{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T07:20:51Z","timestamp":1787988051689,"version":"build-2784847793"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004047","name":"Karolinska Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004047","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Nucl Med Mol Imaging"],"published-print":{"date-parts":[[2026,9]]},"abstract":"Abstract<\/jats:title>\n \n Purpose<\/jats:title>\n \n Neuroblastoma frequently overexpresses somatostatin receptors (SSTR), enabling molecular radiotherapy with [\n 177<\/jats:sup>\n Lu]Lu-DOTATATE (\n 177<\/jats:sup>\n Lu-DOTATATE). Based on prior studies suggesting that dose intensification is required to achieve objective responses, the LuDO-N trial employs a two-fraction, high-activity treatment regimen. This study aimed to evaluate fraction-dependent changes in tumour and risk-organ absorbed doses, as well as the clinical safety of the intensified\n 177<\/jats:sup>\n Lu-DOTATATE treatment approach.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Fourteen patients with high-risk recurrent or refractory neuroblastoma received\n 177<\/jats:sup>\n Lu-DOTATATE in a dose-intensified, dosimetry-guided regimen. Treatment was given in two fractions 2\u20133 weeks apart, targeting a cumulative dose of either 2.4\u00a0Gy to the whole body or 23\u00a0Gy to either kidney. The first fraction was administered at 200 MBq\/kg, while the second fraction was individually adjusted to achieve the dosimetric targets.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Tumour-to-kidney and tumour-to-whole-body absorbed dose ratios both decreased significantly by 44% after the second fraction, compared to the first. Tumours received a median 53% lower absorbed dose per administered activity in the second fraction, while kidney and whole-body doses per activity were reduced by 24% and 18%, respectively. Four of fourteen patients (29%) underwent peripheral blood stem cell reinfusion. No sustained renal toxicity was observed.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n These findings support a front-loaded\n 177<\/jats:sup>\n Lu-DOTATATE strategy to maximise tumour irradiation while maintaining exposure to risk organs within safety limits. Accordingly, the LuDO-N protocol has been amended to increase administered activity to 400 MBq\/kg in the first fraction for subsequent patients. Together, this work contributes to the ongoing optimisation of dosimetry-guided and intensified treatment strategies for SSTR-targeted molecular radiotherapy for high-risk neuroblastoma.\n <\/jats:p>\n <\/jats:sec>\n \n Clinical trial registration<\/jats:title>\n EU Clinical Trials Register, EU CT 2023-503684-42-00. Registered 2021-05-21.<\/jats:p>\n \n https:\/\/euclinicaltrials.eu\/search-for-clinical-trials\/?lang=en&EUCT=2023-503684-42-00<\/jats:ext-link>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1007\/s00259-026-07984-2","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T01:37:48Z","timestamp":1781833068000},"page":"6398-6409","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fraction-dependent dose dynamics and clinical safety in high-risk neuroblastoma treated with [177Lu]Lu-DOTATATE: results from the LuDO-N trial"],"prefix":"10.1007","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1261-7505","authenticated-orcid":false,"given":"Se Whee Sammy","family":"Park","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8290-0974","authenticated-orcid":false,"given":"Fredrik","family":"Sundquist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8941-4619","authenticated-orcid":false,"given":"Leonor","family":"Teles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8546-8283","authenticated-orcid":false,"given":"Rob","family":"van Rooij","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4758-3170","authenticated-orcid":false,"given":"Daniel","family":"Thor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0162-1354","authenticated-orcid":false,"given":"Kasper","family":"Karlsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8824-8697","authenticated-orcid":false,"given":"Arthur