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1   Katelyn Atkins, MD, PhD Oregon Health & Science University RSNA Research Medical Student Grant (2011 - 2012) The Role of PACS-2 in Radiation-Induced Gastrointestinal Syndrome   Abstract:   Understanding the molecular basis of how cells respond to acute radiation will benefit rational approaches to selectively protect healthy cells, thereby increasing the therapeutic index of radiotherapy while minimizing radioresistance of tumors or causing secondary malignancies. The tumor suppressor p53 promotes survival by increasing expression of the cyclin-dependent kinase inhibitor p21, which induces growth arrest of gastrointestinal (GI) epithelial cells following exposure to ionizing radiation (IR). However the molecular mechanism underlying this phenomenon is incompletely understood. We recently identified the multi-functional sorting protein PACS-2 as a critical regulator of IR-induced p21 expression in vivo. PACS-2-/- mice have a repressed induction of p21 following IR, suggesting PACS-2 is a novel regulator of acute radiation damage. The experiments outlined in this proposal will test the hypothesis that PACS-2-/- mice will have a diminished capacity to promote p53-dependent growth arrest and will therefore be sensitized to radiation-induced GI epithelium damage and GI syndrome-mediated death. We will utilize immunohistochemical techniques to analyze proliferation, crypt survival, and mitotic catastrophe in small intestine samples from wild type and PACS-2-/- mice following IR. Additionally, we will determine by survival analysis whether PACS-2-/- mice are sensitized to GI syndrome-mediated death. I will complete these experiments with the guidance of my scientific advisor, as well as our collaborators in the Knight Cancer Institute, the Knight Cancer Diagnostic Laboratories and the Department of Radiation Medicine at OHSU. The proposed work is significant to the radiobiological sciences because the development of targeted adjunct therapies relies on a detailed understanding of the complex molecular machinery controlling the cell’s response to radiation injury. Therefore, understanding the molecular circuitry of PACS-2’s radioprotective role may identify novel therapeutic strategies to enhance protection of normal GI epithelium by protecting or promoting PACS-2 function.   More Activities by Katelyn Atkins, MD, PhD 2   Sophia Bornstein, MD, PhD Oregon Health & Science University RSNA Research Medical Student Grant (2010 - 2011) Stem Cell Therapy for Anorectal Dysfunction After Pelvic Irradiation   Abstract:   Preoperative radiotherapy for rectal cancer leads to significant anorectal dysfunction and fecal incontinence due to secondary fibrosis of the sphincter complex, damage to anorectal nerves and vascular toxicity. The ability to transplant BMDCs autologously into irradiated patients to contribute to functional recovery is attractive, as the therapy is not invasive, and unlike other stem cell therapies can make use of cells outside the radiation field. Improved anal sphincter function with BMDC injection after mechanical sphincter damage has been reported, although the mechanism is unclear. Other investigations into regeneration of the murine Tibialis Anterior (TA) muscle have shown that BMDCs were able to differentiate into skeletal muscle, blood vessels, and nerve fibers within the TA muscle as soon as 4 weeks after injury. We have performed abdominal restricted irradiation and have demonstrated that cells traffic to the intestine and that irradiated epithelium regenerates more rapidly than in non-transplanted animals. These studies indicate that peripheral BMDCs may be able to home to irradiated anorectum, differentiate into anorectal tissues, and thus directly participate in tissue regeneration. If transplanted BMDCs are therapeutic, administration of autologous BMDCs at the time of radiation may lead to improved quality of life for rectal cancer patients.   More Activities by Sophia Bornstein, MD, PhD 3   Marka R. Crittenden, MD, PhD Oregon Health & Science University Philips Medical Systems/RSNA Research Resident Grant (2007 - 2008) Combining Total Body Irradiation with Immunotherapy to Generate Therapeutic Anti-tumor Immune Responses.   Abstract:   The induction of effective anti-tumor immune responses will enhance existing conventional cancer therapies and may provide hope for durable responses in patients with aggressive malignancy. Others and we have demonstrated significant enhancement associated with adoptive transfer of tumor specific T cells with the use of lymphodepletion prior to transfer of T cells. Indeed, the use of chemotherapeutic or radiation induced lymphodepletion prior to adoptive transfer has demonstrated promising results in early clinical trials. The aim of this work is to define some of the mechanisms whereby Total Body Irradiation enhances the immunogenicity associated with T cell adoptive transfer through characterization of the activation of the innate immune system. Specifically we are looking at how circulating endotoxins following Total Body Irradiation, a phenomenon well described in the transplant literature, enhances adoptive transfer immunity. By gaining a deeper understanding of the immunogenicity associated with Total Body Irradiation lymphodepletion we hope to enhance clinical immunotherapy approaches for patients with refractory malignant disease.   