Technologies for Earlier Detection


Research Project Awards



A Non-Invasive Method of Locating Malignant Breast Tumors

Edward J. Hoffman, Ph.D.
University of California, Los Angeles


Mammography is accepted as the best means of screening for non-palpable breast cancer. However, signs of breast cancer, such as micro-calcifications or masses, seen for most malignant tumors, are also seen with many benign tumors. Thus, while mammo-graphy will locate about 85% of all cancers, only about 30% of the masses that are detected in mam-grams are actually malignant. Many of the biopsies now performed, therefore, would not be necessary if the benign (non-cancerous) tumors could be distinguished from malignant (cancerous) tumors by non-invasive techniques.

We propose to develop and test a small nuclear medicine camera, which, in combination with the nuclear medicine imaging agent, Tc-99m-Sestamibi, can locate and identify malignant breast tumors. This camera can be placed in a mammography suite and used after a suspicious finding is seen by mammo-graphy. Recent reports on detection of malignant breast tumors using Tc-99m-Sestamibi show that the tumor was detected more than 90% of the time, and correctly identified as malignant more than 90% of the time. We believe that our camera will surpass the performance of these standard cameras. It will be much smaller and would be capable of being brought in close to image the breast at angles that would avoid the high background from the Tc-99m-Sesta-mibi, which also accumulates in heart and liver. The camera is a miniature scintillation camera with a 5 cm by 5 cm field of view. (Scintillation cameras transform the energy from radioactive decay particles into light images.) This small camera can view the breast from above or below and can be placed under the arm for a medio-lateral oblique view, etc. In each case the field-of-view is free of the activity of the body. For testing, the camera will be fitted to the stereoscopic mammography system designed for core breast biopsies, and images will be obtained of the mammo- graphically positive region on women who are undergoing a biopsy. In this manner the technique will be tested by comparison with the universally accepted procedure for determining malignancy. The goal is to eventually replace a significant fraction of the biopsies using Tc-99m-Sestamibi scans with the miniature camera in the mammography suite. It is our hypothesis that the improvement of the technique made possible by our new camera could make this a cost effective procedure which will significantly reduce the number of unnecessary biopsies that are performed because of the lack of specificity of mammography. The procedure would be less costly than both core and excisional biopsies, and less risky than the excisional biopsy.

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Hybrid Grid Detector for Early Detection of Breast Cancer

John M. Boone, Ph.D.
University of California, Davis

The early detection of breast cancer is presently the single most important factor in terms of improving the prognosis of individuals stricken with the disease. Screen-film mammography is currently the best technology for discovering early breast cancer. However, it is widely recognized that significant improvements can be made to conventional screen-film detectors, and such improvements can lead to even earlier detection of breast cancer. A Hybrid Grid Detector is the topic of this research. This system is designed to specifically improve the detectability of breast cancer. The hybrid grid detector should allow physicians to visualize breast cancer at an earlier phase of development, which will improve treatment prognosis and reduce mortality.

The current generation of x-ray sensors, including the conventional screen-film cassette presently used for mammography, use a two-step process for x-ray detection. First, an x ray is absorbed in an x-ray phosphor, which emits visible light after the x ray is absorbed. Second, the visible light is detected by a sensor that is light sensitive, for example film. Newer, digital sensors such as Charge Coupled Devices (CCDs) can also be used as the light sensor for digital mammography. Coupling the x-ray phosphor with a CCD sensor, however, leads to loss of light because of the optics needed (e.g., lenses). The proposed hybrid grid detector design should markedly increase the amount of light released by the x-ray phosphor, improving spatial and contrast resolution. Spatial resolution is the ability to see very small objects, such as the microcalcifications that are present in about 40% of breast cancers. Contrast resolution is the ability to see objects that have subtle contrast, such as the breast tumor itself. The research plan involves computer simulations of the system, construction of the detectors, and evaluation of their performance in the laboratory. The hybrid detector is constructed of a very fine (0.05 mm) honeycomb of leaded glass, with the pores packed with x-ray phosphor. A special fluid will fill the rest of the pore, allowing efficient light propagation. The glass partitions will also absorb unwanted scattered x-ray radiation. The pores will conduct light without lateral spreading to improve spatial resolution. By increasing the light output, reducing x-ray scatter, and enhancing the spatial resolution, the contrast resolution will be improved.

