rsna 2009 research education foundation awards

8/14/2019 RSNA 2009 Research Education Foundation Awards

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2009Grants and Awards

RSNARESEARCH & EDUCATION

FOUNDATION

FUNDING RADIOLOGYS FUTURE

Improving patient care by supportingresearch and education in radiology and

related scientific disciplines throughfunding grants and awards to individuals

and institutions that will advance radiologicresearch, education, and practice.


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Dear Colleague,

Our commitment to radiology research and education is stronger than ever. This year, the Foundation is celebrating its 25thanniversary and the successful completion of a $15 million campaign. Through the generous support of our corporate,private practice, and individual donors, we will be able to continue funding grant programs for the next 25 years.

We know that getting the first grant can be the hardest, and we are proud of our 25-year history of providing these criticalgrants to launch successful academic careers. To date, the Foundation has awarded over $29 million for radiologicresearch and education. The results are impressivegrant recipients have planted our seed money and turned it into over$900 million in additional funding and countless improvements in patient care.

On behalf of the RSNA Research & Education Foundation, I would like to congratulate this years grant recipients. We lookforward to your discoveries in the years ahead. I would also like to give special thanks to our Vanguard companies for theirsupport. With the backing of the entire community we will keep radiology at the forefront of medicine.

Sincerely,

Jack E. PriceChair, Board of TrusteesRSNA Research & Education Foundation

Agfa HealthCareBayer HealthCarePharmaceuticals

Bracco Diagnostics

Canon U.S.A.

Carestream HealthCook Medical

Covidien Fujifilm Medical Systems

GE Healthcare Hitachi Medical SystemsPhilips Healthcare

Siemens Healthcare USA

Toshiba America MedicalSystems Varian Medical Systems

RSNA R&E Foundation

Vanguard Companies


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Survey data reveal the extraordinarysuccessmeasured in subsequentdollarsof investigators with RSNAR&E Foundation-funded researchearly in their careers. Many of thetopics these creative and inquisitiveinvestigators soon translate intoclinical application and dissemination.There is no better investment inthe future of radiologic practiceanywhere in the world.

Gary J. Becker, MD2009 President, RSNA; ExecutiveDirector, American Board ofRadiology

We have to continue working onadvancing radiology science andresearch to sustain our specialtyand compete with others. RSNAR&E Foundation grants played acritical role in my career, acting as a

springboard to get NIH funding. Thework I have done with my grants hasadvanced contrast medium deliverytechnology and improved diagnosticquality of the images we interpret inour daily clinical practice.

Kyongtae Ty Bae, MD, PhD1996 Research Resident GrantRecipient; 1999 Research SeedGrant Recipient; Member ofResearch Study Section

Research Grant Programs

Research Scholar Grant............................................................................................................. 36To provide protected research time to junior faculty members who have completed theconventional resident/fellowship training program(s). The grant prepares research-orientedfaculty to obtain larger grants from other sources, such as the National Institutes of Health(NIH), and to be able to establish their own fully funded research program. $75,000annually for 2 years ($150,000 total) to be used as salary support for the scholar.

Research Seed Grant .................................................................................................................. 67To enable investigators to gain experience in defining objectives and testing hypotheses inpreparation for major grant applications to corporations, foundations, and governmentalagencies. The grant is intended to support the preliminary or pilot phase of scientificprojects, not to supplement major funding already secured. Up to $40,000 for a 1-yearproject.

Research Resident/Fellow Grant ......................................................................................... 814To support trainees who are pursuing careers in academic medicine by allowing recipientsto devote 50% of their time to an approved research project under the guidance of ascientific advisor/sponsor. The grant provides investigators an opportunity to gain furtherinsight into scientific investigation and to develop competence in research techniques andmethods. $30,000 for a 1-year resident project or $50,000 for a 1-year fellow project to beused for salary and/or non-personnel research expenses.

Research Medical Student Grant ........................................................................................1427To make radiology research opportunities possible for medical students and to encouragethem early in their medical careers to consider academic radiology as an option for theirfuture. Students are expected to complete a 3-month, full-time research project under theguidance of a scientific advisor. $3,000 for a 3-month research project to be matched bythe sponsoring department ($6,000 total) as a stipend for the medical student.

Education Grant Programs

Education Scholar Grant ........................................................................................................2832To provide funding opportunities for individuals with an active interest in radiologiceducation. Any area of education related to the radiologic sciences is eligible for EducationScholar Grant support. Up to $75,000 annually for up to 2 years ($150,000 maximum) for

salary support and/or other project costs.

RSNA/AUR/APDR/SCARD Radiology Education ResearchDevelopment Grant ........................................................................................................................ 33To encourage innovation and improvement in health sciences education by providingresearch opportunities to individuals in pursuit of advancing the science of radiologyeducation. This program will help build a critical mass of radiology education researchersand promote the careers of persons advancing the science of radiology education. Up to$10,000 for a 1-year project to help cover the costs of research materials, researchassistant support, and limited primary investigator salary support.

Recognition Awards

Roentgen Resident/Fellow Research Award ..................................................... 3436To recognize and encourage residents and fellows who have played an active role inradiologic research during the past year. Participating North American residency programsreceive an award plaque with room for the name of each years recipient. The Foundationprovides a personalized award for the department to present to the selected resident orfellow.

Outstanding Researcher/Educator Awards ....................................................... 3738To annually recognize and honor one senior individual in each category who has madeoriginal and significant contributions to the field of radiology or radiologic sciencesthroughout a career of research or teaching and education. Awardees are honored at theopening session of the RSNA Scientific Assembly and Annual Meeting.


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Steve Y. Cho, MDRadiologyDivision of Nuclear Medicine/PETThe Johns Hopkins University

School of Medicine

Bracco Diagnostics/RSNAResearch Scholar Grant

Prostate Specific Membrane Antigen (PSMA) PETImaging for Detection of Metastatic Prostate Cancerand Solid Tumor Neovasculature

Metastatic prostate cancer diagnostic imaging using traditional anatomic modalities including CT, MRIand ultrasound, as well as [18F]-FDG PET metabolic imaging, is limited. PSMA is a protein highlyrestricted to prostate cancer. PSMA is also found to be specifically expressed on the neovasculatureof many solid tumors but, interestingly, not in prostate tumor neovasculature. ProstaScint, aradiolabeled monoclonal antibody binding to the intracellular domain of PSMA, was developed todetect prostate cancer lymph node metastases but has limited accuracy due to antibody targetingcharacteristics. Tumor vascular imaging in a number of solid tumors with another PSMA monoclonalantibody, J591, has been recently demonstrated.

Intact monoclonal antibodies-based tumor detection is limited because of their low permeability insolid tumors and slow clearance from the circulating blood pool. Smaller molecular weight-basedradiotracers are more optimal for tumor detection because of their higher permeability into solidtumors and improved blood clearance in comparison to intact antibodies. [18F]-DCFBC is a novel,low-molecular-weight radiotracer targeting the more accessible extracellular domain of PSMA.

Preclinical mouse prostate cancer tumor model imaging studies of [18F]-DCFBC demonstrate that thisnew ligand has high uptake in PSMA-expressing prostate cancer cells. [18F]-DCFBC is a clinicallypractical PET imaging agent with superior pharmacodynamic and pharmacokinetic characteristics thatwarrants further evaluation in clinical trials.

[18F]-DCFBC PET images will be compared to conventional imaging methods and bone scan tolocalize tumors in patients with advanced metastatic prostate cancer. Radiation dosimetry andbiodistribution of [18F]-DCFBC will be determined by PET imaging in patients with metastatic prostatecancer to calculate whole-body and organ-specific radiation dosimetry.

We will also evaluate the potential of [18F]-DCFBC PET to specifically target neovasculature in solidtumors, excluding prostate cancer. Tumor neovasculature PSMA expression will be obtained by tissueimmunohistochemistry and compared to [18F]-DCFBC PET findings.

Jiang Du, PhDRadiologyUniversity of California, San Diego

Agfa HealthCare/RSNAResearch Scholar Grant

Direct Imaging and Quantification of Cortical Bone ona Clinical 3 T MR Scanner

Imaging of bone has been of fundamental importance to the practice of radiology. Plain radiographsand CT provide images of high spatial resolution, and bone density is readily measurable with DEXAand CT. However, the images and measurements very largely reflect the mineral content of bone, notthe organic matrix or bone water that occupy a larger volume and have important mechanical andbiological properties.

There has been considerable interest in assessing the organic matrix and water in bone with magneticresonance (MR) imaging. But bone has a very short T2, producing no signal with all clinical pulsesequences. Ultrashort echo time (UTE) sequences with TEs 100-1000 times shorter than theseavailable on clinical scanners allow direct visualization of cortical bone. The objective of this proposalis to develop qualitative and quantitative techniques to image and quantify cortical bone on a 3 T

clinical scanner.

The research plan includes three parts: 1) Developing UTE imaging sequences. Technical issuesincluding eddy currents, gradient non-linearity, and long T2 suppression will be addressed. 2)Developing quantitative techniques. A saturation recovery technique will be used for T1 measurementand multiecho techniques for T2* measurement. Reference standards will allow bone water to beestimated. Bone bulk susceptibility will be estimated using a novel UTE spectroscopic imaging(UTESI) technique. 3) Applying UTE imaging and quantitative techniques to normal volunteers andtwo groups of patients (osteoporosis and osteomalacia). Volunteer data will be correlated with age,sex, and weight and will serve as a control group. Patient population data will be compared to thecontrol group.