More Activities by Marka R. Crittenden, MD, PhD 4   Leonel A. Kahn, MD Oregon Health & Science University RSNA Research Medical Student Grant (2012 - 2013) Construction of a Nomogram for Predicting Mortality and Visual Outcomes of Patients Treated with I-125 Plaque Brachytherapy for Choroidal Melanoma   Abstract:   I-125 plaque brachytherapy is an effective technique for treatment of choroidal melanoma. However, some patients experience disease progression and radiation induced side effects. While certain clinical factors have been associated with unfavorable outcomes, it is challenging to predict these outcomes for a particular patient. Our hypothesis is that pre-treatment demographic, tumor, and radiotherapy-based treatment parameters can be used to predict mortality, visual, and ocular outcomes. The aim of this study is to create a nomogram that provides an output of expected survival, ocular, and visual outcomes based on demographic, tumor, and radiation treatment characteristics. Three hundred twenty-one patients treated at our institution and 649 patients treated at Drexel University with I-125 plaque brachytherapy for choroidal melanoma will be used to create a database. Time-to-event outcomes will be analyzed by the Kaplan-Meier method, log-rank test and Cox proportional hazard regression. Binary outcomes will be analyzed using a chi-square test and logistic regression at each time point. The data will be split into training or validation sets. Beta coefficients and predictive probabilities from the models will be used in the nomogram construction. The Receiver-Operating Characteristic curve method will be used to evaluate the predictive performance and determine the cut-off points for the predictive probabilities for sensitivity and specificity to classify each subject into high vs. low risk groups. This information will be will be implemented into an online nomogram. While there are known factors that contribute to treatment failure and poor ocular outcomes, there is no useful nomogram to estimate outcomes based on a patient’s specific risks. Such a nomogram can be used as a pre-treatment shared decision aid for patients and clinicians, prior to treatment. As additional clinical, genetic, and molecular predictive markers become known, these may be added to enhance the accuracy of the nomogram.   More Activities by Leonel A. Kahn, MD 5   Ningcheng Li, MD, MS Oregon Health & Science University RSNA Research Fellow Grant (2022 - 2022) Chronic Post-Thrombotic Venous Biomechanical Changes and Impact on Response to Venous Intervention   Abstract:   Chronic deep-venous obstruction is a common and highly morbid condition. Its long-term symptoms, such as pain, swelling, and skin ulceration, constitute the post-thrombotic syndrome with significant quality of life reduction and socioeconomic impact. The venous biomechanical properties are different from those of arteries, posing unique challenges to venous interventions. Current venous-specific stents, similar to prior stents, continue to experience relatively lower rates of primary patency in post-thrombotic patients. Results from large-animal model computational simulation suggest that the primary issues potentially influencing patency, namely inflow diameter reduction and low wall shear rate, have not been addressed adequately. Major gaps in knowledge, therefore, are confirmation of these computational analyses in vivo and identification of strategies to address venous biomechanical changes for optimal stent design.This proposal aims to bridge these knowledge gaps using both large-animal and computational models. Specifically, the project will first establish baseline chronic venous properties in a validated large-animal venous stenosis and thrombosis model with a 3-month post-thrombotic duration. Ultrasound, angiography, biomechanical testing, histology, and gene expression levels will be characterized and correlated with human post-mortem post-thrombotic veins. The second part of the project will involve parallel analyses on post-thrombotic veins following stent placement. In addition, the project will computationally model the impact of chronic post-thrombotic venous changes and stent placement using experimentally obtained wall biomechanical and blood flow properties. Variations in intervention parameters such as stent length, diameter, location, and post-placement angioplasty will be tested computationally to examine their effects on inflow conformation and luminal flow.The long-term goal of our research is to better understand venous-specific biomechanics in order to more accurately develop strategies to address the current significant unmet clinical needs. This proposal seeks to characterize the impact of chronic post-thrombotic venous properties and better define venous intervention parameters to inform clinical treatment and stent design.   