Yu Saida¹, Tomohiro Seki², Shun Kishimoto¹, Yasunori Otowa¹, Kota Yamashita¹, Kazutoshi Yamamoto¹, Nallathamby Devasahayam¹, Jeffrey R. Brender¹, and Murali C. Krishna^1
1Radiation Biology Branch, National Cancer Institute, Bethesda, MD, United States, ²Laboratory of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama, Japan

PEGylated human hyaluronidase (PEGPH20) has been developed to enzymatically deplete tumor hyaluronan. The purpose of this study is to investigate physiologic and metabolic changes in pancreatic adenocarcinoma xenograft after PEGPH20 treatment by using multi-modal imaging and further determine the utility of PEGPH20 as radiosensitizer. PEGPH20 significantly increased intratumor pO₂ and blood volume and decreased glycolytic flux assessed by EPRI, USPIO-MRI, and hyperpolarized ¹³C-MRI, respectively. PEGPH20 also enhanced treatment effect of radiotherapy in vivo. The results validated the utility of the imaging methods to non-invasively monitor changes in the tumor microenvironment and predicted the radiosensitizing effect upon hyaluronan depletion.

Yasunori Otowa¹, Kota Yamashita¹, Yu Saida¹, Kazutoshi Yamamoto¹, Jeffery R Brender¹, Nallathamby Devasahayam¹, Murali C. Krishna¹, and Shun Kishimoto^1
1National Cancer Institute, Bethesda, MD, United States

Combination of evofosfamide and chemotherapy suppress tumor growth than using these drugs alone. The purpose of this study is to detect physiologic changes in tumor-bearing mouse model in response to combination of evofosfamide and gemcitabine (GEM) using multi-modal imaging methods including DCE-MRI, blood volume imaging, and EPRI. Significantly increased perfusion, maintained blood volume, and maintained hypoxic fraction < 10 mmHg were observed after treatment with combination of evofosfamide and GEM. The results validate the utility of these imaging methods to non-invasively monitor changes in the tumor microenvironment after treatment.

Xiuhong Guan¹, Jiali Cai², Xiangyu Xiong¹, Hong Liu², Shihui Huang², Sheng Wang², Chuanqi Sun¹, Yi Sun³, Tianjing Zhang⁴, Guoxi Xie¹, and Zhiyong Wang^2
1Department of Biomedical Engineering, Guangzhou Medical University, Guangzhou, China, ²School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, China, ³Siemens Healthineers, Shanghai, China, ⁴Philips Healthcare, Guangzhou, China

Due to the high incidence and mortality, breast cancer has become the major cause of cancer death among female. This study reports a kind of functional nanocomposite, which was designed to comprises Pluronic P123 to self-assembly superparamagnetic iron oxide nanocrystals (SPIONs) and IR-780 dyes into one system, exhibiting NIR-II and MR dual-modal imaging guided chem-phototherapy and anti-tumor immunity against triple-negative breast cancer.

Jenny Yang¹, Mani Salarian², Hua Yang³, Shanshan Tan⁴, Oluwatosin Y Ibhagui⁴, Jingjuan Qiao⁴, Zongxiang Gui⁴, and Hans E Grossniklaus^3
1Chemistry, Georgia State University, Atlatna, GA, United States, ²Chemistry, Georgia State University, Atlanta, GA, United States, ³Emory University, Atlanta, GA, United States, ⁴Georgia State University, Atlanta, GA, United States

The liver is the most common organ for metastasis of various malignancies, especially for uveal melanoma (UM), colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). Precision medicine to chronic diseases, especially for liver cancer and metastasis, requires non-invasive precision diagnostics. Non-invasive precision imaging capable of early detection, staging and molecular subtyping/stratification of patients, is a major breakthrough. Rapid development and approval of precision medicine also requires precision imaging to evaluate drug efficacy at animal and patient levels.  There is a pressing unmet medical need to develop MRI contrast agents and imaging methodologies with desired sensitivity and specificity .

