{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T14:19:17Z","timestamp":1788272357434,"version":"build-2803163510"},"reference-count":43,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["aapm.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Medical Physics"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      In skull\u2010base proton therapy (PT), severe toxicity outcomes such as temporal lobe necrosis (TLN) may be associated with inadequate management of the actual radiobiological effectiveness (RBE) of proton beams. Combining dose\u2010averaged linear energy transfer (LET\n                      <jats:sub>d<\/jats:sub>\n                      ) and dose may be crucial in treatment plan optimization and evaluation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>\n                      To gather evidence on the combined effect of LET\n                      <jats:sub>d<\/jats:sub>\n                      and dose on voxel\u2010 and structure\u2010wise levels in determining a high\u2010grade TLN (CTCAE v.5 grade \u2265G2, G2\u2010TLN) in skull\u2010base tumors treated with PT; a dose\u2010LET\n                      <jats:sub>d<\/jats:sub>\n                      \u2010volume histogram (DLVH)\u2010based model was built to predict G2\u2010TLN, combined with an analysis of the Dose\u2010LET\n                      <jats:sub>d<\/jats:sub>\n                      voxel\u2010based distributions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We retrospectively analyzed data of skull\u2010base chordomas (61) and chondrosarcomas (18), treated at CNAO National Center for Oncological Hadrontherapy (Pavia, Italy) with PT between September 2011 and July 2020, with a prescription dose of 74 and 70\u00a0Gy(RBE), respectively. RBE was set to a constant value of 1.1, while TL dose was constrained to D2cc\u00a0&lt;\u00a071\u00a0Gy(RBE) in the optimization process. Only patients experiencing a G2\u2010TLN were included in the voxel\u2010wise analysis and statistically significant differences between dose\u2010matched LET\n                      <jats:sub>d<\/jats:sub>\n                      distributions within necrotic\u2010brain areas (necrosis contoured at onset) and healthy\u2010brain voxels were explored through association tests and mixed\u2010effects logistic regression models within dose bins. On a structure\u2010wise level, G2\u2010TLN association with clinical and DLVH variables was analyzed for each temporal lobe to implement a pre\u2010processing pipeline. Hence, bootstrap enhanced Elastic\u2010Net regularized logistic regression, followed by the area under the receiver operating characteristic curve (AUROC), was used to select the final model. Performance and calibration were evaluated with cross\u2010validation AUROC and Hosmer\u2010Lemeshow test, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      With a median follow\u2010up of 49.7 months, 13 patients experienced G2\u2010TLN (17 TL) after a median time of 21.5 months. Seven out of 13 G2\u2010TLN patients reported a statistically significant difference between LET\n                      <jats:sub>d<\/jats:sub>\n                      in necrotic\u2010 and healthy\u2010brain voxels after dose\u2010matching, with 71.4% of them presenting higher LET\n                      <jats:sub>d<\/jats:sub>\n                      values in necrotic\u2010brain voxels. LET\n                      <jats:sub>d<\/jats:sub>\n                      showed significant associations with the onset of G2\u2010TLN in dose bins 35\u201340\u00a0Gy(RBE) (Odds Ratio, OR: 7.4, 95%CI: 3.5\u201326.5,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a00.001) and 50\u201355\u00a0Gy(RBE) (OR: 2.4, 95%CI: 1.5\u20134.0,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a00.001). Regarding structure\u2010wise modelling, the final logistic regression model was built using two DLVH variables, V\n                      <jats:sub>(dose,LETd)<\/jats:sub>\n                      (V\n                      <jats:sub>(68,0)<\/jats:sub>\n                      and V\n                      <jats:sub>(19,4.6)<\/jats:sub>\n                      ), which showed an independent association with G2\u2010TLN and proved the highest AUROC. Good performance and calibration were reported by the cross\u2010validation AUROC (0.89, 95%CI: 0.78\u20130.95) and Hosmer\u2010Lemeshow test (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a01).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Voxels receiving higher LET\n                      <jats:sub>d<\/jats:sub>\n                      in the low and medium dose ranges (35\u201340 and 50\u201355\u00a0Gy(RBE)) were associated with high\u2010grade necrosis on a voxel\u2010wise level. The volumes of TL receiving high doses (68\u00a0Gy(RBE)) or high LET\n                      <jats:sub>d<\/jats:sub>\n                      (4.6\u00a0keV\/\u00b5m) with doses higher than 19\u00a0Gy(RBE) were the major predictors of G2\u2010TLN. Further evaluation with a larger sample size and an external validation cohort is necessary to assess our findings and validate the presented model.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mp.70562","type":"journal-article","created":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T07:32:50Z","timestamp":1784964770000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Modelling dose and dose\u2010averaged linear energy transfer to predict high\u2010grade temporal lobe necrosis following skull\u2010base proton therapy"],"prefix":"10.1002","volume":"53","author":[{"given":"Giulia","family":"Fontana","sequence":"first","affiliation":[{"name":"Clinical Department CNAO National Center for Oncological Hadrontherapy  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Fiorina","sequence":"additional","affiliation":[{"name":"Sezione di Torino Istituto Nazionale di Fisica Nucleare  Turin Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Lillo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics University of Pavia  Pavia Italy"},{"name":"Radiation