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1   Sharath Bhagavatula, MD Brigham and Women's Hospital GE Healthcare/RSNA Research Scholar Grant (2023 - 2025) Development of Superparamagnetic Iron-Oxide Nanoparticle (SPIO-NP)-Enhanced Microwave Ablation   Abstract:   Percutaneous microwave ablation (MWA) is used to focally treat cancers. However, it generates indiscriminate killing of tumor and non-tumor tissues, which can result in severe complications or incomplete treatment. Here we propose using superparamagnetic iron-oxide nanoparticles (SPIO-NPs) to ‘prime’ tumors for more selective and effective ablation. SPIO-NPs are approved as MRI contrast agents (e.g., Feraheme) and have been shown to enhance microwave energy absorption/heating. They can be injected percutaneously or delivered intravenously with prolonged blood-pool phase, during which high tumor-to-background tissue uptake can be achieved. They have been shown to promote immunogenic cell death, and could enhance MWA anti-tumoral immune effects. Further work is needed to investigate SPIO-NP/MWA thermal and immune synergy, including optimizing intra-tumoral SPIO-NP delivery and conducting animal studies. Our proposal will address these next steps in murine tumor models: In Aim 1, we will identify an optimal SPIO-NP delivery strategy that maximizes tumor-to-background uptake in-vivo. In Aim 2, we will systematically test whether optimally delivered SPIO-NPs enhance MWA heating/killing of tumors relative to common background tissues, using MR thermometry and histopathology. In Aim 3, we will use a powerful, recently-developed spatial analysis method to comprehensively evaluate local and distant (abscopal) MWA-induced immune effects with and without SPIO-NPs. In this study, we expect to demonstrate feasibility of SPIO-NPs to improve MWA by providing thermal and immune synergy. We also expect to generate preliminary data for more ambitious long-term proposals. For example, 1-as SPIO-NPs and MWA are FDA-approved, successful results would support a clinical trial; 2-more tailored SPIO-NP formulations and MWA systems can be developed; and 3-Aim 3 could generate new mechanistic insights into how MWA can be better utilized to enhance immunotherapies. Our team has multidisciplinary expertise in MWA, tumor biology, immuno-oncology, nanomedicine, and MR physics, with the infrastructure to realize the full potential of this treatment paradigm.   More Activities by Sharath Bhagavatula, MD 2   John Michael Bryant, MD Moffitt Cancer Center Fujifilm Medical Systems/RSNA Research Resident Grant (2024 - 2025) In Vivo Magnetoelectric Nanoparticles as a Tumor-Targeting Contrast Agent for T2 Magnetic Resonance Imaging in a Murine Pancreatic Ductal Adenocarcinoma Flank Tumor Model   Abstract:   Magnetic resonance images (MRIs) have demonstrated excellent sensitivity for many tumor types. However, determining the full extent of involvement of local soft tissues remains challenging. Inaccurate identification of these fine features may lead to inappropriate therapies at significant cost to the patient, including worse morbidity and mortality outcomes. Contrast agents have been used to improve MRI efficacy for tumor detection but usually rely on passive targeting and are not always able to fully characterize a tumor’s invading edges or small metastatic lesions. Magnetoelectric nanoparticles (MENPs) are a novel class of nanoparticles that have potential to improve diagnostic MRI efficacy. MENPs rely on their magnetoelectric effect, which allows conversion of magnetic fields into local electric fields. This enables electrostatic tumor targeting on a cellular level by taking advantage of cancer’s relative non-polarity and low electroporation threshold. Once targeted, their superparamagnetic cores act as T2 contrast agents. However, this has not been characterized in an in vivo tumor model yet. We propose to explore MENPs as tumor targeting T2 contrast agents in a pancreatic adenocarcinoma flank tumor model. Our aims include characterization of MENP signal modulation as a function of dose and time for tumors and normal tissues. To achieve this, 30 mice in five dosing cohorts will undergo one non-MENP and two MENP MRIs over the course of one week. Tumors and normal tissues will be contoured to determine mean signal intensity deltas. These data will then be plotted to determine the relationships of MENP signal modulation with dose, time, and tissue types. This work will lay the foundation for to explore in vivo MENP microscopic tumor detection and treatment effects in combination with deep neural networks. In addition, it will aid in the overall development of MENP as a theragnostic anti-cancer modality, adding to its drug-delivery and irreversible electroporation applications.   