abstracts of funded national institutes of health grants

National Cancer Institute

NOVEL MONOMOLECULAR MULTIMODALITY IMAGING AGENTS

Grant Number: 4R33CA100972-02PI Name: Achilefu, Samuel

Abstract: Description (provided by applicant): The era ofmolecular imaging necessitates the development of molecularprobes that can interrogate the molecular basis of pathogene-sis. Unfortunately, aberrant molecular processes in vivo typi-cally involve the expression of small amounts of target fac-tors that can only be detected by highly sensitive diagnosticmethods. For this reason, nuclear imaging methods, whichcan detect minimal amounts of radiopharmaceuticals in tis-sues, are suited for molecular imaging. Recent studies haveshown that accurate and rapid detection of cancer cells canbe achieved by the use of multimodal imaging systems tofurnish complementary and unique diagnostic informationfrom each component imaging method. Molecular imagingof cancer in vivo by multimodality imaging methods wouldbenefit from the development of monomolecular multimodal-ity imaging agents (MOMIAs). Accordingly, this study fo-cuses on the development of novel optical-nuclear MOMIAsfor imaging tumors. The structural framework of the pro-posed molecules will consist of a receptor-specific carrier toenhance tumor specificity, a NIR fluorescent dye for opticalimaging, and a chelated radiometal for gamma scintigraphy(111In), positron emission tomography (64Cu) or combinedgamma scintigraphy and radiotherapy (177Lu). Stability, cy-

totoxicity and subcellular distribution of the new MOMIAswill be performed to select promising candidates for in vivoevaluation. The in vivo studies will include pharmacokineticsand histology of selected MOMIAs. Localization of tumorsin rodents will be performed by fluorescence, gamma, andpositron emission imaging, and the data from all modalitieswill be compared with each other. Successful completion ofthis study will result in the development of at least oneMOMIA for translational research and eventual clinicaluse.

Thesaurus Terms: drug design/synthesis/production, fiberoptics, fluorescent dye/probe, imaging/visualization/scanning,neoplasm/cancer diagnosis, radionuclide, chemical stability,chemical synthesis, copper, cytotoxicity, histology, indium,metal, molecular oncology, neoplasm/cancer, neoplasm/can-cer radiodiagnosis, neoplasm/cancer radionuclide therapy,pharmacokinetics, radionuclide imaging/scanning autoradiog-raphy, bioimaging/biomedical imaging, cell line, laboratorymouse, laboratory rat, nanotechnology, neoplastic cell,positron emission tomography

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

Fiscal Year: 2004Department: RadiologyProject Start: 01-May-2003Project End: 30-Apr-2007ICD: National Cancer InstituteIRG: ZCA1

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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 are printed alphabetically by author according to the funding institute or center.

WASHINGTON UNIVERSITY SMALLANIMAL IMAGING RESOURCE

Grant Number: 5R24CA083060-05PI Name: Ackerman, Joseph J.

Abstract: It is proposed to establish the Washington Univer-sity Small Animal Imaging Resource (WUSAIR) to providestate-of-the-art facilities and infrastructure for magnetic reso-nance imaging (MRI) and positron emission tomography(PET) analysis of mice, rats and other small laboratory ani-mals. Located in the heart of Washington University MedicalCenter in St. Louis, WUSAIR will combine instrumental andintellectual capabilities found at few other institutions.WUSAIR will serve a broad community of scientists non-expert in MRI or PET technology who have a pressing needfor quantitative image analysis of small laboratory animalmodel systems. A particular focus will be on mice and ratmodels of cancer. WUSAIR will also continue research anddevelopment at the frontier of imaging technology in an ef-fort to make the most powerful of the new imaging strate-gies available to its community of users. Purchase of newPET and/or MRI scanners is not requested herein. Indeed,Washington University has generously supported the recentacquisition of such equipment as part of its continuing andsubstantive commitment to basic biomedical research. Cur-rently on site and fully operation in the Imaging ResearchCenter are two Varian INOVA 4.7 T MRI/MRS small ani-mal research scanners. A PET scanner dedicated to smallanimal research, the microPET, will be delivered and sited inthe Clinical Sciences Research Building early next year.These PET and MRI small animal research scanners willform the core instrumentation of WUSAIR.

Thesaurus Terms: bioimaging/biomedical imaging, biomed-ical resource, magnetic resonance imaging, positron emissionTomography, Animalia, laboratory mouse, laboratory rat


Fiscal Year: 2003Department: RadiologyProject Start: 01-Sep-1999Project End: 31-Aug-2004ICD: National Cancer InstituteIRG: ZCA1

TRAINING IN CANCER IMAGING WITHNOVEL TECHNIQUES

Grant Number: 5T32CA093258-02PI Name: Alavi, Abass

Abstract: Description (provided by applicant): The Depart-ment of Radiology, in conjunction with the comprehensive

Cancer Center at the University of Pennsylvania School ofMedicine, proposes a Training Program in Innovative CancerImaging Technologies. The fundamental goal of the programis to develop independent investigators in Radiology whowill focus their scientific efforts in oncology research. The2-year training will prepare MDs and MD-PhDs in radiologyand related programs for academic imaging research careersusing anatomic and functional technologies to address issuesin the detection, diagnosis, staging, monitoring of treatment,and progression of malignant lesions. In addition to trainingin the theory and applications of MR, ultrasound, CT, opticaltomography, PET, SPECT, and small animal imaging (PET,SPECT, MRI, and CT), the trainees will be exposed to abroad spectrum of imaging research from coil and compo-nent design and the development of new technologies to lab-oratory studies, translational research, and clinical trials uti-lizing these imaging modalities. Research training will in-clude 4 categories of experiences: (1) required corecurriculum; (2) preceptor-directed oncology imaging re-search; (3) laboratory and clinical research-structured interac-tive seminars; (4) attendance at scientific meetings and sym-posia. Faculty preceptors have active, funded laboratoriesand a broad base of experience in imaging and oncologyresearch. The Advisory Committee will provide administra-tive guidance to the program director, evaluate programprogress, and suggest directions for future programmatic ef-forts. The Research Advisory Committee consists of facultypreceptors from all of the above training areas that will meetregularly to review applications and to assess the currenttrainees’ research progress. The primary research trainingfacility is the Department of Radiology which, in addition toextensive MR facilities, has active research groups in meta-bolic MR, nuclear medicine, medical informatics, medicalimage processing for tomographic image reconstruction, anda center for the developing technology of optical imaging. Inaddition, the research and clinical facilities of the CancerCenter, the departments of Radiation Oncology and Bio-chemistry and Biophysics, and the Hospital of the Universityof Pennsylvania will be used by trainees. The extensive re-search resources in the Department of Radiology and theCancer Center will ensure high-quality research training in ascientifically sound and cost-effective manner. This will en-able the Department of Radiology to increase the number ofyoung clinical investigators and research scientists commit-ted to excellence in academic oncology research using imag-ing technology.

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

Institution: University Of Pennsylvania3451 Walnut StreetPhiladelphia, PA 19104

Fiscal Year: 2004Department: Radiology

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Project Start: 01-May-2003Project End: 30-Apr-2008ICD: National Cancer InstituteIRG: NCI

IMAGING OF PROGENITOR CELLS INTUMOR ENVIRONMENTS

Grant Number: 5R01CA096978-02PI Name: Allport, Jennifer

Abstract: Both stem cells and progenitor cells hold signifi-cant promise as cell-based therapies. These cells have theunique ability to undergo self-renewal and to differentiateinto a variety of different cell types, allowing the continueddelivery of therapy for a prolonged period. Added benefitsinclude, the use of the patient’s own cells, highly controlledin vitro manipulation of these cells, and the ease of delivery.Little is known, however, regarding the behavior of theseprogenitor cells in vivo, their specific recruitment to tumorsand the magnitude of in vivo cell trafficking. Utilizing anumber of in vitro and in vivo imaging approaches, this pro-posal seeks to 1) determine mechanistic aspects that mediatepreviously identified apparently selective recruitment of pro-genitor cells to tumors, and 2) quantitate recruitments fordifferent cells types, tumors and tumor microenvironmentswith regard to the latter we have recently observed highlyefficient homing and retention capabilities. We hypothesizethat there exist unique tumor endothelium/progenitor cellinteractions that mediate attachment, transmigration and dif-ferentiation of the former in tumors and in particular the tu-mor microvasculature through vasculogenesis. In preliminaryfeasibility studies we have developed a number of tools thatwill allow us to interrogate tumor endothelium/progenitorcell interactions in vitro and in vivo. These tools include 1)isolation and characterization of differentiated endothelialcells (murine heart, murine lung and murine Lewis Lungcarcinoma derived endothelium) and a panel of progenitorcells (murine C17.2 neuronal progenitors, murine CD34�hematopoietic stem cells and CD34�/Flk-1� endothelialprogenitors), 2) in vitro flow chambers, 3) methods for imag-ing progenitor cells in vivo by optical, nuclear and MR im-aging methods and 4) methods for isolation of tumor homedcells for comparative genomic analysis. Together, these tech-niques, and the expertise of a number of collaborators, willprovide a powerful approach in understanding the mecha-nisms that target progenitor cells to tumors. Understandingthe mechanisms that mediate progenitor cell recruitment bothat a cellular and a molecular level, along with the ability tomanipulate these events directly and promote increased re-cruitment of progenitor cells to the target tumor will providea springboard to rapidly improved and more specific cell-based therapies for the direct treatment of tumor.

Thesaurus Terms: angiogenesis, cell-cell interaction, cellmigration, hematopoietic stem cell, neoplastic cell, vascularendothelium, CD34 molecule, CD44 molecule, cell adhesion,cell differentiation, cell type, cytokine receptor, gene expres-sion, integrin, luciferin monooxygenase, molecular film, neu-ron, selectin immunomagnetic separation, laboratory mouse,magnetic resonance imaging, polymerase chain reaction, ra-diotracer

Institution: Massachusetts General Hospital55 Fruit StBoston, MA 02114

Fiscal Year: 2003Department:Project Start: 01-Aug-2002Project End: 31-Jul-2005ICD: National Cancer InstituteIRG: RNM

NOVEL RADIAL MRI METHODS FORABDOMINAL IMAGING

Grant Number: 5R33CA099074-02PI Name: Altbach, Maria I.

Abstract: Description (provided by applicant): The maingoal of the proposed project is to develop novel radial mag-netic resonance imaging (MRI) methods for body imaging toimprove diagnosis and reduce imaging time. The proposedmethods are based in novel acquisition strategies of radialdata and a novel post-processing algorithm used to obtainimages with different signal weighting from a single k-spacedata set. Preliminary results show that significant improve-ments in abdominal imaging can be achieved with a T2-weighted radial fast-spin echo (RAD-FSE) method comparedto conventional 2DFT MRI. RAD-FSE provides motion in-sensitivity comparable to 2DFT single-shot methods, withoutcompromising spatial resolution. Moreover, the detection ofsmall neoplasms (0.5-1 cm3) with RAD-FSE is significantlyimproved. A unique feature of the technique is that charac-terization of benign and malignant lesions can be done fromT2 maps obtained from a single RAD-FSE k-space data setvia post-processing. Thus the combined use of radial acquisi-tion and post-processing methods can significantly improvelesion detection and lesion characterization as well as reduceimaging time. The specific aims of the proposed work are:(1) to further develop radial MRI methods to improve thetime efficiency of the technique while preserving imagequality; (2) to develop and evaluate alternative post-processingmethods to improve characterization of small lesions; (3) tovalidate the acquisition and post-processing strategies pro-posed in Aims 1 and 2 in a clinical study at a magnetic fieldof 1.5 T; (4) to develop and evaluate radial methods at amagnetic field of 3.0 T. The overall goal is to develop the

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acquisition and post-processing methods and then to showthat these lead to improve detection and characterization ofneoplasms.

Thesaurus Terms: diagnosis design/evaluation, gastrointesti-nal disorder diagnosis, gastrointestinal imaging/visualization,magnetic resonance imaging, method development, abdomenneoplasm, image enhancement, magnetic field, noninvasivediagnosis bioimaging/biomedical imaging, clinical research,human subject, mathematics, radio wave radiation

Institution: University Of ArizonaP O Box 3308Tucson, AZ 857223308

Fiscal Year: 2004Department: RadiologyProject Start: 01-Jul-2003Project End: 30-Jun-2006ICD: National Cancer InstituteIRG: ZRG1

TARGETING MATRIXMETALLOPROTEINASESFOR TUMOR IMAGING

Grant Number: 5R21CA098698-02PI Name: Anderson, Carolyn J.

Abstract: Description (provided by applicant): Matrix Met-alloproteinases (MMPs) are a family of over 20 types of en-zymes, both secreted and membrane-bound zinc endopepti-dases, which collectively are capable of degrading all thecomponents of the extracellular matrix. Studies suggest thatMMPs are utilized in cancer, and facilitate both local tumorinvasion and metastasis. MMP-2 and MMP-9 (also known asgelatinases), in particular, are thought to play critical roles intumor cell invasion and are frequently coexpressed in humancancers. The goal of this study is to test a hypothesis regard-ing the ability to image by positron emission tomography(PET) the expression of MMP-2 and MMP-9 in a metastaticbreast cancer tumor model using radiolabeled MMP-2 andMMP-9 peptide inhibitors. The hypothesis to be tested is thatthe accumulation of a radiolabeled gelatinase inhibitor willcorrelate with gelatinase enzyme activity determined in thetumor in an ex vivo assay. It has been demonstrated by Koi-vunen et al. that the synthetic cyclic peptide, CTTHWG-FTLC (CTT), suppressed migration of breast cancer tumorcells in vitro and prevented the growth and invasion ofMDA-MB-435 human breast cancer tumors in mice, suggest-ing that this peptide has potential as an anticancer agent. Inpreliminary experiments relating to this proposal, we conju-gated CTT with the chelator DOTA (1,4,7, 10-tetraazacy-clotetradecane-N,N’,N“,N’”- tetraacetic acid) and initial invitro assays demonstrated that DOTA-CTT inhibits MMP-2activity comparably to the broad-range MMP inhibitor, Ilo-

mastat. Preliminary microPET imaging and biodistributionstudies in tumor-bearing mice show 64Cu-DOTA-CTT istaken up in three histologically different tumor types. Ourpreliminary data show that a 64Cu-labeled negative controlpeptide, DOTA-D-Trp-CTT does not show significant tumoruptake. Our specific aims are as follows: 1) to optimize flu-orogenic assays for determining inhibitory activity ofMMP-2 and MMP-9 inhibitors and for determining MMP-2and MMP-9 concentrations in tumors grown in vivo; 2) Toconfirm specific tumor uptake of 64Cu-DOTA-CTT vs. a64Cu-DOTA-conjngated control peptide in gelatinase-expressing tumor-bearing mouse models from biodistributionstudies and/or microPET imaging data and to correlate up-take of 64Cu-DOTA-CTT with gelatinase expression in thetumor using an ex vivo assay; and 3) to synthesis a series ofgelatinase inhibitors based upon the lead structure CTT thatare conjugated to either DOTA or a cross-bridged macrocy-clic chelator, as well as synthesize negative control peptides.If successful, the outcome of this study may be a PET tracerfor determining the metastatic potential of various types ofcancer.

Thesaurus Terms: antineoplastic, breast neoplasm, collage-nase, drug design/synthesis/production, enzyme inhibitor,metastasis, positron emission tomography copper, enzymeactivity, neoplasm/cancer pharmacology, radiotracer bioimag-ing/biomedical imaging, laboratory mouse


Fiscal Year: 2004Department: RadiologyProject Start: 01-Jun-2003Project End: 31-May-2005ICD: National Cancer InstituteIRG: RNM

LABELING OF OCTREOTIDE WITHPOSITRON EMITTERS

Grant Number: 2R01CA064475-10A1PI Name: Anderson, Carolyn J.

Abstract: Description (provided by applicant): We proposeto address a hypothesis regarding the imaging and therapy ofcancer with copper-64-labeled peptides, using somatostatin(SSTr2) ligands as well-characterized and model agents. Thehypothesis is that the delivery of copper radionuclides fromradiolabeled SSTr2 analogs to the nuclei of tumor cells willenhance their therapeutic efficacy. Although there might beseveral pathways to investigating mechanisms of cell deathby copper radiopharmaceuticals, we will focus on whetherdifferences in dissociation of Cu(II) from macrocyclic chela-tors in SSTR2 analogs (TETA- vs. CB-TE2A-Y3-TATE)


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correlates to different nuclear localization in a SSTr2-posi-tive tumor cell line (Aim 1). These data will be correlated tocell killing data in the same cell line (Aim 2). Aim 2 willalso involve the estimation of absorbed doses to the cell nu-cleus from Cu-64-TETA-Y3-TATE and Cu-64-CB-TE2A-Y3-TATE. Specific Aim 3 will determine whether increasedconcentration of SSTr2 receptors correlates with increasedinternalization and subsequent nuclear localization in vitro,and increased uptake in SSTr2-transfected tumors with sub-sequent increased therapeutic efficacy in vivo. Specific Aim4 will elucidate the mechanisms of trafficking of copper tothe cell nucleus, in particular determining whether copperchaperone proteins are involved in delivery of copper fromcopper radiopharmaceuticals to the cell nucleus. Recentlyobtained data on 64Cu-labeled chelator-SSTr2 analogs hasdemonstrated the importance of 64Cu-chelate stability onnormal organ uptake and clearance. We hope to correlate invivo data with subcellular distribution, which will have im-plications for both imaging and therapy. We will delineatethe importance of 64Cu-chelate stability as it relates to im-proving target: non-target tissue ratios, which are of greatimportance for imaging; however, the lack of chelate stabil-ity may enhance 64Cu localization to the cell nucleus, whichwill enhance therapeutic efficacy. Defining this balance willhelp to shape the future of 64Cu radiopharmaceuticals, arapidly growing area of research. The knowledge gainedfrom this research will then be applicable to a wide varietyof internalizing cell-surface receptor ligands for the develop-ment of new peptide or protein-based radiopharmaceuticalsfor cancer imaging and therapy.

