abstracts of funded national institutes of health grants

National Cancer Institute

MIBG ANALOGUERADIOPHARMACEUTICALS

Grant Number: 5R01CA74817-02PI Name: Vaidyanathan, Ganesan

Abstract: DESCRIPTION (Adapted from Applicant’s Ab-stract): The radiopharmaceutical meta-iodobenzylguanidine(MIBG) has been used in the detection and therapy of neuroen-docrine tumors, especially neuroblastoma and pheochromocy-toma. Although it is a satisfactory agent for diagnostic applica-tions, the outcome of MIBG therapy is inadequate. The goal ofthis proposal is to develop an agent which is metabolicallymore stable, clears faster from normal tissues, and yet is seques-tered and retained in tumor. The initial objectives of this pro-posal are to develop synthetic methods for the preparation ofvarious radioiodinated and [At-211]-labeled MIBG derivativesand to systematically evaluate them in vitro and in vivo. Thestructural alterations planned include introduction of chlorine,bromine, iodine, nitro and sulfonic acid moieties at the 4-posi-tion in the benzene ring of MIBG and replacement of the ben-zene ring itself with a pyridine ring. Solid-phase synthetic meth-ods will be developed for promising agents. The uptake andretention kinetics in vitro and the effect of several pharmacolog-ical agents will be studied using a panel of neuroblastoma,pheochromocytoma and medulloblastoma cell lines. Althoughnot a neuroendocrine tumor, specific uptake of MIBG has beendemonstrated in several human medulloblastoma cell lines, andthis neoplasm is well suited for [At-211]-therapy. The therapeu-tic potential of these new[I-131]- and [At-211]-labeled MIBG

analogues will be evaluated using thymidine uptake and clono-genic assays in monolayer and spheroid models. Tissue distribu-tion of these agents will be determined in normal mice andathymic mice hosting neuroblastoma, pheochromocytoma, andmedulloblastoma xenografts. Strategies to augment tumor-to-normal tissue ratios will be investigated. The outcome of thisstudy should help improve the endoradiotherapy of neuroendo-crine tumors and possibly of medulloblastoma.

Thesaurus Terms: analog, antineoplastic, drug design /syn-thesis /production, guanidine, halogen, radionuclide medullo-blastoma, neoplasm /cancer pharmacology, neuroblastoma,pharmacokinetics, pheochromocytoma, radiopharmacologyathymic mouse, tissue /cell culture

Institution: Duke UniversityDurham, NC 27706

Fiscal Year: 1998Department: RadiologyProject Start: 08-Sep-97Project End: 30-Jun-02ICD: National Cancer InstituteIRG: RNM

METABOLIC IMAGING OF THEPROSTATE USING 3-D MRS

Grant Number: 5R01CA59897-07PI Name: Vigneron, Daniel B.

Abstract: DESCRIPTION: (Adapted from investigator’s ab-stract) The specific aims of the project include: [1] The de-termination of choline and citrate levels in 50 age-matched

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Research Corner

Abstracts of Funded NationalInstitutes of Health Grants

The following abstracts of diagnostic radiology research and training grants funded by the National Institutes of Health (NIH)were awarded to principal investigators (PIs) whose primary appointments are in medical school departments of radiology.These abstracts are listed on the NIH Web page (http://www-commons.cit.nih.gov/crisp/) and are printed here verbatim.

The grant identification number (eg, 1RO1AI12345-01) contains a three-digit activity code (in the previous example, RO1)that identifies a specific category of extramural activity. All current NIH activity code titles and definitions can be ob-tained at the NIH Web page http://silk.nih.gov/silk/brownbooks/actcod.

IRG (Internal Review Group) refers to the study section that reviewed the application. ICD (Institute, Center, Division) re-fers to the NIH funding source.

The abstracts of the funded grants will be printed alphabetically by author according to the funding institute or center.

http://www.commons.cit.nih.gov/crisp/

http://silk.nih.gov/silk/brownbooks/actcod

controls. Spatial resolution for this clinical 3D 1-H MRSIwork will be 0.1-0.2 cc to provide a basis for determiningthe significant spectral differences indicative of cancer inboth the peripheral zone and central gland. The MRSI datawill be measured at two separate exams for each subjectwith the exams spaced one week apart; the aim is to estab-lish reproducibility. [2] The correlation of choline and citratelevels with histologic grade. A total of 150 pre-prostatec-tomy patients will be studied, one exam each, to correlatelevels of choline and citrate with step-section histopathologi-cal analysis of the excised gland. Volume estimates from theMRSI images will be compared with those from transrectalultrasound (TRUS) and step-sectioned pathology. [3] Thedetermination of choline and citrate levels after hormonaltherapy in 50 patients with Stage C prostate cancer enrolledin a multicenter Phase II clinical trial of total hormonal abla-tion therapy with the LH-RH agonist Zoladex, which causesmedical castration, and the anti-androgen flutamide, whichinhibits androgen uptake and/or binding to the nuclear recep-tor. High- resolution 3-D MRI/ MRSI examinations will beperformed 3 times for each patient: prior to the start of hor-mone therapy, at week 8 of treatment, and at week 16 oftreatment just prior to prostatectomy. [4] The determinationof choline and citrate levels in 50 patients approximately oneyear after radiation therapy. These will be patients suspectedof recurrence; MRSI will be performed just prior to ultra-sound guided sextant biopsies.

Thesaurus Terms: benign prostate hyperplasia, choline, ci-trate, magnetic resonance imaging, prognosis, prostate neo-plasm hormone therapy, human therapy evaluation, neoplasm/cancer classification /staging, neoplasm /cancer diagnosis,neoplasm /cancer radiation therapy,noninvasive diagnosis,prostate surgery bioimaging /biomedical imaging, biopsy,clinical research, histopathology, human subject, male, statis-tics /biometry

Institution: University of California San Francisco500 Parnassus AveSan Francisco, CA 94143

Fiscal Year: 1999Department: RadiologyProject Start: 20-May-93Project End: 28-Feb-01ICD: National Cancer InstituteIRG: RNM

IMPROVING VIRTUAL COLONOSCOPYWITH COMPUTER DETECTION

Grant Number: 1R01CA78485-01A1PI Name: Vining, David J.

Abstract: Colorectal carcinoma is the second leading causeof cancer deaths in the United States today. In an effort to

reduce mortality, Congress recently included a provision inthe Balanced Budget Act of 1997 to support screeningcolonoscopy as a means for early detection and removal ofcolorectal polyps, the precursors to cancer. In this countryalone, more than 68 million people are eligible for colorectalscreening, but the majority are unlikely to comply withscreening recommendations because of the costs, risks, dis-comfort, and inconvenience associated with traditional en-doscopy. Furthermore, even if a small fraction of eligiblepersons are examined, the number of available gastroenterol-ogists would be insufficient to perform so many procedures.We have developed a new technique, called virtual colonos-copy (VC), as an alternative to screening diagnostic colonos-copy (DC). The procedure consists of cleansing a patient’scolon, inflating the colon with air, scanning the abdomenwith helical computed tomography (CT), and generating arapid sequence of three-dimensional (3D) images of the co-lon by means of virtual reality computer technology. Al-though VC makes possible the visualization of 3D images ofthe colon in a manner similar to that of DC, a correct diag-nosis depends upon a physician’s ability to identify smalland sometimes subtle polyps within hundreds of 3D images.The absence of visual cues that normally occur with DCmakes VC interpretation tedious and susceptible to error.With support from a National Science Foundation (NSF)grant, we have developed a computer-assisted polyp detec-tion (CAPD) system that calculates areas of abnormal colonwall thickness in helical CT image data in order to highlightpotential polyps in the 3D images. A physician ultimatelydetermines if each detected lesion represents a true abnor-mality. Although we have found CAPD to be sensitive forfinding subtle abnormalities, poor specificity can be attrib-uted to several obstacles, including imprecise image segmen-tation, limied feature analysis, and suboptimal bowel prepa-ration prior to helical CT scanning. With these challenges inmind, we propose research to perfect CAPD. Our specificaims are as follows: 1. To develop an image segmentationalgorithm that accurately isolates the colon from helical CTimage data; 2. To improve our polyp detection algorithmwith expanded feature analysis and artificial intelligencemethods; 3. To optimize bowel preparation with digital sub-traction of opacified feces and controlled gas distention; and4. To validate the accuracy of VC, with the modificationsachieved in the stated aims, by comparing the results of VCand DC in 200 patients undergoing usual-care colonoscopy.If VC with CAPD proves accurate and efficient in the diag-nosis of colorectal polyps, it could evolve into a simple labo-ratory test, thereby meeting the demand for worldwide colo-rectal cancer screening.

Thesaurus Terms: colon neoplasm, computed axial tomog-raphy, computer assisted diagnosis, computer simulation,diagnosis design /evaluation, endoscopy, image enhancement,mathematical model, model design /development biomedicalequipment development, colon polyp, gastrointestinal visual-

Academic Radiology, Vol 8, No 6, June 2001 ABSTRACTS OF NIH GRANTS

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ization, neoplasm /cancer diagnosis bioimaging /biomedicalimaging, clinical research, human subject

Institution: Wake Forest UniversityReynolds StaWinston-Salem, NC 27109

Fiscal Year: 1999Department: Div of Radiologic SciencesProject Start: 01-Jun-99Project End: 31-May-02ICD: National Cancer InstituteIRG: ZRG1

ECOG INSTITUTION GRANT

Grant Number: 7U10CA73590-02PI Name: Wagner, Henry

Abstract: DESCRIPTION: This is the application of the H.Lee Moffitt Cancer Center and Research Institute for institu-tional grant funding as a member of the ECOG CooperativeTrials Group. The Cancer Center is located on the maincampus of the University of South Florida in Tampa, andhas been since 1992, a member of ECOG. In 1993, the Cen-ter applied for and received ECOG consortia membership,bringing the James A. Haley Veterans Administration Hospi-tal and the Tampa General Hospital under the Moffitt con-sortia membership.

