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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   Mark Barahman University of California, San Diego GE Healthcare/RSNA Research Resident Grant (2022 - 2023) Proton Density Fat Fraction Estimation With Point Of Care Nuclear Magnetic Resonance Technology   Abstract:   Objective: To validate non-invasive, diagnostic, nuclear magnetic resonance (NMR) technology with point-of-care (POC) capability for detection and quantification of liver fat. Background: Nonalcoholic fatty liver disease (NAFLD) is highly prevalent, and its complications are burdensome on the US healthcare system. The current noninvasive gold standard for steatosis assessment is chemical shift encoded (CSE) magnetic resonance imaging-based proton density fat fraction (MRI-PDFF), which is limited by availability and patient contraindications such as claustrophobia and severe obesity. An accurate, precise, POC test could facilitate population-level screening and expand access to diagnosis and monitoring for NAFLD patients. POC NMR is a technology developed by our investigative team to measure liver PDFF with POC capability. The custom NMR pulse sequence generates fat / water contrast based on diffusion, not chemical shift. This is an investigational approach for fat quantification and the optimal acquisition parameters are currently unknown. Our pilot study suggests that POC NMR is well-tolerated and accurate in estimating PDFF (R2=0.99 with 4 phantoms, and R2=0.94 compared to MRI PDFF in humans). However, the study was performed using a relatively long acquisition time and it was limited in sample size and PDFF range. The technique requires further optimization, and further validation (linearity, repeatability, reproducibility) in a larger, more diverse cohort. Goal of proposed research: to optimize POC NMR acquisition parameters and advance the validation of POC NMR for liver fat quantification in NAFLD. Methods: We aim to optimize the pulse sequence acquisition through Monte Carlo computer simulation (Aim 1), test the performance in phantom (Aim 2) and in humans (Aims 3-4), and by exploring potential confounders of POC NMR. Quantitative Imaging Biomarkers Alliance (QIBA)-advocated performance metrics will be calculated and compared. Clinical Significance: Improving access to early NAFLD diagnosis could allow for interventions to prevent disease progression and facilitate clinical trial selection.   More Activities by Mark Barahman 3   Krister Barkovich, MD University of California, San Diego Bracco Diagnostics Inc./RSNA Research Resident Grant (2022 - 2023) Developing a Novel Tumor-Targeting Dual NIRF/MRI Imaging Nanoparticle for Longitudinal Molecular Cancer Imaging   Abstract:   Cancer is the second leading cause of death in the United States and disease prevalence is expected to increase with the aging population and longer disease survival. As such, the development of imaging tools to monitor cancer growth, spread, and recurrence is of paramount importance. FDG-PET/CT plays an invaluable role in monitoring cancer progression and response to therapy. However, it suffers from inherently low spatial resolution, is not effective in all tumor types, and multiple tissues are naturally FDG-avid, making the monitoring of disease within these tissues difficult. Conversely, MRI-based molecular imaging tools suffer from low signal:noise due to the high signal requirement for detection. Multiply functionalized nanoparticles carry the possibility of delivering high density MRI contrast agents to specific tissues within the body, offering much higher signal density with the benefit of high spatial resolution of MRI. However, existing inorganic MRI-active nanoparticles are difficult to synthesize homogenously and have ongoing safety concerns. We propose the development of a novel bio-organic molecular imaging reagent based on a plant viral nanoparticle scaffold. We will append these nanostructures with near-infrared fluorescence (NIRF) and MRI contrast agents and cancer neovasculature-targeting peptides to impart tumor homing properties. We anticipate that these nanoparticles will show tumor-specific uptake and long tumor residency, and thus allow for the longitudinal monitoring of cancer progression over time. The feasibility of this proposal is supported by our preliminary data which shows that virus-like nanoparticles can be developed with high affinity for avb3 integrins, which are highly expressed on tumor neovasculature. The success of this proposal will provide a preclinical tool for the longitudinal imaging of cancer that can be further developed to follow disease progression after chemotherapy, radiation, or surgical treatment, as well as a work-flow for the development of MRI molecular imaging tools directed to any extracellular target.   