After the proposed project period, we will have developed UTE sequences for the first quantitativeevaluation of cortical bone in normal volunteers and patients. The noninvasive characterization ofcortical bone could be revolutionary if it proves to have a specific MR signature.

GrantRReesseeaarrcchh SScchhoollaarr


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Prostatic Artery Embolization as a Primary Treatmentfor Benign Prostatic Hyperplasia

A third of men aged 50 years and over will develop bladder outlet obstruction/irritation from benignprostatic hyperplasia (BPH), and a quarter will require surgical intervention. The surgical standard,transurethral resection of the prostate, requires a 5-day hospital stay and has >50% incidence ofcomplications (eg, urethral stricture, urinary incontinence, impotence) leading many to search foralternative, minimally invasive options. Selective embolization of the prostatic artery has been reportedas a safe and effective treatment for prostate bleeding after TURP or biopsy. Along these lines, wegenerated preliminary results in six dogs with BPH and demonstrated a 40% reduction in prostate

volume at 1 month following embolization with microspheres, with subjectively better results, butgreater initial urinary retention, using a bilateral embolization technique.

Specific aims:1. To determine 6-month safety of prostate embolization in a canine model;2. To assess short/mid-term effects of prostate embolization for BPH on gland volume and

perfusion, urethral obstruction, and histology;3. To refine the technique by optimizing embolization particle size and assessing the need for

bilateral versus unilateral embolization.

Dogs with BPH will undergo selective bilateral embolization of the prostatic arteries with 100-300m,300-500m or 500-700m (n=6, each) microspheres. Animals will be monitored clinically for 1 monthafter embolization for infectious, ischemic, or other complications. Retrograde urethrocystography anddynamic contrast-enhanced MRI will be obtained prior to embolization and after 1 month forquantitative and qualitative analysis of urethral stenosis, prostate volume, and enhancement. After 1month, prostates will be excised for radiologic-pathologic correlation and microscopic analysis (particledistribution, necrosis, inflammation). Unilateral versus bilateral embolization with the ideal particle sizewill be compared (n=6, each), with a 6-month follow-up (results of Phase I).

This is a potential revolutionary treatment analogous to uterine artery embolization that has the abilityto evolve into treatment for prostate cancer (radioembolization-Y90, chemo/hormonal embolization).

Salomao Faintuch, MDRadiology

Beth Israel DeaconessMedical Cente

Harvard Medical Schoo

GE Healthcare/RSNAResearch Scholar Gran

Evaluation of Magnetic Nanoparticle EnhancedMagnetic Resonance Imaging in Clinical AutoimmuneDiabetes

Type I diabetes mellitus (DM) is an irreversible, chronic disease causing disproportionately high per-capita healthcare expense (~5 fold greater than non-diabetics), secondary to both long-term glycemicmanagement and occasional devastating acute and chronic complications. Although it is wellestablished that DM results from autoimmune destruction of the insulin producing beta cells of thepancreatic islets, a true understanding of its immunopathogenesis in humans has remained elusive.Previous techniques used to quantify insulitis (to measure the degree of inflammation and isletdestruction) and beta cell mass (BCMa measure to gauge the amount of residual beta cells) areinvasive and impractical for most human studies. Imaging may therefore play an important role inquantifying insulitis and BCM. Radionuclide attempts have shown initial promising results in animal

models of diabetes, without successful translation into human clinical trials. As novelimmunomodulatory therapies evolve in order to prevent beta cell destruction, a noninvasive, accuratemeans of visualizing and quantifying BCM and insulitis becomes critical. Recently, we developed atechnique based on the properties of magnetic resonance imaging (MRI) enhanced with magneticnanoparticles (MNP) to allow indirect quantification and visualization of insulitis in animal models ofDM. We validated this MNP-MRI technique by correlating our findings with the standard invasivetechniques used to study diabetes, including histology and flow cytometry of the pancreas andpancreatic inflammatory infiltrate samples. Initial translation of this technique has resulted in a trial tostudy insulitis in humans, funded by the NIAID (PI Mathis/Weissleder). Twelve patients with earlyonset diabetes have been enrolled with encouraging results. We are now poised to translate andoptimize this technology and apply it to an extended human clinical trial.

Alexander R. Guimaraes, MD, PhDRadiology

Massachusetts General Hospita

Bayer HealthCarePharmaceuticals/RSNAResearch Scholar Gran


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Mizuki Nishino, MDRadiologyBrigham and Women's HospitalDana-Farber Cancer Institute

Agfa HealthCare/RSNAResearch Scholar Grant

Chronological Analysis of Tumor Size, Volume, andCT Attenuation Coefficient in Women with

Adenocarcinoma of the Lung Treated with Erlotinib

Lung cancer is a leading cause of cancer death in the United States and worldwide. One of the recentbreakthroughs in lung cancer treatment was the discovery of the somatic activating mutations of theEGFR tyrosine kinase domain in non-small cell lung cancer, which is associated with a dramaticclinical response to EGFR inhibitors such as gefitinib and erlotinib. Erlotinib is particularly effective inwomen with adenocarcinoma. However, most patients with initial responses to erlotinib treatment

eventually relapse due to acquired resistance to erlotinib.

The purpose of this proposal is to analyze chronological changes in tumor size and volume in womenwith adenocarcinoma of the lung treated with erlotinib, and to determine if the tumor size change rateand the tumor volume change rate precede the actual increase in tumor size and volume due torelapse. If a perceptible tumor size change rate and tumor volume change rate precede the increasein tumor size and volume, oncologists can switch to another therapeutic agent before relapse in orderto prolong disease-free survival.

The study will be performed using data collected in a Phase II prospective clinical trial of erlotinib inwomen with previously untreated advanced adenocarcinoma of the lung at Dana-Farber/HarvardCancer Center, which has enrolled 84 subjects. Data include chest CTs performed every 8 weeks andEGFR mutation analysis. Size, volume, and CT attenuation will be measured using a semiautomaticimage-processing program. Rate of tumor size and volume changes will be calculated and will becorrelated with clinical outcome and genetic analysis results.

The long-term goal is to determine the imaging parameters that most efficiently predict acquiredresistance to erlotinib by correlating the imaging parameters with the genomic characterization of thetumor, in order to optimize the therapeutic benefit of erlotinib and contribute to the prolongation ofsurvival in lung cancer patients.

Myria Petrou, MA, MBChBRadiologyUniversity of Michigan HealthSystem

Covidien/RSNAResearch Scholar Grant

Hyposmia, Septohippocampal CholinergicDenervation, and Amyloidopathy in Mild CognitiveImpairment

Alzheimers disease (AD) is the most common form of dementia, accounting for over 50% of cases ofage-related dementia in the over 65 population. Amyloid misprocessing/deposition and cholinergicneuron degeneration are key aspects of AD pathogenesis. In addition, substantial reductions inneuronal nicotinic Acetyl Choline receptors (nAChRs) in the cortex of AD patients have beendocumented on post mortem specimens.

Given the recent emergence of potential disease modifying anti-amyloid treatments there is acompelling need for biomarkers that can identify subclinical/very early disease. Identification ofamyloidopathy is possible using PET imaging, however, the cost of this technology is prohibitive forscreening large populations.

Olfactory disturbances commonly precede clinical manifestations in a number of neurodegenerativedisorders including AD. There are reports of selective olfactory abnormalities in subjects with mildcognitive impairment (MCI) who convert to fulminant AD; pathophysiological mechanisms underlyingthe hyposmia do however remain unclear.

We propose evaluating the potential of an AD-selective smell identification test as an early screeningtest for AD. For this purpose, we intend to study well-characterized subjects with mild cognitiveimpairment (MCI) with a clinical olfactory test and amyloid PET imaging assessment. We will also goon to explore mechanisms underlying the hyposmia in MCI subjects, specifically that degeneration ofsepto-hippocampal cholinergic projections occurs early in AD and may provide an explanation for theselective deficits in odor identification. We will use well established methodology for imaging ofcholinergic pathways using Acetylcholinesterase (AChE) PET with [11C]PMP. We also propose toinvestigate the specific role of synaptic nicotinic cholinergic receptors in amyloidopathy-relatedhyposmia using [18F]XTRA,a novel Acetylcholine Receptor (nAChR) PET radioligand.

Improved insights in pathobiological mechanisms of hyposmia in AD will not only allow early screeningof at risk subjects but may also provide novel therapeutical targets in patients with very early disease.


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Creation of a Model for Predicting Response toChemoradiation in Head and Neck Squamous CellCarcinoma

Chemoradiation of head and neck squamous cell carcinoma (HNSCC) is challenging due to frequentlocal or regional failures. Our objective is to develop a prediction model using pre-therapydemographic, pathologic, and MRI parameters to identify HNSCC patients who respond poorly tochemoradiation. Our long-term goal is application of the model prospectively in a multicenter clinicaltrial to identify poor responders who may benefit from escalated radiation doses, which are now

feasible and safer due to advances in targeted radiation delivery, and can improve disease-freesurvival.

Among the factors influencing tumor response, we will study tumor cellularity as a key predictor.Diffusion weighted MR imaging (DWI) is a molecular imaging technique measuring apparent diffusioncoefficient (ADC), which is considered a surrogate marker for tumor cellularity. The proposed study ispart of an ongoing trial at the University of Michigan involving serial MRIs in HNSCC patients(baseline, during third week of therapy and at 3 months) to study the utility of serial ADC values inassessing tumor response. Patients undergo standard-of-care chemoradiation and therapeuticresponse is assessed after 3 months. As an additional step to this trial, we propose to use only thebaseline MRI data to construct a prediction model that will provide information on the utility of pre-therapy scans alone in predicting response.