The hybrid grid detector should lead to a significant advance in imaging performance, with concomitant gains in the early breast cancer detection capability of mammography.

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Novel PET Cameras for Earlier Detection of Breast Cancer

William W. Moses, Ph.D.
Lawrence Berkeley National Laboratory

The aim of this project is to develop PET (positron emission tomography) cameras whose geometry is optimized for earlier detection of breast cancer or axillary node involvement. These postmammography tools would: 1) determine whether suspicious structures observed in mammograms have the increased metabolism or chemistry associated with breast cancers; and 2) image the metabolic activity in the axilla (armpit) to determine the extent of axillary node involvement.

The proposal intends to develop new instrumentation to extend an existing nuclear medicine tracer technique. With this technique, a biologically active drug containing a radioactive isotope is injected into the patient. In this case, the drug is FDG (fluorodeoxy-glucose), which is similar to sugar in that most cells that metabolize sugar also attempt to metabolize FDG. However, FDG is not metabolized easily, so it "sticks" in cells that are actively metabolizing sugar. Most breast cancer cells have a much higher glucose (sugar) metabolic rate than normal tissue, so the concentration of FDG in a tumor is typically 8 times higher than in normal tissue. The FDG contains an isotope (I8F) that radioactively decays by emitting a positron (the anti-particle of an electron). When the positron comes in contact with an electron (from the patient), they annihilate and form a pair of back-to-back gamma rays. Instrumentation that detects these pairs of gamma rays is known as PET cameras (positron emission tomography) and uses the direction that these gamma rays are coming from to form an image of those places in the body in which the FDG has accumulated. Using conventional PET cameras that image the entire body, FDG has been shown to be an excellent tracer for breast cancer, with >95% specificity (i.e., probability that it concentrates sufficiently in a tumor to be detected) and >90% selectivity (i.e., probability that it only concentrates in cancerous tumors and not in benign, or non-cancerous ones). The proposed instruments only image the breast or armpit regions, but have higher efficiency (up to 30 times greater), finer spatial resolution (0.9 mm), and lower cost (possibly by a factor of 10) than conventional PET cameras.

This technological advance has the potential to provide a cost effective, non-invasive alternative to biopsy as well as accurate information on axillary node involvement that is not available from existing techniques. It also has the potential to be used as a screening technique (especially for patients with dense breasts) or in follow-up studies to evaluate the effect of therapy.

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Real Time Telemanagement of Mammography Examinations

H.K. Huang, D.Sc., F.R.C.R.
University of California, San Francisco

Breast cancer is the fourth most common cause of death among women in the United States. There is no known means of preventing the disease, and available therapy has been unsuccessful in reducing the national mortality rate over the past 60 years. Current attempts at controlling breast cancer concentrate on early detection by means of mass screening, using periodic mammography and physical examination, because ample evidence is now available to indicate that such screening indeed can be effective in lowering the death rate. However, scarcity of trained experts hinders a better mammography screening delivery system. Real time digital telemammography emerges as a primary candidate to alleviate this problem. In real time digital telemammography, the mammogram is first converted to a digital image at the examination site, transmitted to a breast imaging expert center through telecommunication where trained mammographers are available for immediate consultation. The specific aims of this research project are to develop a real time telemammography system and to study the effectiveness of the system by setting up a test bed in the San Francisco Bay area. The success of this project will allow a better mammography screening delivery system.

Two hypotheses will be tested: 1) telemammography technologies can be developed for routine real-time clinical operation; and 2) real-time telemanagement can be established for mammography practice. In order to test these two hypotheses, four topics will be studied: Telemammography Technologies, Tele-diagnosis, Teleconsultation, and Telemanagement. Telemammography technologies will be investigated by setting up a telemammography chain between a satellite site at Mt. Zion Hospital (a community-based hospital) and the Breast Imaging Center at the University of California, San Francisco as the expert center. The developed methodology will first be used for telediagnosis, and then for teleconsultation. Tele-diagnosis is a response by the expert within 24 hours, whereas teleconsultation is within half an hour. The ultimate goal of telemammography is telemanage-ment which is defined as the remote real-time management and interpretation of mammography examinations performed at the satellite site by mammography specialists at the diagnostic center.

