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1   Emily Ambinder, MD, MSc Johns Hopkins University RSNA Research Scholar Grant (2021 - 2023) Breast Cancer Screening in the Era of Precision Medicine: Evaluating the Role of Liquid Biopsy in Early Breast Cancer Detection   Abstract:   The goal of screening mammography is to diagnose breast cancer when it is early stage since and often curable. However, some patients still develop interval cancers between annual exams or are diagnosed with advanced cancers at the time of routine screening. These patients represent a population inadequately served by our current screening paradigms. We hypothesize that circulating tumor DNA (ctDNA) has the potential to diagnose breast cancer in some patients earlier than screening mammography and could be used as a supplemental screening technique. ctDNA has been shown to have clinical utility in detecting and monitoring metastatic breast cancer, but its role in early detection of breast cancer is currently unknown. In order to determine how ctDNA may fit into current breast cancer screening algorithms, we must (1) establish its diagnostic accuracy and (2) define a population who would most benefit from this technology. We will conduct a prospective pilot study in which we will measure ctDNA in women undergoing breast biopsies and enriched with patients newly diagnosed with breast cancer in order to measure the diagnostic accuracy of this test. We will also perform a retrospective cohort study aimed to identify factors that predict which patients undergoing annual mammographic screening are at risk for being diagnosed with an interval cancer or an advanced cancer, suggesting that their cancer may have been mammographically occult at the time of the most recent screening but potentially detectable with ctDNA. The overall goal of this project is to evaluate the clinical utility of ctDNA in breast cancer detection and identify groups of patients most likely to benefit from this emerging technology. We hypothesize that ctDNA will have a high sensitivity for aggressive breast cancers and can be used as a supplemental screening test in a Precision Medicine Screening Program.   More Activities by Emily Ambinder, MD, MSc 2   Majid Chalian, MD University of Washington RSNA Research Scholar Grant (2021 - 2023) Predicting Treatment Response to Neoadjuvant Radioimmunotherapy (NRIT) in High Grade Soft Tissue Sarcoma (STS) with MRI-based Radiomic Signature   Abstract:   Soft tissue sarcomas (STS) constitute a challenging group of malignancies with wide range of biological behavior and rapidly fatal subtypes in children and young adults. Early treatment response prediction is crucial for therapy planning. Current treatment planning is based on clinical and pathologic factors with a one-size-fit-all approach. Cancer patients have varying degrees of responses to therapies, which have been attributed to tumor heterogeneity and immune microenvironment. Response Evaluation Criteria in Solid Tumors (RECIST), as the only widely adopted metric for response assessment in STS, is known to have substantial limitations, especially in molecular-targeted therapies. Advances in imaging technology have introduced novel quantitative imaging biomarkers. Radiomics is a method to extract higher-dimensional imaging biomarkers that are not necessarily captured by visual assessment. Our group has published MRI-based radiomic features to predict survival, differentiate histopathologic grades, and classify STS based on immune phenotypes. Preliminary data support utility of radiomics for immune phenotype assessment of tumors. Therefore, we hypothesize that MRI-based radiomics, alone or in combination with clinical and semantic MRI features, can be used for prediction of pathologic treatment response to neoadjuvant radioimmunotherapy in STS patients. We will test this hypothesis by applying radiomics on a validated retrospective cohort of STS patients with standard of care MRI. Response predictive models will be created based on MRI radiomics, alone or in combination with clinical and semantic MRI features. An independent cohort of STS patients from a running prospective trial will be used to evaluate these models. The expected output of the project will be a multiparametric method that will provide sarcoma clinicians and researchers with new tools to predict treatment response and guide management. It will also serve as preliminary data for an NIH funding proposal for a multicenter registry of STS to validate models and investigate histology-specific radiomics analysis of STS.   