More Activities by Krister Barkovich, MD 4   Soha Bazyar, MD University of Maryland Baltimore RSNA Research Resident Grant (2022 - 2023) Ultra-high Dose Rate Sparing of Lung Tissue During Radiation Therapy   Abstract:   More than half of all cancer patients will receive radiation therapy (RT) during their course of treatment. Normal tissue complications are the main dose-limiting side effects of RT. FLASH-RT is emerging technology that delivers RT at ultra-high dose-rates. Preclinical studies have shown that compared to conventional dose-rate RT (CONV), FLASH-RT spares normal tissue. In particular, FLASH-RT can be beneficial for lung cancer patients in whom 5-year survival rates remain ~10%. Aside from the embedded sparing effect of FLASH, ultra-high dose rate can “freeze” the physiological motions, decrease the smearing of beam. Nevertheless, research on FLASH-RT is still in its infancy. The preclinical findings remain controversial without better understanding of the underlying mechanisms. Also, various physical and dosimetry parameters need to be refined. Here, our first aim will elucidate the mechanism of FLASH-sparing effects using multi-omic analysis and transmission electron microscopy 8- and 24-hrs post-irradiation. Second, the therapeutic dose-rate range will be calculated using survival up to 180 days post-RT as the main endpoint. The secondary endpoints include longitudinal lung CT-imaging, respiratory examinations, lung weight for edema and histological evaluation for fibrosis. Studies will utilize a well-characterized mouse model of whole thorax lung irradiation-induced pneumonitis and fibrosis. RT will be delivered at ascending FLASH-RT dose rates over a clinically-relevant CONV-RT dose range. All steps are designed with appropriate controls, randomization, and blinding to minimize bias and ensure rigor. All data will be analyzed under supervision of biostatisticians. Deliverables will include the underlying mechanism of FLASH-RT as well as the probit-estimated dose response for each dose rate (eg. LD50/180). If successful, the studies will inform the treatment protocols used in future clinical trials. Proposed studies here are at the intersection of biology, physics and radiology, and provide a unique training for the PI, who is interested in becoming a translational physical scientist.   More Activities by Soha Bazyar, MD 5   Joshua Brown, MD, PhD Emory University Prince Research Resident Grant (2022 - 2023) Chemical Exchange Saturation Transfer MRI in Non-Lesional Temporal Lobe Epilepsy Imaging   Abstract:   This project will investigate the ability of chemical exchange saturation transfer (CEST) imaging to evaluate epilepsy patients for seizure focus lateralization. If successful, it will produce a major paradigm shift in epilepsy evaluation and improve the prognosis of a large medical-refractory epilepsy population. Routine epilepsy diagnosis includes multimodal imaging used to localize the source of seizures and is necessary for successful surgical intervention in drug-resistant cases. Unfortunately, up to one-third of epilepsy evaluations have no clear anatomical source of seizures and have non-lesional, normal brain MRIs. Glutamate levels in the brain are known to be increased in anatomical seizure foci. Conventional magnetic resonance spectroscopy (MRS) is limited in accurately detecting glutamate levels, but glutamate CEST (GluCEST) imaging has demonstrated higher sensitivity and spatial resolution. GluCEST has already demonstrated promising results in epilepsy evaluation on research 7T MRI scanners for patients. We hypothesize that GluCEST can accurately lateralize the epileptogenic hippocampal foci in patients with non-lesional imaging on 3T MRI scanners. We will optimize GluCEST parameters and post-processing on 3T MRI scanners in healthy controls (n = 5) then assess GluCEST in epilepsy patients (n = 10). Patients will be recruited from the Emory Epilepsy Center and GluCEST imaging will be analyzed using routine multimodal comprehensive epilepsy evaluation as the gold standard.This work has the potential to make a significant, positive impact on millions of patients in the epilepsy community. GluCEST would capture drug-resistant, non-lesional epilepsy patients, guide their surgical intervention, and thus greatly improve their prognosis. In addition, this work would facilitate transition of this advanced imaging technique to a clinical environment suitable for the standard hospital setting. This proposal lays the foundation for future multi-center trials and will subsequently make a new profound diagnostic technique widely available to the benefit of epilepsy patients in need.   More Activities by Joshua Brown, MD, PhD 6   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 7   Jason D. Domogauer, PhD NYU Grossman School of Medicine Philips Medical Systems/RSNA Research Resident Grant (2022 - 2023) Pilot Study of an Organ-Based Cancer Screening Electronic Application Tool to Improve Cancer Screenings for Sexual and Gender Minority Persons   Abstract:   LGBTQ (lesbian, gay, bisexual, transgender, and queer) patients also referred to as sexual and gender minorities (SGM) are an understudied and underserved population whom experience health disparities including increased cancer risk and worse cancer outcomes. Access to culturally humble cancer care starts with prevention and early detection; yet, despite known cancer risks, screening rates remain low. Currently, there are very limited early detection and prevention national guidelines specific to SGM persons, with notable gaps for transgender and gender non-binary individuals. Thus, the current recommendation is for organ-based cancer screenings for all SGM individuals; however, such an approach can be confusing, as many providers have not received sufficient training in SGM-health and/or are unaccustomed to completing an organ-inventory, which can result in incorrect recommendations and over- and under-screenings. In this study, we aim to use a community-based approach to better understand the experiences of SGM persons accessing screening services, their experienced and/or perceived barriers/facilitators to cancer screening, and perceptions of an organ-based cancer screening electronic application. To achieve this goal, we will examine responses among a nationally-representative sample of SGM adult cancer survivors via responses from the “OUT” survey, which is the largest national survey of SGM cancer survivors (n=2,700). Findings will help develop focus group guides to further assess cancer screening utilization and barriers/facilitators, as well as perceptions of an organ-based electronic application screening tool among a diverse sample of SGM individuals in NYC. Completion of this study will help develop an inclusive, organ-based cancer screening tool that can be used by patients and/or their healthcare providers that will provide guidance on recommended cancer screening(s) and tailored resources, and subsequent clinical trials examining the efficacy of the tool for reducing the existing cancer screening disparities experienced by SGM persons.   