Thesaurus Terms: copper, octreotide, radiopharmacology,radiotracer chelating agent, cytotoxicity, dosage, hormoneanalog, hormone receptor, intracellular transport, molecularchaperone, neoplasm/cancer radionuclide therapy, neoplasticcell, pharmacokinetics, radiation dosage, radionuclide, recep-tor expression cell line, laboratory mouse, transfection


Fiscal Year: 2003Department: RadiologyProject Start: 18-Jul-1994Project End: 31-Aug-2007ICD: National Cancer InstituteIRG: RNM

COMPUTER-AIDED DIAGNOSIS IN CT OFTHE THORAX

Grant Number: 5R01CA083908-04PI Name: Armato, Samuel G.

Abstract: The broad, long term objective of the proposedresearch is to develop a fully automated, computerized sys-tem that will assist radiologists in the detection and quantita-tive assessment of pulmonary nodules in helical computedtomography (CT) images of the thorax. This system will po-tentially improve the prognosis of patients with lung cancerby contributing to earlier diagnosis. It is widely recognizedthat helical CT is the most sensitive imaging modality forthe valuation of lung nodules. The large amount of imagedata acquired during a CT scan, however, makes nodule de-tection by human observers a difficult task. Moreover, distin-guishing between nodules and normal anatomy such as pul-monary vessels typically requires visual comparison amongmultiple CT sections, each of which contains informationthat must be evaluated by a radiologist and assimilated intothe larger context of the volumetric data acquired during thescan. This evaluation requires the radiologist to mentallyconstruct a three-dimensional representation of patient anat-omy based on over 50 section images acquired during a CTexamination. This task, while cumbersome for radiologists,may be efficiently handled by a computerized method. Theproposed research project will investigate the two-dimen-sional and three-dimensional structure of lung nodules inhelical CT images to fully exploit the volumetric image dataacquired during a CT examination. Gray-level threshold-based techniques will be used to extract three-dimensionalstructures from CT image data. Quantitative geometric andgray-level information computed for nodule candidates willbe used as input to automated classifiers to distinguish be-tween structures that correspond to nodules and structuresthat correspond to normal anatomy. This quantitative infor-mation will also allow for an evaluation of detection perfor-mance based on radiologic appearance of nodules. The spe-cific aims of the proposed research are: (1) to collect data-bases of normal and abnormal helical thoracic CT scans, (2)to develop an automated method to detect and quantitativelyassess pulmonary nodules in these CT scans, (3) to investi-gate differences in the appearance of nodules imaged in low-dose helical thoracic CT scans obtained from a lung cancerscreening program as opposed to standard helical CT and theeffect of these differences on the detection scheme, and (4)to evaluate the performance of the computerized detectionscheme and its effect on the performance of radiologists inthe task of identifying pulmonary nodules.

Thesaurus Terms: computed axial tomography, computerassisted diagnosis, diagnosis design/evaluation, lung neo-plasm, neoplasm/cancer diagnosis biomedical automationbioimaging/biomedical imaging, human data

Institution: University Of Chicago5801 S Ellis AveChicago, IL 60637

Fiscal Year: 2003Department: Radiology


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Project Start: 07-Sep-2000Project End: 31-Aug-2005ICD: National Cancer InstituteIRG: ZRG1

MR PHARMACOANGIOGRAPHY-VASCULAR MODULATION OF DELIVERY

Grant Number: 5R01CA097310-02PI Name: Artemov, Dmitri Y.

Abstract: Description (provided by applicant): Althoughchemotherapy remains a major course of cancer treatment, itfrequently fails to provide a complete cure for solid tumors.Several mechanisms contribute to this failure. Many estab-lished chemotherapeutic agents have significant antiangio-genic activity, which may reduce drug delivery during thecourse of a cycle of therapy. The vascular damage inflictedby the previous cycle(s) of therapy, is therefore a criticallyimportant determinant of tumor drug resistance in vivo. Withour recently developed NMR techniques we can detect thedelivery and spatial distribution of 13C labeled drugs in or-thotopic tumors using 13C magnetic resonance techniques.We have also established that the delivery and spatial distri-bution of a low molecular weight contrast agent such asGdDTPA correlates well with the delivery and spatial distri-bution of the differentiating agent phenylbutyrate. Thereforewe can now assess the efficiency of drug delivery during thecourse of chemotherapy in a preclinical model of humanbreast cancer, and evaluate the potential benefits of modulat-ing tumor vascularization to improve tumor response to ther-apy with the same model genetically modified to overexpressVEGF. Our goals in this application are as follows. (i) Todevelop a clinically translatable surrogate marker for drugdelivery by comparing tumor uptake and distribution of thecarbon-13 labeled anticancer drug temozolomide and theclinically approved contrast agent GdDTPA. (ii) To deter-mine the effect of a cycle of temozolomide chemotherapy onvascular characteristics and drug delivery. (iii) To evaluateeffects of increased angiogenic capacity of tumors, geneti-cally engineered to overexpress VEGF, on drug delivery,development of physiologic drug resistance, and treatmentoutcome. If successful, a clinically applicable surrogatemarker would be of utmost importance for predicting effec-tive drug delivery. Such a surrogate marker can also be usedto follow strategies of improving tumor vascular delivery ofchemotherapeutic agents. The experimental designs in thisapplication will also, for the first time, evaluate the role ofantivascular effects of a chemotherapeutic agent in tumorresistance using noninvasive and spatially informative tech-niques.

Thesaurus Terms: angiography, blood circulation, drug re-sistance, neoplasm/cancer chemotherapy, pharmacokinetics,temozolomide angiogenesis, breast neoplasm, carbon, cyto-

toxicity, diethylenetriaminepentaacetate, disease/disordermodel, gadolinium, neoplasm/cancer blood supply, neoplasm/cancer pharmacology, stable isotope, vascular endothelialgrowth factor, vascular endothelium permeability SCIDmouse, cell line, contrast media, high performance liquidchromatography, magnetic resonance imaging

Institution: Johns Hopkins University3400 N Charles StBaltimore, MD 21218

Fiscal Year: 2004Department: RadiologyProject Start: 01-Apr-2003Project End: 31-Mar-2006ICD: National Cancer InstituteIRG: RNM

REDUCING BENIGN BREAST BIOPSIESWITH COMPUTER MODELING

Grant Number: 5R01CA095061-02PI Name: Baker, Jay A.

Abstract: Description (provided by applicant): The primaryobjective of this project is to improve the diagnosis of breastcancer and reduce unnecessary benign breast biopsies. Anartificial neural network computer-aided ‘advisor’ will beconstructed to assist radiologists in deciding which solidbreast masses warrant immediate biopsy and which can besafely observed. Up to 80% of breast biopsies result in abenign diagnosis because benign and malignant masses oftenappear similar at mammography and sonography. We havepreviously developed computer models - artificial neural net-works - for predicting breast cancer based on mammogramfeatures and the patient’s medical history. Models built withonly mammography findings and the patient’s age demon-strate good preliminary results, potentially eliminating 22%of benign biopsies while identifying all cancers. The princi-pal innovative features of this project are: (1) the focus onsolid breast masses by incorporating high-resolution ultra-sound features, and (2) the use of a novel, standardized lexi-con devised by the American College of Radiology for de-scribing breast ultrasound findings. The goal of the proposedproject is to maintain near perfect sensitivity (�98%) - simi-lar to the accuracy of the present clinical practice of short-interval follow-up for ‘probably benign’ lesions - while theo-retically reducing the number of biopsies of benign breastmasses by half. Mammogram and ultrasound features will beestablished for a large retrospective database of approxi-mately 1000 biopsy-proven cases. Artificial neural networkswill be constructed with ‘supervised’ training to predictwhich masses are very likely benign and which are suspi-cious for malignancy. The computer predictive models willbe tested on a prospective validation database of approxi-


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mately 1350 cases with known biopsy results. Performancewill be evaluated in terms of fraction of benign biopsiesavoided while maintaining greater than 98% sensitivity. Aninterobserver variability study will determine whether thecomputer model reduces interpretation error and inconsis-tency between observers. Assuming performance approach-ing that of the preliminary model, a decision aid based onthis model will be ready for prospective clinical trials at theconclusion of this project.

Thesaurus Terms: biopsy, breast neoplasm/cancer diagno-sis, computer assisted diagnosis, computer simulation, com-puter system design/evaluation, diagnosis design/evaluation,model design/development artificial intelligence, women’shealth clinical research, computer program/software, female,human subject, mammography, patient oriented research,ultrasound imaging/scanning

Institution: Duke UniversityDurham, NC 27710

Fiscal Year: 2004Department: RadiologyProject Start: 01-Jun-2003Project End: 31-May-2007ICD: National Cancer InstituteIRG: RNM

MR SPECTROSCOPY AND IMAGING OFSODIUM IN TUMORS

Grant Number: 5R01CA084434-03PI Name: Bansal, Navin

Abstract: Description (provided by applicant): The mainobjective of this project is to develop and evaluate the use ofmultiple-quantum-filtered (MQF) 23Na magnetic resonance(MR) spectroscopy (MRS) and imaging (MRI) for measuringcompartmental Na� in experimental tumors so that the tech-niques may eventually be applied clinically. The central hy-pothesis in this project is that MQF 23Na MR techniquescan provide completely noninvasive methods for monitoringand imaging abnormalities in transmembrane sodium gradi-ents in tumors. The experiments outlined in the proposal willalso provide information about the physiological role of thetransmembrane sodium gradient and its relationship with cel-lular energy metabolism and pHi during untreated growth,sensitization of tumors to therapy and therapy. At least twoNMR methods have been proposed to distinguish betweenintra- and extracellular sodium (Nai� and Nae�), the use ofparamagnetic shift reagents (SR) and MQF techniques. Weintroduced the in vivo SR, TmDOTP5-, which produces re-solved Nai� and Nae� resonance in tumors and other tis-sues with minimal toxicity to the animal. However, an SRsafe for use in humans is not yet available. Our preliminary

data shows that although, some Nae� contributes to theMQF 23Na signal in the subcutaneously implanted 9L gli-oma, this signal does not change during ischemia. If this istrue under more general conditions, then MQF 23Na MRtechniques can provide completely noninvasive methods formonitoring and imaging changes in Nai� in tumors. Thefirst goal of this study is to determine whether MQF 23NaMRS can be used to measure changes in Nai� during moresubtle acute manipulations. The effects of manipulating thetumor energy metabolism and ion exchange mechanisms willbe studied. The chosen manipulations are used for sensitizingtumor to therapy. Our second goal is to evaluate the use ofMQF 23Na MRS for monitoring changes in Nai� duringchronic physiological changes. For this purpose, effects ofuntreated tumor growth, radiotherapy and chemotherapy willbe studied and the efficacy of MQF 23Na MRS/MRI for de-tecting tumor response to chemotherapy by a broad range ofantineoplastic agents employed in clinical cancer chemother-apy will be investigated in RIF-1 and MCF-7 tumor models.The development of proposed 23Na MR techniques will pro-vide methods for monitoring and imaging Nai� that mayprove useful in experimental studies of tumors and clinicalmanagement of cancer. In addition, the proposed researchwill enhance the understanding of sodium physiology in tu-mors, which may prove useful for designing more effectivecancer treatment, and for predicting and monitoring responseto therapy.

Thesaurus Terms: cell membrane, electrolyte balance, mag-netic resonance imaging, neoplasm/cancer chemotherapy,neoplastic cell, nonhuman therapy evaluation, noninvasivediagnosis, nuclear magnetic resonance spectroscopy, sodium,technology/technique developmentbioenergetics, membrane transport protein, neoplasm/cancerradiation therapy, neoplastic growth MCF7 cell, atomic ab-sorption spectrometry, laboratory mouse, laboratory rat

Institution: Indiana Univ-Purdue Univ AtIndianapolis

620 Union Drive, Room 618Indianapolis, IN 462025167

Fiscal Year: 2003Department: RadiologyProject Start: 01-May-2002Project End: 30-Apr-2005ICD: National Cancer InstituteIRG: RNM

NON-INVASIVE MR THERMOMETRYUSING A PARAMAGNETIC COMPLEX

Grant Number: 5R21CA094040-02PI Name: Bansal, Navin


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Abstract: Description (Provided by Applicant): Noninvasivethermometry is pivotal to the future advances of regionalhyperthermia as a treatment modality. Current magnetic reso-nance (MR) thermometry methods suffer from poor resolu-tion due to relatively weak dependence of chemical shift ofthe 1H water signal on temperature. The main objective ofthis research is to develop noninvasive MR thermometrymethods for reliable and accurate monitoring and imaging oftemperature in tumors using a paramagnetic lanthanide com-plex. Our preliminary data show that 1H chemical shifts of aprototype lanthanide complex, thulium- 1,4,7,10-tetraazacy-clododecane-1,4,7,10- tetraacetate (TmDOTA), are about twoorders of magnitudes more sensitive to temperature than thewater and thus, provide excellent accuracy and resolution. Inaddition, TmDOTA proton shifts are insensitive to the para-magnetic complex concentration, ph, [Ca2�] or presence ofplasma macromolecules and ions. This will greatly simplifythe procedures for using the lanthanide complex for MRthermometry because hyperthermia is known to producechanges in tissue pH and other parameters. The main goalsof this project are: 1) to investigate the use of methyl sub-stituted analogs of TmDOTK, thulium 1,4,7,1 0-Tetraaza-cyclodoecane-a,a,a,“a”-tetramethyl-1,4,7, 1 0-tetraacetate(TmDOTMA) for MR thermometry, 2) to develop MR ther-mometry techniques for reliable, accurate and rapid imagingof temperature using a TmDOTMk complex, 3) to demon-strate feasibility of in vivo monitoring and imaging of tem-perature during hyperthermia in a mouse tumor model, and4) to perform a preliminary study on acute effects of hyper-thermia on tumor lactate and perfusion. The major advantageof the TmDOTMA is that the proton signals from methylgroups are more intense and sharper compared to the protonsignals from TmDOTA. This will greatly help in improvingthe spatial, temporal and thermal resolution in temperatureimaging. TmDOTk and TmDOTMK are expected to be non-toxic because similar complexes of gadolinium are clinicallyused as MR contrast agents.

Thesaurus Terms: contrast media, image enhancement,magnetic resonance imaging, neoplasm/cancer thermother-apy, technology/technique development, thermometry, rareearth element, bioimaging/biomedical imaging, laboratorymouse

Institution: Indiana Univ-Purdue Univ AtIndianapolis

620 Union Drive, Room 618Indianapolis, IN 462025167

Fiscal Year: 2003Department: RadiologyProject Start: 30-Sep-2002Project End: 31-Aug-2005ICD: National Cancer InstituteIRG: DMG

THREE DIMENSIONAL CTCOLONOGRAPHY

Grant Number: 5R01CA072023-08PI Name: Beaulieu, Christopher F.

Abstract: Colorectal cancer (CRC) is the second leadingcause of cancer death in the US. Early detection and removalof polyps could reduce the mortality of this disease by up to90 percent. Current screening methods are either nonspecific,invasive, or hindered by poor patient compliance. Computedtomography colonography (CTC) is a promising techniquefor polyp detection, with some reports of sensitivity over 90percent for 10 mm or larger lesions. If adequately validatedand disseminated CTC could have a major impact on mor-bidity and mortality from CRC. Unfortunately, the search forsmall polyps in a long colon represented by several hundredCT images is tedious and time consuming, requiring up to anhour of costly physician time for accurate interpretation.Without substantially increasing the efficiency of interpreta-tion, CTC has little chance of being cost-effective. There-fore, our primary goal is to minimize the time required forCTC interpretation while maximizing diagnostic accuracy.We will accomplish this by developing and validating com-puter-aided diagnostic (CAD) methods for polyp detection,and making these methods part of the interpretive process.Our Specific Aims are as follows: (1) Computer-Aided De-tection Algorithm Development: We will develop, integrate,and validate three different approaches to CAD for colorectalpolyp detection. (2) Optimization of CTC Interpretation Effi-ciency: Using a sensitive CAD algorithm and reader inter-face development, we will experimentally determine themost efficient and accurate means of augmenting 2D and 3Ddisplays with CAD methods for CTC interpretation. (3) Opti-mization of Image Acquisition - Multidetector Row HelicalCT: We will empirically determine the best acquisitionmethods for depiction of the colon surface using multi-detec-tor row helical CT, optimizing the tradeoff between dose,scan time, and depiction of the colon surface. In a prospec-tive trial, we will compare these state-of-the-art CTC acqui-sition and interpretation methods (human visualization with/without CAD) with the current clinical gold standard of fi-beroptic colonoscopy. Upon completion of this work, wewill have successfully developed new methods that allowradiologists to interpret CTC studies efficiently and accu-rately, thereby enabling the widespread application of CTC.Successful development and deployment of optimized CTChas the potential to improve patient compliance with screen-ing recommendations which, in turn, can increase detectionof potential cancers with a concomitant reduction in morbid-ity and mortality from the disease.

Thesaurus Terms: colon polyp, computed axial tomogra-phy, computer assisted diagnosis, diagnosis design/evalua-tion, early diagnosis, neoplasm/cancer diagnosis, rapid diag-nosis, diagnosis quality/standard, endoscopy, gastrointestinal


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imaging/visualization, human morbidity, bioimaging/biomed-ical imaging, clinical research, human subject, statistics/bi-ometry

Institution: Stanford UniversityStanford, CA 94305

Fiscal Year: 2003Department: RadiologyProject Start: 13-Sep-1996Project End: 30-Jun-2004ICD: National Cancer InstituteIRG: DMG

FUNCTIONAL IMAGING OF THEMETASTATIC PHENOTYPE

Grant Number: 5R01CA073850-07PI Name: Bhujwalla, Zaver M.