More Activities by John Michael Bryant, MD 3   Andrew Lee Chang, MD, PhD Washington University in St Louis Philips/RSNA Research Resident Grant (2024 - 2025) Interrogation of Glioblastoma Fatty Acid Metabolism With Deuterium Metabolic Imaging   Abstract:   Glioblastoma (GBM) is the most common and deadliest malignant primary brain tumor. Current standard-of-care therapy results in a modest improvement in survival, which is primarily limited by tumor recurrence and resistance to therapy. Historically, glucose metabolic imaging with F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) has fallen short in the detection of recurrent GBM due to lack of adequate sensitivity and specificity. However, studies have identified that recurrent GBM undergoes metabolic reprogramming from increased glucose metabolism to increased fatty acid uptake and metabolism, highlighting a potential metabolic Achilles’ heel. We propose that deuterium metabolic imaging (DMI) utilizing palmitate, a fatty acid, can non-invasively characterize this metabolic reprogramming in recurrent GBM. Our long-term goal is to develop a non-invasive method of selecting metabolic therapies tailored specifically to the intratumoral metabolic variants present within each GBM patient. Herein, we test the hypothesis that deuterated palmitate can be used to characterize changes in tumor fatty acid uptake and metabolism following temozolomide and radiation therapy. We will first establish proof of principle with deuterated glucose and deuterated palmitate DMI in an immunocompetent murine model of GBM. We will optimize and validate tumor uptake of intravenously infused deuterated glucose and palmitate via spatially resolved [2H] stable isotope imaging mass spectrometry. We will test the hypothesis that increased fatty acid uptake in response to conventional therapy can be measured with palmitate DMI. We will identify changes in metabolic uptake by performing DMI with deuterated palmitate in GBM murine models before and after the conventional treatment regimen of temozolomide and radiation therapy. If we can identify tumor metabolic reprogramming towards fatty acid metabolism, we may be able to utilize this information clinically to tailor targeted metabolic inhibitors to recurrent GBM to improve survival.   More Activities by Andrew Lee Chang, MD, PhD 4   Tafadzwa Chaunzwa, BEng, MS Brigham and Women's Hospital RSNA Research Resident Grant (2024 - 2025) Comprehensive AI-Driven Radiological Assessment for Non-Small Cell Lung Cancer Immunotherapy Prognostication   Abstract:   Lung cancer accounts for most cancer-related deaths worldwide. Immune checkpoint inhibitors (ICIs) have emerged as an essential pillar in managing advanced non-small cell lung cancer (NSCLC). However, a minority of patients derive long-term benefit from these therapies. Given clinical observations of infrequent but profound and durable responses to ICIs, there has been ongoing interest in developing predictive biomarkers of response. Existing methods, such as PD-L1 staining, lack sensitivity, and specificity. There is an urgent need for better tools to identify patients unlikely to respond to ICIs, which may inform efforts to intensify therapy among these patients while guiding cost-effective public health decisions. In this project, we will develop holistic and automated CT-derived biomarkers for lung cancer risk stratification and prognostication in patients with metastatic NSCLC. We will perform comprehensive radiologic assessment of the advanced NSCLC immunotherapy patient, combining tumor radiomics and body composition analysis. The core premise of the study is that radiologic surveillance with a focus on body composition and tumor characteristics stratifies NSCLC patients and has significant prognostic implications to aid clinical decision-making. Further exploratory analyses will include the discovery of radiologic markers for immune fitness predictive of response to ICIs in the context of thoracic radiotherapy for locally advanced NSCLC.   