Nathaniel Kim¹, Arsen Mamakhantan¹, Kristin Granlund¹, Elisa de Stanchina², Manish Shah³, Lewis Cantley⁴, and Kayvan R. Keshari^1
1Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, United States, ²Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States, ³Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY, United States, ⁴Meyer Cancer Center, Department of Medicine, Well Cornell Medical College, New York, NY, United States

We investigated hyperpolarized [1-¹³C] dehydroascorbic acid (HP DHA) as an imaging agent for probing oxidative stress in patient derived xenograft models (PDXs) of pancreatic cancer. By increasing the T₁ via D­₂O solvation and increasing the dose administered via awake mouse injection, conversion of DHA to ascorbate was readily observed in KRAS and BRCA mutant cancers. HP DHA was then used to characterize oxidative stress in these PDX models and their biochemical mechanism of response to ascorbate therapy. Changes in DHA/ascorbate metabolism were measured in these tumor models, demonstrating a proof of concept method for assessing ascorbate therapy in pancreatic cancer.

Nan Wang¹, Jingjuan Qiao², Zhijun Wang³, Pei Han^1,4, Hsu-Lei Lee¹, Sen Ma¹, Hui Han¹, Zhaoyang Fan¹, Anthony G. Christodoulou¹, Ekihiro Seki³, Stephen Pandol⁵, Debiao Li¹, Jenny Yang², and Yibin Xie^1
1Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States, ²Chemistry Department, Georgia State University, Atlanta, GA, United States, ³Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States, ⁴Bioengineering, University of California, Los Angeles, Los Angeles, CA, United States, ⁵Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, United States

MRI is a promising tool for the non-invasive study of animal model, but continues to face technical challenges. In this work, a Multitasking T1-T2 mapping technique was proposed for mouse abdominal imaging on 3T, which achieved 3D coverage, motion-resolved acquisition, and simultaneous T1 T2 mapping within 10 minutes. The study was performed on a murine model with liver metastasis of colorectal cancer. Data at multiple time points after tumor injection were acquired with different contrast agent, Eovist and ProCA.collagen1. The results demonstrated that 10-min Multitasking technique produced improved images with clear tumor delineation compared to conventional MRI series (50 minutes).

Stefan Markovic¹, Tangi Roussel², Keren Sasson³, Dina Preise³, Lilach Agemi³, Avigdor Scherz³, and Lucio Frydman^1
1Department of Chemical and Biological Physics, Weizmann Institute of Science, Rehovot, Israel, ²Center for Magnetic Resonance in Biology and Medicine, Marseille, France, ³The Moross Integrated Cancer Research Center, Weizmann Institute of Science, Rehovot, Israel

Deuterium Metabolic Imaging (DMI) was used to follow metabolism in two pancreatic cancer mouse models, after tail-vein administration of ²H_6,6’-glucose.  Metabolic maps for the glucose and for its metabolic products ²H_3,3’-lactate and ²H-water were measured over a time course of 2 h by 2H chemical shift imaging (CSI) at 15.2 T. Abdominal images exhibited sharp and specific lactate signals, which generated exclusively in the tumors. Thus, DMI may open valuable opportunities for non-invasively imaging pancreatic cancer –including its diagnosis and treatment.

Lawrence Lechuga¹, Sean B Fain^1,2,3,4, Christian M Capitini^3,4,5, and Matthew H Forsberg^5
1Medical Physics, University of Wisconsin, Madison, Madison, WI, United States, ²Radiology, University of Wisconsin, Madison, Madison, WI, United States, ³Biomedical Engineering, University of Wisconsin, Madison, Madison, WI, United States, ⁴Carbone Cancer Center, University of Wisconsin, Madison, Madison, WI, United States, ⁵Pediatrics, University of Wisconsin, Madison, Madison, WI, United States

Fluorine-19 (¹⁹F) MRI can monitor various cell types in vivo for days to weeks after injection of 1⁹F-labeled cells. To establish cell viability Green Fluorescent Protein (GFP+) murine natural killer (NK) cells were labeled ex vivo using red-fluorescent perfluoropolyether (PFPE-red) and delivered intratumorally into 3 lymphoma-bearing mice. Flow cytometry validated that the infused NK cells retain their ¹⁹F label out to 6 days post-injection (PI). Cells were then tracked and quantified via ¹H/¹⁹F MRI out to 6 days PI. Quantification of the infused cells indicate 87% and 70% were detectible at days 0 and 6, respectively. 

