R21EB002526 DIBELLA The DyRoSH Scanner: SPECT with 2 Second Time Resolution
Over 5 million cardiac single-photon emission computed tomography (SPECT) scans were performed in the USA in 2002, with even more studies anticipated for future years. Modern SPECT scanners consist of (typically two) large area gamma cameras which rotate slowly around the patient in a step-and-shoot mode collecting projection information over a scan duration of roughly 30 minutes. Tomographic reconstruction is only possible after the last projections have been completed and it is assumed that the tracer distribution has remained static (or in equilibrium) during the scan, although data can also be "gated" according to the cardiac cycle to resolve wall-motion effects. The proposed dynamic rotating slant-hole (DyRoSH) SPECT scanner will collect full tomographic information every two seconds, by using stationary detectors mounted with slant-hole collimators which rotate at 30 rpm. With 5 projections being collected simultaneously, the spatial resolution and photon sensitivity of the DyRoSH scanner is anticipated to be at least as good as current conventional SPECT machines. The dynamic capability of DyRoSH scanner will have implications for more extensive motion correction (e.g. respiration, patient movements, upward creep) and more significantly, will open the door to true dynamic imaging and, potentially, the development of a broad spectrum of radiopharmaceuticals whose uptake and clearance from the myocardium will be accurately traced over time. The specific aims of this project are: 1. to compare the imaging performance of the DyRoSH SPECT scanner with a state-of-the-art conventional SPECT scanner; 2. to examine and quantify weaknesses and limitations in the DyRoSH SPECT configuration; and 3. to explore potential benefits of the 2-second temporal resolution of the DyRoSH SPECT scanner. All the methods are based on clinically relevant computer simulations. Monte Carlo methods will be used to generate list-mode data for the scanner. ROC studies will be used for the comparison with conventional systems. Field-of-view limitations will be analyzed based on a patient database of anatomies. Kinetic parameter estimation in dynamic SPECT will be compared to existing technology. New patient motion methods will be explored within the DyRoSH context. Vastly improved clinical cardiac SPECT is anticipated from the successful development of DyRoSH scanning (back)
EB006155 DIBELLA Model-Based Reconstruction for Dynamic MRI
Advancements in biocomputing and MRI acquisition technologies make it possible to consider applying image reconstruction methods that are more complex than the standard inverse Fourier transforms to MRI data. This will have a profound impact on dynamic MRI. Temporal and spatial models are proposed to be incorporated into the reconstruction of dynamic contrast enhanced (DCE) MRI data within an inverse problem framework. Specific aims are (1) Develop and incorporate low level (constraints on changes of intensity over time) and higher level (parameterized) temporal models within reconstruction methods for sparsely sampled dynamic MRI datasets. These models will allow for a large increase in volume coverage without concomitant SNR reductions. (2) Develop spatial model-based reconstruction methods for sparsely sampled dynamic MRI datasets. Low level spatial models will realize spatial constraints, and higher level spatial models will be created from patient-specific spatial reference data. (3) Extend the model-based spatio-temporal acquisition and reconstruction methods to accommodate patient motion. (4) Extend the model-based methods to combine with multi-coil speedup (parallel imaging) methods. (5) Validate the proposed computational methods for the clinical application of myocardial perfusion MR imaging and provide data and software tools to the broader research community. Methods: Our multi-disciplinary team will develop software tools as a collaborative process combining biocomputing and MRI expertise with clinical cardiac imaging expertise. Both Cartesian and radial reduced k-space acquisitions of cardiac perfusion data will be reconstructed with the model-based multi-coil methods and compared. Respiratory motion will be identified and compensated using either software approaches or a respiratory strap and pre-scan calibrations. The resulting software tools will be integrated into ITK and provided for use to the research community. The relevance to public health is that heart disease is the leading cause of death. This proposal offers new reconstruction methods that will advance the field of dynamic MRI and improve the non-invasive assessment of myocardial blood flow. Such improvements will allow better and more timely treatments and monitoring of heart disease. The proposed approach can be extended to improve non-cardiac dynamic MRI applications such as studies of the response of tumors to therapy and the response of the brain to stimuli. (back)
EB000177 DIBELLA Dynamic MRI for Myocardial Perfusion and Viability
This proposal seeks to improve the accuracy of noninvasive diagnosis and prognosis of coronary artery disease by using MRI and a gadolinium-based paramagnetic contrast agent. First-pass MRI with the modeling methods proposed here may be able to provide absolute regional blood flows at a high spatial resolution. These first-pass studies may also offer unique viability information. The specific aims are (1) To develop and optimize acquisition strategies to obtain data tailored for compartmental modeling (2) To develop clinically practical methods for analyzing the cardiac contrast MRI data with models (3) To compare the flow estimates from the MRI methods developed here to an MRI upslope perfusion index and to absolute blood flow measurements obtained with dynamic N-13-ammonia PET. (4) To add viability measures from the first pass modeling approach to delayed images to determine if such an approach improves prediction of viability. Methods: (1) Systematic analysis of temporal sampling strategies and the use of reduced k-space acquisitions to increase volume coverage, reduce artifacts, and maintain signal and high spatial resolution will be pursued using realistic computer simulations and human studies. (2) Linked active contours combined with temporal clustering methods will be developed to automatically segment the endocardium and epicardium in the time series data. Methods for blind identification of the input function (input functions are inaccurate at high gadolinium concentrations) will be developed and validated. Two different physiological models will be developed and compared in their ability to provide absolute flow values and reliable extracellular volume estimates. (3) The comparisons with MRI upslope and PET perfusion will be performed using 34 human studies. (4) The first-pass viability measures and three integrated viability measures will be compared to delayed enhancement Gd MRI images and to post-revascularization data in 17 patients. The outcome of this project will be validated imaging protocols and software for use with first-passMRI studies, and practical and accurate methods for myocardial perfusion and viability assessment in vivo. Such methods will be invaluable for improved health care and for improved basic science research, such as tracking nascent flow changes in gene therapy (back)
R21CA128228 HOFFMAN FDG-PET/CT in the evaluation of persistent febrile neutropenia in cancer patients
Although there have been many advances in the assessment and treatment of infections responsible for febrile neutropenia in cancer patients, it still remains a common complication of cancer therapy and accounts for the majority of chemotherapy-associated deaths. The ultimate goal of our interdisciplinary group of oncologists, infectious diseases experts, imagers, and biostatisticians is to conduct a large, prospective, multi-center trial to establish the utility and cost-effectiveness of PET/CT using the widely available glucose analogue [18F]fluoro-2-deoxy- D-glucose (FDG) in identifying sites of infection in cancer patients with persistent febrile neutropenia without an obvious identifiable source thus improving targeted therapy. The immediate goal of this Quick-Trials Exploratory Grant application is to conduct a pilot project in a smaller group of these patients to provide critical information that will support the concept, and aid in the design, of a larger multi-center clinical trial. The primary aim of this exploratory study is to perform FDG-PET/CT in approximately 130 cancer patients with persistent febrile neutropenia in whom an obvious source of infection has not been identified. Each suspicious site will be confirmed with pathologic ground truth whenever possible. The data will be evaluated to address the following questions, which are the sub-aims of this proposal: 1. How effective is FDG-PET/CT in identifying sites of infection in cancer patients with persistent febrile neutropenia without an obvious cause? 2. To what degree does FDG-PET/CT improve detection of sites of infection over CT alone? 3. What FDG-PET/CT imaging variables best predict the presence of infection at a specific site (e.g. standardized uptake value [SUV], concomitant abnormality on CT)? 4. Can the magnitude of FDG uptake as measured by an SUV at sites of infection predict the identity of the infective agent (bacterial vs. fungal vs. viral)? 5. Does the magnitude of uptake at sites of infection correlate with absolute neutrophil count? 6. Can a clinical scoring system be developed to identify a population of patients in whom FDG-PET/CT is likely to be most efficacious in identifying sites of infection? It is possible that FDG-PET/CT may be able to significantly change the management of the cancer patient with persistent febrile neutropenia resulting in improved clinical care; decrease the morbidity due to toxicities from certain toxic antibiotics; potentially decrease the cost of medical care by improved targeting of antibiotic therapy; and decrease days of hospitalization for these patients. All of these potential benefits may result in significant cost savings. FDG-PET/CT may be able to significantly change the management of cancer patients with persistent febrile neutropenia. FDG-PET/CT may be the most appropriate way to localize sources of occult and potentially life-threatening infections thus directly impacting therapy which may significantly impact the quality of life of very ill cancer patients by reducing morbidity and mortality. (back)
