{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T21:11:38Z","timestamp":1792617098142,"version":"4.5.0"},"reference-count":31,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T00:00:00Z","timestamp":1629676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Ultra-high dose rate FLASH proton radiotherapy (F-PRT) has been shown to reduce normal tissue toxicity compared to standard dose rate proton radiotherapy (S-PRT) in experiments using the entrance portion of the proton depth dose profile, while proton therapy uses a spread-out Bragg peak (SOBP) with unknown effects on FLASH toxicity sparing. To investigate, the biological effects of F-PRT using an SOBP and the entrance region were compared to S-PRT in mouse intestine. In this study, 8\u201310-week-old C57BL\/6J mice underwent 15 Gy (absorbed dose) whole abdomen irradiation in four groups: (1) SOBP F-PRT, (2) SOBP S-PRT, (3) entrance F-PRT, and (4) entrance S-PRT. Mice were injected with EdU 3.5 days after irradiation, and jejunum segments were harvested and preserved. EdU-positive proliferating cells and regenerated intestinal crypts were quantified. The SOBP had a modulation (width) of 2.5 cm from the proximal to distal 90%. Dose rates with a SOBP for F-PRT or S-PRT were 108.2 \u00b1 8.3 Gy\/s or 0.82 \u00b1 0.14 Gy\/s, respectively. In the entrance region, dose rates were 107.1 \u00b1 15.2 Gy\/s and 0.83 \u00b1 0.19 Gy\/s, respectively. Both entrance and SOBP F-PRT preserved a significantly higher number of EdU + \/crypt cells and percentage of regenerated crypts compared to S-PRT. Moreover, tumor growth studies showed no difference between SOBP and entrance for either of the treatment modalities.<\/jats:p>","DOI":"10.3390\/cancers13164244","type":"journal-article","created":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T21:59:00Z","timestamp":1629755940000},"page":"4244","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":113,"title":["Comparison of FLASH Proton Entrance and the Spread-Out Bragg Peak Dose Regions in the Sparing of Mouse Intestinal Crypts and in a Pancreatic Tumor Model"],"prefix":"10.3390","volume":"13","author":[{"given":"Michele M.","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis I.","family":"Verginadis","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denisa","family":"Goia","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Haertter","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khayrullo","family":"Shoniyozov","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Maity","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa M.","family":"Busch","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Metz","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith A.","family":"Cengel","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Costas","family":"Koumenis","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4869-6575","authenticated-orcid":false,"given":"Eric S.","family":"Diffenderfer","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"245ra93","DOI":"10.1126\/scitranslmed.3008973","article-title":"Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice","volume":"6","author":"Favaudon","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.radonc.2017.05.003","article-title":"Irradiation in a flash: Unique sparing of memory in mice after whole brain irradiation with dose rates above 100 Gy\/s","volume":"124","author":"Petersson","year":"2017","journal-title":"Radiother. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.ijrobp.2016.09.018","article-title":"Experimental Platform for Ultra-high Dose Rate FLASH Irradiation of Small Animals Using a Clinical Linear Accelerator","volume":"97","author":"Trovati","year":"2017","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1158\/1078-0432.CCR-17-3375","article-title":"The advantage of Flash radiotherapy confirmed in mini-pig and cat-cancer patients","volume":"25","author":"Vozenin","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.radonc.2019.06.019","article-title":"Treatment of a first patient with FLASH-radiotherapy","volume":"139","author":"Bourhis","year":"2019","journal-title":"Radiother. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Cunningham, S., McCauley, S., Vairamani, K., Speth, J., Girdhani, S., Abel, E., Sharma, R.A., Perentesis, J.P., Wells, S.I., and Mascia, A. (2021). FLASH Proton Pencil Beam Scanning Irradiation Minimizes Radiation-Induced Leg Contracture and Skin Toxicity in Mice. Cancers, 13.","DOI":"10.3390\/cancers13051012"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.ijrobp.2019.10.049","article-title":"Design, Implementation, and In Vivo Validation of a Novel Proton Flash Radiotherapy System","volume":"106","author":"Diffenderfer","year":"2020","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1667\/RADE-20-00068.1","article-title":"FLASH Investigations Using Protons: Design of Delivery System, Preclinical Setup and Confirmation of FLASH Effect with Protons in Animal Systems","volume":"194","author":"Zhang","year":"2020","journal-title":"Radiat. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.radonc.2019.06.024","article-title":"Feasibility of proton FLASH effect tested by zebrafish embryo irradiation","volume":"139","author":"Beyreuther","year":"2019","journal-title":"Radiother. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.ijrobp.2018.06.403","article-title":"Experimental Set-up for FLASH Proton Irradiation of Small Animals Using a Clinical System","volume":"102","author":"Patriarca","year":"2018","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4348","DOI":"10.1002\/mp.14253","article-title":"Feasibility of proton FLASH irradiation using a synchrocyclotron for preclinical studies","volume":"47","author":"Darafsheh","year":"2020","journal-title":"Med. Phys."