Thesaurus Terms: cancer prevention, human therapy evalu-ation, neoplasm /cancer, neoplasm /cancer education, neo-plasm /cancer therapy bone marrow transplantation clinicalresearch, human subject

Institution: University of South Florida4202 E Fowler AveTampa, FL 33620

Fiscal Year: 1998Department: RadiologyProject Start: 16-Jun-97Project End: 30-Apr-99ICD: National Cancer InstituteIRG: NCI

HIGH EFFICIENCY LYMPHOCYTELABELING FOR IN VIVO TRACKING

Grant Number: 1R01CA86782-01PI Name: Weissleder, Ralph

Abstract: DESCRIPTION (adapted from applicant’s abstract):The tracking of labeled immune cells in living small animalsand over time has been a long cherished goal in understandingthe mechanism and function of these cells. The advent of fast

NMR imaging at near microscopic resolution has provided theopportunity to track cells in deep organs. Unfortunately, fewmethods exist for high efficiency magnetic cell labeling unlesslarge magnetic particles are bound to the cell surface, whichtypically has an impact on in vivo homing and biodistributionpatterns. The investigators hypothesized that peptide basedtranslocation signals, for example, those derived from the HIV-Tat protein, could be used to shuttle magnetic nanoparticles intocells more efficiently than is possible by fluid phase endocyto-sis, a method previously developed for magnetic cell tracking.In preliminary studies this group synthesized a number of Tat-derived peptides and determined their capacity to be internal-ized into cells. In one study an 11-mer Tat sequence was cou-pled to a magnetic particle and the investigators showed thatlymphocyte labeling was improved over 100-fold compared tothe non-derivatized preparations. In further studies this grouphas shown that this powerful new technique for the first timeallows 1) tracking of relatively few cells in vivo (� 15 cells pervoxel are detectable by MR microscopy); 2) magnetic recoveryand isolation of in vivo homed lymphocytes; small amounts.The goals of the current study are: 1) to optimize the newlydeveloped magnetic probes for labeling of lymphocytes; 2) tocharacterize labeled and unlabeled immune cells; and 3) to ap-ply the developed techniques to questions regarding cytotoxicT-lymphocyte (CTL) distribution in tumors. The investigatorsbelieve that these and related questions are highly relevant totracking immune cells in vivo over time, and in evaluatingnovel therapies. Furthermore, the investigators believe that theproposed research is in the widest interest to the current NIAIDproram and other research programs in further developing ro-bust tools to track immune cells in vivo.

Thesaurus Terms: cell migration, chemical conjugate, cyto-toxic T lymphocyte, iron oxide, magnetism, virus proteinlaboratory mouse, magnetic resonance imaging, nuclear mag-netic resonance spectroscopy

Institution: Massachusetts General Hospital55 Fruit StBoston, MA 02114

Fiscal Year: 2000Department:Project Start: 10-Apr-00Project End: 31-Mar-05ICD: National Cancer InstituteIRG: ZAI1

MR IMAGING OF GENE EXPRESSION


Abstract: MR imaging can provide high resolution 3D maps ofstructural and functional information in vivo yet its use of map-ping in vivo gene expression is largely unexplored. The major

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obstacle to its implementation is the low threshold of (super)paramagnetic label detection. We have developed a strategy thatrelies on synergistic amplification of biological processes todirectly map transgene expression. The basic concept and gen-eral method relies on 1) uninhibitable internalizing receptors(e.g. engineered transferrin receptor, ETR) and probing the re-ceptor with affinity ligands (e.g. Tf) containing thousands ofiron atoms which increase R2/R2 relaxivity upon cellular inter-nalization. In preliminary feasibility studies we have created celllines stably expressing ETR and are insensitive to iron-induceddown regulation. Using ETR targeted holo-Tf containing ironoxide (Tf-MION), we have furthermore shown that 1) cellularuptake of this probe is specific and inhibitable, 2) cellular accu-mulation of iron from Tf-MION is more efficient for MR imag-ing when compared to iron from Tf, 3) that the probe accumu-lates at significantly higher amounts in ETR� tumors comparedto ETR- tumors and 4) that transgene expression can be visual-ized in vivo by MR imaging (1.5 T) in live animals and byhigh resolution MR microscopy (7.1T). With our expertise inconstructing viral expression vectors we propose to expand thisresearch to test whether the recombinant ETR system can beused as a universal marker gene for MR imaging of gene ex-pression. The hypotheses underlying these experiments is thatETR gene expression will correlate with expression of therapeu-tic genes when driven by the same promoter and/or being partof a polycistronic vector. Using novel HSV/EBV amplicons wewill test this model system in human tumors xenografted intoimmunocompromised mice. The long-term goal of this researchis to extend the capabilities of MR and apply it to in vivo imag-ing of gene expression.

Thesaurus Terms: gene expression, genetic marker, magneticresonance imaging genetic promoter element, iron metabolism,transferrin receptor athymic mouse, bioimaging /biomedicalimaging, cell line, neoplasm /cancer transplantation


Fiscal Year: 2000Department:Project Start: 15-Feb-00Project End: 31-Jan-05ICD: National Cancer InstituteIRG: RNM

LCDIO FOR MR LYMPH NODE IMAGING


Abstract: This research seeks to validate and investigate theutility of long circulating dextran based iron oxide (LCDIO)contrast agents for the assessment of active tumor growth inlocal and regional lymph nodes during cancer spread. During

the current funding we have made considerable progress indeveloping, characterizing and understanding the mechanismof action of lymphotropic drug carriers both for therapeuticand diagnostic purposes. Using this understanding our datasupports the hypothesis that LCDIO imaging is not only fea-sible in humans, but superior to non-contrast MR imagingfor the detection of lymph node metastases. While resultsfrom current phase 3 clinical trials are entirely consistentwith prior observations in animal models, simple image in-terpretation (e.g. overall changes in nodal signal intensity)leaves many of the most interesting questions regarding thenon-invasive assessment of lymph nodes unanswered. Forexample, recent clinical questions regarding the non-invasiveassessment of lymph nodes unanswered. For example, recentclinical trials demonstrate that minimal nodal tumor burdenin non-enlarged nodes is indeed detectable by LCDIO en-hanced MR imaging. We hypothesize that microscopic tumorcell clusters in nodes cause functional lymphatic abnormali-ties detectable my MR imaging, before changes in morphol-ogy or size become apparent. Examples of such functionalabnormalities include altered intranodal lymphatic fluid flowdue to micrometastases in the sinuses, or increased neovas-cular permeability and blood flow. Using genetically engi-neered tumor cells, radiotracer studies and compartmentalanalysis we will now directly correlate nodal tumor burdenwith LCDIO accumulation. Combined with cell biology stud-ies on cellular uptake into different nodal populations a morecomplete picture of LCDIO transport to lymph nodes and itsmagnetic effects will be obtained. The approach will be vali-dated in human lymph nodes using MR imaging, immuno-histochemistry against the dextran coat of LCDIO and or-relative analysis. The latter studies are especially are espe-cially relevant since little data exists on nodal LCDIOdistribution and correlative histology in human lymph nodes.By providing a quantitative assessment of LCDIO transportto lymph nodes. By providing a quantitative assessment ofLCDIO transport to lymph nodes this research should en-hance the non-invasive characterization of nodal status inpatients with known primary cancers and may ultimately aidin the design of novel therapeutic lymphotropic drug carriers.

Thesaurus Terms: contrast media, lymph node neoplasm,magnetic resonance imaging, metastasis, neoplasm /cancerclassification /staging disease /disorder model, iron oxide,neoplasm /cancer pharmacology, neoplastic cell, neoplasticgrowth bioimaging /biomedical imaging, human tissue, im-munocytochemistry, laboratory mouse, lymph node, lymph-adenectomy, radiotracer


Fiscal Year: 2000Department:Project Start: 01-Apr-93


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Project End: 28-Feb-02ICD: National Cancer InstituteIRG: RNM

NMR RECEPTOR IMAGING

Grant Number: 5P01CA48729-120005PI Name: Weissleder, Ralph

Abstract: The goal of this research is to extend our previousmagnetic resonance (MR) receptor imaging research and de-velop novel immunospecific contrast agents for the in vivocharacterization of cancer. These agents ideally act as �mo-lecular probes� for cell surface structures either in normaltissue or in tumor tissue. During the previous funding period,we have successfully synthesized and directed superparamag-netic magnetoconjugates to asialoglycoprotein receptors onhepatocytes and to cholecystokinin (CCK) receptors on pan-creas cells and demonstrated improved differentiation of be-nign and malignant lesions (MR receptor imaging). In thecurrent Project we propose to a) complete the investigationsof MR receptor imaging of the pancreas and b) to extendprevious research to antigenic and/or receptor sites presenton malignant cells. We present data on magnetoimmunocon-jugates based on a monocrystalline iron oxide nanocom-pound (MION) including studies to optimized our couplingstrategies and showed that most of the antibody affinity canbe retained through conjugation. The proposed research ex-pands on successful in vivo cell culture experiments and invivo MR imaging with such antibody MION conjugates di-rected to tumor cell surface structures (MION-L6) or inter-nalized compartments (MION-BR96). We anticipate that re-sults, models and conjugation technology from this researchcan be used to assess cell surface structure in a variety ofneoplastic systems (breast cancer, lung cancer, pelvic malig-nancies, lymphoma etc.) MR imaging of tumor antigens isexpected to allow in vivo typing of malignant tissues, to en-hance detection of cancer and to predict efficacy of immuno-therapy with chemoconjugates and immunotoxins.