More Activities by Tafadzwa Chaunzwa, BEng, MS 5   Florence L. Chiang, MD, PhD Massachusetts General Hospital Ralph Schlaeger Charitable Foundation/RSNA Research Fellow Grant (2024 - 2025) Uncovering the Microstructural Substrate of Functional Changes Associated With Localized Gray Matter Atrophy in Multiple Sclerosis Using Ultra-High Gradient Diffusion MRI   Abstract:   Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system. Recent evidence suggests that neurodegeneration is the substrate of neurological disability in MS. Specifically, gray matter (GM) atrophy is present in all disease subtypes and is localized, the pattern of which is strongly correlated with cognitive impairment and physical disability. Standard-of-care MS therapies are currently centered on decreasing inflammation, which can reduce the severity and disability worsening in the short-term. However, long-term impact appears limited, with progressive insidious accumulation of neurological dysfunction. These findings have spurred ongoing development of neuroprotective and neuroreparative therapies. In clinical trials of putative neuroprotective agents in MS, whole-brain atrophy is currently the most widely used primary outcome measure, but volume assessment is limited to capturing overt, irreversible tissue loss. Therefore, there is a dire need for a more sensitive imaging biomarker of gray matter function to monitor disease progression. Previously, we developed the Atrophy-based Functional Network (AFN) model, which is an MS brain signature of functional network mediation in atrophy-prone GM. To assess potential for monitoring, the AFN model was implemented in resting-state fMRI of MS, which demonstrated disruption of AFN integrity as disease severity worsened. The proposed research will investigate structural underpinnings of this functional neurodegenerative pattern in MS. Specifically, ultra-high gradient diffusion MRI (dMRI) techniques will be used to probe human brain microstructure in vivo. Additionally, a novel dMRI method will be used to provide targeted cytoarchitectural characterization of GM regions in the AFN model. We will leverage synergies of recent technological advancements in MRI hardware and neuroimaging analytics to improve an understanding of neurodegeneration in MS. Findings from this study would lay the groundwork for future development of the AFN model as an imaging biomarker to advance clinical trials of MS neurotherapeutics and improve clinical care.   More Activities by Florence L. Chiang, MD, PhD 6   Jason Chiang, MD, PhD University of California, Los Angeles RSNA Research Scholar Grant (2023 - 2025) Augmenting Microwave Ablation With Supercharged NK Cell Therapy in an Oncopig Liver Tumor Model   Abstract:   Locoregional therapy, using image-guided ablation or transarterial therapy, is the treatment of choice for early to intermediate stage hepatocellular carcinoma (HCC). However, these treatments can sometimes be associated with higher rates of recurrence or local tumor progression, especially for HCCs larger than 3 cm in diameter. Immunotherapy has attracted significant attention recently as it stimulates the patient’s own immune system to recognize the tumor cells as foreign and target them for destruction. Immunotherapy has recently been adopted into standard-of-care guidelines for advanced HCC. However, the efficacy of immunotherapy for early to intermediate stage HCC remains unknown, with mixed results in pre-clinical and clinical investigations. Natural killer (NK) cells are a type of immune cell that uniquely do not rely on antigen presentation and can be leveraged to kill tumor cells upon contact. Our lab uses a new technique that allows for rapid isolation and expansion of NK cells. These “supercharged” NK cells are able to kill tumor cells at higher levels compared to normal NK cells. The goal of this project is to evaluate the feasibility of using adjuvant transcatheter-directed supercharged NK cells to augment the cytotoxic profile of microwave ablation in a novel Oncopig liver tumor model. We will be taking a step-wise approach to evaluate the feasibility of using supercharged NK cells in combination with neoadjuvant locoregional therapy to treat an in-vivo Oncopig liver tumor model. The first aim will focus on isolating NK cells from porcine PBMCs and creating sNK cells. These porcine-derived sNK cells will be tested on an Oncopig liver tumor cell line. The second aim will look at using neo-adjuvant locoregional therapy to augment the cytotoxicity of sNK cells in an immunocompetent Oncopig liver tumor model.   