Qi Qi^1,2,3, Matthew Fox^1,4, Robert Bartha^2,5,6, Miranda Bellyou⁵, Lise Desjardins⁷, Lisa Hoffman^1,2,8, Alex Li⁵, Andrew McClennan^1,2, Ting Yim Lee^1,2,3,5,6, and Jonathan D Thiessen^1,2,3,6
1Lawson Imaging, Lawson Health Research Institute, London, ON, Canada, ²Medical Biophysics, Western University, London, ON, Canada, ³Molecular Imaging, Western University, London, ON, Canada, ⁴Physics and Astronomy, Western University, London, ON, Canada, ⁵Robart Research Institute, London, ON, Canada, ⁶Medical Imaging, Western University, London, ON, Canada, ⁷Lawson Health Research Institute, London, ON, Canada, ⁸Anatomy and Cell Biology, Western University, London, ON, Canada

There is an intrinsic relationship between tumour glycolysis and its pH environment. CEST MRI enables the detection of tumour pH in both intra- (pH_i) and extracellular (pH_e) spaces with AACID and acidoCEST methods. Kinetic analysis of dynamic FDG-PET can provide an accurate measurement of tumour glycolysis. This study demonstrates the capability of simultaneous measurements of pH_i and pH_e using CEST MRI, providing a more complete picture of the tumour pH environment, and explores the intrinsic relationship between tumour glycolysis and its pH environment.

Donghyun Hong¹, Georgios Batsios¹, Pavithra Viswanath¹, Anne Marie Gillespie¹, Russell O Pieper^2,3, Joseph Costello², and Sabrina M Ronen ^1,3
1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States, ²Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, United States, ³Brain Tumor Research Center, University of California San Francisco, San Francisco, CA, United States

Mutant IDH1 inhibitor treatment is currently in clinical trials for glioma patients. However, to date, treatment does not result in tumor shrinkage. Therefore, in vivo biomarkers are needed to assess early therapeutic response. Here we treated mutant IDH1-expressing cells with the emerging inhibitor BAY-1436032. Using ¹H MRS we found a significant decrease in 2-hydroxyglutarate that was accompanied by an increase in glutamate and phosphocholine, and using ¹³C MRS we detected a significant increase in glutamate produced from hyperpolarized [1-¹³C]α-ketoglutarate.

Vanessa L. Franke¹, Justyna Platek¹, Philip S. Boyd¹, Stephanie Laier², Karin Mueller-Decker², Andrey Glinka³, Mark E. Ladd¹, Steffen Goerke¹, Peter Bachert¹, and Andreas Korzowski^1
1Division of Medical Physics in Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany, ²Center for Preclinical Research, Core Facility Tumor Models, German Cancer Research Center (DKFZ), Heidelberg, Germany, ³Division of Molecular Embryology, German Cancer Research Center (DKFZ), Heidelberg, Germany

³¹P MRSI allows for the non-invasive investigation of energy metabolism in vivo and is therewith of interest for research on novel therapies for cancer. The purpose of this study was to investigate suitable acquisition strategies for ³¹P MRSI in tumor-bearing mice at B₀=9.4T in order to monitor in future studies effects of novel therapies affecting energy metabolism and pH values. ³¹P MRSI datasets with a spatial resolution of (2.5x2.5x7.5) mm³ obtained in 50 minutes enabled the quantification of signals in diseased tissue, while maintaining acceptable separation to healthy tissue.

Emma L. Reeves¹, Jin Li^1,2, Konstantinos Zormpas-Petridis¹, Jessica K. R. Boult¹, James Sullivan^1,3, Craig Cummings¹, Barbara Blouw⁴, David Kang⁴, Ralph Sinkus⁵, Yann Jamin¹, Jeffrey C. Bamber¹, and Simon P. Robinson^1
1Radiotherapy & Imaging, Institute of Cancer Research, London, United Kingdom, ²Institutes of Brain Science, Fudan University, Shanghai, China, ³Royal Marsden NHS Foundation Trust, Sutton, United Kingdom, ⁴Halozyme Therapeutics, San Diego, CA, United States, ⁵Division of Imaging Sciences and Biomedical Engineering, King's Health Partners, St Thomas's Hospital, London, United Kingdom

We hypothesised that hyaluronan (HA) degradation by PEGPH20 may alter tumour viscoelasticity measured by MR elastography (MRE). MRE was performed before and after PEGPH20 in three orthotopic breast tumour models (4T1, 4T1/HAS3 and MDA-MB-231 LM2-4). Viscoelastic properties did not change following PEGPH20 in 4T1 and 4T1/HAS3 tumours. However, a dramatic PEGPH20-induced increase in tumour viscoelasticity was seen in MDA-MB-231 LM2-4 tumours, likely the result of collagen network rearrangement and not HA degradation alone. Although MRE is unlikely to provide a robust biomarker of PEGPH20 response, these data clearly demonstrate that MRE-derived biomarkers can inform on increased tumour stiffness in vivo.