Abstract: Description (provided by applicant): Prostate can-cer is the second leading cause of death from cancer in menin the U.S. and mortality from prostate cancer is invariablydue to tumor metastasis. Our overall goals for the first com-petitive renewal application therefore continue to be to un-derstand prostate cancer invasion and hematogenous metasta-sis. We have gleaned several insights from the previous fouryears of studying the role of vascularization and the physio-logical environment in promoting prostate cancer invasionand dissemination. This has led us to formulate five newhypotheses: (1) invasion is necessary but not sufficient, with-out vascularization, for hematogenous prostate cancer metas-tasis; (2) there are combinations of co-registered vascular,physiological and metabolic regions within solid tumors,which are most permissive for invasion and metastasis; (3)anti-angiogenic treatments attenuate or prevent metastasis;(4) there will be a reduction in the “permissive” vascular,physiological and metabolic regions following treatment withanti-angiogenic agents; (5) endothelial cell - cancer cell in-teractions play a significant role in promoting invasion andmetastasis from stressed physiological conditions of hypoxiaand acidic pH found in solid tumors. We will continue towork with the human prostate cancer xenografts we selectedduring our first funding period. We will increase vasculariza-tion in solid tumors by creating transgenic cell lines overexpressing VEGF A or bFGF, and reduce vascularization bytreating solid tumors with the anti-angiogenic agents TNP-470 and endostatin. The technical advances we have made,such as obtaining co-registered maps of vascular volume,permeability, extracellular pH and metabolites will be ap-plied to gain further insight into prostrate cancer metastasis.Our “Metabolic Boyden Chamber” assay that was developedand optimized during the previous funding period now hasan additional facet of a layer of endothelial cells incorpo-rated between the matrigel layer and the cellular layer. This

will allow, for the first time, the noninvasive investigation ofthe interaction between vascular endothelial cells and pros-tate cancer cells under various physiological conditions, sim-ulating conditions found in solid tumors. The proposed stud-ies will continue to identify vascular, physiological and met-abolic characteristics that promote invasion and metastasis.This information is critical for developing strategies to pre-vent metastasis from prostate cancer.

Thesaurus Terms: fluorescence microscopy, metastasis,neoplasm/cancer blood supply, nuclear magnetic resonancespectroscopy, prostate neoplasm acid base balance, angiogen-esis, cell-cell interaction, fibroblast growth factor, lipid me-tabolism, neoplastic cell, vascular endothelium, SCID mouse,bioimaging/biomedical imaging


Fiscal Year: 2004Department: RadiologyProject Start: 11-Jun-1997Project End: 31-Mar-2007ICD: National Cancer InstituteIRG: ZRG1

HOSTILE ENVIRONMENTS PROMOTEINVASION AND METATASIS


Abstract: Description (provided by applicant): In this com-petitive renewal application, we continue to maintain ourfocus on breast cancer invasion and metastasis. Metastaticbreast cancer has pitifully low survival rates, and the chal-lenge of our decade continues to be to find ways to preventcancer cells from disseminating. With the past four years wemade key observations, which have led us to focus on under-standing the role of cyclooxygenase-1 and -2 in breast can-cer invasion and metastasis. The first was that the anti-inflammatory nonspecific COX inhibitor, indomethacin, sig-nificantly reduced breast cancer cell invasion. We also foundthat the choline phospholipid metabolism of invasive breastcancer cells treated with indomethacin reverted towards acholine phospholipid phenotype more typical of a nonmalig-nant cell line. Additionally, we observed an increased ex-pression of COX-1 with malignant progression. These obser-vations have led us to formulate three new hypotheses: (1)Phosphocholine and vascular volume and permeability de-tected by MRS and MRI will be higher in COX-1 andCOX-2 overexpressing cells and solid tumors compared towild-type or vector-transfected control cells and tumors. In-creased expression of COX-1 and COX-2 will result in anincrease in invasion and metastasis; (2) Decreased COX-1


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and COX-2 will decrease invasion and metastasis. A de-crease in phosphocholine and vascular volume and perme-ability will be detected in the MRS and MRI studies of cellsand solid tumors; (3) Cancer cells secrete paracrine factorswhich may primarily be derived from cyclooxygenase activ-ity which significantly alter endothelial cell-cancer cell inter-actions and play a significant role in promoting invasion andmetastasis from inflammation inducing conditions in solidtumors. In this competitive renewal application we will usestate of the art noninvasive magnetic resonance (MR) imag-ing (I) and spectroscopy (S) methods, and molecular biologyapproaches utilizing siRNA technology to test these hypothe-ses. The cyclooxygenase enzymes COX-1 and -2 synthesizePGs from arachidonic acid. Prostaglandins (PGs) producedby tumor cells or tumor-associated host cells such as macro-phages, endothelial cells and stromal cells have long beenknown to play a stimulating role in progression and metata-ses of animal and human tumors. The studies proposed inthis application will lead to the potential identification oftargets and pathways for the prevention of metastatic disease.

Thesaurus Terms: breast neoplasm, metastasis, neoplasm/cancer invasiveness, neoplastic growth arachidonate, bloodglucose, cellular oncology, prostaglandin, prostaglandin en-doperoxide synthase, tumor progression SCID mouse, en-zyme linked immunosorbent assay, mass spectrometry, poly-merase chain reaction, tissue/cell culture, western blotting


Fiscal Year: 2004Department: RadiologyProject Start: 01-Jul-1999Project End: 30-Apr-2008ICD: National Cancer InstituteIRG: ZRG1

IMAGING LYMPHATIC CLEARANCE INTUMOR METASTASIS


Abstract: Description (Verbatim from the Applicant’s Ab-stract): The metastatic phenotype is the single most lethalphenotype which cancer displays, and once a solid tumorevolves into a metastatic phenotype prognosis-is poor. Me-tastasis can occur through vascular as well as lymphatic dis-semination. Although lymph node metastasis is the mostpowerful index of prognosis, particularly in breast cancer,mechanisms underlying lymphatic metastasis have largelybeen overshadowed by the focus on angiogenesis and vascu-lar dissemination. This is partly due to the unavailability,until recently, of techniques to differentiate between lym-

phatic and blood vessels. Similarly, while MR methods havebeen applied to study tumor vasculature, their application tostudying lymphatic drainage and interstitial clearance is lim-ited. The recent discovery that VEGF-C is a lymphangio-genic factor which binds to VEGFR-3 on lymphatic endothe-lial cells now provides an entirely new dimension to identi-fying and understanding lymphatic flow and lymphaticvessels in cancer metastasis. In this application from the’Weizmann Institute and Johns Hopkins, two laboratorieswhich have been studying angiogenesis (Weizmann) and therole of vascularization and the physiological environment incancer invasion and metastasis (Hopkins) have joined forcesto understand the mechanisms and factors which contributeto lymphatic drainage and lymphatic metastasis. The effort atWeizmann will focus on understanding the impact of angio-genesis on lymphatic drain and lymphangiogenesis using aVEGF-A switchable tumor model system, dermal incisions,and transgenic VEGF-C mice. The effort at Hopkins willfocus on understanding the impact of lymphatic drainage andlymphangiogenesis on tumor metastasis using human breastcancer models and their transgenic counterparts. In addition,the role of the matrix and cell-cell interactions will also beinvestigated. Novel MRI approaches will be developed incombination with existing state of the art MRI and 3D re-construction capabilities to quantify lymphatic structure andfunction. The MRI methods will be validated with fluores-cence microlymphography at Weizmann and histology atJohns Hopkins. The’ proposed studies will advance the un-derstanding of factors and mechanisms regulating lym-phangiogenesis and lymphatic drainage in normal tissue andin solid tumors, and will provide answers to critical ques-tions in breast cancer metastasis.

Thesaurus Terms: breast neoplasm, lymph node neoplasm,lymphatic circulation, metastasis, neoplasm/cancer invasive-ness angiogenesis, cell-cell interaction, enzyme activity, en-zyme inhibitor, extracellular matrix, metalloendopeptidase,vascular endothelial growth factor, SCID mouse, fluorescencemicroscopy, magnetic resonance imaging, transgenic animal


Fiscal Year: 2003Department: RadiologyProject Start: 01-Mar-2001Project End: 28-Feb-2005ICD: National Cancer InstituteIRG: RNM

JOHNS HOPKINS UNIVERSITY ICMICPROGRAM

Grant Number: 1P50CA103175-01PI Name: Bhujwalla, Zaver M.


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Abstract: Description (provided by applicant): The twentyfirst century has witnessed an explosion of molecular biologytechniques, amazing advances in imaging, and the design ofunique imaging probes. Despite the tremendous strides madein these areas of science, the cure for cancer remains beyondour grasp. Cancer is a complex disease and the apparent im-penetrability of the disease is largely due to the multiple,often redundant pathways, which appear to evolve throughthe genetic instability of cancer cells. The ability to identifyand image key common pathways specific to cancer cells,and the ability to image the effectiveness and outcome ofstrategies designed against these targets is critically impor-tant in the treatment of this disease. The vision of our JHUICMIC is to combine state-of-the-art imaging capabilitieswith powerful molecular biology techniques to define strate-gies with ‘intent to cure’. In this proposal we have drawnupon our human resources at JHU to create a center consist-ing of a multidisciplinary group of premier individuals withdiverse skills focused on translating molecular capabilitiesinto imaging possibilities with the single purpose of under-standing and curing cancer. Nearly all of the investigatorsparticipating in this ICMIC have interactive collaborativeprojects with one or more of the other investigators. Thesynergism generated by the collective skills of this uniquegroup of individuals will lead to significant advances in theunderstanding of cancer and its treatment. The existing P20program as well as the SAIRP have laid a strong foundationfor the establishment of a world class in vivo cellular molec-ular imaging program at Johns Hopkins. The current pro-posal builds upon this strong foundation. Our JHU ICMICstructure consists of four interactive and closely related re-search components focused on hypoxia, HIF-1, and exploit-ing the hypoxia response element to target cancer cellsthrough choline kinase inhibition. These research compo-nents are anchored by the participation of world renownedexpertise in HIF-1. The research components will utilizeMR, PET and Optical imaging technology to understand can-cer vascularization, invasion and metastasis, to achieve effec-tive cancer therapy. We have selected five developmentalprojects that are highly relevant to the goals of the ICMICand interactive with the research components. Five resourcesdevoted to administration, molecular biology, imaging,probes, and translational application will provide the infra-structure to support the research activities of the ICMIC. Acareer developmental program will train the future champi-ons of molecular imaging in cancer. An advisory board con-sisting of the best scientists at Hopkins, and at several insti-tutions in the US and abroad, will provide critical evalua-tion of the progress made. Strong institutional support andthe advocacy of the Dean, Vice-Dean and Chairs of Radiol-ogy, Oncology and Biomedical Engineering will further en-sure the success of the JHU ICMIC and fulfillment of itsvision.

Thesaurus Terms: imaging/visualization/scanning, neo-plasm/cancer diagnosis, neoplasm/cancer therapy bioimaging/biomedical imaging


Fiscal Year: 2003Department: RadiologyProject Start: 10-Aug-2003Project End: 31-Jul-2008ICD: National Cancer InstituteIRG: ZCA1

3D OPTICAL IMAGING AND DIGITALX-RAY OF BREAST LESIONS

Grant Number: 5R01CA097305-03PI Name: Boas, David A.

Abstract: X-Ray mammography has contributed to a reduc-tion in mortality due to breast cancer. It is inherently limited,though, as it is incapable of direct observation of physiologi-cal information relevant to the “functioning of cancer,”which ultimately limits the specificity and prognostic abilityof X-Ray mammography. Diffuse optical tomography (ortomographic optical breast imaging) is a promising imagingmodality that provides information on the functioning andevolution of cancer - in particular, angiogenesis and hemo-globin oxygen saturation. It suffers, however, from limitedspatial resolution relative to X- Ray, and this inhibits struc-tural guidance and interpretation of the images obtained.This obstacle can be overcome by acquiring diffuse opticaland X-Ray mammographic images “simultaneously” - that is,by combining the two modalities in a pioneering effort toovercome their respective limitations, mammography limitedby specificity and optical limited by resolution, to produce anew multi-modality imaging method with enhanced specific-ity and prognostic value. We propose to advance the clinicalutility of tomographic optical breast imaging by synergisti-cally fusing the diffuse optical technology with state-of-the-art digital X-Ray mammographic 3D tomography (known asTomosynthesis), thus producing a multi-modality imagingmethod that integrates structural and functional informationrelevant to the screening and diagnosis of breast cancer. Webelieve that this combination will ultimately allow better dif-ferentiation of tumors through angiogenic and metabolicmarkers known to have prognostic value. During this grantperiod we propose to further develop the optical technologyand perform a clinical study to explore the optical sensitivityto detecting lesions already indicated by X- Ray, and theoptical specificity to identifying malignant lesions as charac-terized by biopsy. This research project would not be feasi-


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ble without the clinical research expertise of the Breast Im-aging Research Lab, headed by Dr. Kopans.

Thesaurus Terms: X ray, breast neoplasm/cancer diagnosis,diagnosis design/evaluation, digital imaging, mammography,optical tomography, technology/technique development, an-giogenesis, biomedical equipment development, blood vol-ume, diagnosis quality/standard, longitudinal human study,mathematical model, mathematics, model design/develop-ment, oxygen consumption, phantom model, prognosis bio-imaging/biomedical imaging, biopsy, clinical research, hu-man subject


Fiscal Year: 2004Department:Project Start: 01-Aug-2002Project End: 31-Jul-2007ICD: National Cancer InstituteIRG: RNM

NOVEL TYROSINASE MUTANTS ASIMAGING MARKER GENES

Grant Number: 1R21CA085657-01A1PI Name: Bogdanov, Alexei A.

Abstract: Description (Verbatim from the Applicant’s Ab-stract): A number of imaging marker genes have been devel-oped for the much required need of detecting and quantitat-ing gene expression in vivo. The overall goal of this explor-atory research project is to investigate tyrosinase as newbifunctional therapeutic prodrug/imaging enzymatic markersystem. The main reasons for choosing tyrosinase are 1) thepotential for imaging tyrosinase expression by different im-aging modalities including MR imaging (e.g. tyraminyl-DOTA-Gd) and nuclear imaging (e.g. labeled tyrosine), 2)the availability of several non-cytotoxic prodrugs and 3) thelack of expression in non-melanotic cells. We hypothesizedthat certain tyrosinase mutants could be obtained that wouldhave low intrinsic toxicity, similar or even higher specificenzyme activity compared to the wild-type enzyme or couldbe positioned on the cell surface or be secreted for more ef-ficient interaction with the prodrug. So far we have con-structed three C-terminal tyrosinase deletion mutants lackingdifferent elements of transmembrane and sorting domains.The novel tyrosinase variants indeed had higher specific en-zyme activity compared to the wild-type and sensitizedtransfected cells to hydroxyphenyl-propanol and N-acetyl-4-S-cysteaminylphenol treatments, i.e. two of several availablemodel therapeutic prodrugs. We have furthermore confirmedthat tyrosinase expressing cells accumulate/convert 3H-tyrosine opening the possibility of nuclear imaging using

alternative isotopes (e.g. about C-tyrosine). Finally, we havesynthesized a novel paramagnetic tyrosinase substrate(tyrarninyl-DOTA-Gd) that significantly changes R1 relaxiv-ity after tyrosinase interaction. The proposed studies build onthese preliminary data will test the main hypothesis that en-gineered tyrosinase mutants are subject to differential intra-cellular sorting and can be utilized both as efficient prodrug-converting biocatalysts and imaging markers. The long-termgoal of this research is to explore and develop novel anduseful bifunctional “imaging/therapeutic marker genes” for invivo use.

Thesaurus Terms: biomarker, enzyme activity, enzyme in-duction/repression, monophenol monooxygenase, mutant Al-phaherpesvirinae, glioma, intracellular transport, melanin,neoplasm/cancer pharmacology, prodrug, protein transportcell line, nuclear magnetic resonance spectroscopy, polymer-ase chain reaction, scintillation spectrometry, transfection,western blotting


Fiscal Year: 2001Department:Project Start: 01-Feb-2001Project End: 31-Jan-2003ICD: National Cancer InstituteIRG: RNM

FEASIBILITY OF CT IN HIGH RISKBREAST CANCER PATIENTS

Grant Number: 5R01CA089260-03PI Name: Boone, John M.

Abstract: Mammography is used to screen asymptomaticwomen for breast cancer, and typical breast cancer foundusing mammography is approximately 11 mm in diameter.At this small size, removal of lesion results in breast cancercure in the majority of women. However, there is a smallclass of women (about 5% of all breast cancers) who aregenetically predisposed to breast cancer (BRCA1 andBCRA2 genes), and in these women, more aggressive detec-tion methods are needed. In addition to BRCA1 and BRCA2carriers who are at extraordinary risk of breast cancer,women with extremely dense breasts are at higher risk frombreast cancer (by virtue of their dense breasts with odds ratiofrom 4 to 6), and mammography is less sensitive in thesewomen. For women in these high-risk categories, most ofwhom have dense breasts that are poorly imaged by mam-mography, an imaging modality with better lesion detectabil-ity performance (contrast resolution) is needed. While ultra-sound rely on contrast mechanisms that are less reliable thanX-ray contrast-that is why they are not used for screening.


