{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:33:41Z","timestamp":1787045621789,"version":"build-2736575974"},"reference-count":34,"publisher":"IOP Publishing","issue":"16","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/iopscience.iop.org\/info\/page\/text-and-data-mining"},{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/publishingsupport.iopscience.iop.org\/questions\/alternative-author-rights-policies\/"},{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/publishingsupport.iopscience.iop.org\/questions\/alternative-author-rights-policies\/"}],"content-domain":{"domain":["iopscience.iop.org"],"crossmark-restriction":false},"short-container-title":["Phys. Med. Biol."],"published-print":{"date-parts":[[2026,8,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Objective.<\/jats:italic>\n                    Lattice radiotherapy is usually evaluated using physical dose metrics such as target coverage, peak-to-valley dose ratio (PVDR), and organ-at-risk (OAR) dose, but these metrics do not explicitly represent non-local biological signalling. This study developed a hypothesis-generating computational framework to test whether synthetic head-and-neck lattice dose patterns retain the same interpretation after non-local signalling and anatomy-aware vascular uptake are included.\n                    <jats:italic>Approach.<\/jats:italic>\n                    A reaction-diffusion model propagated ROS-like and cytokine-like signals from TOPAS-derived dose distributions evaluated on a body-aware smoothed Monte Carlo dose substrate. The model was calibrated once in a one-dimensional half-field assay and transferred without geometry-specific retuning to stripe, lattice, irregular surrogate, and synthetic head-and-neck geometries. A 10-case algorithmic cohort with tumour, OAR, and vessel masks was rescored as physical-only, biology-informed without vascular uptake, and biology-informed with anatomical vascular uptake. Repeat-run uncertainty, sink falsification, smoothing-kernel sensitivity, and bounded parameter robustness analyses were performed.\n                    <jats:italic>Main results.<\/jats:italic>\n                    In the oxygen-neutral primary cohort, the cohort-mean PVDR-like ratio decreased from 1.817 under physical-dose interpretation to 1.292 without vascular uptake and 1.270 with anatomical uptake. Biology-informed reinterpretation changed ranking in 5\/10 cases for no-sink versus physical-only, 6\/10 for with-sink versus physical-only, and 2\/10 for with-sink versus no-sink. Biology-added brainstem-adjacent burden flags occurred in 2\/10 cases. In repeated runs, 65\/70 sink-related endpoint shifts exceeded the combined 95% Monte Carlo plus uptake-sensitivity band, but 0\/10 cases showed a noise-qualified sink-driven rank change.\n                    <jats:italic>Significance.<\/jats:italic>\n                    Non-local biological rescoring dominated reinterpretation, while vascular uptake acted as a weak secondary perturbation. The framework is hypothesis-generating and requires patient-derived RTDOSE\/RTSTRUCT data, realistic vascular segmentation, and experimental validation before clinical use.\n                  <\/jats:p>","DOI":"10.1088\/1361-6560\/ae94dd","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T22:55:38Z","timestamp":1785884138000},"page":"165001","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Biology-informed reinterpretation of lattice radiotherapy using non-local bystander signalling and anatomy-aware vascular sink modelling"],"prefix":"10.1088","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0626-4899","authenticated-orcid":true,"given":"Kai","family":"Woodger","sequence":"first","affiliation":[{"name":"University of Sydney"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"266","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"pmbae94ddbib1","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1016\/S0168-9002(03)01368-8","type":"journal-article","article-title":"GEANT4: a simulation toolkit","volume":"506","author":"Agostinelli","year":"2003","journal-title":"Nucl. Instrum. Methods Phys. Res. A"},{"key":"pmbae94ddbib2","doi-asserted-by":"publisher","first-page":"7050","DOI":"10.1038\/sj.onc.1206961","type":"journal-article","article-title":"Oxidative metabolism, gap junctions and the ionizing radiation-induced bystander effect","volume":"22","author":"Azzam","year":"2003","journal-title":"Oncogene"},{"key":"pmbae94ddbib3","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1667\/RR2548.1","type":"journal-article","article-title":"Radiation-induced bystander effects: what are they and how relevant are they to human radiation exposures?","volume":"176","author":"Blyth","year":"2011","journal-title":"Radiat. Res."},{"key":"pmbae94ddbib4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmp.2024.104823","type":"journal-article","article-title":"LatticeOpt: an automatic tool for planning optimisation of spatially fractionated stereotactic body radiotherapy","volume":"126","author":"Botti","year":"2024","journal-title":"Phys. Med."},{"key":"pmbae94ddbib5","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1016\/j.ejmp.2015.04.014","type":"journal-article","article-title":"Effects of microbeam radiation therapy on normal and tumoral blood vessels","volume":"31","author":"Bouchet","year":"2015","journal-title":"Phys. Med."},{"key":"pmbae94ddbib6","doi-asserted-by":"publisher","DOI":"10.1088\/1361-6560\/ac3119","type":"journal-article","article-title":"Investigating spatial fractionation and radiation-induced bystander effects: a mathematical modelling approach","volume":"66","author":"Cahoon","year":"2021","journal-title":"Phys. Med. Biol."