Thesaurus Terms: contrast media, diagnosis design /evalua-tion, magnetic resonance imaging, neoplasm /cancer diagno-sis, receptor carbohydrate receptor, cell membrane, chemicalconjugate, histology, immunoconjugate, iron oxide, mem-brane structure, neoplastic growth, nuclear magnetic reso-nance spectroscopy, pancreas neoplasm, pharmacokineticslaboratory rat


Fiscal Year: 2000Department:Project Start: 05-Jan-89Project End: 31-Mar-02

ICD: National Cancer InstituteIRG: NCI

RESEARCH RESOURCE INRADIONUCLIDE RESEARCH

Grant Number: 1R24CA86307-01PI Name: Welch, Michael J.

Abstract: DESCRIPTION (Adapted from the Applicant’sAbstract): The objective of this application is to provide ra-dionuclides for collaborative research and as a service tofunded research investigators throughout the world. Toachieve this objective, three research projects are proposed:1. In research project 1, the investigator will develop routinetechniques for the production of large amounts of importantradionuclides of copper, gallium yttrium, technetium, bro-mine and iodine. 2. In research project 2 the imaging physicsof positron emitting nuclides of different energy and decayschemes on the image quality will be evaluated. 3. Researchproject 3 will develop and evaluate molecular modelingmethods capable of determining the potential usefulness ofradiopharmaceutical labeled with the radionuclides beingdeveloped. The three research projects will support collabo-rative research projects with twelve investigators involvingoncological, cardiovascular and neuroscience applications.The majority of the collaborative research projects will uti-lize a microPET positron emission tomograph designed spe-cifically for imaging transgenic mice and other rodent mod-els. The resource will support several service projects whereradionuclides developed under project 1 will be supplied tofunded investigators. Training and dissemination of informa-tion will be important parts of the resource.

Thesaurus Terms: biomedical resource, health science re-search, radionuclide, radiopharmacology

Institution: Washington UniversityLindell and Skinker BlvdSt. Louis, MO 63130

Fiscal Year: 1999Department: RadiologyProject Start: 01-Sep-99Project End: 31-Aug-04ICD: National Cancer InstituteIRG: ZRG1

TARGETED METAL CHELATORS FORDIAGNOSTIC IMAGING

Grant Number: 5R01CA42925-11PI Name: Welch, Michael J.

Abstract: Metal radionuclides are widely used in diagnosticimaging. Radioisotopes of gallium, indium, technetium and


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copper are used in nuclear medicine studies while gadolin-ium chelates act as paramagnetic contrast agents in conjunc-tion with nuclear magnetic resonance imaging (MRI). Newimproved chelating agents for these metal ions have beendesigned. The properties of these new chelating agents willbe predicted utilizing molecular mechanic calculations, theligands will be synthesized and the characteristics of themetal complexes studied by physicochemical methods aswell as in vivo and in vitro biological evaluation. Chelateshave been designed for maximum thermadynamic stabilityby using ligands with donor groups highly selective for theparticular metals. The charge and lipophilicity of the chelateswill be altered by changing the donor groups as well as theaddition of alkyl groups and other substituents. The metalchelates will be functionalized with several types of linkagesto allow covalent attachment to proteins and peptides. Partic-ular emphasis is being given to new ligands for the metalindium and copper. The stability constants of the new li-gands will be determined and the kinetics of metal dissocia-tion measured. The biological behavior of both the ligandsand bifunctional chelates attached to proteins and peptideswill be determined in vitro and in animal models. The syn-thesis characterization and physicochemical studies will becarried out at Texas A&M University while the in vitro andin vivo evaluation of the pharmaceutical preparations will beundertaken at Washington University.

Thesaurus Terms: chelating agent, drug design /synthesis/production, drug screening /evaluation, radionuclide scan-ning /imaging, radiopharmacology chemical association,chemical binding, chemical conjugate, chemical kinetics,contrast media, copper, gadolinium, gallium, indium, ligand,metal complex, stereochemistry, thermostability autoradiog-raphy, baboon, hamster, laboratory rat, magnetic resonanceimaging, outcomes research, positron emission tomography

Institution: Washington UniversityLindell and Skinker BlvdSt. Louis, MO 63130

Fiscal Year: 1998Department: RadiologyProject Start: 01-Jul-86Project End: 31-Jan-02ICD: National Cancer InstituteIRG: RNM

EARLY REPEAT CT FOR EVALUATION OFSOLITARY LUNG NODULES

Grant Number: 1R01CA78905-01A1PI Name: Yankelevitz, David F.

Abstract: The solitary pulmonary nodule (SPN) is a com-mon and challenging problem, with approximately 150,000new SPNs being detected each year. The most common eti-

ology of SPN remains lung cancer. While progress has beenmade in reducing the occurrence of benign nodules amongresected ones, it continues to be approximately 50 percent.Many approaches to preoperative determination of the natureof the SPN have been tried, including evaluation of differentfeatures such as spiculation, tumor-bronchi relationship, de-gree of contrast enhancement with CT and MRI, metabolicactivity using positron emission tomography as well as clini-cal criteria such as age and smoking history. The only crite-ria widely accepted as reliable for classifying nodules are thepattern of calcification and lack of growth for two years. Thepattern of calcification has been studied extensively usingCT as it allows better density discrimination than chest radi-ography. This approach has met with limited success.Growth, however, defines the very nature of tumors. Al-though, CT scanning, with its current resolution of 0.3 mm,is excellent in measuring size, virtually no work has beendone using it to detect growth. The objective of this proposalis to determine the usefulness of early repeat CT (ERCT)imaging of SPNs for early and rapid diagnosis of lung can-cer. We plan to develop methods of determining whether theSPN is growing, and/or changing its configuration, and forquantifying these changes. Thereupon, we will assess theprobability of malignancy of an SPN as to how this dependson the ERCT findings. Our techniques should allow determi-nation within a short period of time, in some cases withinweeks, of whether an SPN is suspicious for malignancy andto recommend the course of action, whether further diagnos-tics, surgery or follow-up.

Thesaurus Terms: computed axial tomography, diagnosisdesign /evaluation, early diagnosis, lung neoplasm, neoplasm/cancer radiodiagnosis calcification, neoplastic growth bioim-aging /biomedical imaging, biopsy, clinical research, humansubject

Institution: Weill Medical College of CornellUniv

New York, NY 10021Fiscal Year: 1999Department: RadiologyProject Start: 07-Sep-99Project End: 31-Aug-02ICD: National Cancer InstituteIRG: ZRG1

ASTATINE AND IODINE RADIOLABELEDMONOCLONAL ANTIBODIES

Grant Number: 2R37CA42324-14PI Name: Zalutsky, Michael R.

Abstract: The goal of this research proposal is to increasethe clinical utility of labeled monoclonal antibodies (mAbs)


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for diagnostic and therapeutic nuclear medicine through thedevelopment of more effective approaches for labeling mAbsand mAb fragments with radioiodine nuclides and 211At.Iodine-131 is the most frequently used nuclide clinical radio-immunotherapy, but its usefulness has been compromised byin vivo dehalogenation of mAbs labeled via conventionalprocedures. Better mAb radioiodination methods also wouldfacilitate the use of (123)I and SPECT, and 124I and PET,for lesion detection and dosimetry estimation. Astatine-211emits alpha-particles that have a higher radiobiological effec-tiveness and shorter range than beta-particles and, for certaintherapeutic applications, may be better matched to the char-acteristics of the tumor. In this continuation application, wepropose to focus on radiohalogenation strategies for mAbsthat are internalized rapidly into tumor cells after binding toantigen. This emphasis is in response to the emergence ofthe epidermal growth factor receptor variant III (EGFRvIII)as a tumor-specific target on gliomas, breast carcinomas andother tumors. EGFRvIII, a mutant receptor with a deletion inthe BGFR extracellular domain is not found on normal tis-sues. Our hypothesis is that optimizing labeling methods forinternalizing mAbs such as anti-EGFRvIII will enhance tu-mor retention and tumor-to-normal tissue ratios, thereby im-proving their clinical potential as diagnostic and therapeuticagents for tumors expressing EGFRvIII. Our specific aimsare: 1) To label anti-EGFRvIII mAbs and fragments withradioiodine nuclides and 211At using N-succinimidyl 5-iodo-3-pyridinecarboxylate and N- succinimidyl 5-[211At] astato-3-pyridinecarboxylate and evaluate their potential as diagnos-tic and therapeutic radiopharmaceuticals; 2) To investigateother strategies for labeling mAbs and fragments with radio-iodine and 211At including use of alternate positivelycharged templates, D-amino acid lnkers, and new approachesinvolving oligosaccharide conjugation; and 3) To investigatethe nature of the high- and low-molecular weight labeledcatabolites generated in tumor cells in vitro and tumor andnormal tissues in vivo and use these data as a guide for de-veloping improved methods for labeling mAbs.