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However, computed tomography (CT) does depend uponx-ray contrast mechanisms, but has about 10 times the con-trast resolution as projection mammography. CT is very ca-pable of identifying soft tissue lesions in the 3-5mm range-Such lesions are 10 to 50 times smaller in volume than theaverage 11mm lesion found by mammography. Therefore,CT has great potential for much earlier detection of breastcancer than mammography for high-risk patients. In this fea-sibility study, we propose to thoroughly investigate the po-tential of dedicated breast CT using computer simulationtechniques coupled with CT of cadaver breasts and mastec-tomy specimens. Monte Carlo studies will be used to fullyevaluate the glandular dose of breast CT, and imaging stud-ies will be used to define the requirements of optimal CTacquisition. Using CT scans of breast lesions from about 10mastectomy specimens, a breast tumor model will be devel-oped. The tumor model will be used with a series of about20 cadaver breast CT data sets to conduct extensive ROCstudies. Computer observers will be used to define the Azversus tumor diameter curves for both CT and mammogra-phy. Human observers will be used to validate and calibratethe more extensive computer observer results. The results ofthis investigation should provide a clear understanding of thepotential of breast CT as a tool to reduce breast cancer mor-tality in the population of women with dire risk of breastcancer.

Thesaurus Terms: breast neoplasm, breast neoplasm/cancerdiagnosis, computed axial tomography, diagnosis design/evaluation mammography, mathematical model, model de-sign/development bioimaging/biomedical imaging, humantissue, postmortem

Institution: University Of California DavisSponsored Programs, 118 Everson

HallDavis, CA 956165200


NUCLEAR MAGNETIC RESONANCE

Grant Number: 5T32CA009502-17PI Name: Brady, Thomas J.

Abstract: Description (Provided by applicant): The goal ofthis proposal is to obtain continued support for our postdoc-toral training program in nuclear magnetic resonance (NMR)research. Funds are requested to support four trainees peryear. Our program emphasizes the education of basic (Ph.D.)and clinical (M.D.) scientists in the principles and applica-

tions of NMR imaging and spectroscopy. The program con-sists of didactic lectures, laboratory exercises and individualresearch projects. Eighteen of 21 fellows who completed theprogram are currently in academic positions; 12 have re-ceived extramural funding: seven are staff of the MGHNMR Center including two who during their fellowshipmade seminal contributions to the fields of MR angiographyand functional MR Imaging (fMRI). The faculty consists of15 M.D. and/or Ph.D. scientists with extensive experience inNMR research and in pre- and postdoctoral education. Thefaculty has 27 extramural research grants; 10 of the facultyhave NIH P01 or R01 grants including five faculty with NCIgrants that specifically address issues of cancer diagnosis andtherapy using novel NMR approaches. The faculty has suc-cessfully supervised the thesis work of 45 Ph.D. students andover 85 postdoctoral fellows, including the 23 fellowsfunded by this training grant, in various aspects of basic andclinical NMR research. During the past five years, the pro-gram has been enhanced by the addition of several new fac-ulty members, the acquisition of funded research in a broadrange of areas and the availability of additional state-of-the-art NMR facilities at the MGH NMR Center. These factorshave increased the educational and research opportunities fortrainees. The installation of a second 3.0 Tesla 80 cm sys-tem, a 7 Tesla 90 cm system (both currently being installed),and 9.4T 21 cm system (Summer 2001) will provide addi-tional unique resources for imaging and spectroscopy re-search. We continue to develop our successful program inminority recruitment, scientific integrity and cancer relatedtraining and research. We strongly feel that, with our currentfaculty, facilities, scope of supported research, and past ac-complishments, we continue to achieve our stated goal ofproviding highly qualified M.D. and Ph.D. scientists for thebiomedical NMR research community.

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


Fiscal Year: 2003Department:Project Start: 01-Jul-1985Project End: 30-Jun-2007ICD: National Cancer InstituteIRG: NCI

PATIENT SPECIFIC MODELS IN LUNGCANCER SCREENING WITH CT

Grant Number: 5R01CA088973-04PI Name: Brown, Matthew S.


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Abstract: Description (Verbatim from Applicant’s Abstract):The objective of this research is to develop computer-assisted methods to facilitate screening for the early detectionof lung cancer using helical computed tomography (hCT).Proponents of existing screening trials argue that the highestenhance of surgical cure from lung cancer lies in the detec-tion of micronodular neoplasms (of 1-3 mm in diameter).Multi-slice hCT is capable of imaging the entire thorax athigh spatial resolution and has the potential to reliably detectpulmonary micronodules. However, these image sequencesgenerate extremely large volume data sets, consisting of 300-600 axial images, which are impractical to review in currentradiology practice. This proposal involves development andexperimental testing of a method to automatically identifylung nodules from high resolution hCT (HR-hCT) imagedata acquired from multi-slice scanners. The technique in-volves a model-based segmentation approach in which infor-mation about the size, shape, location, density and otherproperties of both normal and pathological structures will beused to automate the discrimination of focal lung nodulesfrom normal bronchovascular anatomy. A generic, a priorimodel of lung nodules and relevant anatomy will be devel-oped to guide segmentation of baseline CT images. Patient-specific models will be derived from the anatomical informa-tion learned from baseline scans and used to analyze subse-quent surveillance CT scans. The specific aims to accomplishthis are: [1] To automatically distinguish lung nodules fromnormal pulmonary bronchovascular structures on baselinelung cancer screening HR-hCT exams. [2] To detect intervalnew nodules and re-localize previously detected nodules onpost-baseline surveillance HR-hCT exams. [3] To measurethe accuracy of automated nodule detection and re-localiza-tion on HR-hCT scans. [4] To compare radiologist accuracyand interpretation times of HR-hCT scans, both with andwithout assistance from the automated detection system,against pre-existing nodule detection methods.

Thesaurus Terms: computed axial tomography, computerassisted diagnosis, diagnosis design/evaluation, lung neo-plasm, neoplasm/cancer diagnosis biomedical automation,computer system design/evaluation, image processing clinicalresearch, human subject

Institution: University Of California Los Angeles10920 Wilshire Blvd., Suite 1200Los Angeles, CA 90024

Fiscal Year: 2004Department: RadiologyProject Start: 16-Feb-2001Project End: 31-Jan-2005ICD: National Cancer InstituteIRG: DMG

CANCER EDUCATION GRANT PROGRAM

Grant Number: 5R25CA044789-12PI Name: Burzynski, Norbert J.

Abstract: Description (provided by applicant): The objectiveof the present application is to continue the long-standing,highly successful, short-term research program in CancerBiology at the University of Louisville. The current programhas been the recipient of over twenty years of near-continuousNIH support. Throughout the tenure of this program, thehighest priority has been given to disseminating, to healthprofessional students, an appreciation for issues in cancerbiology as they relate to diagnosis, prevention and treatmentof the disease, from a clinical and research perspective. Thecurrent program provides a unique venue for student - fac-ulty interaction, and provides highly motivated and qualifiedstudents with the opportunity to gain exposure to cancer bi-ology and enhance their knowledge in this area throughweekly Tumor Board conferences, Program Work confer-ences, special programmatic seminars, a “Cancer CareersMinisymposium,” laboratory research, and presentations atlocal/national meetings. The present application has beenrevised substantially with regard to training faculty, out-comes assessment procedures, and special initiatives to in-crease student awareness of career opportunities in cancerhealth care and research. A new Health Science Center-widetraining venture has been initiated, which benefits from theparticipation of eighteen core faculty, all of whom arefunded extensively through federal/foundation sources andhave a demonstrated commitment to biomedical research andeducation. This multidisciplinary group represents a forgingof research and training partnerships spanning seven Univer-sity departments and incorporating the University of Louis-ville Schools of Dentistry and Medicine, J. Graham BrownCancer Center, Birth Defects Center, Center for Genetics andMolecular Medicine, and Kosair Children’s Hospital Re-search Institute. Seventeen of the program Core Faculty areparticipating members of the J. Graham Brown Cancer Cen-ter. All have committed to provide trainees with exposure to,and involvement in, contemporary research programs in var-ied aspects of cancer biology and molecular mechanisms ofcellular growth control. A noted cancer epidemiologist fromthe MD Anderson Cancer Center has been enlisted as a con-sultant to develop and execute a systematic strategy for pro-gram evaluation and trainee tracking, and to function as aneducational advisor for the program. In summary, it is theobjective of our program to provide a unique and contempo-rary educational venue in cancer biology, designed to trainthe next generation of academic clinical scientists. Theseindividuals will be poised to enter the fields of cancer healthcare and research, and have a long-term impact on reducingcancer incidence, mortality and morbidity . . . the foremosttheme of cancer prevention through cancer biology!


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Thesaurus Terms: curriculum, health care personnel educa-tion, neoplasm/cancer education, education evaluation/plan-ning clinical research

Institution: University Of LouisvilleJouett Hall, Belknap CampusLouisville, KY 40292

Fiscal Year: 2004Department: Diagnostic RadiologyProject Start: 01-Aug-2002Project End: 31-Jul-2007ICD: National Cancer InstituteIRG: ZCA1

IMRI METHODS FOR CANCERDIAGNOSIS AND TREATMENT

Grant Number: 2R01CA077677-06PI Name: Butts, Rosemary K.

Abstract: Description (provided by applicant): Malignantneoplasms of the liver cause significant morbidity and mor-tality in the US. Fortunately, for patients with hepatocellularcarcinoma or metastatic colorectal carcinoma that is limitedto the liver, surgical treatment of the individual hepatic le-sions can result in a favorable prognosis. However, surgeryis limited to 10% of these patients, and for all others, treat-ment options are limited. Minimally invasive thermal abla-tion has the potential to provide a non-surgical treatmentoption. MRI can provide real-time visualization of treatmentdevices within the liver. MRI can also potentially ensureadequate heating of target tumor tissue and sparing of adja-cent critical organs by providing real-time temperature imag-ing. This capability would enhance both the effectivenessand safety of thermal therapy. No other imaging modality iscapable of providing in vivo temperature maps. Unfortu-nately, MRI is generally bypassed as a monitoring modalityin favor of other modalities such as ultrasound and CT. Thisis because the promise of robust real-time thermometry forliver ablation has remained an elusive goal due to respiratorymotion artifacts. At Stanford, we have been successful indeveloping MR temperature-mapping techniques suitable foruse in minimally invasive treatment of stationary tissuessuch as the brain and the prostate. We now extend this workto the liver because of its great clinical importance. The ma-jor focus will be to develop MR methods that will ensureaccurate and precise temperature imaging and to define theachieved accuracy and precision in animal studies. Specifi-cally, we will improve the baseline phase correction with theuse of a gated, navigated, multibaseline, volumetric imagingmethod. These improvements are the key to overcoming thebarriers to the use of MR temperature imaging for guidingthermal therapies.

Thesaurus Terms: diagnosis design/evaluation, diagnosisquality/standard, magnetic resonance imaging, neoplasm/cancer diagnosis, neoplasm/cancer thermotherapy, liver im-aging/visualization/scanning, liver neoplasm, method devel-opment, temperature, thermography, thermometry bioimag-ing/biomedical imaging, biopsy, clinical research, humansubject, swine


Fiscal Year: 2003Department: RadiologyProject Start: 30-Sep-2003Project End: 31-Aug-2007ICD: National Cancer InstituteIRG: RNM

COMBINED DIGITAL X-RAY ANDULTRASOUND BREAST IMAGING

Grant Number: 5R01CA091713-02PI Name: Carson, Paul L.

Abstract: 3D ultrasound will be combined with a full-fielddigital mammography (DX) system via an automatic scan-ning mechanism on the DX gantry. It is proposed to take fulladvantage of the many synergisms among an innovativecombination of modes of these two modalities for breastcancer diagnosis, and, eventually, detection. The basic andadvanced modes implemented and tested in the system arethose which should provide relatively independent informa-tion about the breast tissues and with which we have exten-sive, related research experience in the numerous breast im-aging groups at the University of Michigan and/or GeneralElectric. Advanced modes include tomosynthesis, which,unlike projection imaging, gives x-ray interaction propertiesof the specific tissues evaluated by the ultrasound methods.Nonlinear elasticity and 3D color flow imaging by ultra-sound (UL) provide mechanical and physiological informa-tion unavailable from conventional, noncontrast x-ray andultrasound imaging. Compound and single-view US imagingare complimentary, with the former providing better distaltumor borders and other features helpful to visual and com-puter-aided diagnosis. In a single positioning, with possiblevariation in compression, the breast will be imaged by: 1)the basic modes – projection digital x-ray and full field 3Dgray scale ultrasound: 2) the advanced modes – 3D x-raytomosynthesis and advanced ultrasound of the mass region(nonlinear elasticity, 3D color flow, and compound imaging).In the main clinical evaluations on 160 women with massesgoing to biopsy and 40 with simple cysts, the basic and ad-vanced imaging modes will be compared on the same pa-tients and good combinations of modes revealed. The firsthypothesis is that the basic combined technique is diagnosti-


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cally equivalent to the current best practice of high qualitymammography plus hand-held ultrasound performed byMQSA-certified radiologists. Linear combinations of the ba-sic and advanced modes will be evaluated for relative diag-nostic accuracy. Clinical evaluation of the potential of thecombined system for screening of selected populations mustfollow demonstration of diagnostic equivalence. Develop-ments will be done to objectively illustrate some of the ap-proaches and potential of visual and computer-aided diagno-sis (CAD) and detection with these multiple modes. In addi-tion to the coregistration inherent in the combined system,image based registration will be applied to correct for mod-estly differing views, compressions and tissue motions be-tween modalities, modes, UL transducer sweeps, and studiesat different times.

Thesaurus Terms: breast neoplasm/cancer diagnosis, diag-nosis design/evaluation, mammography, ultrasound imaging/scanning X ray, biopsy, computer assisted diagnosis, earlydiagnosis, image processing clinical research, female, humansubject, women’s health

Institution: University Of Michigan At Ann Arbor3003 South State, Room 1040Ann Arbor, MI 481091274

Fiscal Year: 2003Department: RadiologyProject Start: 27-Sep-2002Project End: 31-Aug-2007ICD: National Cancer InstituteIRG: ZRG1

DIGITAL MAMMOGRAPHY: ADVANCEDCOMPUTER-AIDED BREAST CAN*

Grant Number: 5R01CA095153-02PI Name: Chan, Heang-Ping

Abstract: Description (provided by applicant): The majorgoals of the proposed research are (1) to develop a comput-er-aided diagnosis (CAD) system for full field digital mam-mography (FFDM) using advanced computer vision tech-niques and (2) to evaluate the effects of CAD on interpreta-tion of DMs. Previous CAD methods for lesion (mass andmicrocalcification) detection and characterization have beendesigned for digitized film mammograms and have generallybeen based on image features extracted from a single view.Our proposed approach is distinctly different from the previ-ous approaches in that image information from two-viewmammograms and bilateral mammograms will be fused us-ing machine intelligence techniques. This fundamentalchange will expand the amount of information utilized inCAD and is expected to improve lesion detection and char-acterization. New computer vision techniques will be specifi-cally designed for FFDM in order to exploit the advantages

offered by digital detectors. This will produce a CAD systemthat is integrated with and takes full advantage of the latestimaging technologies to further improve the health care ofwomen. We hypothesize that these advanced multiple-imageinformation fusion techniques will lead to a more effectiveCAD system for FFDMs in comparison to a single-imageapproach, and that the CAD system will significantly im-prove radiologists’ accuracy in the four most important areasof mammography: (i) detection of masses, (ii) classificationof masses, (iii) detection of microcalcifications, and (iv) clas-sification of microcalcifications. A database of digital mam-mograms (DMs) with malignant and benign lesions and a setof normal cases will be collected. We will first adapt ourcurrent film-based CAD algorithms to DMs in each of thefour areas, taking into account the differences in the imagingcharacteristics between DMs and digitized mammograms.New computer vision techniques will then be developed toimprove upon the current methods and to exploit the poten-tial advantages of the high contrast sensitivity, high detectivequantum efficiency, wide dynamic range, and the linear re-sponse to x-ray intensity of digital detectors. Novel regionalregistration methods for identifying corresponding lesions onCC and MLO views and for comparing the density symme-try on bilateral mammograms will be developed. Innovativefuzzy classification schemes will be designed to fusemultiple-image information and one-view information to re-duce false positives and to improve detection sensitivity.Multiple-view morphological and texture features of a lesionwill be merged using neural networks or other statisticalclassifiers for characterization of malignant and benign le-sions. To test the hypotheses, we will (1) compare the per-formance of the multiple-image fusion CAD algorithm forDMs in each area to that of the corresponding one-view al-gorithm, (2) compare the detection accuracy of masses andmicrocalcifications on DMs with and without CAD by ob-server ROC studies, and (3) compare the classification accu-racy of masses and microcalcifications on DMs with andwithout CAD by observer ROC studies. It is expected thatthis research will not only lead to an effective CAD systemfor FFDM, the multiple-image fusion approach and the newcomputer vision techniques will also advance CAD technol-ogy for mammography in general.