Our specific aims are (1) building a prediction model using age, pathological grade, tumor volume,nodal status, whole tumor mean ADC, and fractional tumor volume below an ADC threshold asparameters influencing tumor response to chemoradiation, and (2) assessing the value of adding

fractional tumor volume below an ADC threshold to whole tumor mean ADC in predictingtherapeutic response.

Developing noninvasive imaging parameters that identify poor responders to chemoradiation isimportant since therapy can then be individualized to increase chances of treatment response.

Ashok Srinivasan, MDRadiology

University of MichiganHealth System

Carestream Health/RSNAResearch Scholar Gran

Quantification of Tumor Angiogenesis UsingDiffusion and Perfusion Weighted MR DerivedParameters Correlated with Vascular EndothelialGrowth Factor (VEGF) Expression and MicrovesselDensity in Renal Cell Carcinoma

There is up-regulation of vascular endothelial growth factor (VEGF) in renal cell carcinoma (RCC) andthis VEGF expression has been shown to be an important prognostic marker. Furthermore, newexperimental drugs which target angiogenic tumor pathways in the treatment of metastatic RCC arebeing designed, tested and have been recently introduced in the clinical practice. The aim of thisproject is to correlate quantitative MR markers of tumor angiogenesis with VEGF expression andmicrovessel density (MVD) in RCC. We hypothesize that VEGF expression and MVD measured withpathology is strongly associated with imaging parameters of angiogenesis measured with diffusion

(using intravoxel incoherent motion [IVIM] model) and perfusion-weighted MRI (PWI).

We will prospectively enroll 30 patients with RCC prior to undergoing surgical treatment (total or partialnephrectomy). Imaging will be performed within 60 days of the surgery at 1.5 or 3.0 T utilizing diffusionweighted imaging (DWI) with multiple b values, and PWI with high temporal resolution. DWI data willbe processed to extract the IVIM parameters (perfusion fraction fp and pseudodiffusivity Dp). A two-compartment adiabatic tissue homogeneity (ATHs) model will be used to analyze the PWI data and togenerate perfusion parameters (including tumor blood volume and tumor blood flow). Quantitative MRparameters will be correlated with lesion size and differentiation, MVD, and VEGF expression obtainedat histopathology. If validated, MRI could be used as a non invasive biomarker of angiogenesis, andcould be used for predicting and monitoring response to targeted anti-VEGF and tyrosine kinaseinhibitor drugs which are currently under investigation in RCC. Future work will be oriented towards theprospective use of MRI biomarkers of angiogenesis in prediction and monitoring of RCC response toanti-VEGF treatments.

Hersh Chandarana, MD

RadiologyNew York University

School of Medicine

Toshiba America MedicaSystems/RSNA

Research Seed Gran

GrantRReesseeaarrcchh SSeeeedd


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Kevin Kozak, MD, PhDHuman OncologyUniversity of Wisconsin School ofMedicine and Public Health

Philips Healthcare/RSNAResearch Seed Grant

Exploiting Angiogenic Rebound with IonizingRadiation

Vascular endothelial growth factor receptor (VEGFR) inhibitors represent a promising class of anti-neoplastic agents and early investigations of combined VEGFR blockade and ionizing radiationsuggest impressive clinical activity. However, several critical questions remain. VEGFR inhibitors maylead to compensatory increases in circulating pro-angiogenic and decreases in circulating anti-angiogenic molecules. We hypothesize that these rebound phenomena may drive briskangiogenesis and tumor cell proliferation with inhibitor discontinuation. We further hypothesize thationizing radiation may be uniquely efficacious during this rebound phase.

To rigorously test these hypotheses, we will use a human pancreatic cancer xenograft model. We willquantify changes in the plasma angiogenic proteome with continuous and discontinuous VEGFRinhibition. Combined regimens of VEGFR inhibitors and ionizing radiation will be examined to test forpotential deleterious effects of cyclic VEGFR inhibitor monotherapy and for enhanced tumorradiosensitivity during angiogenic rebound.

These studies will meaningfully address three central clinical questions. First, they will assess theconsequences of VEGFR discontinuation and clarify the merits of continuous versus cyclic anti-angiogenic therapy. Second, these studies will provide insights into the potential value of VEGFRinhibitor continuation even in the face of apparent clinical resistance. Finally, through the identificationof a novel interaction between anti-angiogenic and radiation therapies, these studies will quantitativelyexamine the potential for exploitation of angiogenic rebound with ionizing radiation.

Answers to these questions will provide the foundation for hypothesis-testing in humans in the setting

of translational and Phase I clinical trials. Moreover, continued refinement of our model of angiogenicrebound will permit follow-on preclinical evaluation of potentially useful technologies including, forexample, [18F]-fluorothymidine positron emission tomography to track rebound endothelial and tumorcell proliferation. The proposed project will be the first step in an integrated bench-to-bedside-and-back effort to optimize anti-angiogenic therapy.

Lewis Shin, MDDiagnostic RadiologyStanford University

Hitachi Medical Systems/RSNAResearch Seed Grant

Real-Time MRI Evaluation of the Upper Airway inPatients with Obstructive Sleep Apnea with EEGCorrelation

Obstructive sleep apnea (OSA) is a common and frequently undiagnosed condition where there is

recurrent upper airway collapse during sleep. Patients experience repetitive, brief awakeningsresulting in fragmented sleep which causes fatigue and excessive daytime sleepiness. Consequencesof OSA are numerous but include serious cardiovascular and neurovascular diseases.

OSA treatments are poorly tolerated, ineffective and/or invasive. Patients who can not tolerateconventional positive airway pressure therapy can undergo Phase 1 oral-maxillofacial surgeries toenlarge the upper airway and reduce collapsibility.

Failure rates are as high as 60% and poor surgical outcomes have been attributed to inaccurate pre-operative localization and characterization of airway collapse. Most pre-surgical evaluation isperformed while the patient is awake or under a pharmacologically induced sleep. As a result, airwaycollapse that occurs during natural sleep is not always reflected in these exams.

We hypothesize that pre-surgical MR imaging with EEG correlation under natural sleep will moreaccurately identify site(s) of airway collapse, thereby improving surgical planning and clinicaloutcomes. We will scan 20 subjects who will undergo Phase 1 OSA surgery.

Before and after review of MRI/EEG data, we will evaluate the OSA surgeon for changes in: 1)assessment of characterization of airway collapse; 2) surgical plan; and 3) prediction of successfulcorrection. Surgeon's impression of MRI/EEG usefulness will be investigated. To evaluate forimproved clinical outcomes, we will compare polysomnography and sleepiness scale questionnaireresults with data from matched controls. Appropriate statistical analysis will be performed to determinesignificance.

Dramatic improvements in clinical efficacy may result in a new paradigm for pre-OSA surgicalevaluation. Long-term goals would include: optimizing (shortening) scan protocol for clinical practice;evaluating other existing therapies (dental appliances, radiofrequency ablation, Phase 2 surgery) andemerging treatments to advance improvement strategies; and computational modeling with this datato lay groundwork for developing innovative, minimally invasive treatments.


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Molecular and Bioinformatic Identification ofEpithelial Ovarian Cancer Stem Cells

Stem cells organize and populate the body through a hierarchy of proliferation and differentiation,while retaining the capacity to continuously self-renew. The insight that this physiologic order mirrorsthe deranged orderliness of a developing malignancy led to the cancer stem cell (CSC) hypothesis,which proposes that each tumor consists of a heterogeneous population of cells at various stages ofdifferentiation, but all derived from the same small CSC pool; that purging tumors of this CSC pool willbe sufficient to undermine their accumulated bulk and recurrence risk. Originally conclusivelydemonstrated for AML, this elemental population has since begun to be described in solid tumors,most prominently in breast cancer.

Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological cancers, with14,000 deaths annually. While EOC is thought to arise from the ovarian surface epithelium,pathogenesis is poorly understood. Therapy options are similarly limited, especially with radiotherapyhobbled by toxicity. This study proposes to build on our previous monoclonal antibody library work, inwhich we identified a potential negative marker for EOC stem cells. Aim 1 seeks to exploit this footholdby use of genetic array, single cell expression array, and bioinformatics to rapidly expand the list ofpotential markers. These markers will then be screened against published datasets linked to clinical

outcomes data to screen for clinical significance. Aim 2 seeks to validate the efficacy of these markersboth in vivo by their ability to fractionate ever purer populations of CSCs and in vitro by induction ofeither differentiation or killing of tumorigenic spheroids. Potentially therapeutic antibodies will beevaluated in murine xenograft models.

The CSC hypothesis has far reaching implications for both scientific understanding and therapy. Anidentified CSC population permits more specific screening for vulnerable molecular pathways andimmunologic targets amenable to radioimmunologic therapy.

Robert Chin, MD, PhDRadiation Oncology

Stanford University Medical Cente

Philips Healthcare/RSNAResearch Resident Gran

Increasing Spatial Resolution and Depth of Optical

Fluorescent Imaging Using Microbubble UltrasoundContrast Agents

Optical imaging is the most sensitive molecular imaging tool that can capture molecular and cellularprocesses in real time. Its major limitations are poor spatial resolution (~1cm3) and limited penetration(23cm) due to extremely high scattering and absorption by tissues. The high scattering results in poorspatial resolution because of the inability to accurately localize the exact origin or path of the detectedphoton.

