{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T08:31:32Z","timestamp":1793435492475,"version":"4.5.0"},"reference-count":53,"publisher":"Radiation Research Society","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Radiation Research"],"published-print":{"date-parts":[[2022,2,22]]},"abstract":"<jats:p>Stereotactic body radiation therapy (SBRT) has shown promising results in the treatment of pancreatic cancer and other solid tumors. However, wide adoption of SBRT remains limited largely due to uncertainty about the treatment's optimal fractionation schedules to elicit maximal tumor response while limiting the dose to adjacent structures. A small animal irradiator in combination with a clinically relevant oncological animal model could address these questions. Accurate delivery of X rays to animal tumors may be hampered by suboptimal image-guided targeting of the X-ray beam in vivo. Integration of bioluminescence imaging (BLI) into small animal irradiators in addition to standard cone-beam computed tomography (CBCT) imaging improves target identification and high-precision therapy delivery to deep tumors with poor soft tissue contrast, such as pancreatic tumors. Using bioluminescent BxPC3 pancreatic adenocarcinoma human cells grown orthotopically in mice, we examined the performance of a small animal irradiator equipped with both CBCT and BLI in delivering targeted, hypo-fractionated, multi-beam SBRT. Its targeting accuracy was compared with magnetic resonance imaging (MRI)-guided targeting based on co-registration between CBCT and corresponding sequential magnetic resonance scans, which offer greater soft tissue contrast compared with CT alone. Evaluation of our platform's BLI-guided targeting accuracy was performed by quantifying in vivo changes in bioluminescence signal after treatment as well as staining of ex vivo tissues with \u03b3H2AX, Ki67, TUNEL, CD31 and CD11b to assess SBRT treatment effects. Using our platform, we found that BLI-guided SBRT enabled more accurate delivery of X rays to the tumor resulting in greater cancer cell DNA damage and proliferation inhibition compared with MRI-guided SBRT. Furthermore, BLI-guided SBRT allowed higher animal throughput and was more cost effective to use in the preclinical setting than MRI-guided SBRT. Taken together, our preclinical platform could be employed in translational research of SBRT of pancreatic cancer.<\/jats:p>","DOI":"10.1667\/rade-21-00161.1","type":"journal-article","created":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T13:16:04Z","timestamp":1645535764000},"page":"626-637","source":"Crossref","is-referenced-by-count":3,"title":["Assessing the Accuracy of Bioluminescence Image-Guided Stereotactic Body Radiation Therapy of Orthotopic Pancreatic Tumors Using a Small Animal Irradiator"],"prefix":"10.1667","volume":"197","author":[{"given":"Sara","family":"Rapic","sequence":"first","affiliation":[{"name":"Princess Margaret Cancer Centre, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Samuel","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia E.","family":"Lindsay","sequence":"additional","affiliation":[{"name":"Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Ansell","sequence":"additional","affiliation":[{"name":"Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Weersink","sequence":"additional","affiliation":[{"name":"Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph S.","family":"DaCosta","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1243","reference":[{"key":"16","doi-asserted-by":"crossref","unstructured":"M Ghita, KH Brown, OJ Kelada, et al.  \"Cancers.\"  11, \"Integrating small animal irradiators with functional imaging for advanced preclinical radiotherapy research.