Research Programs and Major Projects
Alternative Breast-Cancer Imaging Program
Now in its eleventh year, the $15 million, NCI-funded Alternative Breast Cancer Imaging Modalities (ABCI) program involves over 40 investigators throughout the Dartmouth community. The program seeks adjunct or alternative techniques to mammography and other existing modalities of breast cancer imaging. Keith D. Paulsen, PhD, Professor of Engineering and of Radiology, is PI for the program overall. Radiology's Dr. Poplack is PI for the clinical core component, with additional clinical leadership provided by surgical oncologist Richard Barth, medical oncologist Peter Kaufman, and pathologist Wendy Wells.
The investigational modalities of the ABCI, unlike mammography, differentiate tissue on the basis of metabolic and electromagnetic properties such as oxygenation, hemoglobin concentration, elasticity, and electrical conductivity. In addition to anticipated improvements in diagnostic efficacy, the new techniques do not subject patients to ionizing radiation or compression of the breast. Described below are the four principal modalities under investigation.
Magnetic resonance elastography (MRE) is based on the association of tissue stiffness and cancer—which is why a clinical breast exam involves physical manipulation to feel for hardness or lumps. MRE uses a modified MRI scanner to create images based on variation in breast-tissue elasticity. Project leader: John Weaver, PhD, Radiology Department physicist.
Electrical impedance spectroscopy (EIS) uses a painless lowvoltage electrode system to create a "tissue map" of the breast based on variations in how cells conduct and store electricity. These characteristics (conductivity and permittivity) are used to reconstruct images differentiating healthy from cancerous tissue. Project leader: Alexander Hartov, PhD, Thayer School of Engineering.
Microwave imaging spectroscopy (MIS) uses microwave deflection patterns to differentiate cell types on the basis of water content. Resultant high-contrast images can be used for diagnosing cancer and treatment monitoring. Project leader: Paul Meaney, PhD, Thayer.
Near-Infrared Spectral Tomography (NIRST) utilizes the blood sensitivity and tissue-penetrating properties of near-infrared light to locate and quantify regions of hemoglobin, a key indicator of the microvascularity characteristic of cancerous tissue. The program is using NIRST in two different configurations: as a stand-alone system designed to monitor tumors being shrunk with chemotherapy, and as a hybrid with MRI in which MR provides precise tumor location and NIR categorizes its vascular makeup. Project leader: Brian Pogue, PhD, Thayer.
Digital Breast Tomosynthesis (DBT)
Recent controversy on the role of mammography screening in younger women highlights the need for further data and for improved screening technologies. Digital breast tomosynthesis ("DBT" or "BTS") is a tomographic application of mammography which may lead to improved cancer-screening sensitivity, and reductions in unnecessary recalls and breast biopsies, particularly in younger women with denser breast tissue. DBT involves multiple low-dose X-ray exposures across an arc of motion, creating 3D views which can reduce the incidence of false positives and false negatives found in conventional mammography.
Dr. Poplack and colleagues have been active in DBT research since its introduction, having conducted a groundbreaking early clinical trial comparing diagnostic tomosynthesis with that of conventional film-screen mammography. Study results strongly support a clinical role for diagnostic DBT and suggested the likelihood of reduced unnecessary recalls when used in conjunction with digital screening mammography (AJR, 2007). Subsequently, we participated in a larger study, as one of five institutions in the nation's first multi-center DBT clinical trial.
With research capabilities enhanced by the 2009 installation of a next-generation DBT scanner, several DBT studies are now underway. The first, a clinical trial sponsored by Hologic, Inc., compares DBT and MRI for diagnostic accuracy in preoperative breast cancer staging. The second is the R01 program, Optical Imaging Fused with Tomosynthesis for Improved Breast Cancer Detection. This five-year program seeks to develop a clinical exam platform combining the functional imaging of near-infrared spectral tomography (NIRST) with the detailed spatial resolution of DBT—a hybrid device which may yield improved sensitivity, specificity, and a reduction in unnecessary patient call-backs. The program is led by Drs. Paulsen and Poplack, with the University of Massachusetts, and DBT industry leader, Hologic, Inc.
Other Breast-Cancer Imaging Studies
Breast-cancer imaging is the clinical focal point of several additional projects. Frequency Domain Optical Imaging of Breast Cancer looks at the diagnostic potential of a single platform combining the functional-imaging advantages of NIR with the spatial resolution of MR. MR Microwave Absorption and Tomography Imaging, another NCIfunded project, seeks the development of two hybrid modalities (possibly in a single combined platform): magnetic resonance microwave absorption (MRMA) imaging, and MR-compatible microwave tomography (MRMT.) Both studies are collaborative efforts led by Thayer's Dr. Paulsen and Radiology Department physicist Dr. Weaver.