Thesaurus Terms: breast neoplasm, computer assisted diag-nosis, computer system design/evaluation, diagnosis design/evaluation, digital imaging, mammography, neoplasm/cancerdiagnosis artificial intelligence, calcification, diagnosis quality/standard, mathematics, neoplastic growth bioimaging/biomedicalimaging, clinical research, data management, human data,information system


Fiscal Year: 2004


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Department: RadiologyProject Start: 01-Jul-2003Project End: 30-Jun-2008ICD: National Cancer InstituteIRG: RNM

COMPUTER-AIDED DIAGNOSIS OF LUNGCANCER

Grant Number: 5R01CA093517-03PI Name: Chan, Heang-Ping

Abstract: Description (provided by applicant): Lung canceris the leading cause of cancer deaths in both men andwomen. A 70 percent five-year survival rate has been re-ported when the lung cancer is diagnosed at a local stage,compared to 2 percent when distant metastases are found.Recent studies indicate that helical CT may be an effectivescreening tool for lung cancer. The American College ofRadiology Imaging Network (ACRIN) will begin a random-ized controlled trial of helical CT for lung cancer screeningto evaluate its efficacy. Analysis of CT images to detect lungnodules is a demanding task for radiologists. Some lung nod-ules will likely be overlooked because of the overwhelmingamount of information to be interpreted. Characterization ofdetected nodules to reduce unnecessary biopsies will alsobecome more important as the number of thoracic CT examsincreases. Computer-aided diagnosis (CAD) can be a viableapproach to improving the accuracy and efficiency of lungcancer detection in CT images. It will be particularly usefulif lung cancer screening with CT is implemented. The goalof the proposed project is to develop a CAD system forearly detection of lung cancers on thoracic helical CT im-ages. We hypothesize that an accurate CAD system (1) canbe developed, (2) can be used as a second opinion to assistradiologists in interpretation of thoracic CT exams, and (3)will improve radiologists’ accuracy for lung cancer detection.We will develop advanced computer vision techniques toautomatically segment helical CT images, detect candidatepulmonary nodules, differentiate nodule and normal pulmo-nary structures, and estimate the likelihood of malignancy ofthe nodules. Computerized image segmentation and featureextraction techniques will be developed based on expertknowledge and image characteristics. Statistical classifiers,fuzzy classifiers, and artificial neural networks will be de-signed to differentiate nodules and normal structures, as wellas to characterize malignant and benign nodules. QuantitativeCT phantom studies will be performed to develop reliablemethods for estimating the calcium concentration of nodulesand estimating nodule volume on CT images so that thesefeatures can be used in our CAD system for malignancy de-tection. Observer performance studies using receiver operat-ing characteristic (ROC) methodology will be conducted toevaluate the effects of CAD on radiologists’ detection and

classification of lung nodules in CT images. A large publicdatabase of helical CT cases to be collected by an NIH-supported consortium will be the main data source for thedevelopment of the computer vision techniques. The innova-tions of this project include: (1) developing region-specificcomputer vision method for detection of lung nodules; (2)eliminating the vascular tree in the helium for false positivereduction, (3) exploring interval change analysis for classifi-cation of malignant and benign nodules; (4) developing aquantitative method for measuring the calcium concentrationof nodules for improved characterization of calcified nodules,and (5) performing ROC studies to evaluate CAD’s ability toassist radiologists in the detection and characterization oflung nodules in CT studies. It is expected that the proposedstudies will result in an effective CAD system for lung can-cer diagnosis. When fully developed and clinically imple-mented, a CAD system for lung nodules will increase theefficacy of lung cancer screening with helical CT, improveearly detection, and improve the chance of survival of pa-tients.

Thesaurus Terms: computer assisted diagnosis, computersystem design/evaluation, diagnosis design/evaluation, lungneoplasm, neoplasm/cancer diagnosis calcification, calcium,calcium disorder clinical research, computed axial tomogra-phy, human subject


Fiscal Year: 2004Department: RadiologyProject Start: 01-Jan-2002Project End: 31-Dec-2006ICD: National Cancer InstituteIRG: RNM

ULTRA HIGH RESOLUTION HUMAN MRIOF GLIOMAS

Grant Number: 5R21CA092846-02PI Name: Christoforidis, Gregory A.

Abstract: Description (provided by applicant): The value of1.5 Tesla magnetic resonance imaging (MRI) in defininggliomas is well established, but does not necessarily identifythe full extent of involvement by tumor cells, or markers fortumor grade such as neovascularity, pleomorphism, nuclearto cytoplasmic ratio, cell density and endothelial prolifera-tion. Images acquired from normal volunteers with 8T ultrahigh field MRI (UHFMRI) system have a 4 fold increase inresolution versus typical 1.5 Tesla commercial clinical sys-tems (i.e. General Electric Signa Horizon MRI System) andtwo-fold increase in signal to noise when compared to thefew 4 Tesla research magnetic resonance systems operating


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at other research sites. This could be critical for enhancingthe sensitivities of MR imaging to gliomas. SPECIFICAlMS: (1) To determine if the improved spatial resolutionand magnetic susceptibility-based vascular enhancement ob-tained with UHFMRI allows for the identification of abnor-mal vascularity in gliomas. (2) To determine whether areasof increased vascularity identified at 8T correspond to areasof increased vascularity on histopathologic analysis. (3) Todetermine whether areas of increased vascularity identified at8T correspond to areas of perfusion one contrast enhanced1.5 T MRI. A group of 80 patients with astrocytoma willundergo pre-operative high-resolution gradient echo imagingat 8T. Subsequently, these same patients will undergo con-trast enhanced MRI and perfusion MRI at 1 .5T. Foci of in-creased vascularity will be identified on 81 images. Semi-quantitative grades for blood vessels will be made from the1.5 and 8 T images by two reviewers. The high vessel densityfoci will then be biopsied using intra-operative stereotactic-guidance. The tissue will be histologically evaluated usingvessel stains and a semi-quantitative vessel grading will bemade. Correlation of the various vessel grades will be madebetween the histologic findings and the MR findings. Reli-ability will be measured on the basis of interobserver andintraobserver agreement. Secondary outcome measures willbe used as pilot data in order to plan future investigations.

Thesaurus Terms: diagnosis design/evaluation, glioma,magnetic resonance imaging, neoplasm/cancer diagnosis as-trocytoma, blood vessel, blood volume, contrast media, ge-netic susceptibility, outcomes research, technology/techniquedevelopment bioimaging/biomedical imaging, biopsy, clinicalresearch, histopathology, human subject, neuropathology,stereotaxic technique

Institution: Ohio State University1960 Kenny RoadColumbus, OH 43210

Fiscal Year: 2003Department: RadiologyProject Start: 01-Aug-2002Project End: 31-Jul-2005ICD: National Cancer InstituteIRG: ZRG1

COMPUTING TUMOR DETECTIONPERFORMANCE IN MEDICAL IMAGING

Grant Number: 5K01CA087017-05PI Name: Clarkson, Eric

Abstract: The overall goal is to optimize the design of med-ical imaging systems and reconstruction algorithms for thepurposes of tumor detection in humans and animals. For im-aging systems this is done by devising efficient methods tocalculate the performance of ideal observers that use the

noisy data from the system on realistic tumor detectionstasks. These methods make use of symmetries of the imag-ing system, consistency conditions on the data, and con-straints on the objects to simplify the computations. Noisemodels are chosen to reflect the measurement noise in thesystem, the background variation in the patient population,and the normal variation in tumor characteristics. Perfor-mance of ideal observers is determined by the area under thereceiver operating characteristic curve. For a given detectiontask, this performance is a function of the parameters in thesystem design. By varying these parameters the optimal de-sign for tumor detection is found by maximizing this figureof merit. When the ideal observer performance is too diffi-cult to compute, the ideal linear observer is substituted. Forreconstruction algorithms, the performance of linear mathe-matical observers using the reconstructed images for tumordetection tasks is computed. These model observers are cho-sen to match the performance of human observers on similartasks. To compute the performance of these observers, thefirst-order and second-order statistics of the reconstructedimages are calculated or approximated. These statistical mo-ments are then used to compute the signal-to-noise ratio forthe model observer on the given tumor detection task. Ofparticular interest is the role of redundant data and null func-tions of the imaging system in the deterministic and statisti-cal properties of the reconstruction algorithms.

Thesaurus Terms: diagnosis design/evaluation, imaging/visualization/scanning, mathematical model, model design/development, neoplasm/cancer diagnosis artificial intelli-gence, performance, statistics/biometry bioimaging/biomedi-cal imaging


Fiscal Year: 2004Department: RadiologyProject Start: 01-Aug-2000Project End: 31-Jul-2005ICD: National Cancer InstituteIRG: NCI

CT FLUOROSCOPY GUIDEDROBOTICALLY ASSISTED LUNG BIOPSY

Grant Number: 1R21CA094274-01A1PI Name: Cleary, Kevin R.

Abstract: Description (provided by applicant): The goal ofthis research project is to extend an existing robotic systemto assist the physician in accurate computed tomography(CT) fluoroscopy-guided needle biopsy of lung nodules. Theresearch will build on a two-year collaboration between theImaging Science and Information Systems (ISIS) Center at


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Georgetown University and the Urology Robotics (URobot-ics) Laboratory at The Johns Hopkins Medical Institutions todevelop a robotic system for precision needle placement nearthe spine. This is an innovative project to develop new tech-niques for accurate lung biopsy. The successful completionof the project will provide the physician with assistance inprecision lung biopsy and enable experienced practitioners tobiopsy difficult lesions more quickly and easily. It shouldalso enable less experienced practitioners to successfully per-form these procedures. The robotic system developed herewill also be applicable to a wide variety of other clinicalapplications, both existing and newly emerging, such as pre-cision biopsy of other organs, drug and gene therapy deliv-ery, and vascular access. The use of CT for lung cancerscreening is rapidly expanding. Percutaneous image-guidedbiopsy of the lung is a moderately difficult procedure withthe potential for morbidity from pneumothorax and hemor-rhage. For those nodules less than one cm in size, biopsy ismore difficult, and there are a limited number of trained per-sonnel who can perform them. We expect the increasing uti-lization of screening CT will result in a rapid growth in de-mand for image-guided percutaneous biopsy of these nod-ules. Therefore, improved methods for biopsy are important.The project consists of an R21 phase and an R33 phase. Thegoal of the R21 phase is to demonstrate the feasibility ofusing a joystick-controlled robotic system to accurately hitsimulated lesions in a phantom under CT fluoroscopy guid-ance. A prototype gripper will be developed and tested on acustom-built respiring lung phantom model. This will alsoestablish the feasibility of our approach for the R33 phase.The goal of the R33 phase is to develop an enhanced gripperalong with a path planning capability and demonstrate thisapproach in phantom and animal studies, In the R33 phase,the gripper will be enhanced to incorporate a force sensingcapability (automatic release of the needle if a certain forcelevel is exceeded - a safety feature which is required forclinical application) and a rotating needle (to minimize theforce needed for needle placement). We will also developvisualization software to provide the operating physician athree-dimensional (3D) image of the anatomy for path plan-ning. The system will be validated in phantom and animalstudies. The R33 phase will result in a system that is readyfor clinical trials.

Thesaurus Terms: biopsy, diagnosis design/evaluation, im-age-guided surgery/therapy, lung neoplasm, neoplasm/cancerdiagnosis, robotics, technology/technique development, diag-nosis quality/standard, disease/disorder model, model design/development, pulmonary respiration computed axial tomogra-phy, computer human interaction, fluoroscopy

Institution: Georgetown UniversityWashington, DC 20057

Fiscal Year: 2003Department: RadiologyProject Start: 11-Apr-2003

Project End: 30-Jun-2004ICD: National Cancer InstituteIRG: ZCA1

DEVELOPMENT OF A CELLULAR ANDMOLECULAR-BASED CANCER IM*

Grant Number: 5P20CA086352-03PI Name: Conti, Peter S.

Abstract: Description: (provided by applicant) Over the lastdecade, medicine has undergone a profound and rapidchange as a result of advances in cellular and molecular bi-ology. Discoveries resulting from the sequencing of the hu-man genome, advances in biotechnology and instrumenta-tion, and a better understanding of tumor metabolism andphysiology have contributed to this evolution as well. Whilewe are rapidly approaching an understanding of the basicmolecular Mechanisms of cancer, our ability to image thisdisease at its earliest of stages, differentiate cell characteris-tics in vivo, and rationally monitor the effects of new thera-pies remains an unrealized goal. Traditional anatomical im-aging approaches in use today, such as radiography, CT andmagnetic resonance imaging, play a fundamental role in clin-ical medicine, but do not provide the in vivo biochemicaldata needed to evaluate the metabolic and biochemical pro-cesses associated with cancer. Recent developments in mag-netic resonance spectroscopy and positron emission tomogra-phy provide new dimensions to cancer imaging, offeringunique ways to measure tumor biochemistry and the pertur-bations resulting from therapy. These technologies have not,however, realized their potential with respect to imaging themolecular basis of disease. This can only be achievedthrough integration of the advances made in several fields,including molecular and cellular biology, chemistry, physics,pharmacology, engineering and computer sciences. The Uni-versity of Southern California and the Norris ComprehensiveCancer Center have developed a application to design a mo-lecular and cellular-based cancer Imaging Center. The con-cept of developing a U.S.C./Norris Cancer Imaging Centerhas attracted productive teams of scientists committed to itssuccessful implementation. Renowned experts in basic sci-ence and medicine are committed to creating the collabora-tive relationships necessary to achieve the ultimate goal ofthis initiative, which is to improve the care of cancer patientsthrough translation of advances in cancer research to theclinical setting. We envision that the introduction of this NCIsponsored Cancer Imaging Center will foster the integrationof advances in biomedical imaging and basic science, lead-ing to improvements in diagnosis and staging of cancer,guidance of therapy and monitoring of treatment by provid-ing more useful and relevant physiological and biochemicalinformation that is available today. The University and Nor-ris Cancer Center are committed to development of the USCCancer Imaging Center. As noted in the application, the


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Cancer Center is making a substantial financial commitmentto the proposed Imaging Center, including partial funding ofa Post-doctoral Research Fellow and matching pilot/projectfunding.

Thesaurus Terms: cellular oncology, molecular oncology

Institution: University Of Southern California2250 Alcazar Street, Csc-219Los Angeles, CA 90033

Fiscal Year: 2003Department: RadiologyProject Start: 12-Jul-2001Project End: 30-Jun-2005ICD: National Cancer InstituteIRG: ZCA1

TECHNIQUES FOR MRI-GUIDEDCRYOSURGERY OF PROSTATE CANCER

Grant Number: 5R01CA092061-02PI Name: Daniel, Bruce L.

Abstract: Description (provided by applicant): This yearprostate cancer will afflict 189,000 new patients in theUnited States[l]. In many, the significant burden of tumorwill be localized within a portion of the gland. New MRItechniques, including MR Spectroscopy and dynamic MRI,are becoming increasingly able to define the extent of dis-ease in these patients. However, current therapies for pros-tate cancer are either systemic, or treat the entire gland. Webelieve advances in MRI guidance will enable minimallyinvasive, super-selective, targeted cryosurgery as an outpa-tient treatment for localized disease with minimal risk andmorbidity. Potential advantages of MRI guidance oversonography are: Monitoring the entire 3D iceball boundary.Mapping tissue temperature inside the iceball non-invasively.The key to successful cryosurgery is achieving a sufficientlylow freezing temperature. Determining the extent and lethal-ity of the cryo-lesion. This would enable re-freezing of anyunder-treated areas during the same procedure. We will pur-sue two specific aims to develop MRI guidance technologyfor prostate cryosurgery: 1. Calibrate MRI-Thermometry dur-ing cryosurgery of prostate cancer: Refine MRI thermometryfor human use. _ Calibrate MRI-thermometry in 25 prostatecancer patients. We will also assess the efficacy, and mor-bidity of MRI-guided cryoablation 2. Develop advanced MRIto assess acute and chronic cryo-induced injury: Refine per-fusion- and diffusion-weighted MRI for imaging immediatelyafter cryosurgery Evaluate post-cryo perfusion- and diffusion-MRI for depicting acute ischemia and cellular injury in ani-mals and tumor necrosis in humans. Evaluate post-cryo per-fusion- and diffusion-weighted MRI for predicting ultimatevolume of lethal cryoablation in an animal survival model.Completing these aims will pave the way for future clinical

trials that definitively measure the efficacy of MRI-guidedselective cryoablation compared to other treatments for local-ized prostate cancer.

Thesaurus Terms: cryosurgery, image guided surgery/ther-apy, magnetic resonance imaging, prostate neoplasm, pros-tate surgery, technology/technique development human ther-apy evaluation, postoperative state, thermometry bioimaging/biomedical imaging, clinical research, dog, human subject,male, patient oriented research


Fiscal Year: 2004Department: RadiologyProject Start: 01-May-2003Project End: 31-Mar-2007ICD: National Cancer InstituteIRG: DMG

MAGNETIC RESONANCE IMAGING OFBREAST CANCER

Grant Number: 5R01CA066785-07PI Name: Daniel, Bruce L.

Abstract: Description (provided by applicant): Contrast-enhanced magnetic resonance imaging (MRI) detects breastcancer with very high sensitivity. MRI is potentially veryattractive as an adjunct screening method for detecting occulttumors in women who are identified with a high risk ofbreast cancer. The success of screening MRI hinges not onlyon its high sensitivity, but also on minimizing the complex-ity and duration of the exam. It must also achieve the high-est possible specificity in order to minimize the number offalse positive lesions that are detected and must be workedup. The long-term objective of our research is to develop afast, practical screening MRI method that delivers the high-est performance, most accurate imaging method available.The major objective of this proposal is to develop and clini-cally evaluate an easily prescribed, quick bilateral version ofa previously developed unilateral method of obtaining bothrapid dynamic and high spatial resolution contrast-enhancedbreast MRI data. The first specific aim, technology develop-ment, includes new methods for bilateral breast shimming,bilateral water-selective spectral-spatial excitations, and bilat-eral simultaneous image acquisition. Subsequently, an inte-grated acquisition will be developed to obtain both high spa-tial resolution and rapid dynamic images using the same spi-ral pulse sequence. Finally, a new web-based breast MRIinterpretation tool will be developed that uses 3D volumerendering of high spatial resolution images that are colorizedwith pharmacokinetic measures of tumor angiogenesis tosimplify and speed-up breast MR image interpretation byradiologists. The second specific aim, clinical evaluation,


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will measure the image quality and diagnostic accuracy ofthe new bilateral technique, compared to the benchmark uni-lateral method. In addition, a pilot screening trial will bestarted, with the limited objective of proving that the highperformance integrated bilateral 3D spiral method generatesfewer false positive lesions than current dynamic-only orhigh resolution-only screening approaches. When completed,these aims will produce a very powerful screening tool forbreast cancer that is simple to perform. Data collected bythis proposal will pave the way for future full-scale screen-ing trials that will prove the superior efficacy of the tech-nique. By simplifying the exam and minimizing the risk offalse-positive lesions, this technology could potentially bene-fit a great number of women than current protocols that aretargeted only at women at very high risk.