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Darafsheh, A., Hao, Y., Zhao, X., Reynoso, F., Zwart, T., Wagner, M., Evans, T., and Zhao, T. (2021). Spread-out Bragg peak proton FLASH irradiation using a clinical synchrocyclotron: Proof of concept and ion chamber characterization. Med. Phys.","DOI":"10.1002\/mp.15021"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Velalopoulou, A., Karagounis, I.V., Cramer, G.M., Kim, M.M., Skoufos, G., Goia, D., Hagan, S., Verginadis, I.I., Shoniyozov, K., and Chiango, J. (2021). FLASH proton radiotherapy spares normal epithelial and mesenchymal tissues while preserving sarcoma response. Cancer Res.","DOI":"10.1158\/0008-5472.CAN-21-1500"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S0360-3016(02)02754-2","article-title":"Relative biological effectiveness (RBE) values for proton beam therapy","volume":"53","author":"Paganetti","year":"2002","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"R155","DOI":"10.1088\/0031-9155\/60\/8\/R155","article-title":"The physics of proton therapy","volume":"60","author":"Newhauser","year":"2015","journal-title":"Phys. Med. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1667\/RR2737.1","article-title":"Variations in the RBE for cell killing along the depth-dose profile of a modulated proton therapy beam","volume":"179","author":"Britten","year":"2013","journal-title":"Radiat. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.ejmp.2020.08.005","article-title":"Technical challenges for FLASH proton therapy","volume":"78","author":"Jolly","year":"2020","journal-title":"Phys. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.radonc.2020.11.002","article-title":"Current Delivery Limitations of Proton PBS for FLASH","volume":"155","author":"Zou","year":"2021","journal-title":"Radiother. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1080\/0284186X.2019.1627416","article-title":"Towards FLASH proton therapy: The impact of treatment planning and machine characteristics on achievable dose rates","volume":"58","author":"Safai","year":"2019","journal-title":"Acta Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1002\/mp.14730","article-title":"FLASH proton irradiation setup with a modulator wheel for a single mouse eye","volume":"48","author":"Kourkafas","year":"2021","journal-title":"Med. Phys."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1134\/S0020441218050123","article-title":"Designing and Experimental Testing of the Beam-Forming Devices in Proton Therapy","volume":"61","author":"Akulinichev","year":"2018","journal-title":"Instrum. Exp. Tech."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1118\/1.1380433","article-title":"A compact ridge filter for spread out Bragg peak production in pulsed proton clinical beams","volume":"28","author":"Kostjuchenko","year":"2001","journal-title":"Med. Phys."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"135013","DOI":"10.1088\/1361-6560\/ab20d9","article-title":"Design and commissioning of an image-guided small animal radiation platform and quality assurance protocol for integrated proton and x-ray radiobiology research","volume":"64","author":"Kim","year":"2019","journal-title":"Phys. Med. Biol."},{"key":"ref_24","unstructured":"Andreo, P., Burns, D., Hohlfeld, K., Huq, M., and Trs, T.K. (2000). Absorbed Dose Determination in External Beam Radiotherapy: An International Code of Practice for Dosimetry Based on Standards of Absorbed Dose to Water, Available online: http:\/\/citeseerx.ist.psu.edu\/viewdoc\/citations?doi=10.1.1.467.5124."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Yin, L., Zou, W., Kim, M.M., Avery, S.M., Wiersma, R.D., Teo, B.-K.K., Dong, L., and Diffenderfer, E.S. (2021). Evaluation of Two-voltage and Three-voltage Linear Methods for Deriving Ion Recombination Correction Factors in Proton FLASH Irradiation. IEEE Trans. Radiat. Plasma Med. Sci.","DOI":"10.1109\/TRPMS.2021.3078885"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Cascio, E.W., and Gottschalk, B. (2009, January 20\u201324). A simplified vacuumless Faraday cup for the experimental beamline at the Francis H. Burr Proton Therapy Center. Proceedings of the IEEE Radiation Effects Data Workshop, Quebec, QC, Canada.","DOI":"10.1109\/REDW.2009.5336294"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"R419","DOI":"10.1088\/0031-9155\/59\/22\/R419","article-title":"Relative biological effectiveness (RBE) values for proton beam therapy. Variations as a function of biological endpoint, dose, and linear energy transfer","volume":"59","author":"Paganetti","year":"2014","journal-title":"Phys. Med. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4644","DOI":"10.1002\/mp.14381","article-title":"The impact of dose delivery time on biological effectiveness in proton irradiation with various biological parameters","volume":"47","author":"Kasamatsu","year":"2020","journal-title":"Med. Phys."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1088\/0031-9155\/60\/7\/2645","article-title":"A critical study of different Monte Carlo scoring methods of dose average linear-energy-transfer maps calculated in voxelized geometries irradiated with clinical proton beams","volume":"60","author":"Carabe","year":"2015","journal-title":"Phys. Med. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1158\/0008-5472.CAN-16-2724","article-title":"A novel mouse model to study image-guided, radiation-induced intestinal injury and preclinical screening of radioprotectors","volume":"77","author":"Verginadis","year":"2017","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.ijrobp.2018.10.007","article-title":"Interleukin 6 signaling blockade exacerbates acute and late injury from focal intestinal irradiation","volume":"103","author":"Bell","year":"2019","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/16\/4244\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:50:08Z","timestamp":1760165408000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/16\/4244"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,23]]},"references-count":31,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["cancers13164244"],"URL":"https:\/\/doi.org\/10.3390\/cancers13164244","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,23]]}}}