J.A.T.","family":"Braat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9543-3957","authenticated-orcid":false,"given":"Jakob","family":"Stenman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7496-9189","authenticated-orcid":false,"given":"Joachim N.","family":"Nilsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,19]]},"reference":[{"key":"7984_CR1","doi-asserted-by":"publisher","first-page":"16078","DOI":"10.1038\/nrdp.2016.78","volume":"2","author":"KK Matthay","year":"2016","unstructured":"Matthay KK, et al. Neuroblastoma. Nat Rev Dis Primers. 2016;2:16078.","journal-title":"Nat Rev Dis Primers"},{"issue":"6_suppl","key":"7984_CR2","doi-asserted-by":"publisher","first-page":"10052","DOI":"10.1200\/JCO.2025.43.16_suppl.10052","volume":"43","author":"DA Morgenstern","year":"2025","unstructured":"Morgenstern DA, et al. Factors associated with survival following relapse of high-risk neuroblastoma: A study from the International Neuroblastoma Risk Group (INRG) Data Commons. J Clin Oncol. 2025;43(16):10052\u201310052.","journal-title":"J Clin Oncol"},{"issue":"8","key":"7984_CR3","doi-asserted-by":"publisher","first-page":"3421","DOI":"10.1007\/s12094-025-03853-w","volume":"27","author":"BM de Las Heras","year":"2025","unstructured":"de Las Heras BM, et al. Management and outcome of children with high-risk neuroblastoma: insights from the Spanish Society of Pediatric Hematology and Oncology (SEHOP) neuroblastoma group on refractory and relapse\/progressive disease. Clin Transl Oncol. 2025;27(8):3421\u201331.","journal-title":"Clin Transl Oncol"},{"issue":"4","key":"7984_CR4","doi-asserted-by":"publisher","first-page":"490","DOI":"10.2967\/jnumed.124.269121","volume":"66","author":"PJ Gawne","year":"2025","unstructured":"Gawne PJ, et al. Theranostics for neuroblastoma: Making molecular radiotherapy work better. J Nucl Med. 2025;66(4):490\u20136.","journal-title":"J Nucl Med"},{"issue":"11","key":"7984_CR5","doi-asserted-by":"publisher","first-page":"4001","DOI":"10.1007\/s00259-025-07246-7","volume":"52","author":"MN Gaze","year":"2025","unstructured":"Gaze MN, et al. Safety and dosimetry of [177Lu]Lu-DOTA-TATE in adolescent patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours, or pheochromocytomas and paragangliomas: Primary analysis of the Phase II NETTER-P study. Eur J Nucl Med Mol Imaging. 2025;52(11):4001\u201315.","journal-title":"Eur J Nucl Med Mol Imaging"},{"issue":"10","key":"7984_CR6","doi-asserted-by":"publisher","first-page":"2348","DOI":"10.1007\/s00259-020-04741-x","volume":"47","author":"JE Gains","year":"2020","unstructured":"Gains JE, et al. A phase IIa trial of molecular radiotherapy with 177-lutetium DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma. Eur J Nucl Med Mol Imaging. 2020;47(10):2348\u201357.","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"7984_CR7","doi-asserted-by":"publisher","first-page":"836230","DOI":"10.3389\/fped.2022.836230","volume":"10","author":"F Sundquist","year":"2022","unstructured":"Sundquist F, et al. A Phase II Trial of a Personalized, Dose-Intense Administration Schedule of 177Lutetium-DOTATATE in Children With Primary Refractory or Relapsed High-Risk Neuroblastoma-LuDO-N. Front Pead. 2022;10:836230.","journal-title":"Front Pead"},{"key":"7984_CR8","doi-asserted-by":"crossref","unstructured":"Park SWS, et al. Heterogeneous SSTR2 target expression and a novel KIAA1549::BRAF fusion clone in a progressive metastatic lesion following 177Lutetium-DOTATATE molecular radiotherapy in neuroblastoma: a case report, Front Oncol. 