Thesaurus Terms: bioimaging/biomedical imaging, breastneoplasm, breast neoplasm/cancer diagnosis, diagnosis de-sign/evaluation computer program/software clinical research,female, human subject, magnetic resonance imaging, wom-en’s health


Fiscal Year: 2004Department: RadiologyProject Start: 01-Aug-1997Project End: 28-Feb-2006ICD: National Cancer InstituteIRG: ZRG1

TOMOSYNTHESIS FOR IMPROVEDPULMONARY NODULE DETECTION

Grant Number: 5R01CA080490-05PI Name: Dobbins, James T.

Abstract: Description (provided by applicant): The purposeof these studies is to evaluate whether digital tomosynthesiscan serve as an adjunct to conventional chest radiography forimproving clinical detection of pulmonary nodules. Digitaltomosynthesis augments a conventional chest exam by pro-viding three-dimensional information through a series of lon-gitudinal slice images. These slice images are reconstructedfrom a set of discrete projection images acquired at differentangles, using a conventional x-ray tube and a new digitalflat-panel x-ray detector. The tomosynthesized images maybe viewed slice-by-slice or as a 3-D volume-rendered projec-tion in a ‘virtual fluoroscopy” viewing environment. Thediagnostic benefit of tomosynthesis is the use of 3-D infor-mation to improve detection and discrimination of pulmo-nary nodules by eliminating the confusion of overlying struc-tures. CT would remain the gold standard for clinicalworkup once nodules are detected, with tomosynthesis pro-viding a low-dose/low-cost method for improving initial de-

tection accuracy. Clinically the tomosynthesis images wouldbe acquired whenever a digital PN lateral chest exam istaken, but with reduced exposure for the lateral image suchthat the total patient dose from the PA/lateral/tomosynthesisexam would be about comparable to the overall dose from aconventional PN lateral chest exam. It is anticipated that to-mosynthesis will enable higher sensitivity and specificity forpulmonary nodule detection than conventional chest radiog-raphy alone, and hence will potentially lead to earlier detec-tion of lung cancer, at a cost significantly less than low-doseCT. This proposal is a competing continuation of a previousstudy that developed and optimized the tomosynthesis tech-nique. The present study will conduct a clinical evaluation oftomosynthesis for pulmonary nodule detection in a cohort ofhuman subjects with CT-proven nodules. This study willhave three parts: (1) an evaluation of tomosynthesis usingradiologists as observers, (2) development and evaluationof a computer-aided diagnosis (CAD) method using three-dimensional tomosynthesis data for pulmonary nodule de-tection, and (3) a measurement of the accuracy with whichradiologists can use tomosynthesis to localize the depth anddiameter of nodules. The specific aims of the project alsoinclude pilot studies to optimize the tomosynthesis methodbefore the large-scale collection of human subject data.These pilot studies will characterize and minimize effects ofpatient motion, optimize the number of reconstructed planesand patient entrance exposure, and evaluate slice viewing vs.volume rendering.

Thesaurus Terms: digital imaging, image enhancement,lung neoplasm, pneumoradiography, radiodiagnosis, technol-ogy/technique development, tomography computer assisteddiagnosis, diagnosis design/evaluation, mathematical model,phantom model bioimaging/biomedical imaging, clinical re-search, human data, human subject

Institution: Duke UniversityDurham, NC 27710

Fiscal Year: 2003Department: RadiologyProject Start: 01-Dec-1998Project End: 31-Jul-2006ICD: National Cancer InstituteIRG: ZRG1

CAD FOR CT NODULES IN LUNGCANCER DETECTION

Grant Number: 1R01CA098119-01PI Name: Doi, Kunio

Abstract: Description (provided by applicant): The goal ofthe proposed research is to develop computer-aided diagnos-tic (CAD) schemes for detection and characterization of pul-monary nodules in computed tomography (CT) lung images.


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The computer output will be used as a “second opinion” toassist radiologists in their interpretation of CT lung nodulesfor early detection of lung cancer. An advanced CADscheme will be developed by incorporating a multiple-template matching technique and also a massive training arti-ficial neural network (MTANN) in order to achieve a highsensitivity of 80-90% with a low false positive rate of ap-proximately 0.1 or less per section of low-dose helical CT(LDCT) images. A novel subtraction CT technique will bedeveloped for enhancing subtle lung nodules by suppressingthe normal background lung structure including pulmonaryvessels. The usefulness of the subtraction CT technique incombination with the conventional CT image will be investi-gated in improving the overall performance in the computer-ized detection of lung nodules. In addition to the detectiontask, a CAD scheme for characterization of nodules will bedeveloped in order to distinguish between benign and malig-nant lesions. This characterization task will be designed toprovide the estimated likelihood of malignancy based onquantitative analysis of image features of nodules detectedby computer and/or radiologists. A new psychophysical mea-sure will be determined based on ANN by use of both objec-tive image features and subjective ratings on pairs of similarimages, and will be used to select a set of benign and malig-nant nodules from a large database, which would be similarto an unknown nodule in question, in order to assist radiolo-gists’ image interpretation. With the high level of detectionperformance that we expect to achieve, a prototype CADworkstation will be developed and observer performancestudies will be carried out to examine the potential useful-ness of CAD schemes on detection and classification of pul-monary nodules in CT images. These CAD schemes willprovide the radiologists with the location of highly suspectedlesions and/or quantitative measures for benign or malignantnodules, and have the potential to improve diagnostic accu-racy in the early detection of lung cancer, which may lead toimproved prognosis of patients.

Thesaurus Terms: computed axial tomography, computerassisted diagnosis, diagnosis design/evaluation, early diagno-sis, lung neoplasm image enhancement, lung imaging/visual-ization/scanning, neoplasm/cancer classification/staging, pul-monary artery, pulmonary vein, radiodiagnosis, radiologybioimaging/biomedical imaging, clinical research, humandata


Fiscal Year: 2003Department: RadiologyProject Start: 19-Sep-2003Project End: 31-Aug-2007ICD: National Cancer InstituteIRG: DMG

COMPUTER-AIDED DIAGNOSIS IN CHESTRADIOGRAPHY

Grant Number: 5R01CA062625-10PI Name: Doi, Kunio

Abstract: Description (Adapted from Applicant’s Abstract):The applicants proposed to develop computer-aided diagnos-tic (CAD) schemes for detection and characterization of pul-monary nodules in digital chest images. For development ofreliable and predictable CAD schemes, they proposed to es-tablish a large database with 2,000 cases of chest radio-graphs, which include 1,000 nodule cases and 1,000 non-nodule cases, in collaboration with Richard M. Slone, M.D.,Mallinckrodt Institute of Radiology, Washington University,under a consortium arrangement. An advanced CAD schemefor detection of lung nodules will be developed by incorpo-rating three subtraction techniques–temporal subtraction, con-tralateral subtraction and energy subtraction–in order toachieve, on average, a high sensitivity of 80-90% with a lowfalse positive rate of approximately 0.5 per chest image.They would investigate the usefulness of the temporal sub-traction technique in increasing the detection of subtle nod-ules overlapped with ribs and also decreasing the number offalse positives due to rib-crossings, when a previous chestimage of the same patient is available. Contralateral subtrac-tion, which is a novel technique for removal of peripheralribs in a single PA chest image, will be examined for en-hancement in the detection of overlapped nodules and reduc-tion in the number of false positives. They would also inves-tigate the usefulness of energy subtraction soft-tissue imagefor improved computerized detection of lung nodules incombination with conventional chest images. In addition tothe detection task, they would to develop CAD schemes forcharacterization of nodules in order to distinguish betweenbenign and malignant nodules. This characterization task isto provide the likelihood of malignance of lung nodulesbased on quantitative analysis of image features of nodulesdetected by computer and/or by radiologists. With the highlevel of detection performance that they expect to achieve,they propose to develop a prototype CAD workstation andcarry out a pilot study to examine the clinical usefulness ofCAD schemes on detection and characterization of pulmo-nary nodules.

Thesaurus Terms: artificial intelligence, computer assisteddiagnosis, computer system design/evaluation, diagnosis de-sign/evaluation, lung neoplasm, neoplasm/cancer radiodiag-nosis, noninvasive diagnosis, pneumoradiography computerhuman interaction, digital imaging, disease/disorder classifi-cation, image processing, information system bioimaging/biomedical imaging, human data



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Fiscal Year: 2004Department: RadiologyProject Start: 10-May-1995Project End: 28-Feb-2005ICD: National Cancer InstituteIRG: ZRG1

SIMULTANEOUS DYNAMIC ANDARCHITECTURAL MR BREAST IMAGING

Grant Number: 5R01CA090699-02PI Name: Dougherty, Lawrence

Abstract: Description (provided by applicant): Breast canceris the most commonly diagnosed cancer and the second lead-ing cause of cancer death among American women. It is es-timated that one out of every nine women will developbreast cancer in her lifetime. While mammography hasclearly become the gold standard in the detection of early,clinically occult breast cancer, it has limitations. These limi-tations in mammography have led to interest in developingnew forms of breast imaging that may offer both higher sen-sitivity and higher specificity. Contrast-enhanced magneticresonance (MR) imaging of the breast has been shown to bea potentially powerful technique for the detection and diag-nosis of breast cancer. Researchers have developed an inter-pretation model based on architectural features extractedfrom high-resolution breast MR images that has a high sensi-tivity for malignant disease. Other research has shown thatan analysis of the time course enhancement can be used topredict malignant disease. Unfortunately, simultaneous acqui-sition of both high resolution and temporal data has beendifficult due to their diverging demands. We have developedan imaging method that allows us to reconstruct high spatialresolution images, as well high temporal resolution images,using the same data. With both kinetic and architectural en-hancement data at our disposal, the overall goal of this studyis to create a combined interpretation model. Three hundredwomen with suspected breast lesions are to be imaged over athree-year period. The first 100 subjects will be used to com-plete construction of the combined interpretation model.With the remaining two hundred exams, the model will beevaluated for the diagnostic performance characteristics (sen-sitivity, specificity, positive predictive value [PPV], and thenegative predictive value [NPV]) of the overall model indifferentiating benign from malignant masses. With an effec-tive prediction model, MR imaging can be a cost-effectivestep in the evaluation of patients with suspicious breast find-ings including a viable alternative to breast biopsy in somepatients.

Thesaurus Terms: breast neoplasm, breast neoplasm/cancerdiagnosis, diagnosis design/evaluation, magnetic resonanceimaging diagnosis quality/standard, diagnostic test, imageenhancement, longitudinal human study, noninvasive diagno-

sis bioimaging/biomedical imaging, biopsy, clinical research,female, histopathology, human subject, patient oriented re-search, women’s health


Fiscal Year: 2004Department: RadiologyProject Start: 05-Mar-2003Project End: 28-Feb-2006ICD: National Cancer InstituteIRG: RNM

INTERVENTIONAL MR: ADVANCEDGUIDANCE/THERMAL MONITORING

Grant Number: 5R01CA081431-04PI Name: Duerk, Jeff

Abstract: Using an open magnet system, we are developingmethods for guiding interventional magnetic resonance imag-ing (IMRI) procedures including thermal ablation. Thermalablation is minimally invasive and cost effective. Interven-tional MRI is different from diagnostic MRI, and in our par-adigm, minimally invasive treatment of cancer tumors is per-formed entirely in the MR imager. MRI provides both guid-ance of the interventional device to the cancer tumor andmonitoring the thermal treatment. This is a achieved by ex-ploiting MRI’s ability to: 1) generate contrast between tu-mors, normal tissues, interventional tools and thermal lesionsand 2) obtain images at any angle (and dynamically adjusted,like ultrasound, via a localization device). Nonetheless, limi-tations exist in the current MRI techniques used for guid-ance, localization and treatment monitoring; unless overcomeIMRI will not achieve it’s vast potential in minimally inva-sive diagnostic and cancer treatment procedures. These limi-tations create a unique opportunity to develop and optimizeadvanced magnetic imaging pulse sequence techniques,which will ultimately improve patient care through more ef-fective IMRI capabilities. The research pursued in thisproject will create new imaging methods meeting the con-straints of the IMRI environment by addressing four primaryissues in which IMRI differs from diagnostic MRI (and thesemust be attained simultaneously): contrast: speed, motioninsensitivity and therapy monitoring. In IMRI patient risk isrelated to time, and so we will create new rapid steady statefree precession imaging methods with specific application forIMRI guidance. They will achieve better contrast betweentissues and interventional devices than methods presentlyavailable for low field dynamic interventional applications.New radial K-space sampling methods which utilize infor-mation on the orientation of the interventional device will bedesigned and evaluated to improve the device tip accuracy


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and reduce sensitivity to motion artifacts better than 2DFTmethods used commonly in IMRI. The most important ana-tomic locations for local control of primary and metastaticcancer are the liver, brain, kidney, pancreas, head/neck andmusculoskeletal system. The research in this application willcreate customized IMRI methods for these anatomic loca-tions and test them on rabbits (implanted with VX2 in theabdominal organs) and pigs. This project will provide thefirst systematic study in which low field IMRI techniques aredesigned by combining the advantages of both the MRI con-trast mechanism and K-space sampling scheme together toachieve optimized IMRI methods for each anatomic location;they will offer greater performance than current 2DFT strate-gies used in virtually all IMRI guided procedures. Further,this project will improve emerging quantitative MR thermalmapping methods and allow attainment of accurate thermalmonitoring of IMRI guided thermal cancer therapy. Based onour success to date, the second generation of IMRI guidancestrategies will be created.

Thesaurus Terms: image enhancement, magnetic resonanceimaging, neoplasm/cancer surgery, technology/technique de-velopment neoplasm/cancer thermotherapy, bioimaging/bio-medical imaging, laboratory rabbit, swine

Institution: Case Western Reserve University10900 Euclid AveCleveland, OH 44106

Fiscal Year: 2003Department: RadiologyProject Start: 01-Jun-2000Project End: 31-May-2005ICD: National Cancer InstituteIRG: ZRG1

PET IN SARCOMA–A CLINICAL TRIAL

Grant Number: 5R01CA065537-10PI Name: Eary, Janet F.

Abstract: Sarcomas are a heterogeneous group of tumorsthat show only moderate response to treatment. In this pro-posal, we build on our previous work using Positron Emis-sion Tomography (PET) to contribute to the management ofsarcoma patients. These studies are also a model for PETapplications in other types of cancer. The specific aims inthis proposal address three important areas where we willexplore PET contributions to the treatment and evaluation ofa patient with sarcoma. Using [F- 18]fluorodeoxyglucose(FDG) and PET, we will perform semi-quantitative imagingstudies on patients to determine tumor metabolism. Thisbaseline patient data will be correlated with patient outcome.This work will continue our evaluation of the ability forFDG PET derived tumor measures to assess and predict timeto local tumor recurrence, metastasis, and death. Rigorous

methods will be applied to determine the statistical signifi-cance of the differences between survival curves. Addition-ally, measures of tumor heterogeneity in FDG metabolismusing specialized statistical image analysis techniques willalso be correlated for their ability to predict tumor responseand overall survival. In another specific aim, [C- 11 ]thymi-dine will be implemented as a direct measure of tumor pro-liferation to be predictive of chemotherapy response in pa-tients receiving neoadjuvant chemotherapy for high gradesarcomas. The [C- 11]thymidine data will be compared di-rectly to the clinical reports of percent tumor viability’ at thetime of resection following neoadjuvant chemotherapy. An-other subgroup of sarcoma patients under study are thosepatients who undergo bone allograft placement in limb sal-vage surgery, for treatment of bony sarcomas. At the sites ofunion between graft and native bone, dense bony callousforms. However, the natural history of bone allograft healingand incorporation with respect to this callous is unclear. Wehypothesize that the [F-18] PET bone scans will be sensitivefor characterizing the normal allograft union process and candistinguish the pathological situations of graft nonunion ver-sus tumor recurrence in this setting. The focus of these stud-ies are to exploit the quantitative data and high level of spa-tial sensitivity in PET images to characterize tissue metabo-lism in specific situations facing sarcoma patients. Thesestudies also serve as a model for study in other types of can-cer.

Thesaurus Terms: bone imaging/visualization/scanning,deoxyglucose, neoplastic growth, positron emission tomogra-phy, sarcoma bone metabolism, bone transplantation, clinicaltrial, glucose metabolism, homologous transplantation, hu-man therapy evaluation, metastasis, neoplasm/cancer chemo-therapy, neoplasm/cancer epidemiology, neoplasm/cancerrelapse/recurrence, prognosis, thymidine bioimaging/biomedi-cal imaging, clinical research, flow cytometry, human subject

Institution: University Of WashingtonGrant & Contract ServicesSeattle, WA 98105

Fiscal Year: 2004Department: RadiologyProject Start: 14-Aug-1995Project End: 31-May-2005ICD: National Cancer InstituteIRG: RNM

CONTRAST-ENHANCED ULTRASOUNDDETECTION OF ANGIOGENESIS

Grant Number: 5R21CA093907-02PI Name: Forsberg, Flemming

Abstract: Description (provided by applicant): The develop-ment of anti-angiogenesis agents and the clinical evaluation


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of anti-angiogenic therapy have produced a need for non-invasive imaging methods to monitor response. The funda-mental hypothesis of this project is that tumor neovascularitycan be quantified and monitored non-invasively using con-trast-enhanced ultrasound imaging modes. Studies will beperformed in rats implanted with human breast and gliomatumors (cell lines NMU and C6, respectively). These tumorsare rapidly growing with marked neovascularity and typi-cally reach an average diameter of 10 mm by 3 to 4 weeks.Half the rats will receive orthotopic tumor implantations andin the remaining animals, heterotopic implantations will beperformed. A microbubble based ultrasound contrast agentwill be used in conjunction with power Doppler, flash echoimaging (FEI), excitation enhanced imaging (EEl) and pulseinversion harmonic imaging (HI) to detect and quantify tu-mor perfusion and vascular volume. Contrast enhanced ultra-sound evaluation of tumors will be performed on day 7, 14or 21 after tumor inoculation. Initial experiments will be per-formed on 432 mice (4 ultrasound modes x 2 tumors x 2implantation techniques x 3 time points x 9 rats/group). Im-mediately after the ultrasound study, the animals will be sac-rificed. Tumor vascularity will be assessed by staining forendothelial ceils (CD31), vascular endothelial growth factor(VEGF), basic fibroblast growth factor (bFGF) as well ascyclooxygenase-2 (COX-2), and correlated with the ultra-sound results. Based on this analysis the best implantationand the best ultrasound technique will be selected. Next, 54rats will be studied after treatment with anti-angiogenesistherapy (1 ultrasound mode x 2 tumors x 1 implantationtechnique x 3 time points x 9 rats/group). The same compar-ison between contrast enhanced ultrasound and pathologywill be performed. If successful, this project will permit non-invasive ultrasound evaluations of anti-angiogenic tumortherapies in animals as well as humans.