More Activities by Majid Chalian, MD 3   Andrea S. Doria, MD, PhD The Hospital for Sick Children RSNA Education Development Grant (2020 - 2023) Towards Enhancing the Value of Imaging by Communicating With Data: Developing the Next Generation of LQ2 (Qualitative-quantitative Leaders)   Abstract:   The Problem: Healthcare organizations are changing rapidly. To deal with these changes, new skills are required by upcoming radiology leaders. In the "evidence-based" era, it has become crucial for imagers to develop strategies that use data to move others to desirable actions that add value to imaging, improving delivery of healthcare through the usage of appropriate analytic and communication tools. Qualitative approaches can drive disruptive innovations towards value-added services. Quantitative models and data analytics, particularly when combined with qualitative frameworks, can be powerful tools for leaders to implement changes in the culture and politics within organizations. LQ2 is an abbreviation that relates to the combination of qualitative and quantitative frameworks and skills needed by the next generation of leaders in radiology to promote innovation in a cost-effective manner. The Solution: To address these educational gaps, we plan to create and assess a "Communicating with Data LQ2 Leadership Curriculum" that should enable participants to make operational decisions in radiology practices. Project Description: We propose a 4-phase program with the following short-term goals: (i) to create the curriculum; (ii) to train a senior target audience of radiology professionals in leadership positions of academic and private practice groups (program directors, chairs, vice-chairs, division chiefs, senior managers, etc) on a 4-day face-to-face course locally administered by RSNA; (iii) to train a junior target audience of radiology fellows, residents, and graduate students who intend to pursue a career in radiology using a similar method as proposed for the senior audience. The long-term goal of this program is to enhance the value of imaging by teaching techniques of practice innovation within and across institutions which can facilitate the achievement of career goals of attendees, implement institutional efficiency, and position radiology professionals as leader communicators and data analytics-based decision-makers in their healthcare ecosystems in the future.   More Activities by Andrea S. Doria, MD, PhD 4   Peiman Habibollahi, MD The University of Texas MD Anderson Cancer Center RSNA Research Scholar Grant (2021 - 2023) Modulation of Immune Response within Hepatocellular Carcinoma Tumor Microenvironment Using Locoregionally Delivered Glypican-3-directed Targeted Immunotherapy   Abstract:   Hepatocellular carcinoma (HCC) in adults is one of the most frequently diagnosed cancers worldwide with high mortality. This poor prognosis issues from lack of effective treatments and resistance of HCC to systemic chemotherapy. Immunotherapy provides a promising alternative to treat HCC by either potentiating the existing immune response against the tumor or stimulating a new immune response. The recent breakthrough in immunotherapy against HCC consisting of atezolizumab and bevacizumab is based on the first strategy, potentiating the existing response. However, the clinical benefit of immunotherapy remains marginal at best. Therefore, there is an unmet need for innovating therapeutics that could further improve patient outcomes by increasing the current immunotherapy paradigms' effectiveness. Bispecific antibodies (bsAb) combine two antibodies' specificities, targeting immune and cancer cells, to generate a new immune response demonstrating potential to address this unmet need. With funding support from RSNA, we have developed a locoregionally delivered GPC3/CD3 bsAb that simultaneously targets CD3 (T-cell biomarker) and Glypican-3 (GPC3, HCC specific tumor marker). By capitalizing on this, we propose to validate this GPC3/CD3 bsAb further and test the feasibility of its incorporation into the current immunotherapy regimen for HCC. We will test this bsAb in an established immunocompetent syngeneic mouse model and in combination with atezolizumab and bevacizumab, followed by studying the alterations in immune profile within tumor microenvironment using single-cell RNA sequencing technology. We hypothesize that the GPC3/CD3 bsAb will increase the tumor-infiltrating lymphocytes and improve tumor response when combined with atezolizumab and bevacizumab. Our long-term goal is to develop treatment paradigms for modulating the immune response within the tumor microenvironment leveraging the power of image-guided delivery.   More Activities by Peiman Habibollahi, MD 5   Christopher D. Malone, MD Washington University in St. Louis RSNA Research Scholar Grant (2021 - 2023) Yttrium-90 Stimulated Photodynamic Therapy to Enhance Radioembolization of Liver Tumors   Abstract:   Y90-radioembolization (Y90-RE) has played a critical role in extending survival and downstaging of patients with hepatocellular carcinoma (HCC) to curative-intent therapies such as surgical resection or transplantation. However, several limitations of Y90-RE remain in patients with advanced stages of HCC and compromised liver function (up to 70% of patients), including achieving tolerable tumoricidal radiation doses to large tumor volumes and increased risk of liver decompensation, both of which can result in lower response rates and survival of less than one year. This highlights the urgent need to enhance the tumoricidal efficacy of Y-90 with additional cytotoxic mechanisms to extend its treatment benefits to these high-risk patients. Y-90's potent emission of ultraviolet to visible light, termed Cerenkov radiation (CR), during beta-particle radioactive decay, has untapped therapeutic potential to address these limitations. CR can stimulate non-toxic, light-sensitive drugs (photosensitizers) to produce