More Activities by Jason Chiang, MD, PhD 7   Elizabeth George, MD University of California San Francisco RSNA Research Scholar Grant (2023 - 2025) Quantitative Susceptibility Mapping of Neonatal Cerebral Oxygenation to Predict Neurodevelopmental Outcomes in Congenital Heart Disease   Abstract:   Advances in the care of congenital heart disease (CHD) have improved survival and neurodevelopmental delay (ND) has emerged as a major morbidity. CHD causes altered oxygenation, contributing to abnormal brain development, greatly impacting quality of life. Quantifying cerebral oxygenation is critical for identifying high-risk children for early intervention and for devising neuroprotective strategies. This proposal evaluates quantitative susceptibility mapping (QSM) of the neonatal brain for assessing cerebral oxygenation due to its ability to measure paramagnetic deoxyhemoglobin vs. diamagnetic oxyhemoglobin. QSM has distinct advantages over existing techniques such as near infrared spectroscopy (NIRS), T2* mapping and MR susceptometry in providing regional tissue oxygenation. However, limited availability of QSM has hindered its validation for this important clinical application. Our team is uniquely positioned to perform this work given access to data from an ongoing longitudinal study of children with critical CHD (n=100) and institutional expertise in QSM. We hypothesize: 1) Susceptibility (?) is a quantitative and sensitive metric of tissue oxygenation. We will test this by correlating bifrontal ? with NIRS-derived oxygenation pre-surgery (SA1A); and by comparing the change in regional ? pre- and post-surgery among those with transposition of great arteries (who undergo definitive surgery with normalized oxygenation) vs. single ventricle physiology (who undergo palliative surgery with persistent hypoxia, SA1B). 2) Susceptibility is associated with macrostructure and ND. We will test this by comparing mean white matter ? among regions with and without white matter injury and by correlating regional ? with regional brain volume on preoperative MRI (SA2A); and by establishing the association of regional ? with short term neurodevelopmental outcomes at 12-18 and/or 30 months (SA2B). Our long-term goal is to validate imaging-based metrics of the pathophysiology of brain oxygenation in CHD which are critical in early identification of high-risk children and for systematic assessment of strategies for neuroprotection.   More Activities by Elizabeth George, MD 8   Roger E. Goldman, MD, PhD University of California, Davis RSNA Research Scholar Grant (2023 - 2025) Artificial Intelligence for Interpretation and Localization in Digital Subtraction Angiography   Abstract:   Accurate interpretation of intraprocedural angiography is critical to safe and efficacious endovascular therapy with significant consequences related to misinterpretation. Despite substantial interpretive challenges including patient motion, subtle pathophysiologic findings, aberrant anatomy, and pressure due to the critical condition of patients in the angiography suite, the current practice relies on human interpretation with near complete exclusively. The ultimate goal of this research program is the development of artificial intelligence (AI) that can augment human interpretation with intraprocedural decision support to decrease error during endovascular intervention. The objective of this proposal is to develop deep learning methods to localize vascular anatomy in the intraprocedural angiographic image sequences and identify vascular aberrancy and pathology. The ephemerality of imaging findings depicting vascular abnormalities within angiograms and the inherent challenges of manual labeling preclude a fully-supervised approach to developing accurate deep learning models. The central hypothesis of this proposal is unsupervised and semi-supervised algorithms may preclude the requirement for large volumes of hand-labeled data while accurately identifying and localizing vascular aberrancies and pathologies. This hypothesis will be tested through two synergistic aims: 1) algorithmic methods for identification of vascular abnormalities through comparison of generated, synthetic images depicting arterial flow to acquired angiographic images and 2) cross-sectional and intraprocedural angiographic image co-registration with prediction of vascular pathology based upon local co-registration error. The expected outcome of this investigation is the development and assessment of novel deep learning models that accurately and autonomously predict the anatomic location of an angiogram and identify downstream vascular abnormalities. The impact of the proposed research is foundational data and methods for the implementation of intraprocedural physician decision support through AI interpretation of angiography. AI augmentation of physician interpretation has the potential to fundamentally shift the current clinical practice with the expectation to significantly improve the safety and efficacy of angiographically-guided intervention.   