Deepti Upadhyay¹, Jinny Sun¹, Joao Piraquive Agudelo¹, Hongjuan Zhao², Rosalie Nolley², Robert Bok¹, James D. Brooks², Donna M. Peehl¹, John Kurhanewicz¹, and Renuka Sriram^1
1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States, ²Department of Urology, Stanford University, Stanford, CA, United States

NMR based stable isotope resolved metabolomics was used for the metabolic characterization of renal cell carcinoma (RCC) patient-derived xenografts (PDXs) and their derived tissue slice cultures (TSCs). Targeted metabolomics and [U-¹³C] glucose-labeling studies indicate metabolic heterogeneity among PDXs of various pathologic and clinical stages. Both PDXs and TSCs exhibit high glycolytic rate and low TCA activity characteristic of RCC. However, there is variability in glycolytic rate and TCA activity among different PDXs and their corresponding TSCs.

Abdullah Bas¹, Banu Sacli-Bilmez¹, Gokce Hale Hatay¹, Alpay Ozcan^2,3, Cansu Levi⁴, Ayca Ersen Danyeli^3,5, Ozge Can^3,6, Cengiz Yakicier^3,7, M.Necmettin Pamir^3,8, Koray Ozduman^3,8, Alp Dincer^3,9, and Esin Ozturk-Isik^1,3
1Institute of Biomedical Engineering, Bogazici University, İstanbul, Turkey, ²Electrical and Electronics Engineering, Bogazici University, Istanbul, Turkey, ³Center for Neuroradiological Applications and Reseach, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey, ⁴Department of Medical Biochemistry, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey, ⁵Department of Medical Pathology, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey, ⁶Department of Medical Engineering, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey, ⁷Department of Molecular Biology and Genetics, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey, ⁸Department of Neurosurgery, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey, ⁹Department of Radiology, Acıbadem Mehmet Ali Aydinlar University, Istanbul, Turkey

Glioma Genetic Diagnosis Software, a clinical decision support tool for non-invasive detection of isocitrate dehydrogenase (IDH) and telomerase reverse transcriptase promoter (TERTp) mutations in gliomas using proton magnetic resonance spectroscopy (1H-MRS) and liquid chromatography-mass spectrometry (LC-MS/MS), was developed in this study. The machine-learning models were trained with the data of 237 gliomas. IDH mutation was identified with 87.04% and of 92.70% accuracies,  and TERTp mutation in IDH wildtype gliomas was identified with 87.53% and 85.96% accuracies, using 1H-MRS and MS, respectively. The software provides data visualization and enables the users to train their own models.

Jessica K.R. Boult¹, Mahmoud El Shemerly², Felix Bachmann², Laurenz Kellenberger², Heidi Lane², Paul McSheehy², and Simon P. Robinson^1
1The Institute of Cancer Research, Sutton, United Kingdom, ²Basilea Pharmaceutica International Ltd, Basel 4005, Switzerland

Derazantinib (DZB), a FGFR inhibitor, has displayed potential anti-angiogenic effects in biochemical assays. In this study, we used in vitro and in vivo assays to explore this activity. Proliferation of human umbilical vein endothelial cells, their pVEGFR expression and downstream signalling, and vascular permeability in mouse skin are dose-dependently supressed by DZB. Susceptibility-contrast MRI using ferumoxytol demonstrated a reduction in fractional blood volume in subcutaneous colorectal cancer xenografts treated with DZB for 48h. This anti-angiogenic effect may be a relevant component of the activity of DZB in tumours bearing FGFR aberrations and may facilitate clinical activity against other solid tumours.

Sourav Bhaduri¹, Samantha Mills², Mark Radon², Michael Jenkinson³, and Harish Poptani^1
1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom, ²Department of Neuroradiology, The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom, ³Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom

We demonstrate the potential utility of DCE-MRI derived pharmacokinetic parameters in differentiating brain tumour types using the extended Tofts and the Shutter Speed Model. Results show an increasing pattern in K^trans, v_e, v_p estimates in GBM and metastasis compared to primary central nervous system lymphoma (PCNSL). The τ_i estimate in GBM was the lowest, while it was highest in PCNSL.

