Pavel Y. Stepanov

Positron emission mammography: initial clinical results.

Background: Evaluation of high-risk mammograms represents an enormous clinical challenge. Functional breast imaging coupled with mammography (positron emission mammography [PEM]) could improve imaging of such lesions. A prospective study was performed using PEM in women scheduled for stereotactic breast biopsy.Methods: Patients were recruited from the surgical clinic. Patients were injected with 10 mCi of 2-[18F] fluorodeoxyglucose. One hour later, patients were positioned on the stereotactic biopsy table, imaged with a PEM scanner, and a stereotactic biopsy was performed. Imaging was reviewed and compared with pathologic results.Results: There were 18 lesions in 16 patients. PEM images were analyzed by drawing a region of interest at the biopsy site and comparing the count density in the region of interest with the background. A lesion-to-background ratio >2.5 appeared to be a robust indicator of malignancy and yielded a sensitivity of 86%, specificity of 91%, and overall diagnostic accuracy of 89%. No adverse events were associated with the PEM imaging.Conclusions: The data show that PEM is safe, feasible, and has an encouraging accuracy rate in this initial experience. Lesion-to-background ratios >2.5 were found to be a useful threshold value for identifying positive (malignant) results. This study supports the further development of PEM.

Positron Emission Mammography: High-Resolution Biochemical Breast Imaging:

Positron emission mammography (PEM) provides images of biochemical activity in the breast with spatial resolution matching individual ducts (1.5 mm full-width at half-maximum). This spatial resolution, supported by count efficiency that results in high signal-to-noise ratio, allows confident visualization of intraductal as well as invasive breast cancers. Clinical trials with a full-breast PEM device have shown high clinical accuracy in characterizing lesions identified as suspicious on the basis of conventional imaging or physical examination (sensitivity 93%, specificity 83%, area under the ROC curve of 0.93), with high sensitivity preserved (91%) for intraductal cancers. Increased sensitivity did not come at a cost of reduced specificity. Considering that intraductal cancer represents more than 30% of reported cancers, and is the form of cancer with the highest probability of achieving surgical cure, it is likely that the use of PEM will complement anatomic imaging modalities in the areas of surgical planning, high-risk monitoring, and minimally invasive therapy. The quantitative nature of PET promises to assist researchers interested studying the response of putative cancer precursors (e.g., atypical ductal hyperplasia) to candidate prevention agents.

Open challenges in magnetic drug targeting

The principle of magnetic drug targeting, wherein therapy is attached to magnetically responsive carriers and magnetic fields are used to direct that therapy to disease locations, has been around for nearly two decades. Yet our ability to safely and effectively direct therapy to where it needs to go, for instance to deep tissue targets, remains limited. To date, magnetic targeting methods have not yet passed regulatory approval or reached clinical use. Below we outline key challenges to magnetic targeting, which include designing and selecting magnetic carriers for specific clinical indications, safely and effectively reaching targets behind tissue and anatomical barriers, real-time carrier imaging, and magnet design and control for deep and precise targeting. Addressing these challenges will require interactions across disciplines. Nanofabricators and chemists should work with biologists, mathematicians, and engineers to better understand how carriers move through live tissues and how to optimize carrier and magnet designs to better direct therapy to disease targets. Clinicians should be involved early on and throughout the whole process to ensure the methods that are being developed meet a compelling clinical need and will be practical in a clinical setting. Our hope is that highlighting these challenges will help researchers translate magnetic drug targeting from a novel concept to a clinically available treatment that can put therapy where it needs to go in human patients.

Increasing the oscillation frequency of strong magnetic fields above 101 kHz significantly raises peripheral nerve excitation thresholds

PURPOSE A time-varying magnetic field can cause unpleasant peripheral nerve stimulation (PNS) when the maximum excursion of the magnetic field (ΔB) is above a frequency-dependent threshold level [P. Mansfield and P. R. Harvey, Magn. Reson. Med. 29, 746-758 (1993)]. Clinical and research magnetic resonance imaging (MRI) gradient systems have been designed to avoid such bioeffects by adhering to regulations and guidelines established on the basis of clinical trials. Those trials, generally employing sinusoidal waveforms, tested human responses to magnetic fields at frequencies between 0.5 and 10 kHz [W. Irnich and F. Schmitt, Magn. Reson. Med. 33, 619-623 (1995), T. F. Budinger et al., J. Comput. Assist. Tomogr. 15, 909-914 (1991), and D. J. Schaefer et al., J. Magn. Reson. Imaging 12, 20-29 (2000)]. PNS thresholds for frequencies higher than 10 kHz had been extrapolated, using physiological models [J. P. Reilly et al., IEEE Trans. Biomed. Eng. BME-32(12), 1001-1011 (1985)]. The present study provides experimental data on human PNS thresholds to oscillating magnetic field stimulation from 2 to 183 kHz. Sinusoidal waveforms were employed for several reasons: (1) to facilitate comparison with earlier reports that used sine waves, (2) because prior designers of fast gradient hardware for generalized waveforms (e.g., including trapezoidal pulses) have employed quarter-sine-wave resonant circuits to reduce the rise- and fall-times of pulse waveforms, and (3) because sinusoids are often used in fast pulse sequences (e.g., spiral scans) [S. Nowak, U.S. patent 5,245,287 (14 September 1993) and K. F. King and D. J. Schaefer, J. Magn. Reson. Imaging 12, 164-170 (2000)]. METHODS An IRB-approved prospective clinical trial was performed, involving 26 adults, in which one wrist was exposed to decaying sinusoidal magnetic field pulses at frequencies from 2 to 183 kHz and amplitudes up to 0.4 T. Sham exposures (i.e., with no magnetic fields) were applied to all subjects. RESULTS For 0.4 T pulses at 2, 25, 59, 101, and 183 kHz, stimulation was reported by 22 (84.6%), 24 (92.3%), 15 (57.7%), 2 (7.7%), and 1 (3.8%) subjects, respectively. CONCLUSIONS The probability of PNS due to brief biphasic time-varying sinusoidal magnetic fields with magnetic excursions up to 0.4 T is shown to decrease significantly at and above 101 kHz. This phenomenon may have particular uses in dynamic scenarios (e.g., cardiac imaging) and in studying processes with short decay times (e.g., electron paramagnetic resonance imaging, bone and solids imaging). The study suggests the possibility of new designs for human and preclinical MRI systems that may be useful in clinical practice and scientific research.