tumoricidal reactive oxygen species (ROS) for photodynamic therapy (PDT) by potentiating cancer cell death via multiple pathways at low toxicities. Given that Y-90 is one of the brightest and most efficient CT emitters among clinically used radionuclides, I hypothesize that it will stimulate nano-photosensitizers (Y90-stimulated-PDT) for enhanced multidimensional treatment of HCC without significant off-target toxicities. This proposal will establish the tumoricidal efficacy and toxicity profile of Y-90-stimulated-PDT over Y-90 alone in a pre-clinical HCC animal model to lay the groundwork for its clinical translation. This will be addressed by 2 specific aims: 1) Determine the complimentary tumoricidal efficacy of Y90-stimulted-PDT over Y-90 alone using clinically translatable nano-photosensitizers and 2) Determine Y-90 and nano-photosensitizer combinations that achieve tumoricidal efficacy at sublethal Y-90 radiation doses while assessing systemic, liver, and off target toxicities. Overall, the experiences facilitated by RSNA Research Scholar Grant will be instrumental for my career growth as a Clinician Scientist and ultimately scientific breakthroughs that will directly benefit patients.   More Activities by Christopher D. Malone, MD 6   Colin D. McKnight, MD Vanderbilt Universiity Medical Center RSNA Research Scholar Grant (2021 - 2023) Magnetization Transfer Imaging of the Human Spinal Cord and Cerebrospinal Fluid to Characterize Myelin Metabolism in Multiple Sclerosis   Abstract:   The overall goals of this proposal are to a) establish cerebrospinal fluid (CSF) as a critical mediator of the metabolism of demyelination products in multiple sclerosis (MS) and to b) demonstrate that magnetization transfer (MT) MRI can depict clinically relevant, regionally specific myelin loss in the spinal cord (SC) which is associated with accumulation of myelin products in the spinal CSF. The discovery of the glymphatic system has prompted reassessment of brain and SC waste product metabolism. Increasing evidence indicates demyelination in MS is associated with the brain/SC located proximate to CSF and penetrating vessels. However, there is scant MS research regarding CSF metabolism and even less focused on CSF imaging. MT MRI detects myelin in vivo and provides strong imaging correlation to MS disease status. We hypothesize that in MS, SC demyelination is coupled to regionally increased CSF demyelination products, and that MT MRI can demonstrate this previously unrecognized, clinically relevant relationship. We further hypothesize that ex vivo CSF MT MRI in MS correlate with laboratory measures of demyelination. Patients with known MS will undergo 3T MT MRI of the SC to assess the relationship between CSF myelin products and clinical measures of disease status. SC MT MRI will be related to regionally specific measures of CSF MT MRI to provide insight into the metabolism of demyelination products. Finally, we will validate the in vivo findings with ex vivo MT MRI of CSF obtained in a separate cohort of patients clinically indicated for MS. Laboratory measures of demyelination will be compared to ex vivo MT imaging, unbound by in vivo limitations. If successful, this study will provide new insight into the mechanisms of MS demyelination, establish a novel, clinically relevant in vivo imaging measure of MS disease status and provide a new candidate biomarker for future MS drug development.   More Activities by Colin D. McKnight, MD 7   Adam C. Mueller, MD, PhD Thomas Jefferson University RSNA Research Scholar Grant (2021 - 2023) Investigating ADAM10 Mediated EMT and Therapeutic Resistance in PDAC   Abstract:   Pancreatic cancer is a deadly disease that is characterized by resistance to cytotoxic therapies like chemotherapy and radiation therapy(RT), and aggressive metastasis. Pancreatic cancer is a fibrous tumor, composed of relatively few cancer cells, with fibrotic scar tissue preventing access by chemotherapy and activating pathways of cancer cell survival and metastasis. High dose RT has the potential to improve outcomes through enhanced tumor killing in patients who cannot have surgery, but RT can increase fibrosis, raising concerns for counterproductive effects in pancreatic cancer. We have identified a pathway of RT-induced fibrosis through a cell surface protein ADAM10, which acts as a molecular scissors, helping activate signaling pathways that drive scar tissue formation, resistance to radiation and metastases. The first aim will establish activation of ADAM10 by association with the cell signaling protein EPHB4. EPH proteins have been shown to be activated by ADAMs, and can activate the molecular scissors activity of ADAMs. We will show that EPHB4 is participating in positive feedback signaling with ADAM10 after activation by RT, increasing ADAM10 and EPHB4 activity, driving resistance to radiation and metastasis. The second aim will examine the effect of radiation induced ADAM10 activity on Notch signaling. Notch is a powerful driver of cancer cell survival and invasion, and is activated by cleavage by ADAM proteins. We will show that RT-induced ADAM10 activity activates Notch, so that it can move to the nucleus of tumor cells and activate gene pathways driving metastasis and resistance to RT. We intend to use these findings to develop new therapeutic strategies targeting ADAM10-mediated pathways, enhancing the effect of high dose RT on PDAC, while preventing the side effects of resistance and metastasis. This could improve outcomes in the 40% of PDAC patients who have localized unresectable disease.   