R21EB005705 High Resolution DTI Using 3D Single-Shot Acquisition
Diffusion tensor imaging (DTI) provides information about the organization of white matter tracts in the central and peripheral nervous systems. DTI has been successfully applied to tractography of the brain, and has potential usefulness in early diagnosis of white matter disorders. Early changes in diffusion tensors may precede white matter changes visible on conventional MRI scans in diseases such as multiple sclerosis. However, limitations in current DTI techniques have prevented its use in much of the brain and in the spinal cord, optic nerves, and peripheral nerves, where early changes of MS may be manifest. Diffusion tensor imaging requires long data acquisitions and is therefore susceptible to image artifacts arising from field inhomogeneity and patient motion. These artifacts are reduced with faster imaging. Single- shot diffusion tensor imaging methods have been developed to image with greater speed, thus reducing motion and inhomogeneity artifacts, at the cost of image resolution. Multi-shot methods have been developed to attain higher resolution, but these methods are subject to artifacts caused by phase inconsistencies between multiple acquisitions. We have developed a novel DTI technique, three-dimensional single shot diffusion weighted imaging with stimulated echo acquisition (3D ss-DWSTEPI) which obtains diffusion information in a single shot acquisition over a limited imaging volume. To our knowledge, this is the first report on singleshot acquisition of three dimensional volume. This technique has the potential to overcome limitations of currently used DTI techniques. Three-dimensional imaging can give improved SNR and no loss of signal at the slice boundary in comparison with two-dimensional imaging. The use of volume-selective excitation to create interleaved three-dimensional subvolumes will allow faster imaging with optimal echo train lengths. In this project, realtime navigation is proposed to monitor any excessive motion related error which may reduce DTI measurement accuracy, and reject/reacquire the specific data. The proposed technique has the potential to make DTI possible in important areas such as the spinal cord, peripheral nerves, optic nerves, and regions of the brain not currently accessible by current DTI methods, allowing earlier diagnosis of white matter diseases such as multiple sclerosis. (back)
R01CA135501 Development of H - F Dual-Contrast MRI Methods and Imaging Agents
This is a collaborative research project between an MR imaging group in University of Utah and a chemistry research group in University of Maryland to improve the accuracy of quantitative drug delivery in small animals that may help the development of a cancer drug. The MRI group will develop and validate, (1) a rapid imaging technique to simultaneously measure T1 and T2 relaxation times with automated variation of imaging parameters TR and TE in dynamic contrast enhanced MRI (ms-DSEPI-T12), and (2) a fluorine MRI technique for MRI of a compound with a large number of 19F nuclei in a molecule. The chemistry group has developed a 19F labeled Gd-chelate compound containing 27 19F nuclei, of which all fluorine nuclei experience the same chemical shift by symmetric arrangement in the molecule. This 19F labeled compound will further evolve to a 1H-19F dual-nuclei MRI agent (fluorine labeled Gd-chelate: F-Gd-DOTA). F-Gd-DOTA will be used not only to validate the imaging technique, ms-DSEPI-T12, for the accurate estimate of drug concentration, but also as an19F MRI agent, an alternative non-proton MRI agent. The success of this project may provide a unique opportunity to further develop a therapeutic drug attached to F-Gd-DOTA, so that the molecule can be used to accurately evaluate the delivery of the cancer drug, the pharmacokinetics, and the response of tumor tissue to the therapeutic drug. (back)
R01CA107353 KADRMAS Statistical PET Image Reconstruction
Positron emission tomography (PET) is undergoing a period of tremendous growth, and the continued development of new tracers and applications for oncology, cardiology, and neurology ensures that this modality will expand for many years to come. Technological advances are pushing PET toward fully-3D imaging with advanced statistical-based reconstruction algorithms. There is a significant need for improved iterative algorithms which are fast enough for routine use with fully-3D PET, and which take the guesswork out of choosing reconstruction parameters and regularization schemes. The objective of this project is to investigate new paradigms for statistical PET reconstruction which are specifically targeted and separately optimized for estimation and detection tasks. Two (2) complementary reconstruction frameworks are proposed: (Aim 1) direct reconstruction from raw LOR histograms using comprehensive modeling of the system transfer matrix, which achieves true maximum-likelihood estimation with exact Poisson statistics to produce lower-noise, higher spatial resolution images; and (Aim 2) statistically-regulated expectation-maximization (StatREM) algorithms, which adapt to the statistical quality of the dataset being reconstructed. The StatREM framework provides a means for selecting subsets and acceleration in a statistically-meaningful way, offering more robust acceleration than current algorithms. It also provides an iterative stopping criterion which may be optimized specifically for estimation and detection tasks. Moreover, StatREM provides spatially-adaptive regularizations which offer high resolution for high statistics regions, while at the same time regularizing low count background regions. We hypothesize that StatREM provides better lesion detection performance than current algorithms. Aims 3 and 4 will evaluate in detail the quantitation and lesion detection performance, respectively, of the new algorithms using experimentally acquired data of a highly-reproducible whole-body phantom. Each algorithm will be optimized with respect to these tasks. Lesion detectability will be evaluated using a detailed human observer study with a multi-slice display and localization receiver operating characteristic (LROC) analysis. The improvements in image quality offered by this research will broadly impact all applications of PET imaging, with specific benefit for tumor detection and quantitation. (back)
R01CA135556 KADRMAS Multi-tracer PET Tumor Imaging
One of the greatest strengths of positron emission tomography (PET) is the ability to image any of a
number of molecular or physiologic targets using different radiotracers. The clinical utility of PET is wellestablished
for cancer detection and staging. The development of new tracers for imaging metabolism,
proliferation, blood flow and numerous other molecular targets offers almost unlimited potential for imageguided
personalized medicine. However, much of this potential remains unrealized because current
technology permits only one PET tracer to be imaged at a time—multiple scanning sessions need to be
scheduled, often on different days, resulting in high costs, image alignment issues, and a long and onerous
experience for the patient. Recent advances have shown that it is technically feasible to image 2-3 PET
tracers in a single scan using staggered injections and dynamic imaging. Measures of each tracer can be
recovered using “signal-separation” algorithms based on kinetic constraints for each tracer. This project
will continue development of such rapid multi-tracer imaging technologies, with emphasis on developing
specific methods of immediate value and translation to clinical patient imaging. Four tracers will be
studied: 18F-fluorodeoxyglucose (FDG) as a marker for glucose metabolism; 18F-fluorothymidine (FLT) for
proliferation; 11C-acetate (ACE) for lipid synthesis and related growth; and 15O-water (H2O) for blood flow
and volume of distribution. Aim 1 will develop and test methods for rapid dual- and triple-tracer imaging of
FDG, FLT, and ACE in a single scan, targeting total scan times of ~70 min. for dual-tracer, and 90-120 min.