It is well known that ultrasound (US) modulates photons passing through its focal zone because theUS wave moves optical scatterers/absorbers to affect the light differently during the US compressionand rarefaction phases. This technique, called acousto-optic imaging (AOI), can accurately localize thedetected US-modulated photons since the location of the US focal zone is known in the 2D space. AOIcan potentially improve optical imaging resolution to nearly that of US resolution (few mm3). Since thedetected optical signal is dominated by near field photons, modulated photons detected from greater

depth improve imaging of deeper tissues. The major challenge in AOI is the recognition of the fewmodulated photons leading to poor signal-to-noise ratio (SNR) that decreases further with depth. Weshowed in preliminary studies that microbubbles not only increase photon modulation amplitudebecause of their greater oscillation in an US field, but also generate harmonic modulation thatimproves sensitivity and specificity of the detected modulation. Since it is known that US can alsomodulate fluorescent signal, we plan to test whether microbubbles will also improve fluorescent SNRto improve spatial resolution and depth of optical fluorescent imaging.

We propose to engineer a custom AOI system to image fluorescent-labeled targets within turbidmedia, produce and optimize fluorescent-labeled microbubbles to be employed as contrast agents forAOI, and determine the improvement in maximum depth of imaging and spatial resolution whenfluorophores are used without, with and when attached to microbubbles.

Mohammad Eghtedari, MD, PhDDiagnostic Radiology

University of California, San Diego

Bracco Diagnostics/RSNAResearch Resident Gran

GrantRReesseeaarrcchh RReessiiddeenntt//FFeellllooww


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Reza Forghani, MD, PhDRadiologyCenter for Molecular ImagingCenter for Systems BiologyMassachusetts General Hospital

RSNA Research Fellow Grant

Molecular Imaging of the Inflammatory EnzymeMyeloperoxidase in Murine Cerebral Ischemia

Inflammation has been shown to correlate with adverse stroke outcome but the specific underlyingmolecular mechanisms and their impact on stroke outcome remain poorly understood.Myeloperoxidase (MPO) activity has been widely used as a pathological marker for inflammation inanimal models of stroke in biochemical and histopathological analyses. However, traditional methodsof investigation that require sacrificing the animals limit serial and longitudinal investigations thatwould greatly facilitate pathobiological and pharmacological investigations, and often requireexcessively large numbers of animals to achieve sufficient statistical power to confirm a therapeutic

benefit. The emergence of molecular imaging methods can largely overcome these obstacles.

We propose to use Gd-bis-5-HT-DTPA (MPO-Gd), a highly sensitive and specific molecular imagingreporter of MPO activity developed in our laboratory, to study the role of inflammation in mousemodels of cerebral ischemia. We will evaluate the role of MPO in infarct propagation by seriallyexamining MPO activity and infarct volume on MPO-Gd enhanced MRIs with and without treatmentwith the specific MPO inhibitor 4-aminobenzoic acid hydrazide. In addition, we will perform a similarevaluation on MPO knock-out mice for comparison. We will then correlate the findings withbiochemical and histopathological analyses to confirm our imaging observations and validate MPOmolecular imaging as a tool for noninvasive in vivo investigation of inflammation.

These investigations could provide the basis for novel therapies to improve stroke outcome inconjunction with an imaging paradigm for assessing the effectiveness of such interventions indiseases with an inflammatory component in animals and potentially in human diagnostic imaging.

A. Paiman Ghafoori, MDRadiation OncologyDuke University Medical Center

Fujifilm Medical Systems/RSNAResearch Resident Grant

Using Micro-CT to Define the Role of EndothelialCells in the Response of Primary Lung Cancers toRadiation Therapy

Despite aggressive treatment with radiation therapy, lung cancer remains the leading cause of cancerdeath in the United States. Efforts to improve the efficacy of radiation therapy are hindered byuncertainties in its mechanism of cell death and in identifying its precise cellular targets. The role ofthe vasculature in the response of carcinomas to radiation therapy is controversial. Furthermore, themechanism of cell death in the vasculature after radiation therapy is unclear, and the role of p53 inmediating these processes is debated.

We aim to resolve this important controversy using sophisticated genetically engineered mousemodels of lung cancer combined with state-of-the-art small animal imaging techniques. Using Cre-loxtechnology we will delete Bax specifically in endothelial cells and determine whether endothelial cellapoptosis regulates the response of primary lung tumors to radiation therapy. We will also clarify therole of the p53 gene in mediating apoptosis in endothelial cells and in the response of primary lungtumors to radiation therapy by deleting p53 specifically in endothelial cells. Microcomputedtomography will be used to follow primary lung tumors in mice and assess the effect of these geneticalterations on the response of tumors to radiation therapy.

We postulate that lung cancers with endothelial cells that lack p53 will be more sensitive to radiationtherapy and that lung cancers with endothelial cells unable to undergo apoptosis will be moreresistant. These studies will enhance our understanding of lung tumor biology and will lay thefoundation for new treatment approaches to cure patients with lung cancer.


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Adenosine Induced Stress Myocardial PerfusionImaging Using Dual Source Cardiac ComputedTomography

The current workup of symptomatic coronary artery disease (CAD) usually includes noninvasiveimaging. Nuclear myocardial perfusion imaging (MPI) provides reliable information on the functionalsignificance of coronary stenosis, yielding important management and prognostic information.However, it cannot assess coronary anatomy, thereby necessitating invasive coronary angiography(ICA) in many patients.

Advances in cardiac CT have enabled noninvasive assessment of coronary stenosis with excellentdiagnostic accuracy. Recent studies have demonstrated that cardiac CT can assess myocardialfunction including perfusion and regional wall motion. In a preliminary study of 27 patients, wedemonstrated that dual-source CT can identify adenosine stress-induced myocardial perfusion defectsin patients with suspected CAD with a diagnostic accuracy at least equal to MPI, with similar radiationdose, while simultaneously assessing coronary anatomy.

In this observational study, we will investigate 50 patients who have undergone recent MPI and arescheduled for ICA. Using a DSCT, we will perform adenosine stress retrospective CT (QCT) followedby rest prospective CT (CTA). Images will be analyzed to assess myocardial perfusion reserve andangiographic evidence of stenosis. We will determine the sensitivity and specificity of QCT on a per-patient and per-vessel basis for the diagnosis of significant CAD, compared to MPI, using ICA as areference.

Aim 1: Determine the feasibility and accuracy of QCT to detect myocardial perfusion defects in a

symptomatic population as compared to MPI. Hypothesis: The accuracy of QCT for the detection ofhemodynamically significant coronary stenosis is equivalent or better than MPI, using ICA as thereference standard.

Aim 2: Determine the incremental value of CTA in conjunction with QCT for the detection of significantcoronary stenosis as compared to MPI. Hypothesis: Incorporation of CTA data with QCT data allowssignificantly greater accuracy for the detection of hemodynamically significant coronary stenosis thanMPI, using ICA as the reference standard.

Brian Ghoshhajra, MDRadiology

Cardiac CT/MR/PET ProgramMassachusetts General Hospita

Siemens Healthcare/RSNAResearch Fellow Gran

Targeted Radioiodinated Nanoparticles for theTreatment of High Grade Glioma

Utilizing biopanning techniques with bacteriophage, we have recently demonstrated that amongscreened phage-displayed peptides, the HVGGSSV peptide binds with high sensitivity and specificityto irradiated xenograft glioma tumors. When bound to near infrared imaging agents, this peptideselectively binds to responding irradiated tumors differentiating responding from non-respondingtumors.

We propose that radioiodination of the HVGGSSV peptide/phage, an HVGGSSV-decorated liposome,labeled nanoalbumin or other biocompatible and biodegradable vector systems could be used todeliver targeted radioactive iodine NP vectors for the treatment of high grade glioma. We will study thebiodistribution and pharmacokinetics of these systems to determine the optimal NP vector system forthe treatment of high grade glioma.

Aim 1: To determine the mechanism by which the HVGGSSV binds to irradiated tumormicrovasculature. We hypothesize that the HVGGSSV peptide binds to a radiation-inducible antigenon tumor vascular endothelium. Utilizing affinity purification techniques and PDZ domain arrays, wewill identify proteins bound by our peptide.

Aim 2: To conjugate radioactive iodine directly to the HVGGSSV peptide and bacteriophage. Wehypothesize that radioactive iodine bound to our polyvalent peptide will retain its tumor specificity. Wewill directly conjugate the HVGGSSV peptide and phage to radioactive iodine and optimize conditionsto achieve tumor-specific targeting. We will also evaluate pharmacokinetics of the radioiodinatedpeptide and phage to determine the best candidate for studies of therapeutic response in xenograftmodels of glioma.

Aim 3: To conjugate radioactive iodine to nanoalbumin and liposome vectors. We hypothesize thatradioactive iodine bound to HVGGSSV-decorated liposomal and nanoalbumin vectors can retaintumor specificity and deliver the nanoparticles to irradiated tumors. To form targeted radioiodinatednanovectors, we will conjugate radioactive iodine to HVGGSSV-decorated liposome and nanoalbuminvectors. We will determine the ability of these nanoparticles to bind to irradiated tumors and altertumor growth kinetics in vivo.