Oncology Unit, Clinical Department CNAO National Center for Oncological Hadrontherapy  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia Pia","family":"Ciccone","sequence":"additional","affiliation":[{"name":"Radiation Oncology Unit, Clinical Department CNAO National Center for Oncological Hadrontherapy  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Riva","sequence":"additional","affiliation":[{"name":"Radiation Oncology Unit, Clinical Department CNAO National Center for Oncological Hadrontherapy  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Vai","sequence":"additional","affiliation":[{"name":"Medical Physics Unit, Clinical Department CNAO National Center for Oncological Hadrontherapy  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Ciocca","sequence":"additional","affiliation":[{"name":"Medical Physics Unit, Clinical Department CNAO National Center for Oncological Hadrontherapy  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Iannalfi","sequence":"additional","affiliation":[{"name":"Radiation Oncology Unit, Clinical Department CNAO National Center for Oncological Hadrontherapy  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Molinelli","sequence":"additional","affiliation":[{"name":"Medical Physics Unit, Clinical Department CNAO National Center for Oncological Hadrontherapy  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ester","family":"Orlandi","sequence":"additional","affiliation":[{"name":"Radiation Oncology Unit, Clinical Department CNAO National Center for Oncological Hadrontherapy  Pavia Italy"},{"name":"Department of Clinical\u2010Surgical, Diagnostic, and Pediatric Sciences University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,25]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2018.07.020"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.1291"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noaa067"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13174423"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2017.30"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0360\u20103016(98)00031\u20105"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.3109\/0284186X.2011.582518"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2024.110668"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/0284186X.2017.1351621"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2022.05.015"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phro.2024.100692"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2024.110590"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/0284186X.2017.1290825"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13014\u2010016\u20100642\u20106"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2009.02.091"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2020.08.058"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2025.110716"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2021.06.016"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1051\/vcm\/2025001"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2013.10.035"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1259\/bjr.20190595"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2011.10.042"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1201\/9780203753736"},{"key":"e_1_2_8_25_1","unstructured":"CTCAE v.5.2017. Accessed November 27 2017.https:\/\/ctep.cancer.gov\/protocoldevelopment\/electronic_applications\/ctc.htm#ctc_50"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2021.02.024"},{"key":"e_1_2_8_27_1","unstructured":"TheR R project for statistical computing. Accessed September 20 2024.https:\/\/www.r\u2010project.org\/"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2010.12.028"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1467\u20109868.2005.00503.x"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1214\/ss\/1177013815"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/1477\u20107525\u201011\u201089"},{"key":"e_1_2_8_32_1","unstructured":"MATLAB version: 9.13.0 (R2022b) The MathWorks Inc.https:\/\/www.mathworks.com"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2022.01.047"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.14338\/IJPT\u201020\u201000014.1"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctro.2024.100814"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1088\/1361\u20106560\/ab0a4d"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2021.08.027"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2022.08.014"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2020.03.013"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1080\/0284186X.2019.1631477"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2021.08.015"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2008.05.023"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2017.06.1526"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2014.10.011"}],"container-title":["Medical Physics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/aapm.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mp.70562","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/aapm.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mp.70562","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/aapm.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mp.70562","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T13:43:44Z","timestamp":1788270224000},"score":1,"resource":{"primary":{"URL":"https:\/\/aapm.onlinelibrary.wiley.com\/doi\/10.1002\/mp.70562"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,25]]},"references-count":43,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/mp.70562"],"URL":"https:\/\/doi.org\/10.1002\/mp.70562","archive":["Portico"],"relation":{},"ISSN":["0094-2405","2473-4209"],"issn-type":[{"value":"0094-2405","type":"print"},{"value":"2473-4209","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,25]]},"assertion":[{"value":"2025-07-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70562"}}