for triple-tracer imaging. These methods will be evaluated in large animal tumor models and in patients
with primary brain tumors. Aim 2 will develop improved multi-tracer algorithms, emphasizing robust
algorithms suitable for routine use. Rapid multi-tracer imaging also provides unique opportunities for
determining inter-linked physiologic parameters. Aim 3 will investigate methods of measuring tumor blood
from derived from the first-pass uptake of all tracers present, using H2O PET as the standard measure of
flow. This will potentially provide reliable measures of blood flow without the need for a focused blood flow
tracer. The overall project is designed to translate multi-tracer PET technologies to clinical tumor imaging,
which will be expressly accomplished through Aim 4. Twenty patients with primary brain tumors will
undergo multi-tracer PET imaging prior to any therapy, after 6 weeks chemoradiotherapy, and at the time
of tumor recurrence. These data will validate the new methods of Aims 1-3, and will begin to explore the
clinical value of multi-tracer PET biomarkers for predicting tumor aggressiveness, assigning patients to
personalized treatment regimens, and assessing response to therapy. (back)
K08CA112449 MORRELL Improved Magnetic Resonance Imaging of Breast Cancer
This is a career development grant proposal to enable Dr. Glen Morrell (the applicant) to develop a long term research program in the application of new methods of magnetic resonance imaging (MRI) of breast cancer. Dr. Morrell received a Ph.D. degree in Electrical Engineering from Stanford in 1998, researching novel methods for MRI. He then completed medical school at Stanford and a Diagnostic Radiology residency and fellowship in MRI at the University of Pennsylvania. He is now in his first year as Assistant Professor of Radiology at the University of Utah. His goal is to combine his knowledge of MRI physics and novel MRI techniques with the clinical practice of radiology, specifically in MRI of breast cancer. Despite the applicant's many years of education, he has had no postdoctoral training in electrical engineering, and has not had opportunity to apply techniques developed in his Ph.D. research to clinically relevant imaging problems. The requested support will allow Dr. Morrell to continue his education in aspects of physics and engineering related to medical imaging, and to continue to gain clinical expertise as a radiologist. During the five-year funding period, Dr. Morrell will apply techniques of multi-dimensional excitation from his Ph.D. research to improve breast MRI and validate these techniques through limited clinical trials. He will gain a greater understanding of quantum mechanics and other principles of physics directly relating to MRI with the aim of developing methods of spectroscopic imaging of the breast. He will be mentored in the design of clinical trials and the conduct of research. The expected benefit of the proposed research plan is improved detection of breast cancer and decreased number of invasive biopsies of benign breast lesions. Based on the pilot studies supported by this grant, Dr. Morrell will submit proposals for funding through R01 or similar mechanisms to maintain and expand a long term research program in MRI of breast cancer, collaborating with well established programs in oncology, pharmaceutics, and genetics at the University of Utah. (back)
R01CA077574 MORTON Tumor uptake of Ga-67 by photodegraded nifedipine
This proposal is the first competing renewal of a 3-year RO1 grant to improve the uptake of gallium-67 for tumor imaging. Uptake of Ga-67 by tumors has traditionally thought to be mediated by transferrin (Tf) and Tf receptor-dependent mechanisms. We have found that uptake of Ga-67 by cells and tumors is also mediated by a Tf-independent process, which appears more important in tumors than normal tissues. More significantly, we have shown that the Tf-independent uptake of GA in cells and tumors can be regulated. It can be specifically induced in tumors by administration of a compound, which we have named "nitrosipine," which is produced when nifedipine, a commonly used dihyropyridine calcium channel blocker, is exposed to fluorescent or UV light. We have generated evidence that nitrosipine may also enhance a variety of other metal cations as well. This may expand the utility of nitrosipine for gamma scintigraphy, PET imaging and radiotherapy. We propose to apply the knowledge gained during the last funding cycle to the following 6 specific aims:
1. To define the molecular features of nitrosipine that are necessary for promoting uptake of Ga-67.
2. To confirm and define the nature of the binding of nitrosipine (or other active derivatives) to metal cations.
3. To define the biological mechanism by which nitrosipine enhances the cellular Ga-67 uptake.
4. To define the in vivo kinetics and optimal method for dosing to maximize the visualization of tumors.
5. To test how broadly effective nitrosipine, and similar active derivatives, are in promoting uptake of GA-67 in tumors of a wide variety of histologic types in a murine tumor models.
6. To explore the potential for nitrosipine or active derivatives, to enhance the uptake of Cu-64. (back)
R21EB005728 MORTON Imaging phenotypes in copper metabolism disease in mice
Copper metabolism disease (CMD) is represents a spectrum of abnormalities characterized by an abnormal distribution of copper and/or abnormally increased or decreased levels of copper in the body. These diseases include nutritional, acquired and genetic abnormalities in one or more of the regulatory steps required in copper homeostasis. These diseases can have serious consequences to the patient, affecting multiple organ systems and resulting in abnormalities in the bioavailability of other essential metal ions. The diseases are also of great interest to scientists who strive to understand basic metallophysiology. Copper-related therapies are also of interest in the treatment of cancer and other diseases. Studies of CMD have traditionally been limited by the lack of relevant animal models for many of the diseases, the availability of Cu isotopes for research, and methods to non-invasively, non-destructively and longitudinally assess the kinetics and distribution of copper in the body. Recent developments have provided opportunities to circumvent these limitations, including novel rodent models of specific CMD, the technology of microPET (positron emission tomography), the availability of Cu-64, a positron emitter with a half life permissive of longitudinal studies from hours to days, provided by an NIH-supported National Research Resource by Washington University, St. Louis. MicroPET imaging, and ex-vivo biodistribution studies of 64-Cu in rodent models of genetically acquired CMD will be utilized to establish whether distinct imaging phenotypes characterize these disorders, and whether phenotypic rescue of specific disorders by novel
Therapies results in a normalization of the imaging phenotype. These pilot data will be used to justify RO1 applications to explore non-invasive methods for the diagnosis and treatment of CMD, in understanding the underlying pathophysiology that contributes to these disorders, and in the development of novel copper-related therapies. The establishment of the imaging phenotypes of CMD animal models is also critical to enable non-invasive, non-destructive and longitudinal methods for evaluating novel gene therapies designed to reverse or ameliorate the consequences of lacking or abnormal gene products that contribute to CMD. The University of Utah has numerous faculty involved in research in normal and
abnormal copper metabolism, its resultant diseases and treatment of patients with these disorders. (back)
R21CA115850 MORTON Characterization of a novel target for cancer imaging
The Sigma family of receptors, Sigma 1 and Sigma 2, are widely distributed in many normal tissues. The Sigma-1
receptor is, most important in the brain, where it may modulate cocaine effects, learning, response to stress, Ca+2
influx, and sterol biosynthesis. The Sigma-2 receptor is over expressed in many tumor cells, and is associated with
rapid apoptosis when bound by exogenous ligands, suggesting it potential as a novel target for anti-tumor therapies.
R. Mach has synthesized a series of ligands that binds selectively to the Sigma-2 receptor. He, we and others have
generated data that suggests that Sigma-2 expression may parallel tumor proliferation and also be involved in a novel
apoptotic pathway. These developments have opened the door for the use of Sigma-2 selective radiotracers as an
imaging surrogate for tumor proliferation and response to therapy. Despite these exciting possibilities, severe
drawbacks currently limit research in the development of Sigma-2 PET ligands in oncologic imaging: we have no
"gold standard" by which to measure expression of the gene or true protein levels in tissues. The reason for these
limitations is that the protein for the Sigma-2 receptor has not been isolated and the gene has not been sequenced.
The goal of this R21 application is to develop these gold standard tools by sequencing the protein, the gene, arid (if
this is a unique sequence) by cloning the gene for the Sigma-2 receptor. The sequential specific aims of this proposal
are: 1)To isolate and purify the protein for the Sigma-2 receptor; 2) To determine the peptide sequence for the
Sigma-2 receptor; 3) To translate the peptide sequence into a mRNA sequence, and from there into a DNA coding
sequence for the Sigma-2 receptor; 4) To compare the coding sequence generated to the gene sequences for the
Sigma 1 receptor, Sigma 1b (a Sigma 1 splice variant which is a potential candidate for Sigma 2), and the Genebank;
and 5) If the coding sequence for Sigma-2 receptor prove unique, we will clone the gene for the Sigma 2 receptor.