More Activities by Roger E. Goldman, MD, PhD 9   Amit Gupta, MD University Hospitals Cleveland Medical Center RSNA Research Scholar Grant (2023 - 2025) Lung T1 Mapping and Non-Contrast MR Angiography: A Noninvasive Method for Assessment of Pulmonary Vasculature and Perfusion Abnormalities in Patients With Chronic Thromboembolic Pulmonary Hypertension   Abstract:   Pulmonary hypertension (PH) is a chronic and progressive debilitating disease associated with high mortality and morbidity. Chronic Pulmonary Thromboembolic Hypertension (CTEPH) is an important cause of PH with complex pathophysiology and nonspecific clinical profile which poses a diagnostic challenge, thus resulting in delayed diagnosis and dismal prognosis. It is important to timely diagnose and differentiate CTEPH from other causes of PH because of available potentially curative treatments, mainly pulmonary endarterectomy, which can significantly improve patient survival and outcomes. At present, there is no single non-invasive imaging modality or diagnostic test than can confidently identify CTEPH and the current guidelines recommend use of multiple image tests, which are either invasive and /or result in significant radiation exposure. The proposed study is designed to investigate the utility of lung T1 mapping along with non-contrast magnetic resonance angiography (MRA) which can serve as a sensitive, objective and quantitative, radiation free and noninvasive imaging method for diagnostic assessment of pulmonary circulation in patients with clinically suspected CTEPH. Preliminary studies at our institution have already highlighted the role of T1 mapping of lung as a valuable biomarker for assessing pulmonary perfusion abnormalities in cystic fibrosis patients. We will also compare the diagnostic performance of the above mentioned novel technique with present standard of care nuclear perfusion and angiographic imaging on patients presenting to our PH clinic. This project will not only generate high quality preliminary data for noninvasive work up of CTEPH patients but will also open new avenues for better understanding the underlying pathophysiology and pulmonary microvascular changes in other pulmonary vascular disorders.   More Activities by Amit Gupta, MD 10   LeMoyne Michael Habimana-Griffin, MD, PhD Washington University RSNA Research Resident Grant (2024 - 2025) Engineering Probiotic Yeast for Theranostic Applications in Radiation Enteritis   Abstract:   Curative-intent pelvic radiotherapy for gynecologic, prostate, and rectal malignancies precipitates collateral damage to the intestines termed radiation enteritis (RE). Unfortunately, limited progress has been made to develop effective treatments for RE. Engineered probiotics may help to mitigate the effects of RE based on their intrinsic radioprotective properties as well as their ability to be genetically manipulated to produce diagnostic and therapeutic payloads. We have developed an innovative engineered probiotic platform for local delivery of biologic therapies using the probiotic yeast Saccharomyces cerevisiae var. boulardii (Sb) as a therapeutic chassis. Sb is well tolerated and does not persistently colonize the mammalian GI tract (GIT), which is favorable for biocontainment and cessation of therapy. However, RE is known to alter intestinal motility and lead to intestinal dysbiosis, both of which can alter the pharmacokinetics of Sb. Furthermore, radiation also enhances intestinal epithelial permeability, and it is unknown how this might alter the biodistribution of Sb after oral administration. Defining the pharmacokinetics and biodistribution ofSb in the context of RE is vital in order to optimize this therapy and translate it to the clinic. Using multimodal imaging, we will longitudinally assess the pharmacokinetics and biodistribution of Sb in preclinical models of RE and correlate these results with stool microbiome profiling to aide in optimizing dosing regimens, ensure Sb remains confined to the GIT, and to provide insight into the degree of intestinal dysfunction and dysbiosis during the course of RE. We will also test the ability of Sb to deliver, IL-22, a radiation mitigator that cannot be safely administered systemically via conventional means, using intestinal organoid models. Altogether, our long-term goal is to develop novel theranostic paradigms using engineered Sb to improve RE outcomes and meet the growing needs of cancer survivors.   More Activities by LeMoyne Michael Habimana-Griffin, MD, PhD              Page 1 of 4 (1 - 10)