Thesaurus Terms: monoclonal antibody, neoplasm /cancerradionuclide diagnosis, neoplasm /cancer radionuclide ther-apy, radionuclide scanning /imaging, radiopharmacology cy-totoxicity, diagnosis design /evaluation, drug metabolism,epidermal growth factor, glioma, growth factor receptor,method development, molecular weight, neoplasm /cancerimmunotherapy, neoplastic cell, nonhuman therapy evalua-tion, pyridine carboxylate, radiation dosage athymic mouse,bioimaging /biomedical imaging, iodine, laboratory rat, ra-dionuclide, radiotracer


Fiscal Year: 1999Department: RadiologyProject Start: 01-Sep-85

Project End: 31-Jan-04ICD: National Cancer InstituteIRG: RNM

RESEARCH TRAINING IN ONCOLOGYIMAGING

Grant Number: 5T32CA09630-11PI Name: Zerhouni, Elias A.

Abstract: DESCRIPTION (Applicant’s Description): Theprogram proposes to provide research training in oncologicalimaging for postdoctoral fellows interested in a career inacademic radiology and related fields. The program structureincludes didactic and laboratory exposure and provides basicscientists and physicians with opportunity to gain researchtraining in state-of- the-art medical imaging facilities. Theunique aspect of this training program is that it combinestraining within an imaging core with training in either a ba-sic science, such as molecular oncology or cancer biology,or in an imaging modality, such as CT or MR. The exposureof both clinical and basic science research is strong featureof this program. The M.D. and Ph.D. trainees who completethis program will be uniquely qualified for a variety of posi-tions in academic radiology oriented towards research inclinical oncology and oncological imaging. This programaddresses the pressing need to encourage physicians and re-searchers in radiology to develop and maintain a researchfocus and to keep pace with the rapid influx of imaging anddiagnostic methods which require an increasing amount oftechnical expertise. Areas of research expertise include: func-tional (MRI, MRS and PET) imaging of human and animaltumors, intraarterial delivery of drugs active in the treatmentof brain tumors, development of inhibitors of tumor angio-gene-sis, applications of bioerodible, sustained-release poly-mers, monitoring of the proliferative state and therapeuticresponse of brain tumors, biochemical and clinical pharma-cology studies of anti-tumor agents, computer modeling ofinteractions of alkylating agents with deoxynucleotides andpolynucleotides, in vivo NMR spectroscopy as a noninvasivemonitor of the biochemistry and physiology of malignanttumors, image guided navigation of surgical instruments fortumor surgery and image processing of CT and MRI data fortumor 3-D reconstruction, interactive 2-D and 3-D imaging,automated volumetrics, and radiation therap planning. Themulti-disciplinary training program described in this proposaldraws its strength from the participation of faculty membersfrom numerous departments, including radiology, oncology,medicine, neurosurgery, biomedical engineering, urology andpathology. Extensive research facilities available to traineesnot only reflect the wide variety of disciplines contributingto the program but also the commitment of the Johns Hop-kins Medical Institutions to training future leaders of bio-medical research.


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Thesaurus Terms: There are no thesaurus terms on file forthis project.

Institution: Johns Hopkins University3400 N Charles StBaltimore, MD 21218

Fiscal Year: 1999Department: RadiologyProject Start: 01-Aug-89Project End: 29-Sep-02ICD: National Cancer InstituteIRG: NCI

MR IMAGING TECHNIQUES FORINTERVENTIONAL APPLICATIONS

Grant Number: 2P01CA67165-04A20004PI Name: Zientara, Gary P.

Abstract: MR guided therapy has a specific requirement fordynamic MRI methods. First, the image field-of-view (FOV)may be selected in a continuously varying fashion by physi-cian using, for example, a pointing device. Second, indepen-dent of the selection of the imaging plane, the objects in theimage FOV may themselves be changing physically (e.g., asa biopsy needle enters) or chemically (e.g., during laser or rfablation, or as a bolus of contrast agent is injected) thereforealtering the resultant MR image. All of these circumstancesrequire a dynamic MR imaging method. Dynamic MRI dif-fers from standard MRI in that a sequence of time-orderedimages is obtained by continually updating or reacquiringimage data. Recent investigations of our laboratory have fo-cused on new dynamically adaptive methods for imaging theprocesses involved in MR guided therapy that evolve so rap-idly that they cannot be adequately resolved both spatiallyand temporally using current dynamic approaches. Dynami-cally adaptive methods are distinguished as those in whichthe image data acquisition strategy is modified dynamicallydepending on information obtained after processing the mostrecently acquired image(s). Our approach is founded on thehypothesis that significant improvement in temporal resolu-tion, without loss of image quality, can be obtained in dy-namic MRI if an adaptive method is used to minimize re-dundancy in image encoding and data acquisition. The MRImethods that are under study in our laboratory, are efficientencoding and acquisition methods. They can be implementedin the context of fast imaging techniques (e.g., echo- planaror fast gradient-echo), which do not exploit redundancy indata acquisition. We will focus on implementing and im-proving three main dynamic MRI approaches: a. Wavelettransform encoding techniques; b. SVD (Singular Value De-composition) encoding techniques; c. Specialized Fouriertransform encoding techniques. We will also evaluate eachmethod in terms of standard performance criteria (signal-to-

nise ratios, spatial and temporal resolution). Finally, we willstudy the physics of selective rf excitation methods for MRI(the basis of each of the imaging methods) and the diagnos-tic utility of new methods using standard ROC methodsmodified to assess the detection and characterization of time-varying information in series of images. This method devel-opment project will have an impact on the program by pro-viding improved spatial and temporal resolution, faster (dy-namic) scanning, and quantitation of spatially dependentinformation tailored to the specific goals of each of the otherfour projects.

Thesaurus Terms: biopsy, image processing, laser therapy,magnetic resonance imaging, method development bioimag-ing /biomedical imaging

Institution: Brigham and Women’s Hospital75 Francis StBoston, MA 02115

Fiscal Year: 2000Department:Project Start: 30-Sep-95Project End: 30-Apr-05ICD: National Cancer InstituteIRG: ZCA1

FAST DYNAMIC 3D MRI USINGADAPTIVE SPATIAL ENCODING

Grant Number: 5R01CA78299-03PI Name: Zientara, Gary P.

Abstract: DESCRIPTION (Adapted from Applicant’s Ab-stract): The main goal of this project is the development of afast dynamic 3D MRI method using adaptive spatial encod-ing that can acquire a high resolution MRI dates(256�256�256) operating in near real-time as possible (1dataset per 1-2 seconds) with minimal hardware modifica-tions to a standard MRI scanner. This goal lies well outsidethe possibilities of current MRI methods like echo planartechniques that employ Fourier encoding and specialized gra-dient hardware. A number of applications of interventionalMRI, a focus in our hospital, have the specific requirementfor dynamic 3D MRI that can operate on an “open” MRscanner with no specialized gradient coils. The most impor-tant of these applications is the MRI monitoring of the time-course of thermal therapies during which non-uniform heat-ing of tissue occurs due to tissue heterogeneity and nearbyvessels. Another important application is the near real-time3D tracking of probes and catheters used for minimally inva-sive therapies. Specifically, we propose to develop, imple-ment, test and optimize a dynamic 3D MRI method that en-codes adaptively in two directions using high flip angle 2Dspatially selective RF excitations to implement a minimal setof near-optimal encodes computed from the multidimen-


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sional Singular Value Decomposition (MSVD) of a 3D im-age estimate (formed from recently acquired data) computedper acquisition, combined with frequency encoding in thethird direction. The accomplishment of the main objective ofthis project is only possible due to three significant techno-logical advances. First, and most important regarding spatialencoding, the applicants reported recently having developedthe MSVD, a powerful numerical mathematical tool that candetermine near-optimal 3D spatial encoding. Second, a sim-ple fast numerical procedure has been developed in their lab-oratory for the computation of RF pulse waveforms for im-plementing non-Fourier encodings using high flip angles(90�A1) for high SNR scans.Third, at their facility, theyhave the operating capability for near real-time adaptive 2DMRI using a commercial MR system with the minor modifi-cation of an additional attached workstation.

Thesaurus Terms: biomedical equipment development, clin-ical biomedical equipment, magnetic resonance imagingcomputer assisted patient care, neoplasm /cancer thermother-apy, patient monitoring device, phantom model bioimaging/biomedical imaging, human data


Fiscal Year: 2000Project Start: 01-Jul-98Project End: 30-Jun-01ICD: National Cancer InstituteIRG: DMG

National Heart, Lung, andBlood Institute

ENHANCED PHYSIOLOGICAL MRI USINGHYPERPOLARIZED 129XE

Grant Number: 5R01HL57563-03PI Name: Albert, Mitchell S.

Abstract: DESCRIPTION (Adapted from Applicant’s Ab-stract): The spin-1/2 nuclei of 3He and 129Xe can be hyper-polarized to 10 5 times their thermal equilibrium value, byspin- exchange collisions with Rb atoms that have been “op-tically pumped” by circularly polarized light entirely intoone electron spin state. The enhanced signal from such hy-perpolarized species makes them intriguing MR probes. Thefile has developed considerably in the past three years, sincethe applicants invented hyperpolarized-Xe MRI (HypX-MRI)by acquiring MR images of an excised mouse lung that hadbeen inflated with hyperpolarized 129Xe. Improved lung gas

space imaging has been demonstrated by others, using thestronger signal from hyperpolarized 3He, but 129Xe is themore interesting nucleus, since its high lipid solubility ren-ders it a promising probe of organs and tissues that have yetresisted MRI techniques. Successful hyperpolarized 129XeMR spectroscopy and MR imaging of tissues, distal to thelung, crucially depends on whether the T1 of the species inblood is long enough for sufficient magnetization to reachthe target tissue. Building on our measurement of a suffi-ciently long T1 (13.5 sec) in oxygenated blood, to encourageHypX-MRI studies of distal tissues, the applicants proposedto undertake a series of hyperpolarized noble gas magneticresonance experiments. The aim is to demonstrate the useful-ness of the new technique in studying physiological states inanimals and humans, and to further its special promise as aclinically important modality. The applicants proposed todevelop a high-power, diode laser-driven, optical pumpingapparatus to produce sufficient quantities of hyperpolarized3He and 129Xe to facilitate a variety of biomedical studies.It incorporates a cryogenic storage and delivery system.Pulse sequences of HypX-MRI will be optimized in order totake advantage of the large, non-equilibrium polarization,and to exploit the large chemical shifts observed for 129Xe.RF coils for simultaneous 129Xe and 1H image acqusitionwill be constructed. Relaxation times (T1 and T2) of 129Xein blood and tissue samples in vitro will be further studies asa guide to optimizing the imaging pulse sequences. Imagingof ventilated animals will attempt to evaluate usefulness ofthis technique to studying lung structure and function, andchemical shift imaging techniques will be used to image thebrain. The possibility of using HypX-MRI to detect changesin blood flow will be explored, in the hope that it may be afirst step towards imaging functional activation of the brain.Finally, experiments will test the feasibility of using thisnovel methodology to the study of morphology, function,and disease states in human with the goal of developingHypX-MRI for clinical diagnosis.