By the end of this three year study, we intend to have validated a standard real-time telemammography protocol. The methodology could then be extended to other mammography screening programs in California for timely diagnosis by experts. This, in turn, would provide a better health care delivery system for the earlier diagnosis of breast cancer for Californians.

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Innovative Developmental and Exploratory Awards (IDEAs)


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Breast Imaging with an Ultrasound CT Scanner

George R. Leopold, M.D.
University of California, San Diego

Breast cancer is a major health care problem that affects an increasing number of younger women. X-ray mammography provides an excellent tool for diagnosis but has a high false positive rate (i.e., wrongly indicating the existence of a cancer tumor) and is possibly even less sensitive in women with dense breasts. Sono-graphy, or ultrasound (a diagnostic technique in which deep structures of the body are visualized by recording the reflection of high frequency sound waves) is an attractive way to examine questionable areas detected on the mammogram, but it is complicated to perform. Furthermore, modern high-resolution sonography instruments image only a small portion of the breast at a time and it is often difficult to identify the suspicious region.

We have developed an ultrasound computed tomography (USCT) scanner that makes cross-sectional images of the breast (CT is a technique that uses computer technology to generate images of thin "slices" of tissue from multiple views around all sides of the object). These novel images are similar to optical holograms and are based on fundamentally different principles from that of conventional sonography. Our new approach uses circular rings of up to 1024 transducers (devices that change sound waves into electrical signals) that surround the entire breast. A single cross-sectional image covers a very large area eight inches (20 cm) in diameter and requires less than one second to acquire. In preliminary studies, this system has been able to display very small details (0.5 mm at 1 MHZ) over a very large image field of view.

This research will examine the suitability of this technique for breast imaging and will examine its ability to identify the many types of lesions in the breast. Two groups of volunteers will be recruited for study: 1) subjects referred for mammography screening will expand our experience with normal anatomy for a wide range of breast types, and 2) subjects with confirmed breast lesions will be studied along with x-ray mammography and sonography for comparison.

This technology has the potential to improve the early detection of breast cancer and to reduce the number of unnecessary biopsies.

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New Imaging Modality for Early Detection of Breast Cancer

William M. Pardridge, M.D.
University of California, Los Angeles

This work attempts to develop a non-invasive diagnostic test that allows for the early detection of breast cancer. This new approach will merge three methodologies in the biological sciences: tumor-specific proteins called monoclonal antibodies; x-ray imaging of these antibodies, which are tagged with radioactivity; and a chemical modification of the antibody, called "cationization" which gives the antibody electric charge. The novel feature of the proposed work is the use of "charged" antibodies as imaging probes for human breast cancer. The original promise of monoclonal antibodies as "magic bullets" has not been realized for a variety of reasons. However, a significant factor is the lack of access of the monoclonal antibody in the blood to the tumor antigen buried within the breast tumor. This lack of access is due to the fact that antibody proteins are too large in size to escape the blood circulation and do not effectively enter into the cancerous tissue from the blood.

The present application will use a new antibody delivery technology that allows circulating antibodies to rapidly escape from the blood to enter the tumor tissue. A specific antibody will be used in these studies, and this antibody targets a specific protein that is produced by many breast cancers. After the "cationization" modification of the antibody, it will be tagged with radioactivity. The tumor uptake of the antibody can then be detected by technologies available in standard x-ray clinics, such as single photon emission computed tomography (SPL7CT).

It is possible that following both the cationization and radioactive tagging, the antibody will no longer recognize the breast cancer protein. Therefore, these studies will test the feasibility of making these modifications in the antibody in such a way that the antibody's high affinity for the target protein is retained. If these studies give positive results, then an entirely new approach to the early detection of breast cancer will have been developed.

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Noninvasive Measurement of Blood Flow Through Breast Tumors

Michael H. Buonocore, M.D., Ph.D.
University of California, Davis

Early detection of malignant (cancerous) tumors and discrimination from benign (non-cancerous) tumors can reduce human and economic costs by reducing the number of missed malignant breast tumors and reducing the number of biopsies performed on benign tumors.