Jerry Jaboin MD, PhDRadiation Oncology

Vanderbilt UniversityMedical Cente

Philips Healthcare/RSNAResearch Resident Gran


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Christopher Lominska, MDRadiation MedicineGeorgetown UniversityMedical Center

RSNA Presidents CircleResearch Resident Grant

An Investigation of EphB1 as a Mediator of the ATPhenotype

Ataxia telangiectasia (AT) syndrome is a rare, autosomal dominant condition characterized by ionizingradiation sensitivity, lymphoid abnormalities, and ataxia with cerebellar degeneration. The molecularresponse to ionizing radiation via ATM (the gene that is mutated in AT) is mediated by a variety ofreceptor tyrosine kinases. The mechanism of cerebellar degeneration is not completely established,although it has been hypothesized to include defective DNA damage repair.

Our work with candidate gene analysis in AT cell lines has suggested that the receptor tyrosine kinaseEphB1 is regulated by ATM. EphB1 is a member of the Eph/Ephrin family of ligands and cellmembrane receptor tyrosine kinases, which play an important role in regulating neural development,cell sorting and synapse formation.

We propose to further characterize the ATM/EphB1 interaction with regard to the response toradiation and the neurological phenotype. Cell culture studies will be performed to confirm regulationof EphB1 by ATM. The effect of EphB1 inhibition on the response to radiation in human cell lines willbe evaluated. We will further characterize the anatomy of the cerebellum in transgenic EphB1 mice.Additionally, we will study EphB1 expression and cerebellar anatomy in AT human brain tissue.

The project will increase our understanding of downstream signaling in the ATM pathway, as well asinvestigating the role of EphB1 in radiation response and development of the cerebellum.

Arta Monjazeb, MD, PhDRadiation Oncology

Wake Forest UniversityHealth Sciences

Philips Healthcare/RSNAResearch Resident Grant

Mechanism of Anti-tumor Immunity Induced by

Radiotherapy and Irradiated Autologous TumorVaccination

Emerging evidence suggests that radiotherapy, although traditionally considered immunosuppressivemay boost anti-tumor immunity. We therefore hypothesize that radiotherapy can be combined withimmunotherapy for therapeutic advantage. Our preliminary data indicate that mice vaccinated withirradiated autologous tumor cells become resistant to future challenge with that tumor. Similar resultsare not seen in mice receiving heat-inactivated or lysed tumor cell vaccines.

We propose to examine the interaction between radiotherapy (XRT) and irradiated autologous tumorvaccines (IATV). Mice with established tumors will be split into five treatment groups: placebo vs IATVvs XRT vs IATVXRT vs XRTIATV. Isobolographic interpretation of tumor growth will determinesynergy or antagonism of modalities.

We will also investigate the underlying immune mechanisms of these therapies. Nave mice will

receive adoptive transfer of immunocytes from vaccinated mice. Transference of tumor resistancewould confirm an immune mediated mechanism.

Mice vaccinated against S-180 will be challenged with CT-26 and vice versa. Lack of cross resistancewould indicate a tumor specific immune response. Tumor infiltrating immunocytes from mice in theaforementioned treatment groups will be analyzed by flow cytometry to determine the types ofimmune cells involved in tumor resistance. To determine which are obligatory for tumor resistance,treated mice will be depleted of individual cell types and then challenged with tumor. Antigen andcytokine expression changes of irradiated tumor cells will be examined in vivo and in vitro.

In light of the growing importance of immunotherapy in cancer treatment, understanding the effects ofradiotherapy on the immune system and how to combine these modalities has significant therapeuticimplications.


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High-Resolution RNA-Based Targeted PET ImagingAgents for Prostate Cancer

Despite advances in screening approaches for prostate cancer (PC), it is anticipated that 28,000 menwill die of the disease this year in the United States alone. This highlights a need for safer and moreeffective imaging technologies for staging and monitoring of PC in these patients.

ProstaScint is the only FDA-approved targeted-imaging agent for PC. However, its clinical utility islimited by low specificity and sensitivity. Therefore, we propose the development of a novel imagingtool for PC that overcomes these limitations.

This imaging agent will comprise a biological targeting moiety (an RNA aptamer) and an imagingmoiety (a chelator) that is conjugated to the aptamer via a molecular linker. The RNA aptamer bindswith high affinity and specificity to an antigen (PSMA) expressed on the surface of PC cells. Theaptamer will be conjugated to a chelator housing a positron emitting radionuclide for use in high-resolution positron emission tomography (PET).

We hypothesize that by optimizing the imaging and targeting moieties of the imaging agent we willenhance binding to its target and improve the overall stability of the radionuclide complex. In specificaim 1, we will test various chelators and linkers used to conjugate the chelator to the RNA aptamer. Inspecific aim 2, we propose the development of structural homologs and multimers of existing PSMA-specific aptamers to increase the aptamers stability and functionality. Finally, in specific aim 3, we testthe binding affinity and specificity of the resulting optimized agents in PSMA-positive PC cell lines. Insummary, we predict that this work will lead to a highly specific PET-based imaging agent that maysubstantially improve the management of PC. The work proposed herein will also contribute to theadvancement of methodologies that can be applied to engineer targeted imaging agents for otherhuman diseases.

William Rockey, MD, PhDRadiation Oncology

University of Iowa Hospitals andClinics

Bracco Diagnostics/RSNAResearch Resident Gran

A Novel CT-based Biomarker for Predicting TherapyResponse in Hepatocellular Carcinoma by Selective

Quantification of Non-necrotic Tumor ComponentsRapid developments in imaging techniques and advent of newer chemotherapeutic agents fortreatment of hepatocellular carcinoma (HCC) have highlighted the limitations of Response EvaluationCriteria in Solid Tumors (RECIST). Estimation of total tumor volume has shown to be more effectivethan RECIST but proves tedious for manual segmentations and poses problems for incorporation inworkflow. Moreover, some targeted chemotherapeutic agents may cause more tumor necrosiscompared to another. This may lead to false positive enlargement of the total tumor size on imaging,which results in overestimation of an otherwise regressed or stable disease, as progressive accordingto existing RECIST or total tumor volumetry criteria. Revisions in tumor response assessment criteriaon imaging are therefore needed.

Our hypothesis is that estimation of interval change in soft tissue volumes in a treated HCC bysegmenting and excluding necrotic portions on baseline and post-treatment MDCT datasets ispossible through automation and can be a better predictor of therapy response than RECIST. This

project will involve retrospective collection of baseline and post-treatment MDCT datasets of patientswith advanced HCC who were treated with the same drug protocol.

Interval change in non-necrotic volume between CTs obtained at different time point by manual andautomated method will be estimated, followed by maximum one-dimensional tumor measurements(RECIST). RECIST measurements and interval change in non-necrotic volume will be obtained bymanual and proposed automated method and correlated with patients overall and progression-freedisease survival. The inter-method and intra-method agreements will also be evaluated by manual andthe proposed automated method.

After successful testing of our hypothesis, this method may have significant impact in clinical oncologyfor therapy response assessment on wider latitude where similar principles for automations can beapplied to other organ tumors.

Anand Singh, MDRadiology (3-D Imaging

Massachusetts General Hospita

Siemens Healthcare/RSNAResearch Fellow Gran


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M. Reza Taheri, MD, PhDRadiologyUniversity of Washington

GE Healthcare/RSNAResearch Fellow Grant

In Vivo MRI Assessment of Erythropoietin Treatmenton the Migration of Iron Oxide-labeled Neuronal StemCells in a Rat Stroke Model

Stroke-related mortality in the Western world is second only to that related to heart disease. Currenttreatment options are of limited benefit. Imaging can play a pivotal role in providing the means fordelineating in vivo molecular mechanisms of the reparative process and site-directed therapy and byoffering early prognostic information. Partial success has been achieved in reversing stroke-induceddeficits with stem cell administration in experimental animals. The conditions required by stem cells to

migrate to peri-infarct tissue and to differentiate into neuronal cells is not yet understood.

Erythropoietin (EPO) promotes angiogenesis in the ischemic boundary region and facilitates migrationof neuroblasts to this area. We hypothesize that co-administration of neural stem cells (NSC) andEPO will result in improved migration of NSC (primary endpoint), decreased size of infarcted tissue,and better functional outcome in a rat stroke model (secondary endpoints). NSC labeled with ironoxide particles with/without the co-administration of EPO will be transplanted into the corpus callosumafter temporary middle cerebral artery occlusion (MCAO) in a rat. The size of the area ofinfarct/ischemia as well as the in vivo rate of migration of NSC will be measured multiple times withMRI during the 3 weeks after MCAO. Evolution of the imaging findings will be correlated to changes inneurologic deficits.

This project will provide new information about the in vivo role of EPO on migration of NSC to peri-infarct tissue and about the importance of this process in post-stroke recovery. This project will allowme to hone my understanding of the pathophysiology of stroke as well as the role of stem cells andimaging in this process. I intend to build on this project and systematically explore the in vivomechanism of migration and differentiation of stem cells.