Using these tools, we will develop the gold standard assays for measuring Sigma 2 expression. This will allow us to
develop specific immunohistochemical and PCR assays for the Sigma 2 receptor, which will allow us to significance
of Sigma 2 as a target for imaging, and to understand the role of this receptor in cancer biology and potential therapy. (back)
R01CA121003 MORTON FDG PET in cancer-associated venothromboembolic disease
The association between blood clot formation, inflammation and cancer is strong. Cancer predisposes patients to the development of blood clots, which may complicate therapy and has a higher risk of morbidity and death than in non-cancer patients. The converse is also true, nearly 50% of patients who develop unprovoked venothromboembolic disease (VTE) harbor an occult cancer, yet a search for cancer in these patients is not considered standard of practice. The diagnosis of blood clot formation is compromised when the clot is in the abdomen or pelvis, and/or the patient has a containdication to iodinated contrast. In cancer patients, multiple anatomic abnormalities associated with the cancer or its treatment, and a heightened propensity for intraabdominal or pelvic clot may further complicate the diagnosis of VTE. Further, no current methods exist to identify patients at particularly high risk for cancer-related thrombosis, a critical step in thrombo-prevention. The link between clot, cancer and inflammation may be due to a host response to cancer resulting in expression of both local and systemic inflammatory cytokines and tissue factors that act on platelets and myeloid leukocytes to produce a cascade of events culminating in blood clot formation. FDG PET imaging has emerged as a powerful tool in the diagnosis, staging, and therapeutic assessment of malignancy. Based on preliminary data and personal observation, we hypothesize that FDG PET may be a useful adjunct in the diagnosis of complicated cases of VTE, in identifying patients with unprovoked VTE that harbor an occult malignancy, and in identifying the systemic state that predisposes many cancer patients to VTE. The specific aims of this project will test these hypotheses in human subjects and also span from benchtop to bedside. In vitro studies complete the molecular imaging loop, by characterizing the relationship between FDG uptake, activation of prothrombotic cells, and expression of known prothrombotic gene products and effectors by these cells. (back)
R01EB000627 NOO Cone-Beam Tomography with Truncated Projections
The long term objective of this project is to solve the truncation problem in cone-beam tomography, and to implement and freely distribute image reconstruction software suitable for the most common cone-beam imaging configurations.
The specific aims are: 1) to devise, implement, and make publicly available, fast accurate image reconstruction code for cone-beam computed tomography (CBCT) geometries where the source and detector rotate once (or slightly more than once) about the patient, and the projections are always truncated axially (and may also be truncated transaxially), 2) to devise, implement, and make publicly available, fast accurate image reconstruction code for CBCT geometries tailored to C-arm based CT with projections measured over an angular range of about 180 degrees, and with relevant patterns of truncation, and 3) to design and implement simple practical calibration methods from which geometric reconstruction parameters are automatically obtained and passed to the reconstruction algorithms for the scanner configurations of aims 1 and 2.
The methods involve devising algorithms that are impervious to the propagation of false information that is normally concomitant with truncated projection data. Six cone-beam configurations will be considered, and algorithms will be devised by assembling fundamental mathematical tools which have been successful in solving certain specific cone-beam truncation problems in the past. The algorithms will be tested with computer simulated data and phantom measurements from benchtop and physical scanners. Automated calibration will be devised by extending existing analytic approaches, and tested against chi-squared approaches using simulated and real data.
The health benefits of this project relate to the transition of cone-beam tomography from its current status as primarily a high-contrast imaging tool to a fast, quantitative, volume imaging modality with widespread applications in image guidance and diagnosis (back)
R01EB007236 NOO Ultra-fast whole-heart CT using z-motion of the X-ray source
X-ray computed tomography (CT) has become a prominent tool for cardiac imaging since the introduction of
multislice CT in 1998. This prominence has come progressively with the increase in the number of detector
rows and in the scanner rotation speed. However, the accuracy of cardiac CT imaging is currently strongly
dependent on the patient (patients with heartbeat arrythmia, who are more at risk, are more difficult to image),
and this accuracy furthermore comes at the cost of a high dose. The long-term goal of this research is to
Enable highly accurate CT imaging of the whole heart independently of the patient condition and with a dose
comparable to typical CT scans. We hypothesize this goal will be reached using a new scanning concept,
called complete single-beat whole-heart (CSWH) scanning, where tomographically-complete data covering the
full heart is obtained within one heartbeat. For this first research on cardiac imaging with CSWH scans, we will
focus on the following aims: (1) development and implementation of reconstruction algorithms for accurate
imaging from cone-beam data on relevant CSWH scans, (2) comparative evaluation of CSWH scans in terms
of data requirement and dose imparted using various collimation strategies, (3) comparative evaluation of
CSWH scans in terms of imaging performance using computer simulated data and real data of
anthropomorphic phantoms and using human ROC observer studies. (back)
R03EB004851 NOO Cardiac Imaging Using Multislice X-Ray CT
This project addresses cardiac imaging with multislice X-ray CT scanners. Multislice CT has great potential
for cardiac imaging with high spatial and high temporal resolution but highly accurate reconstruction
algorithms are needed to realize this potential. This project aims at satisfying this need by thoroughly
investigating the reconstruction problem, and will have indirectly significant impact on the diagnosis and
treatment of cardiac diseases; accurate calcification scoring, non-invasive inspection of coronary arteries,
and visualization and differentiation of soft plaques are the main goals. It is assumed that (i) the number of
detector rows is between 16 and 64, with a slice thickness of 0.75mm, (ii) a 360-degree data acquisition
can be achieved in 370ms. The specific aims are (1) to develop a realistic, (mathematically) parameterized
simulation model of the beating heart (the UCAIR heart) and software for efficient and realistic cardiac CT
data generation, and to provide a website for dissemination of the results, (2) to develop and evaluate an
algorithm for accurate imaging of the whole heart in the three main cardiac phases (mid-to-late diastole,
ventricular systole, early diastole) using helical (spiral) CT scans with retrospective ECG gating. Algorithm
development will use new results obtained by the PI for accurate fan-beam reconstruction from data on
less than a conventional short-scan. The UCAIR heart will be developed with the help of a cardiologist
using comparisons with real CT scans, anatomic images from the Visible Human Project and pigs hearts.