The routine use of preoperative breast MRI is recognized as a potentially powerful, if still controversial, diagnostic adjunct to breast mammography. In 2009, AJR published the results of a significant recent study on the procedure, directed by Radiology's Dr. Petra Lewis. The role of breast MRI in the preoperative evaluation of patients with newly diagnosed breast cancer considered 199 patients with newly diagnosed cancer who underwent breast MRI; for nearly 20 percent of these patients, additional malignant tumors were found by MRI which had not previously been discovered.
In Vivo EPR Programs
Electron Paramagnetic Resonance (EPR) spectroscopy is a technique for studying chemical species that have one or more unpaired electrons, such as organic and inorganic free radicals or inorganic complexes possessing a transition metal ion. The basic physical concepts of EPR are analogous to those of nuclear magnetic resonance (NMR) and MRI, but it is electron spins that are excited instead of spins of atomic nuclei. A number of unique capabilities for the measurement of physiologic parameters are available using EPR, including direct measurement of tissue pO2 through a repeatable non-invasive measurement procedure and the measurement of endogenous free-radical species. In vivo EPR oximetry, the central research activity of Dr. Swartz's EPR lab since inception in 1992, has a number of potentially valuable clinical applications. By means of accurate pO2 detection, EPR can be used to monitor oxygen level in a variety of tissue types. In tumors, hypoxia is associated with angiogenesis as well as with resistance to radiotherapy and chemotherapy; accurate assessment of changes in tumor pO2 can be used in cancer detection and staging, and in monitoring of therapeutic efficacy. Other types of vascular pathology are also associated with decreased tissueoxygen levels, such as the ischemia caused by peripheral vascular disease in diabetic patients and wound healing following radiation damage to normal tissues. EPR oximetry could provide information critical for effective clinical management of these and other oxygen-dependent pathologies and for the assessment of novel therapeutic measures.
Recently, the center has focused on the development of radiation biodosimetry techniques and devices. In a disaster scenario involving the accidental or hostile release of significant levels of ionizing radiation, public health officials remain without effective portable means of determining exposure levels in affected individuals, jeopardizing the ability to carry out appropriate triage strategies. During irradiation, free radicals are created in biologic tissues in proportion to the absorbed dose. In certain tissues, such as tooth enamel, bone, and nails, these radicals remain in a stable state following irradiation and their concentration can be quantitatively measured using EPR to estimate the dose. The center has received major funding from a number of NIH and DoD sources, including the NIH Centers for Medical Countermeasures Against Radiation (CMCR) program and the Defense Advanced Research Projects Agency (DARPA). As this report goes to press, the EPR Center awaits confirmation of an expected new $16.6 million five-year NIH grant for dosimetry research.
In Vivo Optical Spectroscopy
Associated with the EPR Center, Dr. Roger Springett's Redox Laboratory conducts independent research on the uses of visible light spectroscopy for imaging neural processes in the mammalian neocortex through the measurement of changes to mitochondrial oxygenation. Specifically, the current five-year NIH-funded program, Imaging the Mitochondrial Response to Neural Activity, seeks to develop and validate spectral domain imaging technology to collect and reconstruct images of the oxidation state of mitochondrial cytochrome, and of hemoglobin and extrinsic chromophore concentrations. Spectral domain imaging of mitochondrial oxygenation, presently unique to Dr. Springett's lab, has the potential to add significant understanding of the manner in which the cortex process information, and also offers the possibility of precise, non-invasive location of tumors and other metabolically significant structures during certain types of neurosurgery.
Dr. Weaver, Dr. Eskey, and the neuroradiology faculty continue collaborations—with the Dartmouth Brain Imaging Laboratory, the Advanced Imaging Center in projects including innovation in advanced 3T imaging in glioblastoma recurrence, fMRI imaging, MRI in pediatric head trauma, CTA in intracerebral hemorrhage and aneurysm evaluation, imaging of pharyngeal carcinoma, vertebroplasty, and synovial cyst rupture. In addition, the Thayer School, independently and in collaboration with DHMC departments such as Radiology and Psychiatry, has been active in a range of neuroimaging research, including: the development of dynamic multimodal imaging; fluorescence signatures for image-guided neurosurgery; and molecular imaging for the detection of glioma brain tumors.
The Radiology Research Committee, chaired by Dr. Belden (following several years of capable leadership by Dr. Harris), assists faculty, residents and fellows with clinical research guidance and seed grants made possible by the Radiology Chair. In the past 3 years, the committee (also including Drs. Eskey, Weaver, Swartz, and Black) has funded studies on: hemodialysis access outcomes and complications in the elderly; interventional radiology procedure in patients with abnormal coagulation parameters; thyroid nodule ultrasound characterization and differentiation of benign vs. malignant nodules (part of a multi-center trial); and interobserver variability of CTA aneurysm perception.