\" 170 (2019)","DOI":"10.3390\/cancers11020170"},{"key":"6","doi-asserted-by":"crossref","unstructured":"J Bernier, EJ Hall, A Giaccia,  \"Nat Rev Cancer.\"  4, \"Radiation oncology: a century of achievements.\" (2004)","DOI":"10.1038\/nrc1451"},{"key":"1","doi-asserted-by":"crossref","unstructured":"R Baskar, KA Lee, R Yeo, et al.  \"Int J Med Sci.\"  9, \"Cancer and radiation therapy: current advances and future directions.\" (2012)","DOI":"10.7150\/ijms.3635"},{"key":"2","doi-asserted-by":"crossref","unstructured":"S Goyal  and T Kataria  \"Radiology Res Pract.\"  2014, \"Image Guidance in radiation therapy: Techniques and applications.\" 1 (2014)","DOI":"10.1155\/2014\/705604"},{"key":"3","doi-asserted-by":"crossref","unstructured":"C Garibaldi, BA Jereczek-Fossa, G Marvaso, et al.  \"Ecancermedicalscience.\"  11, \"Recent advances in radiation oncology.\" 785 (2017)","DOI":"10.3332\/ecancer.2017.785"},{"key":"4","doi-asserted-by":"crossref","unstructured":"DA Jaffray, S Das, PM Jacobs, et al.  \"Int J Radiat Oncol Biology Phys.\"  101, \"How Advances in imaging will affect precision radiation oncology.\" (2018)","DOI":"10.1016\/j.ijrobp.2018.01.047"},{"key":"5","doi-asserted-by":"crossref","unstructured":"D Thorwarth  and L Muren  \"Phys Imaging Radiat Oncol.\"  12, \"Imaging science and development in modern high-precision radiotherapy.\" (2019)","DOI":"10.1016\/j.phro.2019.11.008"},{"key":"7","doi-asserted-by":"crossref","unstructured":"CN Coleman, GS Higgins, JM Brown, et al.  \"Am Assoc Cancer Res.\"  22, \"Improving the predictive value of preclinical studies in support of radiotherapy clinical trials.\" (2016)","DOI":"10.1158\/1078-0432.CCR-16-0069"},{"key":"8","doi-asserted-by":"crossref","unstructured":"M de Jong  and T Maina  \"J Nucl Med.\"  51, \"Of mice and humans: Are they the same?\u2013Implications in cancer translational research.\" (2010)","DOI":"10.2967\/jnumed.109.065706"},{"key":"9","doi-asserted-by":"crossref","unstructured":"M Brand, S Laban, M-N Theodoraki, et al.  \"Int J Mol Sci.\"  22, \"Characterization and differentiation of the tumor microenvironment (TME) of orthotopic and subcutaneously grown head and neck squamous cell carcinoma (HNSCC) in immuno-competent mice.\" 247 (2020)","DOI":"10.3390\/ijms22010247"},{"key":"10","doi-asserted-by":"crossref","unstructured":"DJ Erstad, M Sojoodi, MS Taylor, et al.  \"Dis Model Mech.\"  11, \"Orthotopic and heterotopic murine models of pancreatic cancer and their different responses to FOLFIRINOX chemotherapy.\" dmm.034793 (2018)","DOI":"10.1242\/dmm.034793"},{"key":"11","doi-asserted-by":"crossref","unstructured":"S Rapic, C Vangestel, J Verhaeghe, et al.  \"Mol Imaging Biol.\"  19, \"Characterization of an orthotopic colorectal cancer mouse model and its feasibility for accurate quantification in positron emission tomography.\" (2017)","DOI":"10.1007\/s11307-017-1051-4"},{"key":"12","doi-asserted-by":"crossref","unstructured":"F Verhaegen, L Dubois, S Gianolini, et al.  \"Radiother Oncol.\"  126, \"ESTRO ACROP: Technology for precision small animal radiotherapy research: Optimal use and challenges.\" (2018)","DOI":"10.1016\/j.radonc.2017.11.016"},{"key":"13","doi-asserted-by":"crossref","unstructured":"DP Clark  and CT Badea  \"Phys Medica.\"  30, \"Micro-CT of rodents: State-of-the-art and future perspectives.\" (2014)","DOI":"10.1016\/j.ejmp.2014.05.011"},{"key":"14","doi-asserted-by":"crossref","unstructured":"CPW Klerk, RM Overmeer, TMH Niers, et al.  \"Biotechniques.\"  43, \"Validity of bioluminescence measurements for noninvasive in vivo imaging of tumor load in small animals.\" (2007)","DOI":"10.2144\/000112515"},{"key":"15","doi-asserted-by":"crossref","unstructured":"RA Weersink, S Ansell, A Wang, et al.  \"Med Phys.\"  41, \"Integration of optical imaging with a small animal irradiator.\" 102701 (2014)","DOI":"10.1118\/1.4894730"},{"key":"17","doi-asserted-by":"crossref","unstructured":"B Zhang, KK-H Wang, J Yu, et al.  \"Int J Radiat Oncol Biology Phys.\"  94, \"Bioluminescence tomography-guided radiation therapy for preclinical research.\" (2016)","DOI":"10.1016\/j.ijrobp.2015.11.039"},{"key":"18","doi-asserted-by":"crossref","unstructured":"B Zhang, JW Wong, II Iordachita, et al.  \"Radiat Res.\"  186, \"Evaluation of on- and off-line bioluminescence tomography system for focal irradiation guidance.\" 592 (2016)","DOI":"10.1667\/RR14423.1"},{"key":"19","doi-asserted-by":"crossref","unstructured":"J Shi, TS Udayakumar, K Xu, et al.  \"Int J Radiat Oncol Biology Phys.\"  102, \"Bioluminescence tomography guided small-animal radiation therapy and tumor response assessment.\" (2018)","DOI":"10.1016\/j.ijrobp.2018.01.068"},{"key":"20","doi-asserted-by":"crossref","unstructured":"J Yu, B Zhang, II Iordachita, et al.  \"Med Phys.\"  43, \"Systematic study of target localization for bioluminescence tomography guided radiation therapy.\" (2016)","DOI":"10.1118\/1.4947481"},{"key":"21","doi-asserted-by":"crossref","unstructured":"RL Siegel, KD Miller, HE Fuchs, et al.  \"Ca Cancer J Clin.\"  71, \"Cancer statistics, 2021.\" 7 (2021)","DOI":"10.3322\/caac.21654"},{"key":"22","doi-asserted-by":"crossref","unstructured":"M Scorsetti, T Comito, E Clerici, et al.  \"Radiat Oncol.\"  13, \"Phase II trial on SBRT for unresectable liver metastases: long-term outcome and prognostic factors of survival after 5 years of follow-up.\" 234 (2018)","DOI":"10.1186\/s13014-018-1185-9"},{"key":"23","doi-asserted-by":"crossref","unstructured":"D von Reibnitz, F Shaikh, AJ Wu, et al.  \"Acta Oncol.\"  57, \"Stereotactic body radiation therapy (SBRT) improves local control and overall survival compared to conventionally fractionated radiation for stage I non-small cell lung cancer (NSCLC).\" 1 (2018)","DOI":"10.1080\/0284186X.2018.1481292"},{"key":"24","doi-asserted-by":"crossref","unstructured":"J Jung, SM Yoon, J Park, et al.  \"Plos One.\"  14, \"Stereotactic body radiation therapy for locally advanced pancreatic cancer.\" e0214970 (2019)","DOI":"10.1371\/journal.pone.0214970"},{"key":"25","doi-asserted-by":"crossref","unstructured":"R Clarkson, PE Lindsay, S Ansell, et al.  \"Med Phys.\"  38, \"Characterization of image quality and image-guidance performance of a preclinical microirradiator.\" (2011)","DOI":"10.1118\/1.3533947"},{"key":"26","doi-asserted-by":"crossref","unstructured":"SJ van Hoof, PV Granton, F Verhaegen,  \"Radiother Oncol.\"  109, \"Development and validation of a treatment planning system for small animal radiotherapy: SmART-Plan.\" (2013)","DOI":"10.1016\/j.radonc.2013.10.003"},{"key":"27","doi-asserted-by":"crossref","unstructured":"K Ray, K Hudak, D Citrin, et al.  \"Biomarkers in toxicology.\"  \"Chapter 39 - Biomarkers radiation injury and response.\" (2014)","DOI":"10.1016\/B978-0-12-404630-6.00039-7"},{"key":"28","doi-asserted-by":"crossref","unstructured":"NM Byrne, P Tambe, JA Coulter,  \"J Personalized Medicine.\"  11, \"Radiation Response in the tumour microenvironment: predictive biomarkers and future perspectives.\" 53 (2021)","DOI":"10.3390\/jpm11010053"},{"key":"29","doi-asserted-by":"crossref","unstructured":"CM Ma, CW Coffey, LA DeWerd, et al.  \"Med Phys.\"  28, \"AAPM protocol for 40\u2013300 kV x-ray beam dosimetry in radiotherapy and radiobiology.\" (2001)","DOI":"10.1118\/1.1374247"},{"key":"30","doi-asserted-by":"crossref","unstructured":"JC Tiffen, CG Bailey, C Ng, et al.  \"Mol Cancer.