Improved cardiac imaging will be obtained by refinement of a recently developed algorithm using a
systematic evaluation methodology against two algorithms supported by CT manufacturers. Evaluation will
involve computer-simulated and real data. A beating UCAIR heart will be used with the FORBILD thorax
phantom for computer simulations, while real data experiments will be based on scans of the QRM
anthropomorphic phantom and of patients at the hospital, obtained both on a Siemens Sensation 16. (back)
R01EB008705 NOO Breast-friendly reconstruction methods for X-ray CT imaging of the lungs
This proposal addresses the problem of reducing dose to the glandular breast tissue in chest multidetector
x-ray computed tomography. Currently, there is community-wide recognition that the effects
of x-ray radiation to the female breast have been greatly underestimated, and there is accordingly
strong consensus that the weighting factor used for glandular breast tissue in the calculation of
effective dose should be more than doubled. Such a change in weighting factor will radically change
the way chest CT is looked at in terms of effective dose. We plan to develop novel scanning
techniques and reconstruction algorithms that have the potential to reduce dose to the breast by
about 30%, depending on patient size and breast position, without significantly affecting image
quality. The dose reduction corresponding to these new scanning techniques will be evaluated in a
multitude of female patient models using Monte Carlo-based dose simulation methods. The impact on
image quality will be evaluated in terms of both detection and volumetry of solid pulmonary nodules,
using human observer studies based on CT scans of a wide variety of anthropomorphic thorax
phantoms. (back)
R01CA132964 NOO New scanning and reconstruction methods for MSCT with reduced breast dose
This proposal addresses the problem of reducing dose to the glandular breast tissue in chest multidetector
x-ray computed tomography. Currently, there is community-wide recognition that the effects
of x-ray radiation to the female breast have been greatly underestimated, and there is accordingly
strong consensus that the weighting factor used for glandular breast tissue in the calculation of
effective dose should be more than doubled. Such a change in weighting factor will radically change
the way chest CT is looked at in terms of effective dose. We plan to develop novel scanning
techniques and reconstruction algorithms that have the potential to reduce dose to the breast by
about 30%, depending on patient size and breast position, without significantly affecting image
quality. The dose reduction corresponding to these new scanning techniques will be evaluated in a
multitude of female patient models using Monte Carlo-based dose simulation methods. The impact on
image quality will be evaluated in terms of both detection and volumetry of solid pulmonary nodules,
using human observer studies based on CT scans of a wide variety of anthropomorphic thorax
phantoms. (back)
R01HL048223 PARKER High Resolution MR Angiography
Our goal in this project is to substantially improve the ability of magnetic resonance imaging (MRI) and angiography (MRA) to provide an unambiguous evaluation of the intracranial vasculature. This is a continuation of our long term objective to improve MRI/MRA to provide diagnostic information competitive to X-ray angiography in a manner that is safer and less expensive. Based upon the work of this and other projects, currently available MRA techniques have replaced many diagnostic X-ray angiography procedures. During the prior funding period (years 7 to 10), we have implemented several novel techniques to improve white blood and black blood intacranial MRA and have tested these as applied to the detection and management of intracranial aneurysms. Although white blood and black blood MRA have been substantially improved, both techniques have residual artifacts and ambiguities. White blood techniques still remain as the standard of care in most intracranial MRA applications. However, using a single image contrast is contrary to other diagnostic MRI procedures, such as evaluating parenchymal lesions, that typically rely on multiple types of image contrast to ensure accurate discrimination of normal and pathologic tissue. Our principle focus during the next funding period (years 11 to 15) will be to develop a novel composite set of MRI/MRA techniques, optimized on both 1.5T and 3.0T MRI scanners, yielding a set of multiple contrasts that collectively overcome ambiguities inherent in any individual technique. These techniques will provide isotropic high spatial resolution with sufficient signal to noise ratio (SNR). The acquisitions will be coupled with novel image registration, visualization, and analysis tools. The goal of this project is to determine an optimal and efficient combination of image contrasts necessary for an unambiguous evaluation of the intracranial vasculature. The value of these techniques will be assessed via application to a population of unruptured intracranial aneurysms, normal controls and eventually other disorders such as intracranial atherosclerosis (back)
R33EB004803 PARKER Gradient Arrays for High Performance Extended FOV MRI
This project will design, construct, and evaluate a prototype novel gradient array system for extended field of view imaging in magnetic resonance imaging. The gradient design consists of novel repetitions of the longitudinal and transverse gradients to create multiple non-adjacent imaging regions. Imaging is performed in the regions where the applied field gradients are linear. Just as the Maxwell pair (composed of two coaxial coils with alternating currents) can be used to generate a Z-gradient to perform imaging over one region, a Maxwell triplet (composed of three coils with alternating currents) might be used to perform image acquisition over 2 non-contiguous regions of linear field variation and thereby improve imaging efficiency. To acquire image data from the central region of non-linear field variation requires a 2nd Maxwell array which overlaps with the first array such that the linear region(s) of the 2nd array are positioned over the central non-linear I region of the first array. Transverse gradient arrays for multiple region imaging will be designed in a similar manner. In the R21 phase we will use numerical methods and computer simulations to investigate the design and predict the performance of such gradient arrays, including efficiency, slew rate, homogeneity, and power requirements as a function of current distribution. We will also study the issues of gradient overlap, transmit and receive RF coils, and pulse sequence design to obtain contiguous imaging regions. In the R33 phase, we will use the designs from the R21 phase to construct a prototype insert gradient system and the RF coils required for multiple region imaging. We will test the gradient arrays and RF coils at various stages of production. We will also construct a whole-body composite gradient array and perform detailed nerve stimulation studies. This novel design will allow complete utilization of all existing high performance pulse sequences. It will also allow the development of new pulse sequences that utilize the complete hardware capabilities to simultaneously attain increased gradient performance, increased imaging field of view, and decreased nerve stimulation. (back)
R01HL057990 High Resolution Cervical Carotid Imaging with MR
Our goal is to develop novel imaging techniques to improve the repeatability and consistency of assessment of carotid artery atherosclerosis. During the past 3 years we have developed methods to improve the repeatability of quantitative measurements of carotid artery lesion morphology in carotid magnetic resonance imaging (MRI) and angiography (MRA) at 1.51. During the next four years we will perform three specific tasks to develop major improvements in carotid MRI/MRA. 1) We will implement efficient MRA and blood suppressed MRI sequences at 3.0T with special attention to reduced RF heating (SAR) to attain maximum efficiency and reduction or elimination of motion effects. Very few, if any, carotid imaging studies have been performed at 3.0T because of SAR limitations and motion effects. 2) We will develop a novel high resolution diffusion weighted imaging (DWI) technique applicable to the cervical carotid artery. Although in vitro studies demonstrate that diffusion weighted imaging helps discriminate between necrotic core, fibrous tissue, and hemorrhage, a pulse sequence adequate for high resolution DWI of the cervical carotid in vivo does not yet exist. 3) We will develop improved multi-coil imaging techniques, including a novel technique to obtain the complete complex coil sensitivities and the noise covariance matrix without a reference scan, and thereby allow the first image-based direct implementation of the optimal multi- coil reconstruction algorithm. This proposal includes development of efficient carotid MRI/MRA techniques at 3.0T, carotid DWI, optimized RF coils, a fully optimal phased array reconstruction technique, and improved post processing techniques. Thus this proposal represents a comprehensive approach to developing a complete set of tools to diagnose, evaluate, and monitor the evolution of this important disease. With improved signal to noise ratio and the capability of diffusion weighted imaging, we will assess the improvements gained at 3.0T over 1.5T. About 90% of our work will be to develop and test carotid imaging technology at 3.0T. The remaining 10% effort, at 1.5T, will provide a valid baseline for comparison with 3.0T. We believe that each aspect of this work will help open the door for improved longitudinal studies of the carotid artery at 3.0T. (back)
R01CA134599 PARKER Non-Invasive Image-Guided HIFU for Breast Cancer Therapy
Improvements in MRI have now made it possible to develop and implement paradigm-shifting, on-line modelpredictive
control systems to make thermal therapy treatments more accurate and clinically practical. Our goal
is to develop and use such a controller in a novel, completely non-invasive, MRI-guided, phased array HIFU
heating system, designed specifically for thermal therapy of breast tumors. This is an important clinical site with
a large population of patients for whom current treatments can be significantly improved. The proposed system
has several unique innovations including: a new, breast-specific, HIFU phased array heating system with
integrated MRI receiver coils; an optimal, adaptive, model-predictive control system; advanced MR
temperature measurement techniques; patient-specific treatment planning based on innovative MR tissueproperty
and perfusion measurements; and interactive 3D displays for clinician treatment monitoring and
supervisory control. These innovations will be achieved through the close academic/industrial partnership
between interdisciplinary scientists, engineers and clinicians at the University of Utah (UU), Siemens Medical
Solutions (SMS) and Image Guided Therapy (IGT). This novel integrated system and its innovative
improvements will not only significantly advance the state of the art of thermal therapies for breast tumors, but
for all clinical sites. (back)
R01EB008062 PARKER Spectroscopic and Thermal-Model-Based MRI Temperature Measurements
The goal of this project is to develop magnetic resonance imaging (MRI) techniques for accurate, precise, and
rapid measurements of temperature distributions over regions sufficiently large to be used in monitoring and
control of thermal therapy procedures. This project is complementary to ongoing projects in MRI guided high
intensity focused ultrasound (HIFU) ablation and MRI guided RF atrial at the University of Utah, and at other
institutions, and the results should be of direct benefit to MRI guided thermal therapy in general. For thermal
treatments to come into wide clinical use, MR temperature mapping techniques need to be improved in three
areas: 1) They must be able to measure absolute temperature and temperature changes in a variety of organs,
including ones containing fatty tissue. 2) They must be made less sensitive to patient motion. And 3) their time
and spatial resolution and coverage must be improved. To accomplish our goals we will first develop a novel
composite set of MR temperature imaging pulse sequences to complement the commonly used proton
resonance frequency (PRF) technique. These will include a proton spectroscopy imaging sequence (PSI), a
hybrid PSI/PRF sequence, and a hybrid PRF/T1 sequence. After developing improved analysis techniques,
we will test that these techniques can provide the means to monitor thermal therapies in terms of absolute
temperature accuracy (+/- 1oC), and precision (+/- 1oC), spatial resolution (3mm isotropic), temporal resolution
(<10s), and field of view (FOV) coverage. We will evaluate MRI temperature (MRIT) protocols that can reduce
temperature measurement errors when motion occurs. Finally, we will use the Pennes bioheat transfer
equation and other appropriate physical relationships to develop model-based reconstruction (MBR) and
model-based predictive filtering (MPF) algorithms to improve the temporal resolution of MR temperature
measurement scans while maintaining FOV coverage, spatial resolution, accuracy and precision. The PSI,
PSI/PRF, and PRF/T1 sequences, and the proposed MBR techniques are novel and if successful, could have
a substantial impact on thermal therapy and other applications where temperature distributions are important. (back)
R03EB007318 SCHABEL Ultrasound tomography of acoustic parameter distributions in soft tissues
Characterization of soft tissue physiology is an important problem in medical diagnostics as it provides a
means to differentiate normal from pathological tissues, such as tumors. Ultrasound is a non-invasive modality
capable of providing cost-effective, real-time information about the state of the tissue by directly imaging spatial
variations in a tissue’s intrinsic acoustical properties: complex speed of sound (i.e., complex compressibility)
and mass density. Conventional, ray-driven ultrasound and the compound ultrasonic technique both provide
images of a single parameter only (the coefficient of reflection from tissue interfaces). In addition, conventional
ultrasound suffers from speckle artifacts and subjective operational errors, while compound imaging is not
suited for many imaging situations, and both techniques use an estimate of the speed of sound in the tissue
instead of its actual distribution. These problems can be overcome by using ultrasound in inverse scattering.
