z","timestamp":1778043917000},"source":"Crossref","is-referenced-by-count":0,"title":["Contrast-induced changes in chemical exchange saturation transfer MRI differentiate tumor progression from pseudoprogression"],"prefix":"10.64898","author":[{"given":"Blake","family":"Benyard","sequence":"first","affiliation":[{"name":"Center for Metabolic Imaging in Precision Medicine (CAMIPM), Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narayan Datt","family":"Soni","sequence":"additional","affiliation":[{"name":"Center for Metabolic Imaging in Precision Medicine (CAMIPM), Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anshuman","family":"Swain","sequence":"additional","affiliation":[{"name":"Center for Metabolic Imaging in Precision Medicine (CAMIPM), Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nishi","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Children\u2019s Hospital of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunil Kumar","family":"Khokhar","sequence":"additional","affiliation":[{"name":"Center for Metabolic Imaging in Precision Medicine (CAMIPM), Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akila","family":"Ramesh","sequence":"additional","affiliation":[{"name":"Center for Metabolic Imaging in Precision Medicine (CAMIPM), Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyoung","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dushyant","family":"Kumar","sequence":"additional","affiliation":[{"name":"Center for Metabolic Imaging in Precision Medicine (CAMIPM), Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi Prakash","family":"Reddy Nanga","sequence":"additional","affiliation":[{"name":"Center for Metabolic Imaging in Precision Medicine (CAMIPM), Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadir","family":"Yehya","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Children\u2019s Hospital of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravinder","family":"Reddy","sequence":"additional","affiliation":[{"name":"Center for Metabolic Imaging in Precision Medicine (CAMIPM), Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Haris","sequence":"additional","affiliation":[{"name":"Center for Metabolic Imaging in Precision Medicine (CAMIPM), Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026052716202603000_2026.05.01.722099v4.1","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1007\/s12094-017-1816-x","article-title":"Treatment-related changes in glioblastoma: a review on the controversies in response assessment criteria and the concepts of true progression, pseudoprogression, pseudoresponse and radionecrosis","volume":"20","year":"2018","journal-title":"Clin Transl Oncol"},{"key":"2026052716202603000_2026.05.01.722099v4.2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.49.6968"},{"key":"2026052716202603000_2026.05.01.722099v4.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"2026052716202603000_2026.05.01.722099v4.4","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(12)70265-6"},{"key":"2026052716202603000_2026.05.01.722099v4.5","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2004.06.082"},{"key":"2026052716202603000_2026.05.01.722099v4.6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.62.6606"},{"key":"2026052716202603000_2026.05.01.722099v4.7","doi-asserted-by":"crossref","first-page":"597608","DOI":"10.3389\/fcell.2020.597608","article-title":"Intracellular Transport in Cancer Metabolic Reprogramming","volume":"8","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"2026052716202603000_2026.05.01.722099v4.8","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(09)70025-7"},{"key":"2026052716202603000_2026.05.01.722099v4.9","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.12.2440"},{"key":"2026052716202603000_2026.05.01.722099v4.10","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(12)70164-X"},{"key":"2026052716202603000_2026.05.01.722099v4.11","doi-asserted-by":"publisher","DOI":"10.1038\/nature12034"},{"key":"2026052716202603000_2026.05.01.722099v4.12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1308345"},{"key":"2026052716202603000_2026.05.01.722099v4.13","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010715-103101"},{"key":"2026052716202603000_2026.05.01.722099v4.14","doi-asserted-by":"publisher","DOI":"10.1002\/jmri.26171"},{"key":"2026052716202603000_2026.05.01.722099v4.15","doi-asserted-by":"publisher","DOI":"10.1148\/radiol.13122024"},{"key":"2026052716202603000_2026.05.01.722099v4.16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.790674"},{"key":"2026052716202603000_2026.05.01.722099v4.17","doi-asserted-by":"publisher","DOI":"10.3348\/kjr.2013.14.4.662"},{"key":"2026052716202603000_2026.05.01.722099v4.18","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61737-992-5_7"},{"key":"2026052716202603000_2026.05.01.722099v4.19","doi-asserted-by":"crossref","first-page":"748","DOI":"10.3171\/2022.12.JNS222173","article-title":"Pseudoprogression