More Activities by Ningcheng Li, MD, MS 6   Tasha L. McDonald, MD Oregon Health & Science University Toshiba Medical Systems/RSNA Research Resident Grant (2007 - 2008) Determining the Relationship Between IL-1beta, TNF-alpha, and IL-6 Response to External Beam Radiation Therapy and Treatment Related Fatigue in Patients with Prostate Cancer   Abstract:   Cancer patients undergoing chemotherapy, radiation, or both experience significant fatigue during treatment that begins during treatment and declines following treatment. Cancer treatment related fatigue (CTRF) has a profound negative impact on physical functioning, quality of life (QOL) and the patient’s ability to receive the prescribed treatment. For patients undergoing potentially curative radiotherapy, such unscheduled breaks can also contribute to tumor re-growth. To date the molecular mechanisms underlying the initiation and perpetuation of CTRF are not well established. We hypothesize that treatment induced inflammatory cytokine production plays an important etiological role in CTRF. Several lines of evidence support our hypothesis. First, in addition to fatigue, cancer patients undergoing treatment often experience several other symptoms including anorexia, cachexia, pain, sleep disturbance, depression, and anemia, which can impact the subjective sensation of fatigue. Considerable evidence generated in animal models and in clinical populations implicates the inflammatory cytokines IL-1, TNF-a and IL-6 in the etiology of these symptoms. In this regard CTRF may be homologous to sickness behavior, a normal response to infection or tissue injury. Total body and localized radiation have been shown to induce the production of inflammatory cytokines both in experimental systems and in clinical populations. The purpose of the proposed study is to determine the relationship between fatigue and plasma inflammatory cytokine levels in prostate cancer patients undergoing external beam radiation therapy (RT) for prostate cancer. Understanding whether CTRF is initiated by the production of IL-1, TNF-a, and IL-6 may lead to new treatment strategies that will improve physical functioning, QOL and the patient’s ability to receive the prescribed treatment.   More Activities by Tasha L. McDonald, MD 7   Gwendolyn J. McGinnis, MD, MS Oregon Health & Science University RSNA Research Medical Student Grant (2017 - 2018) [18F]DPA-714 PET Imaging of Minocycline Treatment for Radioimmunotherapy-related Neuroinflammation and Neurocognitive Impairment   Abstract:   Cancer patients often report behavioral changes and cognitive injury following cancer treatment. These can include difficulty concentrating, memory impairment, and increased anxiety. These symptoms can last for months and years post-treatment and are especially important to consider with improved rates of cancer survivorship. Symptoms are frequently associated with chemotherapy and/or cranial irradiation. However, these effects are also seen in patients who receive peripheral but no cranial irradiation and no chemotherapy. A proinflammatory environment in the brain may mediate these effects, as seen in many other neuropathological conditions. The role of neuroinflammation in cancer-related neurological impairment is especially important given novel cancer therapeutics that rely on activation of the peripheral immune system, which may indirectly activate the immune system in the brain. Although new treatment regimen like radioimmunotherapy (RIT) offer promising anti-tumor effect, a gap exists as to how these therapies affect the brain. Our preliminary research support a role for neuroinflammation in cognitive impairment in the setting of RIT. In this study, we propose in vivo imaging to better characterize this neuroinflammation, as well as potential prophylactic treatment with minocycline, an antibiotic with anti-inflammatory properties. C57BL/6J mice with and without RIT and in the presence or absence of minocycline treatment will be used. Checkpoint inhibitor immunotherapy, using an anti-CTTLA4 antibody, and precision CT-guided peripheral radiotherapy will be combined as RIT. We will assess behavioral and cognitive performance and utilize TSPO as a biomarker for neuroinflammation using the radiotracer [18F]DPA-714 for PET imaging. Immunohistochemistry will be used to confirm in vivo assessment of neuroinflammation. We hypothesize that treatment with minocycline will decrease neuroinflammation as well as improve behavioral alterations and cognitive impairments resulting from RIT. These data will facilitate the development of therapeutic strategies to inhibit or even prevent changes in brain important for the quality of life for cancer survivors.   