Thesaurus Terms: biomedical equipment development, con-trast media, diagnosis design /evaluation, magnetic resonanceimaging, molecular energy level, respiratory function,respira-tory visualization, xenon clinical research, human subject,laboratory rat


Fiscal Year: 2000Department:Project Start: 01-Apr-98Project End: 31-Mar-02ICD: National Heart, Lung, and Blood

InstituteIRG: DMG

NHLBI Academic Radiology, Vol 8, No 6, June 2001

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DETECTION OF ARTERIAL WALLDISORDERS BY MRI

Grant Number: 5K01HL03528-02PI Name: Altbach, Maria I.

Abstract: DESCRIPTION The applicant’s long-term careergoal is to become an independent investigator in the field ofmagnetic resonance imaging (MRI) where she would like toconcentrate her efforts to improve the diagnostic capabilityof the technique and understanding of the relationship be-tween MRI parameters and human pathophysiology (withemphasis in cardiovascular problems). Thus, the goal of theproposed application is to gain hands-on experience in thetechnical aspects of clinical MRI by developing MRI tech-niques for the in vivo detection of structural changes in thearterial wall associated with pathological states, such as ath-erosclerosis, aneurysmal dilation, and hypertension. Theproject focuses on the development of MRI methods to de-tect subintimal lipid deposits and MRI methods that can ac-curately detect changes in the water component of the arte-rial wall in humans. Water-suppression, based on the differ-ences in diffusion properties, spin-lattice relaxation times,and chemical shift between lipid and water spins, will beimplemented for imaging subintimal lipids. These techniqueswill be used to image patients with atherosclerosis. MRImethods to accurately measure spin-spin relaxation (T2),extent of magnetization transfer, and diffusion will be imple-mented to image the water component of the arterial wall.The diffusion anisotropy of the arterial wall will be mea-sured by MRI in patients with aneurysmal dilation in orderto estimate the degree of organization of the elastin/collagenmatrix. Changes in spin-spin relaxation times, extent of mag-netization transfer, and diffusion will be measured in hyper-tensive and normotensive individuals and correlated withaortic compliance and severity of disease. To interpret thechanges in MRI parameters in terms of changes in the struc-ture of the arterial wall due to hypertension, the spontaneoushypertensive rat (SHR) will be used as an animal model ofhypertension. MRI measurements will be carried out in thearteries of SHR and normotensive rats and correlate with invivo arterial passive mechanical measurements and with thecomposition of the arterial wall. The project will be carriedout under the sponsorship of Professor Arthur F. Gmitro,Ph.D., a physicist with extensive experience in medical im-aging, and Professor Steven Goldman, M.D., a cardiologistwith extensive experience in clinical research. Most of theproject will be carried out at the Clinical MRI and Biologi-cal NMR facilities at the University of Arizona where theapplicant will be working in an environment with MR tech-nologists, cardiologists, radiologists, and physiologists. Toobtain the necessary background for the research and train-ing parts of the project, the applicant will take courses inmedical imaging, electronics, and physiology during the firstyears of the grant.

Thesaurus Terms: artery, blood vessel disorder, cardiovas-cular disorder diagnosis, diagnosis design /evaluation, mag-netic resonance imaging aneurysm, atherosclerosis, diseasemodel, hypertension clinical research, human subject, labora-tory rat, spontaneous hypertensive rat

Institution: University of ArizonaTucson, AZ 85721

Fiscal Year: 1998Department: RadiologyProject Start: 01-May-97Project End: 30-Apr-02ICD: National Heart, Lung, and Blood

InstituteIRG: ZHL1

INTRAVASCULAR MRI—TOWARDCLINICAL INTERVENTIONS

Grant Number: 1R01HL61672-01PI Name: Atalar, Ergin

Abstract: In recent years, we have developed new intravas-cular MRI (IVMRI) probes in the form of guidewires andcatheters for use in animal models. We have also developedIVMRI techniques that enable acquisition of high resolutioncross-sectional images of the vessel wall, as well as trackingtechniques for real-time visualization of the catheters. Webelieve that using these techniques, valuable information canbe obtained for the diagnosis and treatment of atherosclerosisof other vessel diseases in humans. In this proposal, we willtest the hypotheses that our IVMRI technique () is a low-riskmethod and (b) can be used for the visualization of interven-tional techniques, namely balloon angioplasty and stentplacement procedures. Specifically, we will (1) refine andadapt our existing IVMRI probes in the form of cathetersand guidewires that will be suitable for use in human pa-tients, and (2) evaluate the safety of these devices in accordwith FDA-established guidelines by calculating/measuringthe additional heating caused by the presence of the intravas-cular MRI devices and assessing any potential for tissuedamage. We will also (3) evaluate whether currently avail-able perfusion MR imaging and non-invasive MR angiogra-phy (MR) techniques can be combined with IVMRI tech-niques to perform intravascular MR fluoroscopy (IVMRF)-guided interventional procedures, namely, balloonangioplasty and stent placement in animal models. In thefinal phase of the project, we plan to have enough data toapply for IRB approval for investigational use of these tech-niques in human patients.

Thesaurus Terms: angiography, diagnosis design /evalua-tion, magnetic resonance imaging, technology /technique de-velopment atherosclerosis, blood vessel prosthesis, intralumi-


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nal angioplasty bioimaging /biomedical imaging, dog, fluo-roscopy, laboratory rabbit


Fiscal Year: 1999Department: RadiologyProject Start: 01-Jan-99Project End: 31-Dec-02ICD: National Heart, Lung, and Blood

InstituteIRG: DMG

INTRAVASCULAR MAGNETICRESONANCE TECHNIQUES

Grant Number: 5R29HL57483-02PI Name: Atalar, Ergin

Abstract: DESCRIPTION (Adapted from Applicant’s Ab-stract): Early diagnosis and monitoring of the progression andregression of atherosclerosis have a crucial importance in thefight against the world’s number one fatal heart disease. Mag-netic resonance imaging and spectroscopy methods providevaluable information about the morphology and chemical com-position of atherosclerotic plaques but suffer from low signal-to-noise ratio and low image resolution. We propose to develop anew intravascular magnetic resonance imaging method that willinvolve using an MR probe on the tip of a catheter. This willallow more complete characterization of atherosclerotic plaquesas well as providing a novel method of monitoring interven-tional therapy that is not currently possible. The specific aims ofthis project include the development of a novel real-time MRfluoroscopy technique (5 frames/sec) for 3-D visualization of acatheter probe, and the development of novel encoding tech-niques to achieve near-microscopic resolution imaging (100microns) and highly localized spectroscopy. The applicants pro-posed to validate these techniques on phantoms, dogs and on ahigh cholesterol-fed atherosclerotic rabbit model. The develop-ment of intravascular magnetic resonance techniques will leadto an innovative, practical system that will be used routinely forthe diagnosis of atherosclerosis as well as for monitoring vari-ous interventional techniques such as laser therapy.

Thesaurus Terms: angiography, atherosclerotic plaque, bio-medical equipment development, fluoroscopy, image en-hancement, magnetic resonance imaging cholesterol dog,laboratory rabbit, phantom model


Fiscal Year: 1998

Department: RadiologyProject Start: 01-Jun-97Project End: 30-Apr-01ICD: National Heart, Lung, and Blood

InstituteIRG: ZRG7

DEVELOPMENT OF NEW MRI METHODTO STUDY CARDIAC MOTION

Grant Number: 5R01HL43014-08PI Name: Axel, Leon

Abstract: Heart disease, a major cause of morbidity andmortality in the Western World, generally leads to abnormal-ities of heart wall motion. The goals of this project are 1) todevelop improved methods for measuring regional heart wallmotion using magnetic resonance imaging (MRI); and 2) toapply them to a sample of normal subjects in order to definethe normal patterns of cardiac motion. This will be usefulboth for improving our understanding of normal cardiac mo-tion and for providing a set of baseline normal valuesagainst which patients with heart disease can be compared.In addition, improved methods for cardiac imaging with MRIthat will be developed for this project will have broader ap-plicability to general cardiac MRI. A major focus of thisproject is on development of technical aspects of the wallmotion studies. Methods will be developed for the acquisi-tion of tagged MR cardiac images with improved spatial andtemporal resolution, including investigations of tagged imag-ing during suspended respiration with rapid gradient echoand echo planar imaging and development of surface coilsspecifically adapted for receiving signals from the heart.Analysis methods will be developed for estimating the 3-di-mensional motion and deformation from both stacked bi-plane series and phase velocity encoding. Validation methodsfor verification of measurement results will be further devel-oped. Image registration methods will be developed for stud-ies of reproducibility and comparison of different subjects.The improved imaging and analysis methods developed inthis project will be applied to a broad sample of normal sub-jects, stratified for gender, age and race. This will be ana-lyzed for within and between subject patterns of variation.