versus true progression in glioblastoma: what neurosurgeons need to know","volume":"139","year":"2023","journal-title":"J Neurosurg"},{"key":"2026052716202603000_2026.05.01.722099v4.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2022.100424"},{"key":"2026052716202603000_2026.05.01.722099v4.21","doi-asserted-by":"publisher","DOI":"10.1002\/jmri.25108"},{"key":"2026052716202603000_2026.05.01.722099v4.22","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.24315"},{"key":"2026052716202603000_2026.05.01.722099v4.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2013.03.047"},{"key":"2026052716202603000_2026.05.01.722099v4.24","doi-asserted-by":"publisher","DOI":"10.1002\/nbm.2899"},{"key":"2026052716202603000_2026.05.01.722099v4.25","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-2265"},{"key":"2026052716202603000_2026.05.01.722099v4.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2018.03.057"},{"key":"2026052716202603000_2026.05.01.722099v4.27","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1002\/jmri.26702","article-title":"Early response assessment of glioma patients to definitive chemoradiotherapy using chemical exchange saturation transfer imaging at 7 T","volume":"50","year":"2019","journal-title":"J Magn Reson Imaging"},{"key":"2026052716202603000_2026.05.01.722099v4.28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0121220"},{"key":"2026052716202603000_2026.05.01.722099v4.29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0104181"},{"key":"2026052716202603000_2026.05.01.722099v4.30","doi-asserted-by":"crossref","first-page":"28772","DOI":"10.18632\/oncotarget.25594","article-title":"Chemical exchange saturation transfer MRI serves as predictor of early progression in glioblastoma patients","volume":"9","year":"2018","journal-title":"Oncotarget"},{"key":"2026052716202603000_2026.05.01.722099v4.31","doi-asserted-by":"crossref","unstructured":"Y. Shen et al., Imaging of nuclear Overhauser enhancement at 7 and 3 T. NMR Biomed 30, (2017).","DOI":"10.1002\/nbm.3735"},{"key":"2026052716202603000_2026.05.01.722099v4.32","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1021\/acschemneuro.6b00173","article-title":"Nuclear Overhauser Enhancement-Mediated Magnetization Transfer Imaging in Glioma with Different Progression at 7 T","volume":"8","year":"2017","journal-title":"ACS Chem Neurosci"},{"key":"2026052716202603000_2026.05.01.722099v4.33","doi-asserted-by":"publisher","DOI":"10.1002\/jmri.24441"},{"key":"2026052716202603000_2026.05.01.722099v4.34","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.22761"},{"key":"2026052716202603000_2026.05.01.722099v4.35","doi-asserted-by":"publisher","DOI":"10.1002\/nbm.3283"},{"key":"2026052716202603000_2026.05.01.722099v4.36","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s10334-021-00996-z","article-title":"3D APT and NOE CEST-MRI of healthy volunteers and patients with non-enhancing glioma at 3 T","volume":"35","year":"2022","journal-title":"MAGMA"},{"key":"2026052716202603000_2026.05.01.722099v4.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2015.02.040"},{"key":"2026052716202603000_2026.05.01.722099v4.38","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.26396"},{"key":"2026052716202603000_2026.05.01.722099v4.39","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2268"},{"key":"2026052716202603000_2026.05.01.722099v4.40","doi-asserted-by":"publisher","DOI":"10.3174\/ajnr.A5538"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.05.01.722099","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T23:20:36Z","timestamp":1779924036000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.05.01.722099"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,5]]},"references-count":40,"URL":"https:\/\/doi.org\/10.64898\/2026.05.01.722099","relation":{},"subject":[],"published":{"date-parts":[[2026,5,5]]},"subtype":"preprint"}}