Terence Williams, MD, PhDRadiation Oncology

University of Michigan

Toshiba America MedicalSystems/RSNAResearch Resident Grant

Identification of Anti-Neoplastic FADD Kinase

Inhibitors Utilizing a Molecular Imaging-Based HighThroughput Screen

Despite advances in our understanding of the derangements in genes and signal transductionpathways associated with neoplastic initiation and progression, there has been minimal impact onsurvival for many types of cancer. For instance, the 5-year overall survival for lung cancer over thepast 15 years remains poor, with mortality in the range of 7090% for locally advanced disease.Previous work has identified that Fas-associated death domain (FADD) overexpression andphosphorylated FADD (p-FADD) serve as prognostic biomarkers in a number of human malignanciesincluding lung cancer, where they are associated with higher proliferation and poor survival.Furthermore, increased p-FADD expression correlated with elevated NF-kB activation. These resultssuggest a relationship between FADD phosphorylation and NF-kB activation, a hallmark of therapy-resistant cancers. I hypothesize that inhibiting FADD phosphorylation may sensitize cancer cells tochemotherapeutic agents. To aid in identification of FADD kinase inhibitors, I will utilize a previouslygenerated pan-FADD kinase reporter (FKR), which non-invasively senses FADD-kinase activity in

real-time through bioluminescent imaging.

In aim 1, the sensitivity and specificity of FKR will be characterized. In aim 2, a high-throughput screenwill be performed to identify compounds that target FADD phosphorylation from a diverse set ofcompound libraries. Utilizing secondary screens, the toxic and less sensitive lead molecules will beeliminated. Their relative efficacy will be evaluated by quantifying IC50 of the top lead compounds.Finally, the specificity of candidate molecules in inhibiting FADD kinases will be investigated usingwestern blotting and protein kinase arrays.

The long-term goals are to identify compounds which inhibit FADD kinase activity and which can betested in pre-clinical models, perhaps in combination with other chemotherapies to determine whetherinhibition of FADD phosphorylation sensitizes cells to chemotherapeutics. Ultimately, thesecompounds may benefit the treatment of tumors that are resistant to conventional therapies.


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Ultra-High Resolution Clinical Imaging of the HumanMedial Temporal Lobe with 7 T MRI

My research goal for neuroradiology fellowship is to investigate the medial temporal lobe at ultra-highresolution with high-field magnetic resonance imaging. I will develop a novel methodology for in vivoimaging of human hippocampal microanatomy using 7 Tesla MRI, employing both structural imagingand diffusion tensor imaging with tractography for microanatomic functional correlation.

In order to obtain maximum resolution under controlled conditions, this protocol will be applied topostmortem specimens of normal brains as well as brains from Alzheimer patients. We then plan to

apply this imaging procedure to patients with clinically defined Alzheimer disease and mild cognitiveimpairment to facilitate the diagnosis of Alzheimer pathology before dementia ensues. Additionally, wewill scan epilepsy patients with possible medial temporal sclerosis to identify with greater accuracyearlier signs of hippocampal derangement.

Michael Zeineh, MD, PhDRadiology

Stanford University

RSNA Research Fellow Gran

Investigating the Role of the Gradient Index inPredicting Side Effects from Gamma KnifeRadiosurgery in the Treatment of Meningiomas

During the development of radiosurgery treatment plans, clinicians use several different approaches tochoose the best plan, clinical expertise being the most important factor. Several measures are in useclinically, such as the conformality index, to help clinicians objectively assess the merits of differenttreatment plans. Recently, Paddick and Lippitz suggested that the gradient index, a measure of thedose falloff outside the tumor volume, might be an effective approach for choosing among plans withsimilar conformity.

The goal of this project is to investigate whether clinicians can use the gradient index (GI) in additionto other dosing parameters to develop treatment plans that will lead to fewer side effects post-gammaknife radiosurgery (GKRS) for the treatment of meningiomas, one of the most common brain tumors.Specifically, we are interested in studying whether the gradient index is correlated with the frequencyand occurrence of side effects post-GKRS treatment in these patients. We are also interested instudying whether treatment plans with lower isodose volumes have the same effect on tumor volumereduction but lead to fewer side effects.

These studies are novel as they will use patient follow-up data to study the efficacy of the gradientindex and will close the gap between the theoretical benefit of the gradient index and its clinicalbenefit. Our study has the potential of having tremendous impact in the treatment planning process. Ifthe GI is found to be correlated with the occurrence of fewer side effects, clinicians can supplementtheir expertise by using this simple and objective calculation to assess the quality of treatment plansleading to significantly fewer side effects and better overall outcomes.

Ehsan Balagamwala, BARadiation Oncology

Cleveland Clinic Foundation

RSNAResearch Medical Student Gran

GrantRReesseeaarrcchh MMeeddiiccaall SSttuuddeenntt


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Brad Barnett, BSRadiologyThe Johns Hopkins UniversitySchool of Medicine

RSNAResearch Medical Student Grant

Evaluation of MR-Visible ThermaSphereMicrospheres for Simultaneous Chemoembolizationand Thermal Ablation

Evaluate the efficacy of transarterial chemoembolization with different MR-visible ThermaSphereformulations that simultaneously provide thermal ablation and doxorubicin release when exposed toan external alternating magnetic field on tumor kill in vitro and in the rabbit Vx-2 liver tumor model.Tumor kill efficacy will be compared to four optimized microsphere formulations including 1) BlandChemoSpheres, 2) Doxorubicin Loaded ChemoSpheres, 3) Bland ThermaSpheres and 4)

Doxorubicin Loaded ThermaSpheres.

It is our hypothesis for this study that control and efficacy can be achieved by localizing, combining,and synchronizing the heat delivery and doxorubicin release. We further hypothesize that such adelivery can be achieved using the appropriate combination of micron- and nano-scale materials andenergy-based remote activation of these materials.

The rationale for this approach is three-fold: First, localizing heat and chemotherapeutic deliveryprovides tissue-sparing control of both agents. Further, synchronizing the delivery of the two agentscan potentially enhance the tumoricidal effects of each agent, increasing the therapeutic benefitsthrough potentiation or synergy. Finally, potential benefit arises from the remote activation and controlof dose and rate by adjusting the heat level with AMF power. In this proposal it is only the initialhypothesis that will be tested. An understanding of the mechanism will be the subject of future efforts.

Waleed Brinjikji, BSRadiologyMayo Clinic


Improving Specificity and Sensitivity of a Computer-Aided Detection Algorithm for Intracranial Aneurysms

Early detection of intracranial aneurysms is important for prevention of the morbidity and mortality thatresult from aneurysm rupture. Detection rates of small intracranial aneurysms (3 mm7 mm) withMRA are low, with sensitivities for trained neuroradiologists of 60%70%. We have designed acomputer-aided-detection (CAD) algorithm designed to detect small intracranial aneurysms on MRAimages. The goal of this project is to enhance the sensitivity and specificity of this algorithm throughdetailed analysis of output data and identification of typical false-negative and false-positive results.

Using available clinical reports and consultation with the scientific advisor, I will analyze 200 MRApatient datasets with angiographically confirmed aneurysms and 500 MRA patient datasets with

angiographically confirmed absence of aneurysms establishing ground truth for presence or absenceof aneurysms. I will then manually delineate a region of interest (ROI) containing each aneurysm.Each segment of the intracranial vasculature will be assigned a unique number to allow for automatedanalysis of vessel location. The ROI will be compared to the results of the CAD algorithm to identifyfalse-negative and false-positive CAD outcomes on a location-by-location basis. We will assess thecharacteristics of false-negative and false-positive cases, including: 1) aneurysm location; 2)aneurysm neck and dome size; 3) diameter of branch vessels near false-positive aneurysm neck;and 4) degree of imaging artifact in parent artery. The dataset generated will then be used by thecomputer scientist group to identify specific, reproducible, and problematic arterial locations oraneurysm types that lead to erroneous CAD outputs. This enhanced understanding of the CADalgorithm will lead to improvements in the algorithm itself, with the long-term goal of optimizingaccuracy.


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Evaluation of the Coagulation State in Relation toTransarterial Chemoembolization for HepatocellularCarcinoma

Transarterial chemoembolization (TACE) is an effective treatment for patients with unresectablehepatocellular carcinoma (HCC). Incidences of both hypercoagulability and bleeding disorders havebeen reported following TACE for HCC, though these findings are complicated by the baselinehypercoagulable state of malignancy and the transient prothrombotic state observed following otherembolization procedures. Therefore, it is unclear what net effect TACE has on coagulability in the

setting of HCC and whether certain patients may be more at risk of complications due to bleeding orclotting.

We propose to obtain serial longitudinal peri- and intra-procedural measurements of coagulation andhyperfibrinolysis markers for this investigation including: thrombin-antithrombin (TAT) complex,prothrombin fragment 1 and 2 (F1.2), platelet factor 4 (PF4), plasmin-2-antiplasmin (PAP) complex,and D-dimer. Samples will be obtained at intervals before and within the first 24 hours aftertransarterial chemobolization. We hope to determine if clotting and/or bleeding risk is high enough towarrant special precautions for some patients undergoing this procedure.

Jacob Brown, BARadiology

Georgetown University & NationaInstitutes of Health MD/PhD

Partnership Program


Detecting Complicated Plaque in the CoronaryArteries using Magnetic Resonance Intraplaque

Hemorrhage (MRIPH) Technique in a Porcine Model ofDiabetes-Induced Accelerated Atherosclerosis

Atherosclerosis is a complicated disease process that is implicated in a number of conditions includingcoronary artery disease (CAD). Despite much research, its pathogenesis is not yet fully elucidated;therefore, good animal models are required in order to learn more about the disease process.

