Automated in Vivo Assessment of Vascular Response to Radiation Using a Hybrid Theranostic X-Ray Irradiator/Fluorescence Molecular Imaging System

Hypofractionated stereotactic body radiotherapy treatments (SBRT) have demonstrated impressive results for the treatment of a variety of solid tumors. The role of tumor supporting vasculature damage in treatment outcome for SBRT has been intensely debated and studied. Fast, non-invasive, longitudinal assessments of tumor vasculature would allow for thorough investigations of vascular changes correlated with SBRT treatment response. In this paper, we present a novel theranostic system which incorporates a fluorescence molecular imager into a commercial, preclinical, microCT-guided, irradiator and was designed to quantify tumor vascular response (TVR) to targeted radiotherapy. This system overcomes the limitations of single-timepoint imaging modalities by longitudinally assessing spatiotemporal differences in intravenously-injected ICG kinetics in tumors before and after high-dose radiation. Changes in ICG kinetics were rapidly quantified by principle component (PC) analysis before and two days after 10 Gy targeted tumor irradiation. A classifier algorithm based on PC data clustering identified pixels with TVR. Results show that two days after treatment, a significant delay in ICG clearance as measured by exponential decay (40.5± 16.1% P = 0.0405 Paired t-test n = 4) was observed. Changes in the mean normalized first and second PC feature pixel values (PC1 & PC2) were found (P = 0.0559, 0.0432 paired t-test), suggesting PC based analysis accurately detects changes in ICG kinetics. The PC based classification algorithm yielded spatially-resolved TVR maps. Our first-of-its-kind theranostic system, allowing automated assessment of TVR to SBRT, will be used to better understand the role of tumor perfusion in metastasis and local control.

[1]  E M Sevick-Muraca,et al.  Translation of near-infrared fluorescence imaging technologies: emerging clinical applications. , 2012, Annual review of medicine.

[2]  E. Keller,et al.  Estimation of Cerebral Oxygenation and Hemodynamics in Cerebral Vasospasm Using Indocyaningreen Dye Dilution and Near Infrared Spectroscopy: A Case Report , 2001, Journal of neurosurgical anesthesiology.

[3]  V. Ntziachristos,et al.  Concurrent MRI and diffuse optical tomography of breast after indocyanine green enhancement. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[4]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[5]  Kuldip K. Paliwal,et al.  Feature extraction and dimensionality reduction algorithms and their applications in vowel recognition , 2003, Pattern Recognit..

[6]  Kevin Welsher,et al.  Deep-tissue anatomical imaging of mice using carbon nanotube fluorophores in the second near-infrared window , 2011, Proceedings of the National Academy of Sciences.

[7]  Paul A. Dayton,et al.  Early Assessment of Tumor Response to Radiation Therapy using High-Resolution Quantitative Microvascular Ultrasound Imaging , 2018, Theranostics.

[8]  K. D. Castle,et al.  Establishing the Impact of Vascular Damage on Tumor Response to High-Dose Radiation Therapy. , 2019, Cancer research.

[9]  E. Hillman,et al.  All-optical anatomical co-registration for molecular imaging of small animals using dynamic contrast. , 2007, Nature photonics.

[10]  David T Delpy,et al.  Theoretical investigation of measuring cerebral blood flow in the adult human head using bolus Indocyanine Green injection and near-infrared spectroscopy. , 2007, Applied optics.

[11]  Albert C Koong,et al.  High-dose single-fraction radiotherapy: exploiting a new biology? , 2008, International journal of radiation oncology, biology, physics.

[12]  Shuo Diao,et al.  Through-skull fluorescence imaging of the brain in a new near-infrared window , 2014, Nature Photonics.

[13]  Edward E Graves,et al.  Imaging radiation response in tumor and normal tissue. , 2015, American journal of nuclear medicine and molecular imaging.

[14]  W Budach,et al.  Impact of stromal sensitivity on radiation response of tumors. , 1993, Journal of the National Cancer Institute.

[15]  Per B. Brockhoff,et al.  Confidence ellipses: A variation based on parametric bootstrapping applicable on Multiple Factor Analysis results for rapid graphical evaluation , 2012 .

[16]  Ravindra Uppaluri,et al.  Comparative Analysis of Tumor-Infiltrating Lymphocytes in a Syngeneic Mouse Model of Oral Cancer , 2012, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[17]  Robert J. Griffin,et al.  Indirect Tumor Cell Death After High-Dose Hypofractionated Irradiation: Implications for Stereotactic Body Radiation Therapy and Stereotactic Radiation Surgery. , 2015, International journal of radiation oncology, biology, physics.

[18]  Evis Sala,et al.  Dynamic contrast-enhanced MRI as a predictor of tumour response to radiotherapy. , 2007, The Lancet. Oncology.

[19]  Chulhee Choi,et al.  Dynamic fluorescence imaging of indocyanine green for reliable and sensitive diagnosis of peripheral vascular insufficiency. , 2010, Microvascular research.

[20]  John P Kirkpatrick,et al.  A hypothesis: indirect cell death in the radiosurgery era. , 2015, International journal of radiation oncology, biology, physics.

[21]  Gultekin Gulsen,et al.  Tumor characterization in small animals using magnetic resonance-guided dynamic contrast enhanced diffuse optical tomography. , 2011, Journal of biomedical optics.