Jonghyun Bae^1,2,3, Zhengnan Huang^1,2,3, Florian Knoll^2,3, Krzysztof Geras^2,3, Terlika Sood^2,3, Laura Heacock^2,3, Linda Moy^2,3, Li Feng⁴, and Sungheon Gene Kim^5
1NYU School of Medicine, New York, NY, United States, ²Center for Advanced Imaging Innovation and Research, New York, NY, United States, ³Center for Biomedical Imaging, NYU, New York, NY, United States, ⁴Icahn School of Medicine at Mount Sinai, New York, NY, United States, ⁵Weill Cornell Medicine, New York, NY, United States

This study proposes a deep learning approach to estimate the capillary level input function(CIF) for contrast kinetic model analysis of dynamic contrast enhanced (DCE)-MRI data. Estimation of the CIF for each voxel eliminates the need for the arterial input function and allows automatic end-to-end analysis. We hypothesize that the CIF serves as a more accurate input function that could yield accurate kinetic parameter estimation, which can be used for the diagnosis between the malignant and the benign cancer in the clinical setting. This hypothesis has been tested with a numerical simulation and breast MRI data from an abbreviated exam.

Santosh Kumar Bharti¹, Raj Kumar Sharma¹, Paul T Winnard¹, Marie-France Penet¹, and Zaver M. Bhujwalla^1,2,3
1Div. of Cancer Imaging Research, The Russell H. Morgan Dept of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States, ²Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, United States, ³Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, United States

In addition to anorexia, fat and muscle tissue wasting, psychological distress, lower tolerance to chemotherapy, and a poor quality of life, cachexia causes profound metabolic dysregulation in cancer patients that affects multiple organs. Here, for the first time, we have characterized metabolic changes in the spleen, liver, pancreas, lung, heart and kidney induced by pancreatic cancer xenografts to expand our understanding of the metabolic dysregulation caused by cachexia. These results highlight the systemic changes in metabolism that occur with cancer and with cancer induced cachexia that may lead to the development of early biomarkers as well to metabolic treatment strategies.   

Dadi Zhao^1,2, James T. Grist^1,2, Heather E.L. Rose^1,2, Yu Sun^1,2, and Andrew C. Peet^1,2
1Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom, ²Department of Oncology, Birmingham Children's Hospital, Birmingham, United Kingdom

Classifying imbalance childhood brain tumours through ¹H-MRS metabolite profiles remains a challenging problem. We presented an alternative oversampling method, wavelet oversampling (WvOS). Different from the classic Synthetic Minority Oversampling TEchnique that oversamples the metabolite profiles, WvOS used the wavelet processed ¹H-MRS as the oversampled ¹H-MRS, followed by quantification and classification. As the result, WvOS can provide dramatically better classification performance than non-oversampled or classic oversampled metabolite profiles. An optimal balanced classification accuracy is achieved as 96% and 72% from 84% and 52% for the 1.5T and 3T cohorts of childhood brain tumours, respectively.

Farzad Alizadeh^1,2, Anahita Fathi Kazerooni^3,4, Hanieh Bahrampour⁵, Hanieh Mobarak Salari^1,2, and Hamidreza Saligheh Rad^1,2
1Department of Medical Physics and Biomedical Engineering, Tehran university of Medical Science, Tehran, Iran (Islamic Republic of), ²Quantitative MR Imaging and Spectroscopy Group, Research Center for Molecular and Cellular Imaging, Tehran, Iran (Islamic Republic of), ³Center for Biomedical Image Computing and Analytics (CBICA), University of Pennsylvania, Philadelphia, PA, United States, ⁴Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States, ⁵Biomaterials Engineering, School of Metallurgy and Materials Engineering, Iran University of Science and Technology, Tehran, Iran (Islamic Republic of)

Characterization of intra-tumour subregions in diffuse gliomas helps to guide biopsy procedure and to determine extent of tumour infiltration in the brain tissues. Conventional MRI cannot accurately differentiate intra-tumour subregions, including the most active tumour component and infiltrated edema (IE) from each other and from the normal tissue (NT).  In this work, we explore the potential of differentiation of brain tumorous tissue subregions (tumour core, infiltrated edema, normal tissue, bone, and non-brain areas) based on 1H-MRS data using artificial intelligence (AI) techniques.