\"  9, \"Luciferase expression and bioluminescence does not affect tumor cell growth in vitro or in vivo.\" 299 (2010)","DOI":"10.1186\/1476-4598-9-299"},{"key":"31","doi-asserted-by":"crossref","unstructured":"B Rubio-Viqueira, A Jimeno, G Cusatis, et al.  \"Clin Cancer Res.\"  12, \"An in vivo platform for translational drug development in pancreatic cancer.\" (2006)","DOI":"10.1158\/1078-0432.CCR-06-0113"},{"key":"32","doi-asserted-by":"crossref","unstructured":"AS Crystal, AT Shaw, LV Sequist, et al.  \"Science.\"  346, \"Patient-derived models of acquired resistance can identify effective drug combinations for cancer.\" (2014)","DOI":"10.1126\/science.1254721"},{"key":"33","doi-asserted-by":"crossref","unstructured":"JB. Little,  \"Hematology Oncol Clin North Am.\"  7, \"Cellular, Molecular, and carcinogenic effects of radiation.\" (1993)","DOI":"10.1016\/S0889-8588(18)30244-2"},{"key":"34","doi-asserted-by":"crossref","unstructured":"JM Straub, J New, CD Hamilton, et al.  \"J Cancer Res Clin.\"  141, \"Radiation-induced fibrosis: mechanisms and implications for therapy.\" (2015)","DOI":"10.1007\/s00432-015-1974-6"},{"key":"35","doi-asserted-by":"crossref","unstructured":"R Tuli, A Surmak, J Reyes, et al.  \"Transl Oncol.\"  5, \"Development of a novel preclinical pancreatic cancer research model: bioluminescence image- guided focal irradiation and tumor monitoring of orthotopic xenografts.\" 77 (2012)","DOI":"10.1593\/tlo.11316"},{"key":"36","doi-asserted-by":"crossref","unstructured":"J Bolcaen, B Descamps, K Deblaere, et al.  \"J Neurooncol.\"  120, \"MRI-guided 3D conformal arc micro-irradiation of a F98 glioblastoma rat model using the small animal radiation research platform (SARRP).\" (2014)","DOI":"10.1007\/s11060-014-1552-9"},{"key":"37","doi-asserted-by":"crossref","unstructured":"M-S Kim, W Kim, IH Park, et al.  \"Radiat Oncol J.\"  33, \"Radiobiological mechanisms of stereotactic body radiation therapy and stereotactic radiation surgery.\" (2015)","DOI":"10.3857\/roj.2015.33.4.265"},{"key":"38","doi-asserted-by":"crossref","unstructured":"KJ McKelvey, AL Hudson, M Back, et al.  \"Mamm Genome.\"  29, \"Radiation, inflammation and the immune response in cancer.\" (2018)","DOI":"10.1007\/s00335-018-9777-0"},{"key":"39","doi-asserted-by":"crossref","unstructured":"E Taylor, J Zhou, P Lindsay, et al.  \"Sci Rep-uk.\"  10, \"Quantifying reoxygenation in pancreatic cancer during stereotactic body radiotherapy.\" 1638 (2020)","DOI":"10.1038\/s41598-019-57364-0"},{"key":"40","doi-asserted-by":"crossref","unstructured":"LS Davis, M Sackler, RI Brezinschek, et al.  \"Am J Pathology.\"  160, \"Inflammation, immune reactivity, and angiogenesis in a severe combined immunodeficiency model of rheumatoid arthritis.\" (2002)","DOI":"10.1016\/S0002-9440(10)64379-9"},{"key":"41","doi-asserted-by":"crossref","unstructured":"M Suker, JJ Nuyttens, FALM Eskens, et al.  \"Eclinicalmedicine.\"  17, \"Efficacy and feasibility of stereotactic radiotherapy after folfirinox in patients with locally advanced pancreatic cancer (LAPC-1 trial).\" 100200 (2019)","DOI":"10.1016\/j.eclinm.2019.10.013"},{"key":"42","doi-asserted-by":"crossref","unstructured":"L Jones, J Richmond, K Evans, et al.  \"Clin Cancer Res.\"  23, \"Bioluminescence Imaging Enhances Analysis of Drug Responses in a Patient-Derived Xenograft Model of Pediatric ALL.\" (2017)","DOI":"10.1158\/1078-0432.CCR-16-2392"},{"key":"43","doi-asserted-by":"crossref","unstructured":"M Zabala, P Alzuguren, C Benavides, et al.  \"Mol Cancer.\"  8, \"Evaluation of bioluminescent imaging for noninvasive monitoring of colorectal cancer progression in the liver and its response to immunogene therapy.