Thesaurus Terms: biomedical equipment development, heartdisorder diagnosis, heart motion, magnetic resonance imaging,noninvasive diagnosis computer assisted diagnosis,diagnosisdesign /evaluation, heart function, heart pharmacology, heartventricle, human therapy evaluation, longitudinal human study,nitric oxide, phantom model, prognosis, pulmonary hyperten-sion, vasodilation clinical research, human subject

Institution: University of PennsylvaniaPhiladelphia, PA 19104

Fiscal Year: 1998


556

Department: RadiologyProject Start: 01-Apr-90Project End: 31-Dec-99ICD: National Heart, Lung, and Blood

InstituteIRG: RNM

MRI EVALUATION OF THE EFFECTS OFCORONARY ARTERY DISEASE

Grant Number: 1R01HL60009-01A1PI Name: Axel, Leon

Abstract: Coronary artery disease (CAD) is a major publichealth problem; current conventional imaging methods toevaluate the heart in CAD have many limitations. Magneticresonance imaging (MRI) of the heart has great potential toimprove the diagnosis and management of CAD, but it needsfurther development and evaluation. The long term objec-tives of the work proposed in this application are to producean improved, clinically practical method for MRI evaluationof CAD and to demonstrate its utility. The specific aims are:1) development of improved MRI perfusion imaging andanalysis techniques and their integration into a comprehen-sive cardiac MRI examination, 2) validation of these MRItechniques in an animal model of chronic myocardial isch-emia, and 3) preliminary evaluation of these techniques in aseries of human cardiac patients. The technical developmentof cardiac imaging methods will include development ofrapid perfusion imaging (through rapid imaging of the firstpassage of a bolus of MR contrast agent) and tissue charac-terization MRI techniques, and their integration with previ-ously developed regional function MRI techniques (usingtagging with spatial modulation of magnetization(SPAMM)). The corresponding image analysis programs willbe developed within a program previously developed for theanalysis of tagged MR images, SPAMMVU. Data visualiza-tion programs will be developed both to aid the primary in-terpretation of the study and to convey the results of theanalysis to the referring clinician. These imaging and analy-sis techniques will be validated in a porcine model ofchronic ischemia, including independent perfusion measure-ment with microspheres. Human studies will include bothnormal subjects and a limited series of patients with CAD;this will enable us to perform an initial evaluation of theusefulness of these MRI methods in CAD and to plan for amore definitive evaluation. The results of the MRI studieswill be compared with both conventional radionuclide imag-ing studies and the patient’s cinical course.

Thesaurus Terms: cardiovascular disorder diagnosis, coro-nary disorder, diagnosis design /evaluation, magnetic reso-nance imaging contrast media, pharmacokinetics bioimaging

/biomedical imaging, clinical research, human subject, singlephoton emission computed tomography, swine

Institution: University of PennsylvaniaPhiladelphia, PA 19104

Fiscal Year: 1999Department: RadiologyProject Start: 01-Jan-99Project End: 31-Dec-02ICD: National Heart, Lung, and Blood

InstituteIRG: RNM

MRI OF VASCULAR FUNCTION IN THEHYPERTENSIVE HEART

Grant Number: 5K01HL03837-02PI Name: Beache, Garth M.

Abstract: DESCRIPTION (Adapted from applicant’s ab-stract) This proposal will provide the candidate with in-depthtraining in the concepts and methods relevant to the noninva-sive imaging of vascular function in heart disease usingmagnetic resonance imaging (MRI). The proposed researchwill build on the candidate’s previous focus on the use ofMRI to characterize mechanical and perfusion abnormalitiesin heart disease. The long-term goal is to develop broad-based skills that are essential for elucidating the multifacto-rial pathophysiology underlying many heart conditions. Thecandidate will be guided by a team of basic scientists andclinicians who are currently conducting related cardiac re-search. Through closely working with this interdisciplinaryteam of senior investigators, the candidate is expected todevelop a model for his own career. Specifically, the re-search aims to refine and implement a noninvasive MRImethod, based on the sensitivity of MRI to blood oxygen-ation changes that accompany changes in hemodynamics andoxygen metabolism, to detect and qualify microvascular dys-function in the heart. The method will be applied to thestudy of hypertension since it is a disease with major publichealth impact, affecting 10-20% of US adults, in which mi-crovascular dysfunction is believed to contribute to symp-toms and cardiac performance, and for which adequate non-invasive vascular function methods do not exist. The appli-cants will then relate a new MR measure of vasculardysfunction to establish indicators of cardiac disability. Theyhave obtained preliminary data confirming the ability to de-tect these effects in rats and in human subjects. This researchhas the potential to characterize the functional manifestationsof hypertension and has the potential to contribute to a morecomprehensive explanation of symptoms, which will aid intailoring therapeutic regimen related to the vascular aspectsof this disease. (End of Abstract)


557

Thesaurus Terms: heart disorder diagnosis, heart function,hypertension, magnetic resonance imaging, microcirculation,noninvasive diagnosis, pathologic process respiratory oxy-genation, vasodilation, ventricular hypertrophy bioimaging/biomedical imaging, clinical research, human subject


Fiscal Year: 1999Department: RadiologyProject Start: 01-Jul-98Project End: 30-Jun-03ICD: National Heart, Lung, and Blood

InstituteIRG: ZHL1

IMAGING APOPTOSIS IN VIVO WITHTECHNETIUM 99M ANNEXIN

Grant Number: 1R01HL61717-01A1PI Name: Blankenberg, Francis G.

Abstract: The biochemical characterization of rejecting tis-sues suggests that apoptosis plays a major role in acute car-diac rejection. We propose to use a novel radiopharmaceuti-cal, radiolabeled (99m Tc) annexin V, to monitor the earlyand specific biochemical properties of cardiac allografts un-dergoing acute rejection. Annexin V, a 35kD a human pro-tein, is useful to detect and quantify dying cells in vitro andin situ well in advance of other cell markers of death. Ourgroup has adapted annexin V for use as an imaging agent byradiolabeling this protein with technetium 99m without af-fecting its bioreactivity. Our work so far has shown that ra-diolabeled annexin V can detect and monitor dying cells inthe liver undergoing fulminant apoptosis in response to Fasantibody, and in normal bone marrow and spleen, as well aslymphomatous tumors following anti-cancer treatment. Wealso have demonstrated that radiolabeled annexin V can beused to noninvasively detect and monitor acute liver, lung,and heart transplant rejection. In this proposal we will opti-mize the parameters needed for radiolabeled annexin V de-tection of acute cardiac rejection imaging by: 1) determiningthe relationships of administered protein dose, and rate ofintravenous infusion with respect to the biodistribution ofradiolabeled annexin V; 2) increasing the serum half life ra-diopharmaceutical by dimerizing annexin V (which retainsthe same binding capacity as monomeric annexin V) to im-prove target localization; 3) studying the influence of com-peting binding sites on tracer distribution using PS contain-ing polymerized liposomes which bind to annexin V in thecirculation. The optimized imaging approach will be thenapplied to study the time course of apoptosis within cardiac

allografts during acute rejection. We will then determine thesensitivity and specificity of radiolabeled annexin V to moni-tor apoptosis during immunosuppressive therapy with cyclo-sporine of heterotopic cardiac allografts undergoing acutesection. Finally we will selectively bloc apoptosis in reject-ing cardiac allografts using the caspase inhibitor, ZVAD-.fmk, to determine the contribution of apoptotic relative tonecrotic cell death to the uptake of radiolabelled annexin V.The data from our project may allow for direct monitoringof apoptosis in cardiac transplant recipients without the needfor endomyocardial biopsy. Using radiolabeled annexin V asa clinical imaging tool may permit more rapid assessmentand development of therapies designed to inhibit cardiac ap-optotic cell death and decrease immunotherapy related mor-bidity via more precise adjustment of the intensity and dura-tion of immunosuppression to the severity of rejection.

Thesaurus Terms: annexin, heart transplantation, prognosis,programmed cell death, radionuclide scanning /imaging,technetium, transplant rejection acute disease /disorder, bind-ing site, cell cell interaction, cyclosporine, cysteine endopep-tidase, dimer, enzyme inhibitor, homologous transplantation,immunosuppressive, kidney metabolism, liposome, proteinmetabolism, protein transport, transplantation immunologybioimaging /biomedical imaging, laboratory rat, radiotracer

Institution: Stanford UniversityStanford, CA 94305


InstituteIRG: RNM

NONINVASIVE HIGH ENERGYPHOSPHATE IMAGING

Grant Number: 5R21HL62332-02PI Name: Bottomley, Paul A.