Thesaurus Terms: angiogenesis, neoplasm/cancer bloodsupply, technology/technique development, ultrasound imag-ing/scanning blood circulation, contrast media, fibroblastgrowth factor, noninvasive diagnosis, prostaglandin endoper-oxide synthase, vascular endothelial growth factor bioimag-ing/biomedical imaging, laboratory rat, ultrasound blood flowmeasurement

Institution: Thomas Jefferson UniversityOffice Of Research AdministrationPhiladelphia, PA 191075587

Fiscal Year: 2004Department: RadiologyProject Start: 15-Aug-2003Project End: 31-Jul-2005ICD: National Cancer InstituteIRG: RNM

PHOTOPHYSICS OF PHOTODYNAMICTHERAPY

Grant Number: 5R01CA068409-10PI Name: Foster, Thomas H.

Abstract: Description (provided by applicant): Photody-namic therapy (PDT) of cancer and of various other condi-tions continues to gain clinical acceptance. The approvals ofthree photosensitizing drugs, Photofrin, Visudyne and Levu-lan, in the United States and the ongoing clinical evaluationof several promising new agents throughout the world pro-vide the context for ongoing laboratory studies that are de-signed to understand further and to optimize this therapy.During the past several years, the field has gained a deeperappreciation of the complex and dynamic interactions amongthe photosensitizing drug, light, and oxygen that togetherdefine the dosimetry of PDT. Research in this laboratory hasbeen directed at defining quantitatively the consequences oftherapy-induced, photochemical oxygen consumption fortherapeutic outcome. A critically important aspect of thiseffort is to define more precisely and in a manner that canbe translated into clinically relevant measurements the rela-tionship between the photodegradation of the sensitizingdrug, the PDT-induced consumption of oxygen, the detaileddeposition of photodynamic dose and the biological re-sponse. This in turn requires improved methods for perform-ing and analyzing results from fluorescence spectroscopy intumors and for the noninvasive assessment of tumor oxygen-ation. Toward these general ends, the application poses thefollowing three specific aims: (1) to expand the experimentalinvestigation and theoretical analysis of the oxygen problemin PDT; (2) to establish the ability of sensitizer fluorescencespectroscopy to report biological response of tumors in vivoand to investigate the feasibility of simultaneous spectro-scopic assessment of blood oxygen, NADH and sensitizerbleaching/photoproduct kinetics from spatially resolved mea-surements of fluorescence; and (3) to determine the PDTthreshold dose for induction of specific genes and the spe-cific severity and duration of PDT-induced hypoxia requiredto induce the expression of hypoxia-inducible factor-10c.The experimental methods that will be used to accomplishthese aims include the use of O2-sensitive microelectrodes,laser scanning optical sectioning fluorescence microscopyand microspectrofluorimetry, fluorescence spectroscopy invivo and diffuse reflectance absorption spectroscopy.

Thesaurus Terms: biophysics, chemical kinetics, neoplasm/cancer photoradiation therapy, photochemistry disease/disor-der model, free radical oxygen, gene expression, heat shockprotein, hypoxia inducible factor 1, mathematical model, nic-otinamide adenine dinucleotide, outcomes research, oxygenconsumption, photosensitizing agent, radiation dosage atomicabsorption spectrometry, confocal scanning microscopy, fluo-rescence microscopy, fluorescence spectrometry, genetically


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modified animal, laboratory mouse, microelectrode, mi-crospectrophotometry

Institution: University Of RochesterOrpa - Rc Box 270140Rochester, NY 14627

Fiscal Year: 2004Department: RadiologyProject Start: 01-Jul-1995Project End: 28-Feb-2007ICD: National Cancer InstituteIRG: RAD

MECHANISMS OF DIFFUSION MRI WITHCHEMOTHERAPY

Grant Number: 5R01CA088285-04PI Name: Galons, Jean-Philippe

Abstract: Description (Verbatim from Applicant’s Abstract):A challenge to oncologists in the future is to individualizeeach and every tumor by tailoring treatments to those whichare the most effective. Ideally, these choices must be madeat the earliest point possible following the beginning of ther-apy. Monitoring therapeutic response is best done non-invasively, and can include molecular biological assays aswell as radiological methods. A potentially powerful methodto non-invasively monitor treatment response is DiffusionMagnetic Resonance Imaging (DWI). Diffusion MRI canaccurately and quantitatively determine the apparent diffu-sion coefficient of tissue water (ADCW). Studies in experi-mental animals have shown that ADCW in tumors increasesin cells undergoing successful chemotherapy. The observa-tion of a increases ADCW is potentially useful for clinicalevaluation of chemotherapeutic response and this will beinvestigated in a companion R2 I proposal. However, adeeper understanding of the relationship between the diffu-sion properties of tumor water and the metabolic state ofcells would increase its utility in assessing the state of tumortissue, predicting outcome and designing therapies. In thisproposal, we will examine the mechanisms underlining theADCW changes using well-defined in vitro and in vivo sys-tems. The two main hypothesis behind the proposed researchplan are that 1) The ADCW in tumors is a surrogate mea-sure of cell volume, and 2) The changes in ADCW in re-sponse to chemotherapy are a marker for apoptosis. Thisproposal represents a thorough evaluation of the relationshipbetween ADCW, cell volume and response to chemotherapy.An well-characterized in vitro bioreactor system will providethe necessary control over system parameters to understandthe basic mechanisms responsible for the observed changesin vivo.

Thesaurus Terms: breast neoplasm, breast neoplasm/cancerdiagnosis, diagnosis design/evaluation, magnetic resonance

imaging, noninvasive diagnosis apoptosis, cell morphology,etoposide, necrosis, neoplasm/cancer chemotherapy, pacli-taxel, tumor necrosis factor alphaMCF7 cell, SCID mouse, bioreactor, flow cytometry, nuclearmagnetic resonance spectroscopy


Fiscal Year: 2004Department: RadiologyProject Start: 01-Jun-2001Project End: 31-May-2006ICD: National Cancer InstituteIRG: ZRG1

REPORTER IMAGING OF PROTEIN-PROTEIN INTERACTIONS

Grant Number: 2R01CA082214-05PI Name: Gambhir, Sanjiv S.

Abstract: Description (provided by applicant): Molecularimaging continues to evolve into a discipline in its own rightwith applications to many areas of biology and clinical med-icine. The long-term goal of this first-time competitive re-newal application is to develop technologies focused on re-porter genes for use with PET, optical, and other emergingmodalities for applications to gene therapy, cancer biology,developmental biology, as well as many other areas. Thegeneral hypothesis is that reporter gene technologies can bedeveloped and utilized to study fundamental molecular/cellu-lar events in living subjects. Excellent progress has beenmade in this regard over the last 4 year funding period. Wehave helped to push the field forward by developing and val-idating enzyme based (Herpes-simplex Virus Type 1 thymi-dine kinase (HSVI-tk)) and receptor based (Dopamine Type2 receptor (D2R)) reporter gene assays. We have appliedthese reporter genes primarily in the area of imaging genetherapy. The specific aims of the current renewal are to takethe developed approaches to the next level by providingtools “systems imaging” by imaging intracellular networks inliving subjects. Protein-protein interactions are at the heart ofmany biological process including normal and diseased tis-sue. In Aim 1 we refine a recently developed strategy to im-age protein-protein interactions that occur in the cell nucleusthrough an inducible yeast two-hybrid (IY2H) strategy. InAim 2 we refine an alternate approach referred to as an in-ducible split reporter (ISR) strategy, which is capable ofmeasuring protein-protein interactions in many locationswithin a cell. In Aim 3 we test the imaging strategies devel-oped in Aims 1 and 2 using new approaches being used totarget the interaction of heat shock protein 90 (Hsp90) withp23 using geldanamycin analogs in tumor therapy models in


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living mice. Finally, in Aim 4 we develop transgenic modelsto further test methods for imaging protein-protein interac-tions in deep tissues of living mice. In all aims, care is takento develop generalizable approaches that should be applica-ble to other studies using multimodality reporter gene ap-proaches. The significance of the proposed work is it willhelp to develop and validate new technologies focused onimaging intracellular communication networks. This shouldlead to many applications including methods to image theinteraction of drugs designed to inhibit protein-protein inter-action in living subjects. More rapid methods to validate andtranslate pre-clinical models for cancer therapeutics into theclinic will likely result.

Thesaurus Terms: bioimaging/biomedical imaging, molecu-lar dynamics, protein-protein interaction, reporter gene, tech-nology/technique development antihypercholesterolemicagent, biological signal transduction, cell nucleus, disease/disorder model, heat shock protein, intracellular, model de-sign/development, neoplasm/cancer chemotherapy, neoplasm/cancer pharmacology bioluminescence, heterologous trans-plantation, laboratory mouse, optics, positron emissiontomography, tissue/cell culture, transfection, transgenic ani-mal, yeast two hybrid system


Fiscal Year: 2003Department: RadiologyProject Start: 30-Sep-2003Project End: 31-Aug-2008ICD: National Cancer InstituteIRG: RNM

CORRELATIVE IMAGING OF TUMORANGIOGENESIS

Grant Number: 1R21CA099060-01PI Name: Gambhir, Sanjiv S.

Abstract: Description (provided by applicant): In the R21phase of this proposal we plan to develop new molecularlybased imaging technologies for use as noninvasive markersof angiogenic endothelial cells and their death in response totreatment. Polymerized vesicles (PVs) chelated with radionu-clide and coated with the monoclonal antibody directedagainst the alphavbeta3 integrin (antialphavbeta3-AbPVs)will be used as a molecular imaging agent for the detectionof newly proliferating angiogenic endothelial cells in bothuntreated tumors and tumors treated with anti-angiogenicagents. In combination we will also evaluate regional tumorblood flow using the previously validated technique ofthallium-201 perfusion imaging. We will determine the timecourse of tumoral and intratumoral localization of contrast intumors using 99mTc-anti-alphavbeta3AbPVs and thallium-

201 (tumor perfusion) uptake as seen with dual energymicro-SPECT (single photon emission computed tomography)radionuclide imaging. We will also perform immunohisto-chemistry for specific markers of angiogenesis and apoptosisand correlate these markers with changes in the localizationof 99mTc-anti-alphaV beta3 AbPVs and thallium 201. TheR33 phase of the program will be to non-invasively detectand quantify neovascularity (angiogenesis) and choose thebest imaging regimen for angiogenesis based on these moreadvanced preclinical studies and develop synthesis and label-ing protocols. We plan to perform pharmacokinetics and tox-icology studies with preclinical materials and prepare anagent for gamma and SPECT imaging in clinical studies andfile an IRB for cancer angiogenesis evaluation.

Thesaurus Terms: angiogenesis, neoplasm/cancer bloodsupply, radionuclide imaging/scanning, vascular endotheliumangiostatin, apoptosis, blood flow, doxorubicin, monoclonalantibody, noninvasive diagnosis, perfusion, radionuclide,thallium, toxicology, vesicle/vacuoleautoradiography, bioimaging/biomedical imaging, immunocy-tochemistry, laboratory rabbit, single photon emission com-puted tomography


Fiscal Year: 2003Department: RadiologyProject Start: 30-Sep-2003Project End: 31-Aug-2005ICD: National Cancer InstituteIRG: ZCA1

MRS AND MRI OF BREAST CANCER ATVERY HIGH MAGNETIC FIELD

Grant Number: 5R01CA092004-03PI Name: Garwood, Michael G.

Abstract: Currently no diagnostic imaging method offerssufficient specificity to reliably differentiate between benignand malignant breast lesions in patients. Pathologic evalua-tion is presently the only way to obtain a definitive diagno-sis. This research will use new methods in magnetic reso-nance spectroscopy (MRS) and a very high magnetic field (4Tesla) to distinguish malignant from benign breast lesions.The required specificity will be gained from biochemicalproperties measured non- invasively with proton (1H) MRS.This work will further investigate the earlier finding that thepresence of choline- containing compounds (Cho) at 3.2 ppmin 1H spectra may be a marker for malignancy in breast le-sions. It is hypothesized that false-positive diagnoses canresult from a resonance at 3.2 ppm that does not arise fromCho, but instead originates from lipids or other macromole-cules with reduced mobility and short transverse relaxation


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time (T2). A macromolecular resonance at 3.2 ppm has beenshown to occur in 1H spectra of brain. In the present project,the measured difference in intrinsic T2 should permit macro-molecular and lipid resonances at 3.2 ppm to be distin-guished from free Cho, thus eliminating false-positives. Theimproved SNR offered by the proposed MRS methods andthe 4 Tesla magnetic field will significantly reduce the inci-dence of false-negative diagnoses. As an alternative means tocharacterize breast lesions, the ability of MRS to measureglucose metabolism in breast lesions will also be investi-gated, by detecting 13C-labeled lactate following an intrave-nous injection of glucose enriched with the stable 13C iso-tope. Breast lesions will be visualized by dynamic contrast-enhanced two-dimensional MRI and high resolution three-dimensional MRI. MRI and MRS scans will be performedon clinically identified suspicious breast lesions prior to bi-opsy or surgical removal. Correlation with pathologic find-ings will reveal whether the proposed MRS measurementsprovide the additional specificity needed to accurately iden-tify and characterize malignant lesions in breast patients.

Thesaurus Terms: breast neoplasm, breast neoplasm/cancerdiagnosis, diagnosis design/evaluation, magnetic field, mag-netic resonance imaging, neoplasm/cancer classification/stag-ing, neoplastic growth, noninvasive diagnosis, nuclear mag-netic resonance spectroscopycarcinogenesis, choline, glucose metabolism, histopathology,lactate, method development, phosphorylcholine bioimaging/biomedical imaging, carbon, clinical research, human sub-ject, mammography, stable isotope, ultrasonography

Institution: University Of Minnesota Twin Cities200 Oak Street SeMinneapolis, MN 554552070

Fiscal Year: 2004Department: RadiologyProject Start: 01-May-2002Project End: 30-Apr-2007ICD: National Cancer InstituteIRG: RNM

INTERDISCIPLINARY STUDY OF ACID-MEDITATED TUMOR INVASION

Grant Number: 1R01CA093650-01A2PI Name: Gatenby, Robert A.

Abstract: Description (provided by applicant): The proposedstudy investigates a novel, conceptually simple mechanismfor cancer invasion developed by the investigators. Its goal isa fuller understanding of the structure and dynamics of thetumor-host interface through an interdisciplinary approachwith continuous interaction between laboratory experimentsand the formulation and analysis of mathematical models.This work was initiated by extensive evidence that tumor

metabolism is consistently different from normal tissue withincreased reliance on glycolytic pathways for energy produc-tion. The investigators hypothesized that excess H� ionsexcreted by tumor cells would diffuse into the tumor-hostinterface and adjacent normal tissue creating an acidic mi-croenvironment favorable for tumor invasion because: 1.Normal cells are significantly less tolerant to acidic pile thanare tumor cells 2.acidic pHe promotes release of proteolyticenzymes breaking down extracellular matrix facilitating tu-mor invasion 3. acid pHe increases release of IL8 and VEGFpromoting angiogenesis. This hypothesis is formalizedthrough mathematical models using both coupled partial dif-ferential equations and a modified cellular automata ap-proach. Critical parameter values in these models such asH� production and diffusion coefficient have been deter-mine experimentally. This has allowed the mathematicalmodels to produce detailed predictions of the peritumoralacid gradient and the resulting morphology of the tumor-hostinterface. These predictions have been investigated using adorsal skin fold chamber technique. Preliminary data measur-ing pHe using fluorescence ratio imaging (FRIM) has con-firmed a gradient of H� ions extending from the tumor edgeinto adjacent normal tissue. Using dye exclusion techniquesloss of viability has been demonstrated in peritumoral nor-mal cells exposed to the acidic environment - a key compo-nent of the hypothesis. The proposed study will extend theexperimental observations by comparing the peritumoral pHegradients and the resulting changes in the peritumoral normaltissue and tumor growth dynamics in the MCF7/s and MDA-mb-435 tumor lines which have markedly different acid pro-duction rates and in-vivo behavior. The mathematical modelswill be further refined as additional parameter values can bedetermined. Perturbations that produce slowing or reversal ofthe traveling wave solution to the state equations (ie tumorgrowth) will be explored to predict possible new treatmentstrategies.

Thesaurus Terms: acidity/alkalinity, carcinogenesis, glycol-ysis, interdisciplinary collaboration, mathematical model,neoplasm/cancer invasiveness, neoplastic growth acidosis,angiogenesis, cell transformation, computer simulation, dis-ease/disorder model, extracellular matrix, gene environmentinteraction, model design/development, morphology, neoplas-tic cell, phenotype, SCID mouse, charge coupled devicecamera, computer program/software, digital imaging


Fiscal Year: 2003Department: RadiologyProject Start: 01-Jul-2003Project End: 30-Jun-2006ICD: National Cancer InstituteIRG: MEP


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COST EFFECTIVENESS OF LIVERTUMOR ABLATION AND RESECTION

Grant Number: 1R01CA083960-01A1PI Name: Gazelle, G Scott.