},{"key":"pmbae94ddbib7","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.radonc.2021.11.023","type":"journal-article","article-title":"LITE SABR M1: A phase i trial of lattice stereotactic body radiotherapy for large tumors","volume":"167","author":"Duriseti","year":"2022","journal-title":"Radiother. Oncol."},{"key":"pmbae94ddbib8","doi-asserted-by":"publisher","DOI":"10.1016\/j.adro.2020.100639","type":"journal-article","article-title":"Spatially fractionated stereotactic body radiation therapy (Lattice) for large tumors","volume":"6","author":"Duriseti","year":"2021","journal-title":"Adv. Rad. Oncol."},{"key":"pmbae94ddbib9","doi-asserted-by":"publisher","first-page":"1334","DOI":"10.3109\/0284186X.2010.487874","type":"journal-article","article-title":"A mathematical framework for separating the direct and bystander components of cellular radiation response","volume":"49","author":"Ebert","year":"2010","journal-title":"Acta Oncol."},{"key":"pmbae94ddbib10","doi-asserted-by":"publisher","first-page":"3625","DOI":"10.3390\/cancers14153625","type":"journal-article","article-title":"Should peak dose be used to prescribe spatially fractionated radiation therapy? a review of preclinical studies","volume":"14","author":"Fernandez-Palomo","year":"2022","journal-title":"Cancers"},{"key":"pmbae94ddbib11","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1259\/0007-1285-62-740-679","type":"journal-article","article-title":"The linear-quadratic formula and progress in fractionated radiotherapy","volume":"62","author":"Fowler","year":"1989","journal-title":"Br. J. Radiol."},{"key":"pmbae94ddbib12","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1083\/jcb.119.3.493","type":"journal-article","article-title":"Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation","volume":"119","author":"Gavrieli","year":"1992","journal-title":"J. Cell Biol."},{"key":"pmbae94ddbib13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmp.2023.102616","type":"journal-article","article-title":"Clinical aspects of spatially fractionated radiation therapy treatments","volume":"111","author":"Grams","year":"2023","journal-title":"Phys. Med."},{"key":"pmbae94ddbib14","doi-asserted-by":"publisher","first-page":"97","DOI":"10.21105\/joss.00097","type":"journal-article","article-title":"SALib: an open-source Python library for sensitivity analysis","volume":"2","author":"Herman","year":"2017","journal-title":"J. Open Source Softw."},{"key":"pmbae94ddbib15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctro.2022.100569","type":"journal-article","article-title":"Lattice radiation therapy in clinical practice: a systematic review","volume":"39","author":"Iori","year":"2023","journal-title":"Clin. Transl. Rad. Oncol."},{"key":"pmbae94ddbib16","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.radonc.2021.12.003","type":"journal-article","article-title":"LITE SABR M1: Planning design and dosimetric endpoints for a phase i trial of lattice SBRT","volume":"167","author":"Kavanaugh","year":"2022","journal-title":"Radiother. Oncol."},{"key":"pmbae94ddbib17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctro.2023.100691","type":"journal-article","article-title":"Combining spatially fractionated radiation therapy (SFRT) and immunotherapy opens new rays of hope for enhancing therapeutic ratio","volume":"44","author":"Lu","year":"2024","journal-title":"Clin. Transl. Rad. Oncol."},{"key":"pmbae94ddbib18","doi-asserted-by":"publisher","first-page":"657","DOI":"10.52547\/ijrr.20.3.20","type":"journal-article","article-title":"Potential implications of the radiation-induced bystander effect for spatially fractionated radiotherapy: a theoretical simulation study","volume":"20","author":"Mahmoudi","year":"2022","journal-title":"Int. J. Rad. Res."},{"key":"pmbae94ddbib19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0054526","type":"journal-article","article-title":"A kinetic-based model of radiation-induced intercellular signalling","volume":"8","author":"McMahon","year":"2013","journal-title":"PLoS One"},{"key":"pmbae94ddbib20","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1080\/00401706.1991.10484804","type":"journal-article","article-title":"Factorial sampling plans for preliminary computational experiments","volume":"33","author":"Morris","year":"1991","journal-title":"Technometrics"},{"key":"pmbae94ddbib21","doi-asserted-by":"publisher","first-page":"7028","DOI":"10.1038\/sj.onc.1206882","type":"journal-article","article-title":"Radiation-induced bystander effects, carcinogenesis and models","volume":"22","author":"Mothersill","year":"2003","journal-title":"Oncogene"},{"key":"pmbae94ddbib22","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1118\/1.598063","type":"journal-article","article-title":"Reporting and analyzing dose distributions: a concept of equivalent uniform dose","volume":"24","author":"Niemierko","year":"1997","journal-title":"Med. Phys."},{"key":"pmbae94ddbib23","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-77415-5","type":"journal-article","article-title":"Tumor growth and vascular redistribution contributes to the dosimetric preferential effect of microbeam radiotherapy: a Monte Carlo study","volume":"14","author":"Ortiz","year":"2024","journal-title":"Sci. Rep."},{"key":"pmbae94ddbib24","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.jtbi.2018.06.027","type":"journal-article","article-title":"Models for the bystander effect in gradient radiation fields: range and signalling type","volume":"455","author":"Peng","year":"2018","journal-title":"J. Theor. Biol."