Abstract: DESCRIPTION (Adapted from the applicant’sabstract): Oxidative energy metabolism is essential for mostcellular function including muscular contraction and iontransport. Phosphorus (31P) magnetic resonance spectroscopy(MRS) is unique in its ability to provide non-invasive accessto key HEP metabolites such as adenosine triphosphate(ATP), the body’s essential energy currency, and phospho-creatine (PCr), a key energy reserve. In the heart, clinicalMRS shows reduced levels of PCr and ATP in infarction,and PCr/ATP ratios during ischemia. These and other MRSabnormalities seen in muscle disease, cancer, and the brain(e.g., stroke, some dementia), highlight the role of altered


558

energy metabolism in common disease states, and its poten-tial for evaluating therapeutic response. However, studies ofHEPs access to deep-lying tissue, and the complexity ofspectroscopic analysis. To address these critical problems,the investigators first demonstrated that the sensitivity of hu-man HEP in the torso can be significantly increased by nu-clear Overhauser enhancement (nOe) technique. Second, theyseparately showed that the use of (31)P phased-array coilscan greatly increase sensitivity and access to PCr and ATPlevels in the body. Third, to simplify MRS analysis, it hasbeen demonstrated that HEP (PCr or PC and ATP) can bedirectly imaged in the body in the normoxic and ischemicconditions with chemical-selective (31)P MRI. The appli-cants now propose to combined phased-array with nOe tech-nologies to provide critically important sensitivity gains of3-fold and higher for (31)P studies of HEP in the body.They further propose that the combination of direct chemi-cal-selective MRI of HEP will largely eliminate the analysisburden for MRS with phased-arrays. In addition, it is pro-posed that HEP imaging will further benefit from a priorispatial information acquired by routine proton MRI. The in-tegration of these diverse new technologies presents newchallenges requiring innovate solutions. Success in their inte-gration wil create a new biomedical research tool to non-invasively probe energy metabolism in human disease. Thus,the applicants propose to combine, for the first time, the sen-sitivity advantages provided by the physics technique of nOewith the engineering technique of phased arrays, chemical-selective MRI of medical imaging and new science analysismethods to create HEP imaging.

Thesaurus Terms: high energy compound, imaging /visual-ization, magnetic resonance imaging, method development,nuclear magnetic resonance spectroscopy, phosphate adeno-sine triphosphate, creatine phosphate bioimaging /biomedicalimaging, human subject


Fiscal Year: 1999Department: RadiologyProject Start: 21-Sep-98Project End: 31-Aug-00ICD: National Heart, Lung, and Blood

InstituteIRG: ZRR1

PROTON MAGNETIC RESONANCESTUDIES OF MYOCARDIAL CREATINE

Grant Number: 5R01HL56882-02PI Name: Bottomley, Paul A.

Abstract: Oxidative energy metabolism is essential for nor-mal cardiac contractile function. Phosphorus (31P) magneticresonance spectroscopy (MRS) is unique in its ability to pro-vide noninvasive access to key metabolites such as adeno-sine triphosphate (ATP) and phosphocreatine (PCr) in theheart. Patient MRS studies show reduced levels of PCr andATP in myocardial infarction, and altered PCr/ATP ratios inheart failure that correlate with clinical severity. Biopsy andautopsy date demonstrate that total myocardial creatine (CR,however, have been limited by the invasive nature of exist-ing techniques. But CR can be observed in vivo by protonMRS. Moreover, due to the higher 1H MRS sensitivity andthe extraordinarily greater proton concentration of the CRN-CH3 moiety, CR MRS can potentially provide a morethan 20 fold gain in signal-to-noise relative to 31P studies ofPCr. Thus 1H MRS of CR MRS offers a new, sensitive,window for quantifying, mapping, and even imaging, an im-portant myocardial energy metabolite. We have demonstratedCR detection and mapping in normal human heart and CRreductions in human myocardial infarction in our preliminary1H MRS work. Here, the development and validation of 1HMRS as a tool for quantifying regional myocardial CR in thehuman heart is proposed using phantom, MRS, and biopsystudies of canine myocardium, as well as noninvasive humanMRS studies. The use of CR MRS for differentiating in-farcted myocardium from noninfarcted myocardium will beassessed via quantitative MRS and tissue assays in a well-defined canine model of infarction, and by MRS studies ofpatients with myocardial infarction. The hypothesis thatmyocardial CR and PCr levels in the CK reaction are re-duced in the failing human heart in proportion to the severityof heart failure will be tested with noninvasive1H and 31PMRS studies of patients with heart failure. The developmentof a new, sensitive, noninvasive method for quantifyingmyocardial energy metabolism would significantly advanceour understanding of the ole of energy deprivation in heartdisease, and potentially provide us with a new probe for as-sessing cardiac tissue viability.

Thesaurus Terms: cardiovascular disorder diagnosis, cre-atine, diagnosis design /evaluation, myocardial infarction,myocardium, noninvasive diagnosis adenosine triphos-phate, bioenergetics, chemical kinetics, creatine kinase,creatine phosphate, disease model, heart failure, heart me-tabolism, phosphorus metabolism biochemistry, biopsy,clinical research, dog, human subject, magnetic resonanceimaging, nuclear magnetic resonance spectroscopy, post-mortem


Fiscal Year: 1998Department: Radiology


559

Project Start: 01-May-97Project End: 30-Apr-00ICD: National Heart, Lung, and Blood

InstituteIRG: RNM

SODIUM IMAGING IS ISCHEMIC HEARTDISEASE

Grant Number: 1R01HL61695-01A1PI Name: Bottomley, Paul A.

Abstract: The exchange of intra- and extra-cellular sodium andpotassium ions is essential to cell function and integrity. In theheart, evidence from animal and human radionuclide imagingstudies of potassium and potassium analogs, and from biochem-ical and magnetic resonance spectroscopy (MRS) studies ofanimal models, indicates that sodium- potassium pump functionis compromised during periods of myocardial ischemia and thatit is lost in non-viable, infarcted tissue as intra- and extra-cellu-lar pools equilibrate. Sodium (23Na) magnetic resonance imag-ing (MRI) is uniquely able to image and measure noninvasivelynaturally abundant, endogenous sodium in the body. 23Na MRIat magnetic fields of � 2.7 Tesla (T) in animal models demon-strate a 2-fold increase in 23Na signal levels in nonviable, his-tologically-confirmed, acute reperfused myocardial infarction(MI). Owing to its higher tissue concentration and sensitivityand its short relaxation time, 23Na MRI has an enormous sensi-tivity advantage compared, for example, with the detection ofhigh-energy phosphate metabolites by phosphorus (31P) MRI(approximately 80- fold). Thus 23Na MRI is a potentiallyunique and important tool for assessing cellular metabolic andionic function through altered sodium levels in patients withischemic heart disease and/or MI. Yet 23Na is not now rou-tinely possible on clinical 1.5T MRI scanners. Moreover, hu-man 23Na MRI has never benefitted from new MRI hardwareand software technology. In preliminary studies we imple-mented 23Na MRI on a clinical MRI scanner, and demonstratealtered 23Na MRI levels in MI. We show preliminary stress-23Na MRI data from patients with stress-induced ischemia de-tected metabolically by 31P MRS. Here we propose to developand optimize human cardiac 23Na MRI on a clinical 1.5 TMRI/MRS system, by implementing high-speed MRI, 23Naphased-array detection, resolution-enhancement using a priorianatomic information, and methods of suppressing 23Na signalsfrom ventricular blood. We will use optimized 23Na MRI toharacterize normal and infarcted human myocardium, and totest the hypotheses that 23Na MRI can differentiate normalfrom non-viable reperfused MI in patients as detected by radio-nuclide imaging, and compared with contrast- enhanced MRI.Further, the hypothesis that optimized 23Na MRI can detectstress-induced changes in sodium in energetically- compromisedmyocardium will be tested in combined stress-23Na/3 1P meta-

bolic studies. The availability of thousands of clinical MRIscanners offers a great opportunity for advancing 23Na MRI asa tool for assessing sodium pump function in human heart dis-ease.

Thesaurus Terms: magnetic resonance imaging, methoddevelopment, myocardial infarction, myocardial ischemia/hypoxia, sodium potassium exchanging ATPase blood flow,contrast media, heart disorder diagnosis, heart ventricle, non-invasive diagnosis, nuclear magnetic resonance spectroscopy,phosphorus metabolism, transient ischemic attack bioimaging/biomedical imaging, clinical research, echocardiography,electrocardiography, human subject, proton beam, radionu-clide scanning /imaging, sodium, thallium



InstituteIRG: RNM

VASCULAR BUBBLE GENERATION FORDIAGNOSIS AND THERAPY

Grant Number: 5R01HL54201-03PI Name: Carson, Paul L.

Abstract: This is a revised proposal to develop and evaluatecontrolled generation of arterial microbubbles using intense,focused ultrasound pulses for possible diagnostic and thera-peutic use. Since the previous submission, arterial micro-bubbles have been generated in flowing whole blood in vitrowith 725 kHz ultrasound passing through canine tissues sim-ulating human transcutaneous generation. Threshold intensi-ties observed in blood were 2.3 times less than at the previ-ous 1.8 MHz and temperature rise on realistically-placedvertebral bone was acceptable. Short boluses of ultrasoni-cally imageable, less than 40 micron bubbles, generated inselected arteries, should be usable for diagnosis and monitor-ing of those vascular and perfusion abnormalities which cur-rently are evaluated more slowly and expensively, and prob-ably more invasively, with MRI or with angiography requir-ing arterial catheterization. Sparse distributions of 20 to 40micron bubbles should be usable to refocus ultrasoundbeams for high resolution imaging through aberrating overly-ing tissues, even for imaging through the skull. The first andmost certain medical use of bolus generation is expected tobe identification of feeder arteries to therapeutic targets suchas tumors and arterio-venous malformations. Coagulation of


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the feeder arteries, or thrombus generated by repeated, moreextensive boluses, will occlude the target for safer, more ef-fective ultrasound or chemical therapy or surgery. Knowl-edge of ultrasonic fields which produce vascular micro-bubbles of negligible damage up to vascular occlusion willhelp improve guidelines for safe diagnostic and therapeuticultrasound. Bubbles will be produced and characterized un-der various conditions directed to the above goals. Studieswill include bubble size distributions, constituents and lon-gevity with and without contrast agent seeding and at two ormore ultrasound frequencies, pulse amplitudes and durationsand blood velocities. Current success at bolus production inexposed arteries with minimal arerial wall damage appar-ently is due to focusing within the vessel. Lower frequenciesand other techniques will be utilized for desired bubble gen-eration with lower thermal and cavitational damage, even,possibly, in smaller, deeper vessels where luminal contain-ment of the focus is not possible. In vivo studies will be per-formed initially on the cerebral vasculature, as there is agood chance of success and the brain is the most sensitiveand best studied major organ for arterial gas damage, albeitat volumes 750,000 times the minimum ultrasonically image-able volume. Neurologic diagnosis and treatment is in needof better techniques and, finally, transcutaneous arterial gen-eration will be easiest in the carotid. Generation of the twotypes of diagnostic carotid boluses is planned in animalmodels for verification of thresholds, demonstration of intra-cranial imaging and initial evaluation of possible adverseeffects demonstrable by optical histology, colored micro-spheres and autoradiography. Demonstration of feeder arterydelineation for lesion treatment by vascular occlusion will beperformed in the canine thyroid vasculature.