Abstract: Description (Applicant’s abstract): The proposedresearch seeks to apply decision analytic techniques in orderto evaluate recently developed, minimally invasive tech-niques for percutaneous, in-situ tumor ablation in patientswith liver metastases from colorectal carcinoma (CRC). It isnow well documented that long term survival can be im-proved in patients with limited hepatic metastases by opera-tive metastasectomy. However, the impact of in-situ ablativetechniques on long-term survival is unknown. In addition,the importance of diagnostic imaging in selecting candidatesfor therapy, specifically the impact of diagnostic accuracy ontreatment outcomes, has received relatively little attention.None of these techniques have been formally evaluated inorder to determine their relative cost effectiveness. We haverecently developed a Markov decision model based on thecosts, performance characteristics, and outcomes of variousdiagnostic tests and surgical treatment strategies, in order toevaluate the cost effectiveness of operative metastasectomyin patients with CRC liver metastases. In the proposed re-search, we will further develop, verify, and refine this modelin order to perform cost effectiveness analysis of strategiesfor diagnostic imaging and in-situ ablation in patients withCRC liver metastases. We will also explore the possibilitythat in-situ ablation, given its generally lower cost, morbid-ity, and mortality, could provide relatively cost effective lifeextension for patients in whom cure is impossible. Finally,we will investigate the effect of different analytic perspec-tives on health outcomes and costs at the population level.The research is multidisciplinary in nature, and represents acollaborative effort between researchers in the fields ofhealth economics, health services research, and clinical can-cer care. It will add to our knowledge base concerning theeconomic aspects of cancer management, and will provideguidance in the appropriate use of diagnostic and therapeuticinterventions in patients with hepatic metastases. The re-search may also identify areas for potential clinical trialsproviding direct comparisons of surgical and percutaneoustechniques, and/or evaluations of strategies for diagnosticliver imaging.

Thesaurus Terms: colorectal neoplasm, cost effectiveness,health care cost/financing, liver neoplasm, mathematicalmodel, metastasis, model design/development, neoplasm/cancer palliative treatment, neoplasm/cancer surgery humandata


Fiscal Year: 2003

Department:Project Start: 11-JUL-2000Project End: 30-JUN-2003ICD: NATIONAL CANCER INSTITUTEIRG: ZRG1

PROGRAM IN CANCER OUTCOMESRESEARCH TRAINING (PCORT)

Grant Number: 5R25CA092203-02PI Name: Gazelle, G Scott.

Abstract: Description (provided by applicant): We proposeto establish a Program in Cancer Outcomes Research Train-ing (PCORT) within the Dana-Farber/Harvard Cancer Center(DF/HCC). The Program will be curriculum-based, highlyinterdisciplinary and involve collaboration across the entireCancer Center and affiliated institutions. The goal of the Pro-gram will be to train pre- and post-doctoral candidates whowill become leaders in cancer outcomes research. We requestfunding to support 4 M.D. and/or Ph.D. trainees and 2 pre-doctoral trainees per year, all of whom will spend at leasttwo years in the Program. We will seek to recruit individualswith diverse prior research experience and training, and willintegrate all trainees into a highly collaborative research en-vironment. We will also actively recruit highly qualified mi-nority and women applicants to the program. The Programwill involve 3 components: 1) a specialized curriculum; 2)other didactic experiences; and 3) mentored, multidisci-plinary cancer-related outcomes research. The specializedcurriculum will involve weekly seminars alternating betweendidactic lectures and “research-in-progress” presentations bytrainees and faculty. Appropriately qualified trainees willalso attend the Harvard Program in Clinical Effectiveness, anintensive, seven-week, 15 credit classroom-based programthat includes required courses in epidemiology and biostatis-tics, as well as a variety of electives. Qualified trainees maycontinue to take courses at HSPH, leading to a Master’s de-gree. Trainees will also be permitted to attend additionalcourses throughout Harvard University and its affiliatedschools. Trainees will spend the largest part of their timeparticipating in mentored cancer outcomes research under thedirect supervision of PCORT faculty. All research projectsundertaken by trainees will be multidisciplinary and highlycollaborative. Trainees will be exposed to a broad range ofcancer outcomes research. Trainees will be evaluatedthroughout and upon completion of the Program. After suc-cessful completion of the training program, they will be wellprepared to conduct independent, externally funded, canceroutcomes research, and to do so effectively as part of a mul-tidisciplinary research team.

Thesaurus Terms: education evaluation/planning, healthcare personnel education, neoplasm/cancer education, out-comes research, training, training program/project curricu-


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lum, health science research, health science research support,postdoctoral investigator, predoctoral investigator clinicalresearch


Fiscal Year: 2003Department:Project Start: 01-Sep-2002Project End: 31-Aug-2007ICD: National Cancer InstituteIRG: NCI

COMPUTER-AIDED DIAGNOSIS INBREAST IMAGING

Grant Number: 5R01CA089452-04PI Name: Giger, Maryellen L.

Abstract: Description (Verbatim from Applicant’s Abstract):While screening mammography has been shown to be aneffective method for the early detection of breast cancer,currently, 5-30 percent of women with breast cancer have amammogram that is interpreted as normal. It has been re-ported that interpretation errors (when the radiologist seesthe cancer but reports it as benign) are the cause of 54 per-cent of missed cancers. In addition, only 10-40 percent ofwomen who have a biopsy actually have breast cancer; withbiopsies being expensive, invasive and traumatic to the pa-tient. In addition, there is large inter-observer variability inthe interpretation of mammographic lesions. The long-termgoal of this research is to develop and evaluate computer-aided diagnosis and prognosis methods for multi-modalityimaging of the breast. The main hypotheses to be tested arethat, combined information from the computerized analysisof mammography, breast ultrasound, and MR images, alongwith clinical data, should yield improved methods for (a)distinguishing between malignant and benign lesions, i.e.,diagnosis and (b) predicting prognosis. The objectives are tocreate databases containing mammogram, ultrasound, andMR images along with clinical information, malignant/be-nign status, and patient outcomes; to develop computerizedmethods for characterizing the essential morphological, tex-tural, sonographic, and vascular features of the lesions; andto evaluate the accuracy of these methods in distinguishingbetween malignant and benign lesions and in predicting pa-tient prognosis. It is expected that the results from this re-search will aid radiologists/oncologists in determining thelikelihood of malignancy and in predicting patient prognosis.The proposed work is novel in that such a comprehensivesystem for computer-aided diagnosis has not yet been at-tempted. We believe that with the combined information

from multimodality imaging and clinical information, overallpatient outcome will improve.

Thesaurus Terms: computer assisted diagnosis, diagnosisdesign/evaluation, magnetic resonance imaging, mammogra-phy, ultrasound imaging/scanning cancer information system,computer system design/evaluation, diagnosis quality/stan-dard, image processing, prognosis, bioimaging/biomedicalimaging, female, human data


Fiscal Year: 2004Department: RadiologyProject Start: 24-Apr-2001Project End: 31-Mar-2006ICD: National Cancer InstituteIRG: DMG

SMALL ANIMAL MULTI-MODALITYIMAGING CENTER (SAMMIC)

Grant Number: 5R24CA083105-05PI Name: Glickson, Jerry D.

Abstract: Creation of a Small Animal Imaging ResourceProgram (SAIRP) at the University of Pennsylvania support-ing research by investigators at this institution and also atthe Fox Chase Cancer Center and Thomas Jefferson Univer-sity is proposed. This SAIRP will provide three imaging mo-dalities – 1) Magnetic Resonance Imaging and Spectroscopy(MRI/S). 2) optical imaging covering the ultraviolet throughnear infrared (UV-NIR), and positron emission tomography(PET). The MRI/S facilities are now in place; the UV-NIRand PET facilities are now operational on the scale of humanpatients and will be adapted to studies of small animals(mice and rats) by the end of the first year. The SAIRP willsupport the research of 13 NIH funded projects dealing with1) modification of tumor response to radiation and hyperther-mia, 2) methods of monitoring tumor hypoxia, 3) gene ther-apy of brain tumors, 4) immunotherapy of tumors, 5) detec-tion of breast cancer and 6) detection of tumor response tochemotherapy and radiation therapy. Ancillary facilities forredox scanning, NIR time resolved spectroscopoy, electron-ics, animal management, synthesis of contrast agent andphysiological probes, histology, computer resources, biosta-tistics and MR of perfused cells will be provided. Researchand development and D) projects will be directed towardsthe development of novel NMR capabilities that will en-hance the research capabilities of the base projects. These Rand D projects are: A. MRI of Small Animal Tumors, in-cluding: A1. Small Animal Microimaging. A2. FunctionalImaging of Tumors, B. Multinuclear Spectroscopy, includ-ing: B1. Chemical Shift Selective MR Imaging of 31P in


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Animal Tumors, B2. 1H{17O} MRI of Tumors, B3. In VivoImaging of Intra- and Extracellular Na� and pH in Tumors,and C. NMR Techniques for Monitoring Gene Therapy ofBrain Tumors.

Thesaurus Terms: bioimaging/biomedical imaging, biomed-ical resource magnetic resonance imaging, positron emissiontomography


Fiscal Year: 2003Department: RadiologyProject Start: 01-Sep-1999Project End: 31-Jul-2004ICD: National Cancer InstituteIRG: ZCA1

Grant Number: 5R33CA094287-03PI Name: Gmitro, Arthur F.

Abstract: Description (provided by applicant): The objectiveof this research is to develop a practical effective instrumentfor in-vivo microscopic imaging. The confocal microendo-scope is a catheter-based instrument that utilizes a fiber-opticimaging bundle to view tissue at the cellular level in situ.Encouraging preliminary results have been obtained withfluorescence imaging of tissues using a prototype confocalmicroendoscope system. The primary aims of this researchare to complete the technical development of the instrument,to identify and evaluate suitable fluorescent molecular labels,and then to evaluate clinical applications that can exploit thistechnology. The technical development includes improve-ments in the catheter and the confocal imaging system. Thecatheter of the confocal microendoscope consists of a minia-ture microscope objective and focusing mechanism attachedto the distal end of a fiber-optic imaging bundle. A specificaim of the research is to build a small and optimized cathe-ter that can be routed through the instrument channel of clin-ical endoscopes or through small openings of the body. Thedevelopment of the catheter represents a significant technicalchallenge given the desired size and performance characteris-tics. Improvements in the confocal system and modificationsto incorporate multispectral imaging capability are also pro-posed. The confocal microendoscope can image endogenoustissue autofluorescence or fluorescence from suitable exoge-nous dyes or fluorescent probes. A major aspect of the workis to investigate the imaging properties and the clinical/scien-tific utility of the fluorescent signals. Investigations of tissueautofluorescence, disease-specific fluorescent probes, andcell-permeant vital stains are described. The confocal mi-croendoscope is a fundamental tool that could be used toimprove the accuracy of diagnosis or the efficacy of thera-

peutic intervention. An aim of this grant is to investigate andevaluate the potential of the instrument for imaging cancersor pre-cancerous conditions of the colon, pancreas, esopha-gus, and prostate, which are applications where the instru-ment could have a significant clinical impact. These studieswill be performed using ex vivo human tissues obtainedfrom surgery and biopsy. Successful development and dem-onstration of the confocal microendoscope will lead to sub-sequent in vivo clinical trials.

Thesaurus Terms: biomedical equipment development, con-focal scanning microscopy, diagnosis quality/standard, en-doscopy, fiber optic microscopy, miniature biomedical equip-ment, neoplasm/cancer diagnosis colon neoplasm, esophagusneoplasm, pancreas neoplasm, preneoplastic state, prostateneoplasm SCID mouse, bioimaging/biomedical imaging,clinical research, fluorescent dye/probe, human tissue, labora-tory mouse, laboratory rat


Fiscal Year: 2004Department: RadiologyProject Start: 06-May-2002Project End: 30-Apr-2005ICD: National Cancer InstituteIRG: ZCA1

QUANTIFYING RADIATION-THERAPYBRAIN INJURY WITH 1H-MRS

Grant Number: 5R21CA092547-02PI Name: Gonen, Oded

Abstract: Description (provided by applicant): Brain metas-tases present in 50-80 percent of small-cell-lung-cancer(SCLC) survivors within two years. To reduce this risk andimprove their outcome, prophylactic-cranial-irradiation (PCI)is now offered to certain SCLC patients even in the absenceof distinct visible brain pathology. Although neurotoxicity isalways a concern in brain radiation-therapy (RT), there iscurrently no direct method to quantify its damage to the cen-tral nervous system (CNS). Such knowledge is critical for (a)risk/benefit assessment; and (b) dose determination. Pres-ently, such damage can only be assessed indirectly, usingneurocognitive tests. Unfortunately, the results of such testsare often confounded by other factors such as language bar-riers, patients’ state of mind and/or their level of fatigue, fearand depression. Clearly, an objective, i.e., preferably instru-mental, non-invasive and, most importantly, sensitive methodto quantify RT neurotoxicity is necessary. We propose toquantify the extent of neurona1 cell loss imparted to thebrain by RT through the decline of the amino acid derivativeN-acetylaspartate (NAA) using state-of-the-art proton mag-


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netic resonance spectroscopy (1H-MRS). Since NAA is be-lieved to be present in neuronal cells only, its amount is pro-portional to their number and/or integrity. Consequently, wewill obtain the amount of whole-brain-NAA (WBNAA) in40 patients pre, immediately post- (2-3 weeks later) and sixmonths after whole-brain radiation-therapy (WBRT). Sincewe will evaluate the amount of NAA in the entire brain, itssignal-to-noise-ratio (SNR) will be excellent, facilitatingshort, � 15 min. examinations. It will also not be susceptibleto misregistration errors that currently beset serial studies,nor will it be sensitive to the local transient edema commonin WBRT. The WBNAA measurements will be augmentedby the current tool used to evaluate CNS injury - the mini-mental status examination (MMSE) for correlation and com-parison. We will use these observations to test the followingthree hypotheses, H1- H3: H1: That WBRT induces neuronalinjury quantifiable with WBNAA in these patients. H2: ThatWBNAA is more sensitive than MMSE to detect neuronalinjury consequences of WBRT. H3: That this neuronal injurymay be transient, in part, and could resolve within severalmonths after WBRT.

Thesaurus Terms: brain disorder diagnosis, brain injury,neoplasm/cancer radiation therapy, noninvasive diagnosis,therapy adverse effect aspartate, brain, disease/disorder pre-vention/control, longitudinal human study, metastasis, ner-vous system regeneration, neuron, neurotoxicology, smallcell lung cancer adult human (21�), clinical research, humansubject, hydrogen ion, nuclear magnetic resonance spectros-copy, patient oriented research, psychological test

Institution: New York University School OfMedicine

550 1st AveNew York, NY 10016


WISCONSIN INTERDISCIPLINARYMOLECULAR IMAGING CENTER

Grant Number: 5P20CA086278-03PI Name: Grist, Thomas M.

Abstract: Description: (provided by applicant) The Univer-sity of Wisconsin is unique in that two federally fundedCancer Centers, The UW Comprehensive Cancer Center, andthe McArdle Laboratory for Cancer Research are both lo-cated on campus. These two centers are now in the processof merging to form a single comprehensive cancer center

with tremendous cancer biology and clinical intellectual andtechnical resources. In conjunction with this merger, the Uni-versity recently unveiled its HealthStar-2000 initiative, onefacet of which includes building a new 350,000 ft2 twin-tower medical research facility to be know as the Interdisci-plinary Research Complex (IRC). The IRC will be strategi-cally located adjacent to the current UW Hospital and Com-prehensive Cancer Center complex and equidistant from boththe Waisman Center and new School of Pharmacy building(completion in 2000). The IRC will house cancer, heart andvascular, molecular medicine, neuroscience, transplantation,aging, and women’s health programs. The IRC is intended tocatalyze and nurture interdisciplinary research. A strong em-phasis will be placed on research with a molecular theme.Indeed, molecular biology applied in translational researchwill serve as the intellectual theme of the IRC. Moreover,the new IRC will house a 50,000 ft2 Image Science Centerwhere collaborating medical physicists, radiologists, oncolo-gists, and cardiologists will develop noninvasive diagnostictechnologies. Therefore, the long term objective of this P20pre-molecular imaging Ii center planning grant, nicknamedthe Wisconsin Interdisciplinary Molecular Imaging Center(WIMIC), is to form the foundation of a I subsequent P50interdisciplinary molecular imaging center grant in order tomeld the vast cancer research and imaging sciences commu-nity at UW into a leading interdisciplinary molecular imag-ing center. The specific objectives of this application are to:1) Organize a structure to encourage and foster the interac-tion of basic cancer biology researchers with imaging scien-tists in an effort to answer unique cancer-related questions.2) To provide scientists access to novel targeted cell-selectiveimaging agents and to evaluate these agents in new biologi-cal systems. 3) To utilize shared institutional funds to pro-vide funding for interdisciplinary post doctoral and graduatestudent support. 4) Initiate a bimonthly seminar series featur-ing elite molecular imaging scientists and state of the artimaging technologies and open to scientists of all disciplines.5) Provide opportunities for women, minority, and younginvestigators through interaction with WIMIC members andsmall seed grants.

Thesaurus Terms: bioimaging/biomedical imaging, neo-plasm/cancer, neoplasm/cancer diagnosis

Institution: University Of Wisconsin Madison750 University AveMadison, WI 53706

Fiscal Year: 2003Department: RadiologyProject Start: 06-Jun-2001Project End: 31-May-2004ICD: National Cancer InstituteIRG: ZCA1


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abstracts of funded national institutes of health grants

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