Using magnetic resonance intraplaque hemorrhage (MRIPH), we propose to visualize the progressionof coronary artery atherosclerosis in a previously established porcine model of diabetes-inducedaccelerated atherosclerosis. Six pigs (812 weeks of age) will be randomly allocated to one of twogroups: diabetic-hyperlipidemic (D-HL) (n=4) and nondiabetic-normolipidemic (N-NL)(n=2). In the D-HL group, the diabetic pigs will receive an intravenous injection of streptozotocin (a b-cell cytotoxin) toinduce diabetes and a high-cholesterol (15%), high-fat (15% lard) diet to induce hyperlipidemia. TheN-HL group will not receive streptozotocin and will be on a regular diet. Both groups will receive anMRIPH scan every 5 weeks for 20 weeks and blood work (cholesterol, lipids, fasting blood glucose)

every week for 20 weeks. The animals will be sacrificed at 20 weeks and the left anterior descendingand right coronary arteries will be dissected. The tissue will be analyzed for histological characteristics(evidence of complicated plaque) and the lumen stenosis will be measured. A trained, blindedobserver will interpret the MRIPH images. Imaging results will be correlated with blood work andhistological data.

We hypothesize that diabetic, fat-fed pigs will be more likely to have a positive MRIPH than the non-diabetic, normolipemic group and that there will be an increase in the prevalence and the size of theMRIPH signal with increased progression of the disease.

The goal of this project is to develop the use of imaging to follow disease progression in animalmodels and to determine the usefulness of the MRIPH technique in detecting complicated plaque inthe coronary arteries.

Helen Cheung, BScRadiology

University of Toronto



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Michael Connolly, BMScRadiation OncologySchulich School of Medicine &Dentistry, The University of WesternOntario


Correlation Between Tumor Perfusion Measurementsand Tumor Growth Delay with Radiation Therapy inan Autochthonous Prostate Cancer Murine Model

Todays radiation therapy treatments offer unprecedented radiation delivery flexibilities and ifoncologists knew which tumor sub-volumes are radioresistant and which sub-volumes are radio-sensitive, dose could be prescribed on the basis of biologic target volumes. Prior to implementing thistumor or normal tissue functional imaging for radiotherapy, we have to overcome two hurdles. First,we need to find an imaging modality that yields information relevant to radiation sensitivity. Second,

such information needs to be translated quantitatively into an increase or decrease in radiation dosefor the intended response (enhanced tumor kill or reduced normal tissue damage). CT-perfusion(CTP) and power doppler ultrasound (PDUS) imaging of tumors are two promising techniques forimaging biologic responses to radiation. The use of image-guided animal irradiation experiments canbe an effective pre-clinical assay for novel radiotherapy targeting.

Our study represents the first known attempt at radiotherapy delivered to intact prostate in anautochthonous prostate cancer animal model with image guidance. Using a murine model of prostatecancer, the tumor growth delays (time to reach 5x pre-radiation volume) will be derived from theweekly micro-CT scans following radiation, and we seek growth delays correlation with the level oftumor perfusion from pre-treatment micro-CT and micro-US scans.

The changes in tumor blood flow and volume will be monitored weekly after irradiation by micro-CTand every other day by micro-US. The micro-PDUS data will be cross-correlated with the micro-CTPdata (that we considered to be the gold standard) to see how well measurements with one modality

can be predicted based on measurements with the other modality.

I will be responsible for the micro-US scans as well as the cross-correlation of data between micro-CTP and micro-USPD scans. The supervisor will be responsible for overseeing the entire project,including micro-CT perfusion scans and the radiation therapy.

Cristian Coroian, BSRadiologyUniversity of California, Los AngelesDavid Geffen School of Medicine

Fujifilm Medical Systems/RSNAResearch Medical Student Grant

Retrospective Review of Extra Hippocampal WhiteMatter Abnormality in Patients with Hippocampal

Sclerosis, Using Diffusion Tensor Imaging: ThreeAutomated Post Processing Methods

Detection of white matter abnormality by visual inspection has played an instrumental role inidentification and diagnosis of brain pathology. High resolution scanning and increased computationalpower provide an overwhelming quantity of data for analysis. Minute anatomical abnormalitiesdetected are at a level not visually apparent. Therein lies the motivation for an algorithm that candetect these changes and distinguish the pathological change. To this end, the diffusion tensormagnetic resonance imaging (DT-MRI or DTI) technique has arisen, to characterize white matterconnectivity as a means of inferring pathological change at the neural tract level.

MRI has been particularly successful in demonstrating hippocampal pathology in patients with MTLE.Approximately 1% of the worlds population suffers from epilepsy and current surgical treatmentsleaves 10%30% of patients with persistent disease. Studies have shown putative extra-hippocampalchanges may be of importance. Currently, DTI has improved detection of hippocampal pathology with

significant diffusivity and fractional anisotropy parameter changes. Furthermore, detected whole brainparameter changes suggest that in conjunction with a detection algorithm, DTI can yield a moreeffective diagnostic study. There are multiple methods that can be employed to programmaticallydetect anatomical changes.

We propose to perform a blind retrospective study to analyze pre-surgical DTI imaging of patients whobecame seizure-free or not seizure-free post-surgically. Three methods will be utilized to researchoptimal detection of minute abnormal anatomical change. Correlation will be made between identifiedregions of white matter and neuropsychological testing, electro-encephalographic data, and post-surgical seizure frequency. Consequently false positive and negative rates can be quantified tooptimize the choice of method with corresponding threshold values. Automatically detecting minutewhite matter abnormalities will supplement visual diagnosis and improve pre-surgical planning andpatient's post-surgical outcome.


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Comparison of Quantification Techniques for Long T2Components in Patellar Articular Cartilage at 3 T:Multi-Echo Spin Echo (ME-SE), 2D Spiral ChoppedMagnetization Preparation (2D-SCMP) and T2Preparation with Ultrashort Echo Time (UTE)

Acquisition

Osteoarthritis (OA) is the most common type of arthritis, affecting an estimated 20.7 million adults andcosting nearly $60 billion per year in the United States alone (Buckwalter JA, et al.ADDR58 [2006]150-67). Conventional imaging modalities capture later stages of OA in the form of tissue loss, whichis too late for preventative treatment. In contrast, noninvasive MR evaluation has proven effective incharacterizing both morphologic change in articular cartilage as well as biochemical change reflectinginfrastructural degradation. Specifically, T2 values (an intrinsic MR tissue characteristic) have beenshown to reflect collagen integrity within articular cartilage, offering a noninvasive means of detectingthe earliest structural changes in the degenerative cascade (Gray ML, et al. J MSK Neuron Interact2004; 4(4):365-68, Dijkgraaf LC, et al., J Oral MF Surg1995;53(10):1182-92). Articular cartilage has aknown zonal variation in T2 relaxation times that ranges from 1 msec in the deepest layers to 40 msecin the more superficial layers, the former definitely representing a technical challenge for conventionalMR evaluation.

We propose to test the feasibility of two novel pulse sequences for T2 quantification, the 2D-SCMPand T2 Preparation UTE acquisition, against the standard clinical reference (ME-SE). All pulse

sequences will be tested first in phantoms and subsequently in cadaveric patellar specimens.Cadaveric patellae will be sectioned into 3 mm axial slices using a high-precision saw. MR imagingdata will be collected with a home grown finger coil on a GE Signa Hdx 3.0T clinical scanner. For thephantoms, calculated T2 values from each technique will be compared with known T2 phantomvalues. For the patellar slices, T2 relaxation times will be processed off-line using a Matlab subroutine.In addition, to determine if the novel sequences are sensitive to articular cartilage degeneration, thecadaveric patellae will be subsequently analyzed by biochemical assay and immuno-histochemicalevaluation. Sequence efficiency will be assessed by duration of scan time.

Eric Diaz, BSRadiology

University of California School oMedicine, San Diego


Development of a Decision-Analytic Model toEstimate Long-Term Outcomes of Cryoablation and

Radiofrequency Ablation for Renal CancerA rise in the incidental detection of renal tumors by diagnostic imaging has contributed to anincrease in the incidence of renal cell carcinoma (RCC). Despite improved detection rates, mortalityrates from RCC have not improved, suggesting that current RCC surgical treatment paradigmsrequire reexamination. Determining conditions under which ablative therapies are effective willimprove the quality of patient care significantly and prevent the unnecessary use of invasive andcostly surgical procedures.

The use of ablative therapies in RCC treatment is of considerable interest as they are less invasiveand expensive than the standard surgical treatment, nephron-sparing surgery (NSS). However, theymay be associated with higher local recurrence rates. Our group's preliminary work suggests thatradiofrequency ablation (RFA) is preferred to surgery under most assumptions. Now, building uponthe groups current decision model, we will assess and compare the long-term outcomes ofpercutaneous imaging-guided radiofrequency ablation, cryoablation, laparoscopic, and open NSS

for the treatment of small RCC in a refined, updated decision-analytic model.

To accomplish this, we will first collect data by performing a systematic review of the literature onRFA, cryoablation, and laparoscopic and open nephron-sparing surgery (NSS) for renal tumors. Wealso will perform a systematic review on renal tumor growth/behavior and recurrence, and use theSEER cancer registry to obtain relevant outcomes data.

The cumulative data elicited will provide insight into the current performance status ofradiofrequency ablation, cryoablation, and laparoscopic and open NSS for treating renal tumors, andwill be used to build an updated decision-analytic model that will estimate the life expectancy andlifetime costs consequent to each strategy.

The long-term effectiveness, cost, and cost-effectiveness of each strategy will be compared.