More Activities by Jason D. Domogauer, PhD 8   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 9   Matthew Gallitto, MD Columbia University RSNA Research Resident Grant (2022 - 2023) Focused Ultrasound-Enhanced STAT3 Inhibition and Radiosensitization for Diffuse Midline Glioma   Abstract:   Diffuse midline glioma (DMG) is the most aggressive primary pediatric brain tumor. It is an infiltrative disease of the vital brainstem, extending to areas of the brain in which the blood brain barrier (BBB) remains relatively intact. As such, there is no role for surgical resection, and drug delivery remains quite limited. The current treatment paradigm is conventionally fractionated radiotherapy (RT), which has remained unchanged for several decades, and offers only a temporary response. As we begin to understand the molecular characteristics of DMG, targeted therapies are making their way into clinical trials. However, the efficacy of these agents remains variable. More recently, it has been shown that aberrant signal transducer and activator of transcription 3 (STAT3) signaling is associated with oncogenesis in CNS tumors as well, including patient-derived DMG cell lines. Inhibition of STAT3 signaling in DMG cell lines is known to decrease cell proliferation, and our preliminary data show that genetic inhibition of STAT3 signaling decreases tumor volume in DMG mouse models. One of the major barriers to the success of targeted therapies for patients with DMG is the difficulty of penetrating an intact BBB to gain access to the tumor. To overcome this, we propose the use of focused ultrasound (FUS), which offers a safe and non-invasive method for achieving localized image-guided BBB-opening for drug delivery. This method has proven efficacy in improving chemotherapy delivery for patients with recurrent glioblastoma (GBM). We hypothesize that in pre-clinical DMG mouse models, FUS drug delivery of a STAT3 inhibitor will improve DMG cell death and have an additive effect with concurrent standard of care RT. The proposed study offers a novel approach to battling DMG in which a mechanistic intervention is being investigated along with consideration for the tumor location and bioavailability of treatment.   More Activities by Matthew Gallitto, MD 10   Ruoqi Gao, MD The University of Texas Southwestern Medical Center RSNA Research Resident Grant (2022 - 2023) Targeted Acoustic Activation of Systemic Immunomodulating Nanodroplets as a Novel Immunotherapeutic Platform   Abstract:   Cancer immunotherapy enhances a patient’s natural immune system to eliminate tumor cells. However, response rates are limited because most agents only target the adaptive immune system, which eventually leads to T-cell exhaustion. Moreover, these monotherapies often fail to overcome the multitude of resistance mechanisms within tumor microenvironments. Current research therefore has heavily focused on synergistically activating the innate immune system by targeting antigen-presenting cells (APCs). Our team has recently developed an ultrasound-guided immunotherapeutic platform in which we loaded 2’3’ cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) to APC-targeted microbubbles. cGAMP is the natural and most potent agonist of the cytosolic DNA sensor cyclic GMP-AMP Synthase-Stimulator of Interferon Genes (cGAS-STING) pathway. However, clinical translation of cGAMP has been hindered by delivery and toxicity challenges, which we addressed with our immunomodulating microbubbles (iMBs) platform. Upon intratumoral injection into syngeneic tumor-bearing mice, iMBs bound to local APCs and released cGAMP into their cytosol when exposed to ultrasound, resulting in potent antitumor responses through STING activation. While remarkably effective, iMB delivery is limited to physically-accessible tumors due to the lack of extravasation of micron-sized iMBs. Here, we will use the same design principles to establish a platform that enters the tumor parenchyma following systemic administration. We plan to do this by loading macrophages ex vivo with immunomodulating nanodroplets (iNDs). These iNDs will be formulated by incorporating cGAMP into the shell of low boiling point perfluorobutane nanodroplets (PFB-ND). The PFB-NDs will vaporize and release cGAMP only when exposed to ultrasound energy, allowing spatiotemporal control over STING activation in loaded macrophages. We will inject these loaded macrophages intravenously into tumor-bearing mice followed by acoustic droplet vaporization in the tumor using a clinical scanner, resulting in tumor-specific STING activation. Our iND platform, if successful, would complement our iMB system to treat difficult-to-reach cancers that are unamenable to intratumoral injection.   More Activities by Ruoqi Gao, MD              Page 1 of 5 (1 - 10)