More Activities by Gwendolyn J. McGinnis, MD, MS 8   Gwendolyn J. McGinnis, MD, MS Oregon Health & Science University RSNA Research Medical Student Grant (2014 - 2015) Suppression of the T cell Response and Enhancement of Detrimental Effects of Radiation on the Brain   Abstract:   In colorectal cancer, the immune infiltrate has been correlated with outcome. Patients with higher infiltrations of T cells have increased survival, independent of disease stage, while patients with poor immune infiltrates have a severely limited survival. Because the colorectal cancer patients studied received conventional cancer therapies, the pre-treatment tumor environment might increase the efficacy of treatments such as chemotherapy, surgical resection and radiation therapy. An improved immune environment in the tumor at the time of treatment increases the efficacy of radiation therapy but it is unclear how immunotherapy might modulate the effects of radiation therapy on the brain. Radiation therapy is associated with cognitive impairments. The temporal lobe, and in particular the hippocampus, is sensitive to detrimental effects of radiation on cognition. The mechanisms underlying hippocampus-dependent cognitive impairments are not clear but are likely multifactorial and may involve alterations in neurogenesis, the expression of the plasticity-related immediate early gene Arc, and inflammation. Here the hypothesis that suppression of the T cell response using anti CTLA4 pretreatment will enhance the detrimental effects of radiation therapy on cognition and that this will be associated with enhanced CNS inflammation, including activation of newly born CD68-positive microglia, and reduced hippocampal neurogenesis and Arc expression in a mouse model of colorectal cancer will be tested. Cognitive testing and analysis of immunohistochemical markers will be used to establish effects of combination therapy on the brain. Based on characterization of the CTLA4-mediated potentiation of radiation-driven brain inflammation, the long-term goal of this project is to test compounds able to reduce this inflammation to improve brain function in cancer survivors.   More Activities by Gwendolyn J. McGinnis, MD, MS 9   Timur Mitin, MD, PhD Oregon Health & Science University Toshiba America Medical Systems/RSNA Research Seed Grant (2016 - 2017) Novel Imaging of Lymph Nodes in Patients with Rectal Cancer Using Ferumoxytol-enhanced MRI   Abstract:   Management of locally advanced rectal cancer involves total mesorectal excision with preoperative concurrent chemoradiotherapy. Total mesorectal excision removes mainly lymph nodes (LN) in the mesorectum. The therapeutic management of lateral pelvic lymph nodes (defined as obturator, external iliac and common iliac) is not well defined and, they are considered distant metastases by the American Joint Committee on Cancer (AJCC) staging system. However, in Asia, these lymph nodes are considered regional and are routinely dissected per a large multi-institutional registry study in Japan which showed improved overall and cancer-specific survival in patients with lateral pelvic LN metastases who underwent a curative resection than in patients with Stage IV disease. Radiation therapy (RT) is able to sterilize pelvic lymph nodes, and detailed knowledge of involved lymph nodes may facilitate formulation of better targeted chemo-RT options resulting in better outcomes. We have discovered highly efficient lymph node ta...   More Activities by Timur Mitin, MD, PhD 10   Nima Nabavizadeh, MD Oregon Health and Science University RSNA Research Resident Grant (2014 - 2015) Noninvasive, In Vivo Contrast-enhanced Ultrasound and Molecular Imaging of Early Microvascular Changes Following High-dose Radiation Therapy   Abstract:   In recent years, an increasing number of cancer patients have been treated with stereotactic radiosurgery (SRS) or stereotactic body radiation therapy (SBRT), where large radiation doses per fraction are delivered. Despite the rapid advances in radiation technology and image-guidance, the biologic response to high-dose radiation therapy (RT) remains poorly understood. Alterations in the tumor microenvironment have been implicated as a significant contributor to tumor response to high-dose RT. Oxidative stress and ceramide production represent two major microenvironmental changes which activate the inflammatory response and cellular apoptosis. The overall goal of this research proposal is to better understand the determinants of success of high-dose RT by applying contrast-enhanced ultrasound (CEU) perfusion and molecular imaging to temporally and spatially evaluate the tumor microcirculation. This proposal will analyze murine subcutaneous prostate adenocarcinoma models following targeted delivery of whole-tumor or partial-tumor high-dose RT. We hypothesize that early changes in the anatomy and molecular phenotype of the tumor microvasculature are radiation dose-responsive and can be detected utilizing CEU and molecular imaging. The specific aims for this proposal are: 1) Spatially evaluate microvascular involution relative to radiation dose by analyzing microvascular blood flow on CEU, microvascular density with maximum intensity projection (MIP) microangiography, and degree of endothelial oxidative modification measured by microSPECT and 2) Correlate microvascular involution with endothelial inflammatory response and apoptosis using CEU molecular imaging with microbubbles targeted to inflammatory cells, P-selectin and phosphatidylserine. In the long term, completion of these aims may lead to better clinical tools to rapidly assess likelihood for tumor regression. Data obtained from this pre-clinical study will be used as support for larger funding sources for subsequent phase I/II studies in humans.   More Activities by Nima Nabavizadeh, MD              Page 1 of 3 (1 - 10)