\" 2 (2009)","DOI":"10.1186\/1476-4598-8-2"},{"key":"44","doi-asserted-by":"crossref","unstructured":"A Rehemtulla, LD Stegman, SJ Cardozo, et al.  \"Neoplasia.\"  2, \"Rapid and quantitative assessment of cancer treatment response using in vivo bioluminescence imaging.\" (2000)","DOI":"10.1038\/sj.neo.7900121"},{"key":"45","doi-asserted-by":"crossref","unstructured":"O Lamid-Ochir, T Nakajima, M Miyazaki, et al.  \"J Vasc Interv Radiol.\"  29, \"Bioluminescence Image as a quantitative imaging biomarker for preclinical evaluation of cryoablation in a murine model.\" (2018)","DOI":"10.1016\/j.jvir.2018.03.013"},{"key":"46","doi-asserted-by":"crossref","unstructured":"J-B Kim, K Urban, E Cochran, et al.  \"Plos One.\"  5, \"Noninvasive detection of a small number of bioluminescent cancer cells in vivo.\" e9364 (2010)","DOI":"10.1371\/journal.pone.0009364"},{"key":"47","doi-asserted-by":"crossref","unstructured":"S Chin, CL Eccles, A McWilliam, et al.  \"J Med Imag Radiat On.\"  64, \"Magnetic resonance-guided radiation therapy: A review.\" (2020)","DOI":"10.1111\/1754-9485.12968"},{"key":"48","doi-asserted-by":"crossref","unstructured":"SM Bentzen  and V Gregoire  \"Semin Radiat Oncol.\"  21, \"Molecular imaging-based dose painting: A novel paradigm for radiation therapy prescription.\" (2011)","DOI":"10.1016\/j.semradonc.2010.10.001"},{"key":"49","doi-asserted-by":"crossref","unstructured":"M Cremonesi, L Gilardi, ME Ferrari, et al.  \"Eur J Nucl Med Mol I.\"  44, \"Role of interim 18F-FDG-PET\/CT for the early prediction of clinical outcomes of non-small cell lung cancer (NSCLC) during radiotherapy or chemo-radiotherapy. A systematic review.\" (2017)","DOI":"10.1007\/s00259-017-3762-9"},{"key":"50","doi-asserted-by":"crossref","unstructured":"M Unterrainer, C Eze, H Ilhan, et al.  \"Radiat Oncol.\"  15, \"Recent advances of PET imaging in clinical radiation oncology.\" 88 (2020)","DOI":"10.1186\/s13014-020-01519-1"},{"key":"51","doi-asserted-by":"crossref","unstructured":"N Boute, P Lowe, S Berger, et al.  \"Front Pharmacol.\"  7, \"NanoLuc luciferase \u2013 a multifunctional tool for high throughput antibody screening.\" 27 (2016)","DOI":"10.3389\/fphar.2016.00027"},{"key":"52","doi-asserted-by":"crossref","unstructured":"X-J Han, L-F Sun, Y Nishiyama, et al.  \"Plos One.\"  8, \"Theranostic protein targeting ErbB2 for bioluminescence imaging and therapy for cancer.\" e75288 (2013)","DOI":"10.1371\/journal.pone.0075288"},{"key":"53","doi-asserted-by":"crossref","unstructured":"H Dehghani, SC Davis, BW Pogue,  \"Med Phys.\"  35, \"Spectrally resolved bioluminescence tomography using the reciprocity approach.\" (2008)","DOI":"10.1118\/1.2982138"}],"container-title":["Radiation Research"],"original-title":[],"link":[{"URL":"https:\/\/meridian.allenpress.com\/radiation-research\/article-pdf\/doi\/10.1667\/RADE-21-00161.1\/3018311\/10.1667_rade-21-00161.1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/meridian.allenpress.com\/radiation-research\/article-pdf\/doi\/10.1667\/RADE-21-00161.1\/3018311\/10.1667_rade-21-00161.1.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T07:45:27Z","timestamp":1793432727000},"score":1,"resource":{"primary":{"URL":"https:\/\/bioone.org\/journals\/radiation-research\/volume-197\/issue-6\/RADE-21-00161.1\/Assessing-the-Accuracy-of-Bioluminescence-Image-Guided-Stereotactic-Body-Radiation\/10.1667\/RADE-21-00161.1.full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,22]]},"references-count":53,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6,1]]}},"URL":"https:\/\/doi.org\/10.1667\/rade-21-00161.1","relation":{},"ISSN":["0033-7587","1938-5404"],"issn-type":[{"value":"0033-7587","type":"print"},{"value":"1938-5404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,22]]}}}