Inverse scattering, as proposed here, is a tomographic technique which can generate images of the intrinsic
acoustical properties of the tissue directly, and make ultrasonic imaging quantitative by rigorously accounting
for the multiple interactions between the propagating wave and the tissue matrix. Furthermore, acoustical
imaging is frequently done for speed of sound alone while either neglecting the mass density variation or
considering it in an unrealistic linearized approximation. Incorporation of the mass density is a more
challenging problem. However, in addition to providing information complementary to that obtained from the
compressibility image, taking mass density into account is important when bones, calcifications or foreign
bodies are present. This proposal will consider simultaneously imaging all three parameters: speed of sound,
attenuation coefficient of the wave and mass density. The technique proposed is the recently developed
equivalent source formulation of the scattering problem. This approach avoids the two major disadvantages of
the traditional nonlinear optimization techniques for solving inverse problems, namely, the computationally
intensive and time consuming repeated calculations of the forward problem, and the gradient. Inverse
scattering algorithms will be applied to realistic tissue equivalent phantoms in two different scattering
geometries, one of which will simulate the situation in which the source/receiver device is intra-organ, as for
example, in the recent TUUS imaging of the prostate. (back)
R21EB006779 SCHABEL Computational/Experimental Feasibility Study of Endoluminal Ultrasound Tomography
Intravascular ultrasound (IVUS) is an imaging modality of broad applicability in the diagnosis and treatment
of coronary artery and other vascular diseases. By imaging at high frequencies (20-40 MHz), it provides
high spatial resolution (~0.1-0.2 mm) morphological images of the vessel walls and peri-vascular structures
including atherosclerotic plaques, arterial dissection, congenital defects, and aneurysms. IVUS is also
widely applied in the placement of stents and in assessing the quality of such placements as well as in the
monitoring of restenosis. In addition, spectral analysis of radiofrequency backscatter has been utilized to
provide structural information on plaque composition. Nevertheless, IVUS remains a semi-quantitative
technique due to fundamental limitations of processing algorithms that do not accurately model the effects
of multiple scattering and wave diffraction of ultrasound in human tissues. Signal-to-noise is relatively low
and speckle artifacts limit the ability to identify fine details. As an emerging technology, transmission
ultrasound tomography has demonstrated the capability to provide accurate quantitative reconstructions of
tissue compressibility (or, equivalently, speed of sound) and attenuation. In the proposed project we intend
to 1) extend the applicability of ultrasound tomography to endoluminal geometries through the formulation of
an accurate theoretical model for acoustic scattering in objects for which the sources and detectors are
coincident and lie within the scattering object; 2) develop an efficient computational implementation of these
equations based on the conjugate gradient fast Fourier transform method; 3) develop fully 3D iterative
nonlinear algorithms for solution of the inverse scattering problem in this geometry with multiple frequencies
and multiple sources/detectors; and 4) construct an ultrasound test apparatus capable of performing
measurements in both the external and internal scattering geometries to provide experimental data for
validation and refinement of the model and algorithms. In conjunction, achievement of these objectives will
result in a validated system capable of producing accurate and quantitative three-dimensional
reconstructions of the peri-vascular space that will be applicable to existing IVUS catheter-based transducer
arrays and could be rapidly translated to clinical practice. (back)
K25EB005077 SCHABEL Computer-Aided Detection for MRI Breast Screening
We propose to design, develop and implement a computer-aided detection system for integrating multiple magnetic resonance imaging (MRI) modalities for EARLY DETECTION OF BREAST CANCER IN HIGH RISK PATIENTS, using structural, dynamic contrast enhanced (DCE), and diffusion-weighted (DW) MRI, and magnetic resonance spectroscopy (MRS). Incorporation of morphological and parametric information from structural and DCE MRI data leads to notable improvements in both sensitivity and specificity. However, sensitivity remains suboptimal, particularly for screening purposes. By incorporating additional contrast information derived from DW images and MRS data, further improvements in detection accuracy are expected. A hierarchical set of algorithms will be implemented, using a combination of static feature descriptors, neural networks, and decision tree analysis to integrate the multimodality data.
Early detection of breast cancer is an extremely active area of research, driven by the mediocrity of current mammographic screening methodologies and the consequent expense and inconvenience of unnecessary biopsies of breast lesions ultimately identified as benign. Dr. Schabel will apply his strong background in computational simulation and modeling, spectroscopic data analysis, and image processing toward the detection system described above while developing MRI expertise. Concomitantly he will test and develop appropriate methodologies for application of our new Siemens 3T MRI system. With the significant benefits in signal-to-noise to be gained from using the 3T system, it is likely that this will develop into a fertile area for future work in screening and early detection.