More Activities by Adam C. Mueller, MD, PhD 8   Jennifer Soun, MD University of California, Irvine AGFA HealthCare/RSNA Research Scholar Grant (2021 - 2023) Evaluation of the Implementation of an AI Tool for Large Vessel Occlusion: Impact on Radiologists' Workflow and Patient Outcomes   Abstract:   Timely and accurate diagnosis of a large vessel occlusion (LVO) is critical for prompt initiation of thrombectomy treatment to reduce morbidity and mortality in acute ischemic stroke patients. Recently, several artificial intelligence (AI) tools have been introduced into the clinical setting to aid stroke triage, including LVO detection. While these AI tools show promise for their accuracy and speed, little is known about the impact of AI integration in the clinical workspace on efficiency metrics and patient outcomes, as most AI studies focus on detection of an abnormality, rather than patient-centered and clinically meaningful endpoints. This proposal aims to address this challenge by evaluating the impact of an AI-based LVO detection tool on three main areas: (1) stakeholder engagement and performance metrics, (2) a radiologist's workflow, and (3) stroke outcome benchmarks. The study will leverage a comparative effectiveness framework with a pre post implementation study design for assessment. The success of this proposal will lead to a better understanding of the role of AI in stroke triage for clinicians and potential for future widespread implementation across various practice settings.   More Activities by Jennifer Soun, MD 9   Jessica K. Stewart, MD University of California, Los Angeles RSNA Research Scholar Grant (2021 - 2023) Effectiveness of Fallopian Tube Embolization With N-butyl-2-cyanoacrylate Using Selective Catheterization for Sterilization in a Rabbit Model   Abstract:   Over a half million women annually undergo tubal sterilization procedures annually in the United States, and surgical tubal ligation is the most popular method. This exposes patients to the risks of anesthesia and surgical complications. Interventional radiologists could offer a safe, minimally-invasive, inexpensive method of permanent sterilization for women who have completed their family. The long-term objective of this investigation is to develop a new method of fallopian tube occlusion/embolization that can be offered to women desiring permanent sterilization. This study expands on a feasibility study which determined that embolizing the fallopian tubes using n-butyl-2-cyanoacrylate (NBCA) mixed with lipiodol via a microcatheter was technically feasible, and resulted in tubal occlusion in the majority of rabbits over a 1-month period. The objective of this study is to test the hypothesis that embolization of the fallopian tubes using NBCA via a microcatheter in a rabbit model will result in prevention of pregnancy over 6 months of breeding and durable tubal occlusion on salpingography, without significant inflammation, cystic changes, or increased tube diameter on histopathologic analysis.   More Activities by Jessica K. Stewart, MD 10   Neil K. Taunk, MD, MS University of Pennsylvania RSNA Research Scholar Grant (2021 - 2023) Evaluation of [18F]FTT PET/CT as an Imaging Biomarker to Select for PARPi Therapy in Patients with Metastatic Castrate-Resistant Prostate Cancer   Abstract:   Poly (ADP-ribose) polymerase (PARP) inhibitor drugs (PARPi) are a critical new therapeutic that targets germline abnormalities in prostate, breast, and ovarian cancer. Nearly 20% of patients with metastatic castrate resistant prostate cancer (mCRPC) have mutations in DNA-damage response and may benefit from PARPi therapy, which is recently FDA-approved. However, response rates are variable and current assays included tissue staining or germline status for patient selection for PARPi therapy are not optimal to demonstrate who will benefit from this therapy. In the proposed application, we use [18F]FTT a PARP imaging biomarker, to predict who may optimally respond to PARPi therapy. In the proposed research, patients will receive a [18F]FTT PET/CT scan before and soon after PARPi therapy. Quantitative changes in PARP-1 expressing tumors, compared to standard assays, will be used to predict which patients may benefit from PARPi therapy and determine effect size for future study. We will further compare PARP-1 expressing tumors against standard of care imaging to better characterize tumor heterogeneity, and the dependency of [18F]FTT uptake compared to PARP-1 autoradiography and other tissue markers. This application builds upon the extremely successful work we have done in ovarian and breast cancer with [18F]FTT. With successful translation and validation of this non-invasive imaging biomarker, we expect to perform a large Phase III randomized study to validate using novel imaging to optimally select patients who are recommended for PARPi therapy.   More Activities by Neil K. Taunk, MD, MS              Page 1 of 2 (1 - 10)