[22]  A Harvey,et al.  Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial. CHART Steering committee. , 1999, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[23]  Susanta Hui,et al.  Radiation-Induced Vascular Damage in Tumors: Implications of Vascular Damage in Ablative Hypofractionated Radiotherapy (SBRT and SRS) , 2012, Radiation research.

[24]  Robert J. Griffin,et al.  Is indirect cell death involved in response of tumors to stereotactic radiosurgery and stereotactic body radiation therapy? , 2014, International journal of radiation oncology, biology, physics.

[25]  Yuting Lin,et al.  Quantitative fluorescence tomography using a combined tri-modality FT/DOT/XCT system , 2010, Optics express.

[26]  Shankar Siva,et al.  Mobilization of viable tumor cells into the circulation during radiation therapy. , 2014, International journal of radiation oncology, biology, physics.

[27]  I. Toma-Dasu,et al.  Radiation-induced Vascular Damage and the Impact on the Treatment Outcome of Stereotactic Body Radiotherapy , 2019, AntiCancer Research.

[28]  Robert J Griffin,et al.  Radiobiology of stereotactic body radiation therapy/stereotactic radiosurgery and the linear-quadratic model. , 2013, International journal of radiation oncology, biology, physics.

[29]  Rainer Macdonald,et al.  Detection of rheumatoid arthritis using non-specific contrast enhanced fluorescence imaging. , 2010, Academic radiology.

[30]  Shuo Diao,et al.  Near-Infrared II Fluorescence for Imaging Hindlimb Vessel Regeneration With Dynamic Tissue Perfusion Measurement , 2014, Circulation. Cardiovascular imaging.

[31]  S. Karam,et al.  Hypofractionated Radiotherapy Is Superior to Conventional Fractionation in an Orthotopic Model of Anaplastic Thyroid Cancer. , 2018, Thyroid : official journal of the American Thyroid Association.

[32]  W Budach,et al.  Re: impact of stromal sensitivity on radiation response of tumors. , 1993, Journal of the National Cancer Institute.

[33]  K. Camphausen,et al.  Radiation therapy to a primary tumor accelerates metastatic growth in mice. , 2001, Cancer research.

[34]  R. Leahy,et al.  Digimouse: a 3D whole body mouse atlas from CT and cryosection data , 2007, Physics in medicine and biology.

[35]  J. Frangioni In vivo near-infrared fluorescence imaging. , 2003, Current opinion in chemical biology.

[36]  David J Brenner,et al.  The tumor radiobiology of SRS and SBRT: are more than the 5 Rs involved? , 2014, International journal of radiation oncology, biology, physics.

[37]  Oliver T. Bruns,et al.  Next-generation in vivo optical imaging with short-wave infrared quantum dots , 2017, Nature Biomedical Engineering.

[38]  Chulhee Choi,et al.  Principal component analysis of dynamic fluorescence images for diagnosis of diabetic vasculopathy , 2016, Journal of biomedical optics.

[39]  Vasilis Ntziachristos,et al.  Spatiotemporal analysis for indocyanine green-aided imaging of rheumatoid arthritis in hand joints , 2013, Journal of biomedical optics.

[40]  Evis Sala,et al.  Single-dose radiotherapy disables tumor cell homologous recombination via ischemia/reperfusion injury , 2019, The Journal of clinical investigation.

[41]  Michael P. MacManus,et al.  Does the mobilization of circulating tumour cells during cancer therapy cause metastasis? , 2017, Nature Reviews Clinical Oncology.

[42]  Gultekin Gulsen,et al.  A thermo-sensitive fluorescent agent based method for excitation light leakage rejection for fluorescence molecular tomography. , 2019, Physics in medicine and biology.

[43]  Triantafyllos Stylianopoulos,et al.  Reengineering the Physical Microenvironment of Tumors to Improve Drug Delivery and Efficacy: From Mathematical Modeling to Bench to Bedside. , 2018, Trends in cancer.

[44]  Jae-Hoon Jung,et al.  Radiobiological mechanisms of stereotactic body radiation therapy and stereotactic radiation surgery , 2015, Radiation oncology journal.

[45]  Chulhee Choi,et al.  Segmental analysis of indocyanine green pharmacokinetics for the reliable diagnosis of functional vascular insufficiency. , 2011, Journal of biomedical optics.

[46]  Lixia Luo,et al.  Deletion of Atm in Tumor but not Endothelial Cells Improves Radiation Response in a Primary Mouse Model of Lung Adenocarcinoma. , 2018, Cancer research.

[47]  I-Chih Tan,et al.  Near-Infrared Fluorescence Imaging in Humans with Indocyanine Green: A Review and Update. , 2010, Open surgical oncology journal.

[48]  Ozlem Birgul,et al.  A simulation study of the variability of indocyanine green kinetics and using structural a priori information in dynamic contrast enhanced diffuse optical tomography (DCE-DOT) , 2008, Physics in medicine and biology.

[49]  C T Badea,et al.  Micro-CT of rodents: state-of-the-art and future perspectives. , 2014, Physica medica : PM : an international journal devoted to the applications of physics to medicine and biology : official journal of the Italian Association of Biomedical Physics.

[50]  H. Dvorak,et al.  Heterogeneity of the Tumor Vasculature , 2010, Seminars in thrombosis and hemostasis.

[51]  L. Liotta,et al.  Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. , 1974, Cancer research.