Thesaurus Terms: cardiovascular disorder diagnosis, diag-nosis design /evaluation, ultrasonography artery occlusion,artery stenosis, blood cell count, brain scanning, carotid ar-tery, cerebral circulation, cerebral ischemia /hypoxia, endo-crine disorder diagnosis, neuromuscular disorder diagnosis,thyroid gland, ultrasound blood flow measurement, ultra-sound therapy autoradiography, dog, histology, laboratoryrabbit, radioactive microsphere technique

Institution: University of Michigan at Ann ArborAnn Arbor, MI 48109

Fiscal Year: 1998Department: RadiologyProject Start: 15-Mar-96Project End: 28-Feb-99ICD: National Heart, Lung, and Blood

InstituteIRG: RNM

MECHANISTIC STUDIES OF METAIODOBENZYLGUANIDINE IN HEART

Grant Number: 5R29HL54882-04PI Name: Degrado, Timothy R.

Abstract: DESCRIPTION: The kinetics of I-131 labeledmeta-iodobenzylguanidine (MIBG) in the heart will be stud-ied using an isolated perfused rat heart model. Uptake, reten-tion and release of I-131-MIBG will be studied under vari-ous conditions and correlated with variables such as cate-cholamine transport and metabolism, ischemia, andvariations in cardiac metabolic substrate. Neuronal and extra-neuronal uptake will be distinguished using agents that blockspecific uptake pathways. A comprehensive mathematicalmodel of MIBG kinetics in the heart will be developed. Thegoal is to define the physiologic mechanisms that governuptake of MIBG in the heart. The investigations will attemptto clarify the role of specific transporters and binding sitesand seek to define the relationship of these processes to 1)the kinetic behavior observed by external monitoring tech-niques, and 2) the corresponding disposition of endogenouscatecholamines in normal and ischemic conditions.

Thesaurus Terms: analog, biomaterial development/prepara-tion, biomaterial evaluation, drug metabolism, guanidine,heart circulation, pharmacokinetics 3 methoxy 4 hydroxyphe-nylethyleneglycol, blood flow measurement, catecholamine,clearance rate, electrostimulus, exocytosis, heart metabolism,mathematical model, membrane transport protein, model de-sign /development, molecular site, myocardial ischemia /hyp-oxia, myocardium, neurotransmitter metabolism, norepineph-rine, radiocardiography, vesicle /vacuole laboratory rat



InstituteIRG: RNM

ROBUST CONTRAST FOR AUTO-ANALYSIS OF CARDIAC MRI

Grant Number: 1R01HL58147-01A2PI Name: Dixon, William T.

Abstract: DESCRIPTION (Adapted from Applicant’s Ab-stract): The applicants presented preliminary experimentsshowing Tlrho weighting and enhancement with Gd-DTPAinjection combine to improve contrast of cine images of the


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heart greatly and to bring results of automated analysiscloser to results of manual analysis. The applicants hypothe-sized this improved contrast could improve diagnostic accu-racy and make automated analysis of cardiac function reli-able enough to replace physician-intensive, manual analysisof multislice, multiphase images. Such replacement is impor-tant because manual analyses are not usually performed.When they are, generally only ejection fractions and systolicthickening are estimated. Routine cine images also determinerates of change, which may be more sensitive to disease, butanalyzing images manually is so tedious that these data areusually wasted. The applicants proposed, starting from theirpresent, Tlrho/Gd-DTPA method, to develop high-contrast,robust protocols using navigator echoes to control the effectof normal breathing during examination and, to providegreater coverage in less time, echo planar imaging. Theyproposed to compare diagnoses made from conventional andimproved images and to compare automated analyses of con-ventional and improved images using an existing softwarepackage that automatically detects edges to draw endocardialand epicardial contours and to extract functional indices.They would determine which aspects of image quality aremost important to automated analysis. With the developersof the software, they would modify and improve the analysisprogram to exploit improved image contrast fully. The imagegeneration and optimization effort would require simulationof pulse sequences, then testing promising ones on patients.Patients with questionable ventricular function due to coro-nary artery disease, cardiomyopathy, or end-stage lung dis-ease or who are candidates for heart or lung transplantwould be examined, comparing diagnoses from conventionaland improed images. To test automated analyses, automaticresults would be compared to manual results on the sameimages and to automatic results on repeated scans. For refer-ence, manual results would be compared to repeated manualanalysis of the same data and of repeat scans. Comparisonswould include endocardial areas and volumes in the left andright ventricles, ejection fractions, the peak rates of ejectionand filling, and the times at which end systole, end diastole,and the peak flow rates occur.

Thesaurus Terms: cardiography, computer data analysis,contrast media, diagnosis quality /standard, heart disorderdiagnosis, image enhancement, magnetic resonance imagingbiomedical automation, cineangiocardiography, computerassisted diagnosis, diagnosis design /evaluation, diethylene-triaminepentaacetate clinical research, human subject

Institution: Emory UniversityAtlanta, GA 30322

Fiscal Year: 1998Department: RadiologyProject Start: 15-Jul-98Project End: 30-Jun-01

ICD: National Heart, Lung, and BloodInstitute

IRG: ZRG7

DYNAMIC ANALYSIS OF LEFTVENTRICULAR DEFORMATION FROM 4DIMAGES

Grant Number: 5R01HL44803-07PI Name: Duncan, James S.

Abstract: The accurate quantification of transmural left ven-tricular (LV) regional function is crucial for managing pa-tients with ischemic heart disease. Previous imaging-basedefforts have been hampered by the limitations of conven-tional two-dimensional imaging and inadequate image analy-sis methodology (e.g., the inability to handle out-of-planemotion). More recently, these limitations are starting to beovercome by three- dimensional (3D) imaging strategies andmethods to estimate pointwise myocardial displacementsand/or velocities. However, the task of assembling dense 3Dsets of image-derived displacement/velocity data into trans-mural, quantitative measurements of LV function remains adifficult one. The research proposed here is aimed at furtherdevelopment of an image analysis strategy to more accu-rately, robustly and reproducibly characterize 3D LV func-tion over time (i.e., 4D datasets) by quantifying the transmu-ral deformation of the LV from any one of several imagingmodalities. At the core of the effort is an approach that usesboth kinematic and biomechanical Finite Element models,computer vision-related strategies based on differential geo-metric features and mathematical optimization reasoningmethods to estimate the non-linear, non-rigid deformation ofthe left ventricle of the heart. A key feature of this approachis that it can combine surface displacement information atthe endocardial and epicardial boundaries derived from thegeometric, shape- based tracking strategies developed in thefirst three years of this grant with midwall velocity informa-tion, such as that found from MRI phase velocity data, echo-cardiographic Doppler tissue velocity data or velocity dataestimated using a physical flow approach to form 3D mapsof transmural myocardial strain estimates which can be bro-ken down into directional components. The accuracy andreproducibility of the approach, as well as the importance ofusing multiple sources of displacement/velocity information,will be demonstrated by validating the imag-derived strainmeasurements obtained from a range of imaging modalities(cine gradient echo and echo planar MRI, 3D echocardiogra-phy (3DE) and 3D cine Computed Tomography from theDynamic Spatial Reconstructor (DSR)) to those made using1.) well-characterized material samples and ii.) arrays of im-age-visible markers implanted in acute dogs. The utility ofthe approach for deriving clinically-relevant measurements


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related to the transmurality of infarct morphology will betested by comparing MRI-derived measurements of strain intwo groups of acute dogs having different post mortem-de-termined degrees of transmural and non- transmural infarc-tion. Finally, we will test the algorithm on a number of 4Dimage datasets of normal human subjects in each of two mo-dalities (MRI and 3DE) to establish clinical feasibility andreproducibility.

Thesaurus Terms: cardiography, diagnosis design /evalua-tion, heart disorder diagnosis, heart function, heart ventricle,image processing computer assisted diagnosis, computer sim-ulation, heart dimension /size, heart scanning, heart ventricu-lography, mathematical model, myocardial infarction, vaso-motion bioimaging /biomedical imaging, cineradiography,

clinical research, computed axial tomography, dog, dynamicspatial reconstructor, echocardiography, human subject, mag-netic resonance imaging

Institution: Yale UniversityNew Haven, CT 06520

Fiscal Year: 1999Department: Diagnostic RadiologyProject Start: 01-Jan-93Project End: 30-Jun-00ICD: National Heart, Lung, and Blood

InstituteIRG: ZRG7


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abstracts of funded national institutes of health grants

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