},{"key":"pmbae94ddbib25","doi-asserted-by":"publisher","first-page":"6818","DOI":"10.1118\/1.4758060","type":"journal-article","article-title":"TOPAS: an innovative proton Monte Carlo platform for research and clinical applications","volume":"39","author":"Perl","year":"2012","journal-title":"Med. Phys."},{"key":"pmbae94ddbib26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jtbi.2016.04.010","type":"journal-article","article-title":"Bystander effects and their implications for clinical radiation therapy: insights from multiscale in silico experiments","volume":"401","author":"Powathil","year":"2016","journal-title":"J. Theor. Biol."},{"key":"pmbae94ddbib27","doi-asserted-by":"publisher","first-page":"e3","DOI":"10.1017\/erm.2021.34","type":"journal-article","article-title":"Divide and conquer: spatially fractionated radiation therapy","volume":"24","author":"Prezado","year":"2022","journal-title":"Expert Rev. Mol. Med."},{"key":"pmbae94ddbib28","doi-asserted-by":"publisher","first-page":"10TR02","DOI":"10.1088\/1361-6560\/ad4192","type":"journal-article","article-title":"Spatially fractionated radiation therapy: a critical review on current status of clinical and preclinical studies and knowledge gaps","volume":"69","author":"Prezado","year":"2024","journal-title":"Phys. Med. Biol."},{"key":"pmbae94ddbib29","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1038\/nrc2603","type":"journal-article","article-title":"Radiation-induced bystander signalling in cancer therapy","volume":"9","author":"Prise","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"pmbae94ddbib30","doi-asserted-by":"publisher","first-page":"5858","DOI":"10.1074\/jbc.273.10.5858","type":"journal-article","article-title":"DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139","volume":"273","author":"Rogakou","year":"1998","journal-title":"J. Biol. Chem."},{"key":"pmbae94ddbib31","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1038\/nrc1277","type":"journal-article","article-title":"Radiation-induced bystander effects: implications for cancer","volume":"4","author":"Seymour","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"pmbae94ddbib32","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1667\/RADE-20-00066.1","type":"journal-article","article-title":"The technical and clinical implementation of LATTICE radiation therapy","volume":"194","author":"Wu","year":"2020","journal-title":"Radiat. Res."},{"key":"pmbae94ddbib33","doi-asserted-by":"publisher","first-page":"467","DOI":"10.21037\/atm-21-6631","type":"journal-article","article-title":"Feasibility of lattice radiotherapy using proton and carbon-ion pencil beam for sinonasal malignancy","volume":"10","author":"Yang","year":"2022","journal-title":"Ann. Transl. Med."},{"key":"pmbae94ddbib34","doi-asserted-by":"publisher","first-page":"7359","DOI":"10.1002\/mp.16572","type":"journal-article","article-title":"Lattice position optimization for LATTICE therapy","volume":"50","author":"Zhang","year":"2023","journal-title":"Med. Phys."}],"container-title":["Physics in Medicine &amp; Biology"],"original-title":[],"link":[{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1361-6560\/ae94dd","content-type":"text\/html","content-version":"am","intended-application":"text-mining"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1361-6560\/ae94dd\/pdf","content-type":"application\/pdf","content-version":"am","intended-application":"text-mining"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1361-6560\/ae94dd","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1361-6560\/ae94dd\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1361-6560\/ae94dd\/pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1361-6560\/ae94dd\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1361-6560\/ae94dd\/pdf","content-type":"application\/pdf","content-version":"am","intended-application":"similarity-checking"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1361-6560\/ae94dd\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:18:01Z","timestamp":1787044681000},"score":1,"resource":{"primary":{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1361-6560\/ae94dd"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,18]]},"references-count":34,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8,18]]},"published-print":{"date-parts":[[2026,8,28]]}},"URL":"https:\/\/doi.org\/10.1088\/1361-6560\/ae94dd","relation":{},"ISSN":["0031-9155","1361-6560"],"issn-type":[{"value":"0031-9155","type":"print"},{"value":"1361-6560","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,18]]},"assertion":[{"value":"Biology-informed reinterpretation of lattice radiotherapy using non-local bystander signalling and anatomy-aware vascular sink modelling","name":"article_title","label":"Article Title"},{"value":"Physics in Medicine & Biology","name":"journal_title","label":"Journal Title"},{"value":"paper","name":"article_type","label":"Article Type"},{"value":"\u00a9 2026 The Author(s). Published on behalf of Institute of Physics and Engineering in Medicine by IOP Publishing Ltd","name":"copyright_information","label":"Copyright Information"},{"value":"2026-05-17","name":"date_received","label":"Date Received","group":{"name":"publication_dates","label":"Publication dates"}},{"value":"2026-08-04","name":"date_accepted","label":"Date Accepted","group":{"name":"publication_dates","label":"Publication dates"}},{"value":"2026-08-18","name":"date_epub","label":"Online publication date","group":{"name":"publication_dates","label":"Publication dates"}}]}}