The specific aim of the project is to develop and test a new noninvasive Magnetic Resonance Imaging (MRI) technique for measurement of blood flow through breast tumors. MRI (a technique based on the interaction of hydrogen protons with magnetic fields) has been proposed as a screening tool and our technique would make such screening more specific for malignant tumors. Our hypothesis is that malignant tumors can be distinguished from benign tumors by measurement of the higher blood flow through the malignant tumors. We plan to establish a definitive diagnosis via tissue biopsy which will be made in all subjects and will establish the technique's potential for early detection and diagnosis of malignant tumors.

Blood flow through tissue is referred to as tissue perfusion and measured in milliliters per minute per gram of tissue. The proposed MRI technique is referred to as arterial spin-tagging, first reported in 1992 for brain tissue perfusion. In this technique, flowing blood, prior to entering the tumor, is magnetically labeled and observed by imaging within the tumor. Greater flow into the tumor causes greater image intensity changes compared to images obtained without magnetic labeling. Enhanced angiogenesis (growth of blood vessels) of malignant tumors is the reason for the increased flow, and appears to be a reliable discriminator of benign versus malignant tissue. Arterial spin tagging techniques will show MRI signal enhancement in malignant tumors similar to that shown in dynamic contrast-enhanced MRI, in which signal enhancement results from passage and accumulation of contrast material. Arterial spin-tagging offers greater sensitivity and higher reliability because it can be applied repeatedly to systematically investigate the tissue parameters. It is not limited to observations over a single pass.

The technique may also reduce the incidence of false-negative diagnoses by revealing high tissue blood flow in small tumors that are not observable with standard MRI or other modalities. The technique may have an important role in detection of small tumors at multiple distinct locations that change management. In larger tumors, this technique may be useful to reveal optimal biopsy sites, which will reduce the number of false-negative biopsies and the total number of negative biopsies.

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New Investigators Awards


Digital Imaging for Hospital and Community-Based Mammography

Daniel J. Valentino, Ph.D.
University of California, Los Angeles

Early detection is crucial in reducing the economic and human costs of breast cancer. Digital mammo-graphy, which generates electronic images of the breast instead of the traditional photographic films, offers a significant advance in the early detection and diagnosis of breast cancer. In addition to providing earlier detection, digital mammography will facilitate the use of advanced computer programs to help all California women obtain more prognostic breast cancer examinations. The goal of this project is to develop an innovative computer information system to provide cost-effective digital mammography in a hospital or community clinic.

The proposed system includes the following technological advances, many of which have been developed in our laboratory and will be evaluated for use with digital mammography: direct digital acquisition and storage of whole-breast images; lossless image compression (reducing the size of images without losing any information); 'intelligent' image management including the integration of images, radiology reports, and medical records; and an innovative computer workstation. We will develop an innovative workstation that we call the "virtual view box." The virtual view box allows a radiologist to view pairs of images, and quickly switch to other images for additional comparisons; this is ideally suited to the rapid comparisons that mammographers currently perform using film. We will develop new electronic tools to optimize the brightness and contrast of the images depending upon the density of the breast and type of lesion, as well as to rapidly view reports and image databases. We will use a rapid prototyping technique to develop and implement the mammo-graphy workstation so that it accommodates the actual tasks the mammo-grapher is required to perform. Finally, the proposed system will facilitate the use of other advanced digital technologies, such as teleradiology (providing radiological services remotely) and computer-aided diagnosis (programs that provide additional diagnostic information to radiologists), by providing a digital environment in which computerized tools can help doctors screen more patients at lower cost.

The primary benefits of this system will be the ability to quickly and accurately screen young women under the age of 50; the decreased cost of operating digital systems versus film-based systems; and a unique potential to provide improved access for underserved populations via the use of a mobile digital mammo-graphy unit and teleradiology to provide subspecialist diagnosis to poor and minority women. In addition, using computerized tools that are being developed by institutions across the nation, digital mammography can improve the detection of suspicious lesions during screening. The intended result of this research is a test-bed for whole-breast digital mammography that, working with medical industry leaders, will be used to ensure that digital mammography products will be widely available to benefit California women.

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