2024;14.","DOI":"10.3389\/fonc.2024.1408729"},{"issue":"1","key":"7984_CR9","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s40658-022-00436-4","volume":"9","author":"JC Malcolm","year":"2022","unstructured":"Malcolm JC, et al. Impact of cyclic changes in pharmacokinetics and absorbed dose in pediatric neuroblastoma patients receiving [177Lu]Lu-DOTATATE. EJNMMI Phys. 2022;9(1):24.","journal-title":"EJNMMI Phys"},{"issue":"6","key":"7984_CR10","doi-asserted-by":"publisher","first-page":"900","DOI":"10.2967\/jnumed.124.269389","volume":"66","author":"G Kayal","year":"2025","unstructured":"Kayal G, et al. Multicycle dosimetric behavior and dose-effect relationships in [177Lu]Lu-DOTATATE peptide receptor radionuclide therapy. J Nucl Med. 2025;66(6):900\u20138.","journal-title":"J Nucl Med"},{"issue":"6","key":"7984_CR11","doi-asserted-by":"publisher","first-page":"923","DOI":"10.2967\/jnumed.123.267023","volume":"65","author":"K Hebert","year":"2024","unstructured":"Hebert K, et al. Absorbed dose-response relationship in patients with gastroenteropancreatic neuroendocrine tumors treated with [177Lu]Lu-DOTATATE: One step closer to personalized medicine. J Nucl Med. 2024;65(6):923\u201330.","journal-title":"J Nucl Med"},{"issue":"3","key":"7984_CR12","doi-asserted-by":"publisher","first-page":"399","DOI":"10.2967\/jnumed.121.262069","volume":"63","author":"D Roth","year":"2022","unstructured":"Roth D, et al. Dosimetric quantities in neuroendocrine tumors over treatment cycles with 177Lu-DOTATATE. J Nucl Med. 2022;63(3):399\u2013405.","journal-title":"J Nucl Med"},{"issue":"1","key":"7984_CR13","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/s40658-022-00473-z","volume":"9","author":"O Ardenfors","year":"2022","unstructured":"Ardenfors O, Nilsson JN, Thor D, Hindorf C. Simplified dosimetry for kidneys and tumors in 177Lu-labeled peptide receptor radionuclide therapy. EJNMMI Phys. 2022;9(1):44.","journal-title":"EJNMMI Phys"},{"issue":"2","key":"7984_CR14","doi-asserted-by":"publisher","first-page":"236","DOI":"10.2967\/jnumed.123.265987","volume":"65","author":"M Mileva","year":"2024","unstructured":"Mileva M, et al. Prediction of 177Lu-DOTATATE PRRT outcome using multimodality imaging in patients with gastroenteropancreatic neuroendocrine tumors: Results from a prospective phase II LUMEN study. J Nucl Med. 2024;65(2):236\u201344.","journal-title":"J Nucl Med"},{"issue":"1","key":"7984_CR15","doi-asserted-by":"publisher","first-page":"33","DOI":"10.2967\/jnumed.112.107524","volume":"54","author":"M Sandstr\u00f6m","year":"2013","unstructured":"Sandstr\u00f6m M, et al. Individualized dosimetry of kidney and bone marrow in patients undergoing 177Lu-DOTA-octreotate treatment. J Nucl Med. 2013;54(1):33\u201341.","journal-title":"J Nucl Med"},{"issue":"1","key":"7984_CR16","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1186\/s13550-021-00860-0","volume":"11","author":"U Jahn","year":"2021","unstructured":"Jahn U, Ilan E, Velikyan I, Fr\u00f6ss-Baron K, Lubberink M, Sundin A, Receptor depletion and recovery in small-intestinal neuroendocrine tumors and normal tissues after administration of a single intravenous dose of octreotide measured by 68Ga-DOTATOC PET\/CT. EJNMMI Res. 2021;11(1):118.","journal-title":"EJNMMI Res"},{"issue":"2","key":"7984_CR17","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1210\/jc.2008-1919","volume":"94","author":"S Lesche","year":"2009","unstructured":"Lesche S, Lehmann D, Nagel F, Schmid HA, Schulz S. Differential effects of octreotide and pasireotide on somatostatin receptor internalization and trafficking in vitro. J Clin Endocrinol Metab. 2009;94(2):654\u201361.","journal-title":"J Clin Endocrinol Metab"},{"issue":"5","key":"7984_CR18","doi-asserted-by":"publisher","first-page":"1942","DOI":"10.1016\/j.ajpath.2012.01.041","volume":"180","author":"B Waser","year":"2012","unstructured":"Waser B, et al. Phosphorylation of sst2 receptors in neuroendocrine tumors after octreotide treatment of patients. Am J Pathol. 