The University of Utah provides a unique constellation of resources for this project. UCAIR has faculty and staff with extensive practical experience with all proposed MRI modalities, and is equipped with cutting edge MRI instrumentation. A group of high-risk breast cancer patients willing to participate in clinical trials is already in place at the Huntsman Cancer Institute, forming a body of prospective participants for the clinical work proposed. Finally, the close participation of clinical radiologists with Dr. Schabel will significantly facilitate the algorithmic work by providing the knowledge and expertise in interpreting radiologic images against which algorithms will be tested. (back)
R33EB001489 ZENG Image Reconstruction with Solid State SPECT
The main objective of this project is the development and evaluation of image reconstruction methods for a rotating, strip gamma camera for SPECT (single photon emission computed tomography). The strip gamma camera consists of a CdZnTe detector and a tungsten slat collimator. This solid-state detector is photomultiplier-tube free and has higher energy resolution (about 3% FWHM at 140 keV photopeak) than a regular Anger camera. In order to reduce the cost of CdZnTe material, the detector is a narrow rectangular strip. Instead of using a parallel-hole collimator, a set of parallel slats that define a series of planes are used to collimate the incoming photons. As a result, the measured projection data are planar integrals as opposed to the line integrals that are generally encountered in traditional Anger camera applications. The measured planar integral of the radioactivity distribution is weighted by a factor l/r, where r is the distance from the point of interest to the detector. One important goal of this proposal is to develop reconstruction algorithms that can exactly compensate for the detectors distance dependent sensitivity. Another important goal of this proposal is to develop algorithms that make the images immune from truncation errors. This will make our imaging system a local tomographic device. Still another important goal of this proposal is to evaluate the performance of the combination of the new detector and reconstruction algorithms. Special emphasis will be placed on developing a novel solid-state imaging system that will provide nearly scatter-free and truncation-error-free images. High image spatial resolution will be achieved by using convergent slat collimators. The work has the potential to significantly improve the diagnostic capabilities of SPECT imaging. This proposal will (a) promote the development of very novel (high risk, high gain) technologies, including continued support for their maturation and full exploitation, (b) promote system integration of technologies for targeted applications, and (c) improve technology transfer by promoting partnerships between academia and industry (back)
R21EB003298 ZENG Breast Cancer Imaging Using a Solid-State SPECT Camera
The main objective of this project is the development of breast cancer imaging methods using a rotating gamma camera for SPECT (single photon emission computed tomography). The gamma camera consists of a CdZnTe detector and a tungsten or lead slat collimator; therefore this solid-state detector does not use photomultiplier-tubes. Instead of using a parallel-hole collimator, a set of parallel slats that define a series of planes are used to collimate the incoming photons. As a result, the measured projection data are planar integrals as opposed to the line integrals that are generally encountered in traditional Anger camera applications.
One advantage of this new gamma camera is its higher energy resolution (about 3% FWHM at 140 keV photopeak) than a regular Anger camera (about 10% FWHM at 140 keV photopeak). Therefore we are able to acquire nearly Compton scatter free data. Another advantage is that the resultant SPECT image will be local. This means that the reconstructed region-of-interest (ROI) is not affected by the radioactivities outside the ROI and in other organs. The radioactivities in the heart and liver are usually high and usually contaminate the projection data of the breast. Our reconstruction algorithm is able to exclude the activities outside the ROI
The overall goal of the project is to develop efficient and accurate three-dimensional SPECT reconstructions for breast imaging using the new CdZnTe camera. The work has the potential to significantly improve the detection of small cancerous lesions in the breast, and significantly improve the diagnostic capabilities of SPECT imaging of the breast. This proposal promotes the development of very novel (high risk, high gain) technologies, including continued support for their maturation and full exploitation, and promote system integration of technologies for targeted applications (back)
R21CA100181 ZENG Radio-Immunotherapy (RIT) Planning Using SPECT
Radioimmunotherapy (RIT) provides an opportunity to deliver more specific radiation to tumor cells while sparing normal tissue. This new medical technology uses millions of cancer seeking antibodies to guide radiation to the cancer. The radiation is conjoined to the antibodies, accompanying them as they flow through the bloodstream. When the antibodies arrive at the cancer site, they attach and remain there, giving their radioactive counterparts the opportunity to destroy the cancer cells. Clinical trials have shown RIT to be successful in treating leukemia and lymphoma, and studies have opened the way for testing these methods on a wide range of cancers. The antibodies used in RIT are monoclonal antibodies (MAbs). In RIT planning, the MAbs are modified to bind to radioactive metals (e.g., Indium-111), which can be visualized with a gamma camera in nuclear medicine imaging. Images from the gamma camera show areas where the Mabs localize in the body. In RIT therapy, the radioactive metal is switched to Yttrium-90, which delivers local radiation to the tumor. In RIT planning the conjugate-view planar imaging method is most widely used for radioactivity quantitation. However, photon scattering and superposition of overlying activities reduce the contrast of planar images. Uncertainty in activity quantitation therefore increases. Recent research using CT and MRI combined with planar imaging is encouraging, yet has drawbacks because the physiological uptake of antibodies may not correspond exactly to the anatomical configuration of an organ or tumor. This difficulty can be overcome by using SPECT. In this proposed research, alternating transmission/emission quantitative SPECT is suggested as a replacement for planar imaging. The proposed method will not increase acquisition time. It is hypothesized that quantitative SPECT will outperform planar imaging in terms of lesion detection and dose estimation in lesions and organs. Novel image reconstruction algorithms will be developed to provided quantitative SPECT images. Our hypothesis will be verified through human observer studies and Channelized Hotelling observer studies. (back)
R21EB006830 ZENG Small Animal SPECT Using a Skew-Slit Collimator
The main objective of this project is the development and evaluation of small animal SPECT (single photon
emission computed tomography) using skew-slit collimators. The state-of-the-art configuration for small animal
SPECT imaging uses a pinhole or a multi-pinhole collimator. We propose the use of a skew-slit collimator to
replace the pinhole or multi-pinhole collimator, in order to significantly reduce image artifacts and increase
transaxial resolution. A pinhole forms a cone-beam imaging geometry. If the collimator rotates around the object
(e.g., a small animal) in a circular orbit, the projection measurements acquired by the cone-beam imaging
geometry are incomplete and not enough for an artifact-free image reconstruction. The severity of the artifact is
proportional to the cone-angle of the pinhole in the direction of the axis of rotation. By transforming a pinhole
into a pair of skew slits, the imaging cone-angle can be controlled by the distances of the two slits to the
detector. We are able to use a large cone-angle in the transaxial direction to increase image magnification, and
a small cone-angle in the direction of axis of rotation in order to reduce the data-insufficiency artifacts. This is
achieved by placing a vertical slit (that is, the slit is parallel to the axis of rotation) close to the object and placing
a horizontal slit farther out.
The multi-pinhole collimator is able to significantly reduce the cone-beam artifacts and to increase the
detection sensitivity by tiling the detector with multiple cone-beam images. To avoid multiplexing as much as
possible, the cone-beam image magnification in the multi-pinhole collimator is smaller than that in the singlepinhole.
The smaller image magnification could result in poorer spatial resolution. We therefore propose a
multiple-skew-slit collimator that has one vertical slit and several horizontal slits. Compared with the multipinhole
system, the multi-skew-slit system has a larger image magnification in the transaxial direction, and thus
has better image resolution.
This grant application promotes the development of very novel technologies in small animal imaging. While
we show great potential for the skew-slit system in theory, further development of reconstruction algorithms and
construction and testing of an actual physical system are required to move this idea into a lower risk category
suitable for R01 type funding. A key goal is to generate preliminary data from a physical skew-slit system.