Rebecca Hartman, BAInstitute of Technology Assessmen

Massachussetts General Hospita

Rebecca is enrolled at theUniversity of Pennsylvania

School of Medicine



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Wesley Haynes, BSRadiation OncologyWashington University School ofMedicine


64Cu-ATSM Uptake In Vitro and Ex Vivo in CervicalCancer

The objective of this research is to evaluate 64Cu-ATSM uptake in cervical cancer cell lines and intumor explants from biopsy specimens of patients with newly diagnosed cervical cancer. This is anexploratory study to demonstrate the feasibility of this technique in anticipation of developing furthertranslational research. This is especially important in light of the soon to be activated AmericanCollege of Radiology Imaging Network study (ACRIN 6682), (Phase II Trial of 64Cu-ATSM PET/CT inCervical Cancer). Cervical cancer ranks among the top three cancer diagnoses in women worldwide.

In the United States, the SEER Cancer Statistics Review identified cervical cancer as the third leadingcause of average years of life lost per person dying of cancer for all races and both sexes. About one-third of cervical cancer patients develop recurrent disease, with the majority of these recurrencesdetected within the first 2 years after completion of therapy. Proven predictors of disease recurrenceinclude tumor stage, lymph node status, and tumor hypoxia. Copper (II)-diacetyl-bis (N4-methylthiosemicarbazone), Cu-ATSM, labeled with a positron emitting isotope of copper has beenshown, in vitro and in vivo, to be selective for hypoxic tissue. In silico studies have explored themechanism of its hypoxia selectivity, and clinical studies with this agent have shown noninvasiveimaging data that are predictive of cervical cancer patients response to conventional therapy. Tumorhypoxia is an important prognostic factor in cervical cancer and predicts for decreased overall anddisease-free survival. In part, this is because hypoxic tumors are resistant to radiation andchemotherapy.

Kristina Hoot, PhDRadiation OncologyOregon Health & Science University

Canon U.S.A./RSNAResearch Medical Student Grant

Efficacy of Targeted Molecular Therapies Combinedwith Irradiation on Skin Squamous Cell Carcinomas

Skin cancers are the most common cancer in the United States, of which squamous cell carcinomas(SCCs) are the second most common type. Loss of transforming growth factor beta (TGFb) signalingmediators, Smad2 and Smad4, are among the most common alterations seen in skin SCCs.Keratinocyte-specific Smad2 knockout mice were more susceptible to skin carcinogenesis viatranscriptional upregulation of Snail subsequently downregulating Ecadherin leading to epithelial-to-mesenchymal transition. Keratinocyte-specific Smad4 knockout mice developed spontaneous SCCsmediated by increased TGFb and Smad3 resulting in increased inflammation and genomic instability.Further, both Smad2 and Smad4 knockouts developed increased angiogenesis compared to

chemically induced tumors in wildtype mice mediated by hepatocyte growth factor (HGF) and vasculaendothelial growth factor (VEGF), respectively. Radiation therapy is commonly used in the treatmentof skin SCCs of the head and neck or as adjuvant treatment with a salvage rate of


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Development of Magnetic Resonance Imaging-VisibleEmbolic Agents

Transcatheter arterial chemoembolization (TACE) is a minimially invasive procedure and the currentstandard treatment for unresectable hepatocellular carcinoma. Chemotherapeutics and embolicmaterials such as polyvinal alcohol (PVA) particles are injected locally to produce a combination ofcytotoxic and ischemic effects to induce tumor necrosis. However, difficulty in assessing embolizationendpoint sometimes leads to incomplete treatment, liver damage, or non-target embolization, whichcan decrease treatment response rate or increase mortality and morbidity. To overcome this limitation,we aim to devise and validate MR contrast agent-modified PVA particles (CA-PVA) that can be

visualized intra- and post-procedurally.

Commercially available PVA particles 300700 m in size used clinically will be modified with Gd(III)complexes. Building on previous work in PVA modification done at Northwestern, a new chemicalmodification strategy will be used to improve the loading of Gd(III) per particle and maximize MRsignal. The synthesized CA-PVA will be validated and the imaging parameters optimized using in vitroand ex vivo model systems on a clinical MR scanner. Specifically, CA-PVA will be imaged in capillarytubes, agarose phantoms, rabbit liver tissues, and a dynamic flow model mimicking human arteries.

The long-term goals of this work include validation of CA-PVA using in vivo rabbit tumor models tomonitor real-time delivery and in vivo fate of the embolic material, and eventual clinical translation ofCA-PVA to help optimize TACE protocols to improve success rate.

Hsiang-Hua Hung, BASc, MAScRadiology

Northwestern UniversityFeinberg School of Medicine


Comparison of CT Perfusion and MR PerfusionDerived Cortical Grey Matter CBF in CognitivelyImpaired and Unimpaired Multiple Sclerosis Patients

Quantitative MRP derived CBF correlates with CTP derived values in MS patients. A similar reductionof cortical grey matter CBF is expected for each modality in patients with and without cognitiveimpairment. Our primary objective is to compare measured CTP and MRP derived cortical CBF.Secondarily, we will analyze whether the correlation is maintained in the presence of cognitiveimpairment. The single center pilot study will evaluate 44 MS patients; 22 with cognitive impairmentand 22 without. Patients will be matched for disease duration, age, sex, and their EDSS scores. I will

use my learned expertise to assist with image analysis and compiling research data.

MRP will be performed on a Philips 3 T with a quadrature coil to ensure compatibility with our currentin-house software applications. To allow for direct comparison of the different image sequences, thevolumetric T1 and T2/PD weighted images will be coregistered with the DSC images. These imageswill then be analyzed in a stepwise sequence. CTP will be performed on a 64-slice VCT (GE,Lightspeed VCT). The calculation of CBF, CBV, BBB PS maps from the acquired CT perfusion datawill be performed on a GE advantage workstation (ADW4.2) with the CT perfusion software.

No prior study has evaluated the correlation between CTP and quantitative MRP-derived cortical CBF.Validating this association provides an opportunity for MS patient follow-up using either modality. It issecondarily anticipated that perfusion parameters may provide an important correlation with impairedneurocognition and that this may be used as a surrogate marker of disease activity.

Marcus Jansen, BSCRadiology

University of Ottawa

Philips Healthcare/RSNAResearch Medical Student Gran


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Brian Jin, BARadiologyNorthwestern University

Brian is enrolled at Albert EinsteinCollege of Medicine


The Correlation of Tumor Perfusion with ClinicalOutcomes during Chemoembolization of HepatocellularCarcinoma

Transcatheter arterial chemoembolization (TACE) is an established treatment for non-resectablehepatocellular carcinoma. However, optimal angiographic endpoints of the procedure have not beenestablished. Transcatheter intraarterial perfusion (TRIP) magnetic resonance (MR) imaging offers anobjective method to quantify intraprocedural tumor perfusion change. This study will test the

hypothesis that intraprocedural tumor perfusion change, as detected and quantified by TRIP-MRimaging, correlates with clinical outcomes of TACE on non-resectable hepatocellular carcinomas.

We will recruit 100 consecutive patients with non-resectable hepatocellular carcinoma patients whoare scheduled for TACE using MR monitoring. TACE will be performed in a combinedMR/interventional radiology (MR-IR) suite that allows intra-procedural monitoring. Using TRIP-MR, wewill measure the immediate pre-procedural and post-procedural perfusion by calculating the forwardvolume transfer constant (Ktrans). Pre-procedural, post-procedural, and interval change in Ktrans willbe separately correlated with clinical outcomes immediately after the procedure, and at 1, 3, and 6months follow-up.

Clinical outcomes will consist of a) MR response b) functional MR response as indicated by diffusionweighted MR c) toxicity levels , and d) survival. We expect that baseline and interval reductions inTRIP-MR detected perfusion levels during TACE can predict future clinical outcomes. If so, thenTRIP-MR could be used as a prognostic biomarker during therapy and be used to establish an

endpoint for TACE. It could also potentially help stratify which patients should receive TACE oranother therapy.

Jennifer Kung, BARadiologyUniversity of California, Los AngelesDavid Geffen School of Medicine


Anatomopathological Correlation of Diffusion TensorImaging in Epilepsy Patients with Focal CorticalDysplasia

Focal cortical dysplasia (FCD) is the most common cause of pediatric intractable epilepsy. For the30% of epilepsy patients who cannot be treated with medication, surgical resection is an effectivetherapy. However, subtle forms of cortical dysplasia may be difficult to define on MRI. Pilot studieshave suggested that diffusion tensor imaging (DTI) may improve recognition of FCD in epilepsysurgery patients, but the correspondence between imaging anatomy and pathology remains unclear.The purpose of this study is to relate changes in imaging parameters apparent diffusion coefficent(ADC) and fractional anisotropy (FA) with histopathological changes in patients with focal corticaldysplasia. Further insight into this relationship should enhance the utility of DTI in directing themanagement of epilepsy patients.

ADC and FA measurements will be made in 25 cases of surgically proven FCD between 2003 and2008 in whom DTI was a component of presurgical evaluation. Values will be obtained in the region ofFCD as well as in the surrounding tissue and in the contralateral equivalent region. Histopathologicalstudies of the resected tissue will be performed using Kluber Barrera myelin stain, GFAP, MAP2,NeuN, Vimentin, Ki67, CD68 and HE stains. Statistical analysis will be performed to explor

rsna 2009 research education foundation awards

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