2012;180(5):1942\u20139.","journal-title":"Am J Pathol"},{"issue":"1","key":"7984_CR19","doi-asserted-by":"publisher","first-page":"86","DOI":"10.3109\/0284186X.2011.618511","volume":"51","author":"U Garske","year":"2012","unstructured":"Garske U, et al. Minor changes in effective half-life during fractionated 177Lu-octreotate therapy. Acta Oncol 2012;51(1):86\u201396.","journal-title":"Acta Oncol"},{"issue":"1","key":"7984_CR20","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1186\/s40658-021-00422-2","volume":"8","author":"PF Staanum","year":"2021","unstructured":"Staanum PF, Frellsen AF, Olesen ML, Iversen P, Arveschoug AK. Practical kidney dosimetry in peptide receptor radionuclide therapy using [177Lu]Lu-DOTATOC and [177Lu]Lu-DOTATATE with focus on uncertainty estimates. EJNMMI Phys. 2021;8(1):78.","journal-title":"EJNMMI Phys"},{"issue":"3","key":"7984_CR21","first-page":"214","volume":"37","author":"S Kamaldeep","year":"2022","unstructured":"Kamaldeep S, Loharkar T, Das S, Basu, Banerjee S. Estimation of absorbed doses of indigenously produced \u2018direct-route\u2019 lutetium-177-[177Lu]Lu-DOTA-TATE PRRT in normal organs and tumor lesions in patients of metastatic neuroendocrine tumors: Comparison with no-carrier-added [177Lu]Lu-DOTA-TATE and the trend with multiple cycles. Cancer Biother Radiopharm. 2022;37(3):214\u201325.","journal-title":"Cancer Biother Radiopharm"},{"issue":"3","key":"7984_CR22","doi-asserted-by":"publisher","first-page":"449","DOI":"10.2967\/jnumed.124.268903","volume":"66","author":"L Bodei","year":"2025","unstructured":"Bodei L, et al. Dosimetry of [177Lu]Lu-DOTATATE in patients with advanced midgut neuroendocrine tumors: Results from a substudy of the phase III NETTER-1 trial. J Nucl Med. 2025;66(3):449\u201356.","journal-title":"J Nucl Med"},{"issue":"6","key":"7984_CR23","first-page":"659","volume":"24","author":"ML Sierra","year":"2009","unstructured":"Sierra ML, et al. Lymphocytic toxicity in patients after peptide-receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE and 90Y-DOTATOC. Cancer Biother Radiopharm. 2009;24(6):659\u201365.","journal-title":"Cancer Biother Radiopharm"}],"container-title":["European Journal of Nuclear Medicine and Molecular Imaging"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00259-026-07984-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00259-026-07984-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00259-026-07984-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T07:00:46Z","timestamp":1787986846000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00259-026-07984-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,19]]},"references-count":23,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["7984"],"URL":"https:\/\/doi.org\/10.1007\/s00259-026-07984-2","relation":{},"ISSN":["1619-7070","1619-7089"],"issn-type":[{"value":"1619-7070","type":"print"},{"value":"1619-7089","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,19]]},"assertion":[{"value":"20 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The study was conducted in accordance with ICH-GCP, EU-directive (2001\/20\/EC) and the Declaration of Helsinki. Ethical approval was obtained from the Swedish Ethical Review Authority (Dnr 2021\u2009\u2212\u200900470) and the Medical Research Ethics Committee of the Netherlands (CCMO NL78372.041.22).","order":1,"name":"Ethics","label":"Ethics approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All patients and\/or their legal guardians provided written informed consent prior to inclusion in the study.","order":2,"name":"Ethics","label":"Consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Novartis supplied the study drugs Lutathera\n \u00ae\n and LysaKare\n \u00ae\n free of charge and provided partial financial support for the LuDO-N trial. AB is a consultant for Boston Scientific, Telix Pharmaceuticals and GE Healthcare, and receives research support from Boston Scientific, Telix Pharmaceuticals, GE Healthcare, Ariceum Therapeutics and Siemens Healthineers. JS and KK received research support from Novartis. JN, RR, LT, FS, SP, KK and DT have no competing interest to declare.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}]}}