Success in the aims here will provide evidence that skew-slit SPECT systems offer substantial improvements
for small animal applications. The achievements will naturally form the basis for an R01 for rigorous evaluation
and further optimization and improvements. (back)
R21CA120885 ZENG Spinning-Slit Collimatin for Small Animal SPECT
The main objective of this project is the development and evaluation of image reconstruction methods for
small animal SPECT (single photon emission computed tomography) using spinning single-slit and multi-slit
collimators. The state-of-the-art configuration for small animal SPECT imaging uses a pinhole or a multipinhole
collimator. We propose the use of a slit or multi-slit collimator to replace the pinhole or multi-pinhole
collimator, in order to significantly increase the detection sensitivity and the signal-to-noise ratio in the
reconstructed image. Transforming a pinhole into a slit increases the geometric efficiency of the detector,
allowing more gamma-ray photons to reach the detector while retaining the same spatial resolution as a
pinhole collimator. The pinhole collimator provides the line-integrals of the radioactivity distribution in the
object (small animal), while the slit collimator provides the planar integrals. A planar integral does not
contain as much of the information that is necessary for image reconstruction as a line-integral; more
angular measurements are needed for a slit collimator camera. In conventional SPECT, the detectors rotate
around the object with collimators attached to the detectors. There is no relative motion between the
detector and the attached collimator. For the slit collimator, we require the slit-collimator to spin continuously
in front of its attaching detector. The slit-collimator needs to spin by itself and rotate around the object with
the detector. The spinning motion is the price we pay in order to use a slit collimator for higher sensitivity
detection. The use of a multi-slit collimator can further increase the detection sensitivity and also reduce
data insufficiency artifacts. Another advantage of using a slit collimator is its unique property of providing
local tomography. This grant application promotes the development of very novel technologies in small
animal imaging. It is anticipated that by the end of the grant we shall have developed a high sensitivity small
animal SPECT system and the necessary reconstruction algorithms. (back)
R21EB008792 ZENG Cardiac SPECT using a Low-Energy High-Sensitivity Collimator
The goal of this project is the development of high-sensitivity super-resolution SPECT (Single Photon
Emission Computed Tomography). A well-known limitation of clinical SPECT is the relatively low photon count,
resulting in noisy reconstructions. If a SPECT collimator is designed to accept more photon counts, the spatial
resolution of the resulting image suffers. The trade-off of detection sensitivity versus spatial resolution has been
investigated for a long time, which has resulted in some standard collimator designs, such as LEHR (low-energy
high-resolution), GAP (general all-purpose), and UHR (ultra high resolution). The design of such collimators is
based on planar imaging as follows: For a given source energy and a given distance, the spatial resolution in
terms of FWHM (full-width at half maximum) is specified. A collimator design is then made to meet these
requirements and to achieve the largest detection sensitivity. Recent developments in tomography suggest that
using modern computational and filtering techniques, tomographic images can achieve better spatial resolution
than the spatial resolution specified by the collimator at a certain distance. This phenomenon is often referred to
as super-resolution. Taking advantage of super-resolution, we propose the following: For a desired SPECT
image resolution FWHM(img), a corresponding detector resolution FWHM(det) is estimated. A collimator is then
chosen according to FWHM(det). Since we always want FWHM(img) < FWHM(det), the resultant collimator will
have a much larger detection sensitivity than the collimator associated with the specification of FWHM(img).
The increased sensitivity is expected to give a higher signal-to-noise ratio SPECT image and this may be
accompanied by better lesion detectability. However, the super-resolution techniques themselves usually
amplify high frequency noise, so that the amplified noise may swamp the noise reduction achieved by increased
photon counts with a higher sensitivity collimator. The goal of this project is to develop an optimal high-sensitivity
super-resolution SPECT system by reaching the maximum signal-to-noise ratio with a specified resolution. Our
proposed technology requires only a fraction of the scanning time (or smaller dose) routinely used for the same
resolution and same signal-to-noise ratio requirements. A novel, fast, non-iterative method is developed to
compensate for the non-stationary collimator and scatter blurring effects. The proposed technologies are costeffective
and will have a significant impact in the clinic by providing an equivalent SPECT image for a shorter
scanning time. (back)
R01EB007267 ZENG Single Photon Emission Local Tomography (SPELT)
The main objective of this project is the development of breast cancer imaging methods using a rotating gamma camera for SPECT (single photon emission computed tomography). The gamma camera consists of a CdZnTe detector and a tungsten or lead slat collimator; therefore this solid-state detector does not use photomultiplier-tubes. Instead of using a parallel-hole collimator, a set of parallel slats that define a series of planes are used to collimate the incoming photons. As a result, the measured projection data are planar integrals as opposed to the line integrals that are generally encountered in traditional Anger camera applications.
One advantage of this new gamma camera is its higher energy resolution (about 3% FWHM at 140 keV photopeak) than a regular Anger camera (about 10% FWHM at 140 keV photopeak). Therefore we are able to acquire nearly Compton scatter free data. Another advantage is that the resultant SPECT image will be local. This means that the reconstructed region-of-interest (ROI) is not affected by the radioactivities outside the ROI and in other organs. The radioactivities in the heart and liver are usually high and usually contaminate the projection data of the breast. Our reconstruction algorithm is able to exclude the activities outside the ROI.
The overall goal of the project is to develop efficient and accurate three-dimensional SPECT reconstructions for breast imaging using the new CdZnTe camera. The work has the potential to significantly improve the detection of small cancerous lesions in the breast, and significantly improve the diagnostic capabilities of SPECT imaging of the breast. This proposal promotes the development of very novel (high risk, high gain) technologies, including continued support for their maturation and full exploitation, and promote system integration of technologies for targeted applications. (back)
R01EB005179 ZENG Small Animal SPECT With a Spinning-Slit Collimator
The main objective of this project is the development and evaluation of imaging reconstruction methods for
small animal SPECT (single photon emission computed tomography) using spinning single-slit and multi-slit
collimators. The state-of-the-art configuration for small animal SPECT imaging uses a pinhole or a multipinhole
collimator. We propose the use of a slit or multi-slit collimator to replace the pinhole or multt-pinhole
collimator, in order to significantly increase the detection efficiency (i.e., sensitivity). Transforming a pinhole
into a slit increases the geometric efficiency of the detector, allowing more gamma-ray photons to reach the
detector while retaining the same spatial resolution as a pinhole collimator. The pinhole collimator provides
the line-integrals of the radio-activity distribution in the object (small animal), while the slit collimator provides
the planar integrals. A planar integral does not contain as much of the information that is necessary for
image reconstruction as a line-integral; more angular measurements are needed for a slit collimator camera.
In conventional SPECT, the detectors rotate around the object with collimators attached to the detectors.
There is no relative motion between the detector and the attached collimator. For the slit collimator, we
require that the slit-collimator spin continuously in front of the detector to which it is attached. As a result, the
slit-collimator needs to spin while simultaneously and rotating around the object with the detector. The
spinning motion is the price we pay in order to use a slit collimator for a higher sensitivity detection. The use
of a multi-slit collimator can further increase the detection sensitivity and also reduce data insufficiency
artifacts. Another advantage of using a slit collimator is its unique property of providing local tomography.
This grant application promotes the development of very novel technologies in small animal imaging. It is
anticipated that by the end of the funding period a high sensitivity small animal SPECT system with
accompanying reconstruction algorithms will have been developed. (back)
AN:3033257 ZENG High Resolution Super Sensitivity SPECT
The goal of this project is the development of high-sensitivity super-resolution SPECT (Single Photon
Emission Computed Tomography). A well-known limitation of clinical SPECT is the relatively low photon count,
resulting in noisy reconstructions. If a SPECT collimator is designed to accept more photon counts, the spatial
resolution of the resulting image suffers. The trade-off of detection sensitivity versus spatial resolution has been
investigated for a long time, which has resulted in some standard collimator designs, such as LEHR (low-energy
high-resolution), GAP (general all-purpose), and UHR (ultra high resolution). The design of such collimators is
based on planar imaging as follows: For a given source energy and a given distance, the spatial resolution in
terms of FWHM (full-width at half maximum) is specified. A collimator design is then made to meet these
requirements and to achieve the largest detection sensitivity. Recent developments in tomography suggest that
using modern computational and filtering techniques, tomographic images can achieve better spatial resolution
than the spatial resolution specified by the collimator at a certain distance. This phenomenon is often referred to
as super-resolution. Taking advantage of super-resolution, we propose the following: For a desired SPECT
image resolution FWHM(img), a corresponding detector resolution FWHM(det) is estimated. A collimator is then
chosen according to FWHM(det). Since we always want FWHM(img) < FWHM(det), the resultant collimator will
have a much larger detection sensitivity than the collimator associated with the specification of FWHM(img).
The increased sensitivity is expected to give a higher signal-to-noise ratio SPECT image and this may be
accompanied by better lesion detectability. However, the super-resolution techniques themselves usually
amplify high frequency noise, so that the amplified noise may swamp the noise reduction achieved by increased
photon counts with a higher sensitivity collimator. The goal of this project is to develop an optimal high-sensitivity
super-resolution SPECT system by reaching the maximum signal-to-noise ratio with a specified resolution. Our
proposed technology requires only a fraction of the scanning time (or smaller dose) routinely used for the same
resolution and same signal-to-noise ratio requirements. A novel, fast, non-iterative method is developed to
compensate for the non-stationary collimator and scatter blurring effects. The proposed technologies are costeffective
and will have a significant impact in the clinic by providing an equivalent SPECT image for a shorter
scanning time. (back)
