{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:43:02Z","timestamp":1792788182273,"version":"4.5.0"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Universit\u00e4tsklinikum Hamburg-Eppendorf (UKE)","id":[{"id":"https:\/\/ror.org\/01zgy1s35","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Transl Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>In advanced melanoma, longitudinal disease monitoring remains limited by infrequent biomarker assessment and predominantly categorical imaging readouts. Although circulating tumor DNA (ctDNA) correlates with tumor burden, its behavior under high-frequency sampling and its relationship to quantitative metastatic tumor volume are poorly defined. Clarifying these dynamics is essential to establishing ctDNA as a clinically actionable tool for real-time treatment monitoring.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We retrospectively analyzed 42 patients with unresectable stage III\/IV melanoma treated with immune checkpoint inhibitors. Plasma ctDNA was quantified longitudinally across 241 time points using a UMI-based amplicon next-generation sequencing (NGS) assay detecting BRAF, EGFR, KRAS, NRAS, and PIK3CA. We paired ctDNA measurements with radiologic staging and correlated them with response categories (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200999 time points) and volumetric tumor burden (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200973 time points) using nonparametric statistics and receiver operating characteristic (ROC) analyses, including stratification by the ctDNA-imaging time interval and descriptive assessment of discordant patterns.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      ctDNA levels were significantly associated with radiologic response according to RECIST 1.1, increasing across worsening response categories (Spearman \u03c1\u2009=\u20090.31, 95% CI 0.20\u20130.52,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.002). Discriminative performance for identifying progression was moderate (AUC\u2009=\u20090.69). Threshold analyses demonstrated a sensitivity\u2013specificity trade-off, with higher ctDNA levels providing greater specificity (e.g. \u226525 mutant molecules (MM)\/mL: specificity\u2009\u2265\u200983%, sensitivity\u2009\u2264\u200930%), while lower thresholds showed limited sensitivity and specificity (e.g. 1\u20132\u2009MM\/mL: ~56% each). ctDNA concentrations were positively associated with total tumor volume (\u03c1\u2009=\u20090.46,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001), with stronger correlations observed for temporally aligned measurements (0\u201330\u2009days: \u03c1\u2009=\u20090.56). In contrast, dynamic changes in ctDNA were not significantly correlated with changes in tumor volume (\u03c1\u2009=\u20090.20,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.25). Organ-associated analyses demonstrated marked heterogeneity in ctDNA shedding, with stronger associations in lymph node and peritoneal metastases and limited detectability in lung, liver, and brain metastases. Concordance between ctDNA dynamics and radiologic response was high in responding disease (CR\/PR: 85.0%) but lower in stable or progressive disease (72.9%), with discordant cases associated with tumor heterogeneity, timing differences, and treatment-related factors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>ctDNA reflects radiologic disease status and tumor burden, with increasing levels observed as response worsens. Despite heterogeneity in ctDNA shedding across metastatic sites, its significant correlation with tumor volume, particularly when closely timed to imaging, supports the potential value of ctDNA as a complementary biomarker for longitudinal disease monitoring while highlighting important biological and methodological factors that influence its clinical interpretation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-08899-0","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T13:44:22Z","timestamp":1789652662000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated longitudinal analysis of ctDNA, radiologic response, and tumor volume reveals spatial and temporal heterogeneity in advanced melanoma"],"prefix":"10.1186","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6894-1913","authenticated-orcid":false,"given":"Isabel","family":"Heidrich","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Streckenbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Rautmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Freiberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"K\u00f6tt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glenn","family":"Geidel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"R\u00fcnger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Zell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Roeper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inga","family":"Hansen-Abeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Finn","family":"Abeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan W.","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3190-9511","authenticated-orcid":false,"given":"Daniel J.","family":"Smit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Pantel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7090-9584","authenticated-orcid":false,"given":"Christoffer","family":"Gebhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"issue":"3","key":"8899_CR1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. 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Breast Cancer Res. 2014 Aug 9;16(4):421. https:\/\/doi.org\/10.1186\/s13058-014-0421-y.","journal-title":"Breast Cancer Res"}],"container-title":["Journal of Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12967-026-08899-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-026-08899-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-026-08899-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T13:06:14Z","timestamp":1789736774000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12967-026-08899-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,17]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["8899"],"URL":"https:\/\/doi.org\/10.1186\/s12967-026-08899-0","relation":{},"ISSN":["1479-5876"],"issn-type":[{"value":"1479-5876","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,17]]},"assertion":[{"value":"14 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 September 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study involves human participants, and the local ethics committee of the Hamburg Medical Association approved the study (PV5392). All participants provided informed consent before inclusion in the study. The study was conducted in accordance with the Declaration of Helsinki.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"IH has received honoraria from BMS and Sysmex for lectures and presentations outside the submitted work. SWS has received honoraria from GSK, Leo, Sanofi, Pfizer, Almirall, and Novartis. SWS is a board member of the Hiege Stiftung \u2013 Die Deutsche Hautkrebsstiftung, unpaid. JK received grants from Hiege-Stiftung \u2013 Die Deutsche Hautkrebsstiftung, Roggenbuck-Stiftung, UCCH-fellowship, and MSNZ, outside the submitted work. GG received honoraria from Almirall Hermal GmbH, Bristol-Myers Squibb GmbH & Co. KGaA, and Janssen-Cilag GmbH for lectures and presentations. C.G. has received honoraria by Almirall, Biofrontera, BMS, Delcath, Immunocore, Janssen, Medscape, MSD, NAOS, Novartis, Onkowissen, Pierre Fabre, Regeneron, Sanofi, SUN Pharma, Sysmex. C.G. has received travel expenses by BMS, Pierre-Fabre, SUN Pharma. C.G. is a member of the advisory board of Almirall, Beiersdorf, BioNTech, BMS, Delcath, ImCheck, Immunocore, Immatics, Iovance, Moderna, MSD, Novartis, Pierre Fabre, Regeneron, Sanofi, SkylineDX, SUN Pharma, Sysmex. C.G. is a board member of the DeCOG (ADO), EADO, and MWS, unpaid; C.G. is a board member of the Hiege Stiftung, and the Roggenbuck-Stiftung, unpaid. C.G. is co-founder of Dermagnostix and Dermagnostix R&D. KP has received funding from the EU\/IHI (GUIDE.MRD).","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"1199"}}