Dynamic inversion enables external magnets to concentrate ferromagnetic rods to a central target.

The ability to use magnets external to the body to focus therapy to deep tissue targets has remained an elusive goal in magnetic drug targeting. Researchers have hitherto been able to manipulate magnetic nanotherapeutics in vivo with nearby magnets but have remained unable to focus these therapies to targets deep within the body using magnets external to the body. One of the factors that has made focusing of therapy to central targets between magnets challenging is Samuel Earnshaw’s theorem as applied to Maxwell’s equations. These mathematical formulations imply that external static magnets cannot create a stable potential energy well between them. We posited that fast magnetic pulses could act on ferromagnetic rods before they could realign with the magnetic field. Mathematically, this is equivalent to reversing the sign of the potential energy term in Earnshaw’s theorem, thus enabling a quasi-static stable trap between magnets. With in vitro experiments, we demonstrated that quick, shaped magnetic pulses can be successfully used to create inward pointing magnetic forces that, on average, enable external magnets to concentrate ferromagnetic rods to a central location.

Applications of a PET device with 1.5 mm FWHM intrinsic spatial resolution to breast cancer imaging

Operation of a high resolution compact clinical PET Scanner (PEM Flex/spl trade/) device as a breast scanner is described. The device features high spatial resolution (1.5 mm FWHM intrinsic resolution) as a result of small crystals and compact position-sensitive photomultipliers. The compactness of the system allows it to reside within a stereotactic X-ray mammography unit, or as a separate standalone system capable of breast compression. The gamma rays are detected for a volumetric reconstruction by two heads, each of which contains 2,028 2 mm by 2 mm by 10 mm lutetium-containing crystals. The heads travel within X-ray transparent compression paddles. A window is provided in one of the paddles for direct correlation with ultrasound transducers and for interventional access. To enable real-time interventions, images are reconstructed and displayed while the detectors are still acquiring data. The maximum-likelihood reconstruction provides quantitative images with threefold improved contrast as compared to simple back-projections.

Goodbye wires and formers: 3-D additive manufacturing and fractal cooling applied to construction of MRI gradient coils

The high pulse frequencies employed in MRI gradient and RF coils call for the use of dedicated construction techniques involving special wires and cooling systems. These requirements are needed because conventional (e.g., solid-core) wires exhibit skin effects at frequencies above 10 kHz, which effectively concentrate all the current in the periphery of the wire, leading to heating losses due to high resistance. To mitigate the resistance problem due to skin-depth, many gradient coils (and some RF coils) employ cords of twisted and/or woven thin insulated wires (e.g., Litz wires) that force currents to traverse the entire wire cross-section. Litz wires are hard to configure into the complex designs required for gradient coils, due to a minimum turning radius of several millimeters and the asymmetric bending forces required for winding the wires onto formers. Another challenge in MRI gradient coil manufacturing is the ability to cool RF and gradient coils, especially at high pulse rates. Our approach to this problem has been to replace traditional wire-coil construction methodology with multi-layer additive manufacturing methods, which lend themselves to design and manufacture automation. Additive manufacturing can enable dramatic (i.e., nearly three-fold) improvement in cooling efficiency, through the use of bio-mimetic fractal approaches. Building gradient and/or RF coils layer by layer, we have added conductive, insulating and cooling elements with appropriate interconnects as necessary. A prototype multi-layer Litz wire structure was developed, with fractal cooling, which showed superior performance (in terms of 80% reduced resistive losses at high frequency) to the comparable non-Litz wire configuration.

Design and additive manufacturing of MRI gradient coils

The current manufacturing process of MRI gradient coils is a lengthy process because of material property requirements that address high voltages and currents, and complex 3D geometries (necessary to achieve desired gradient profiles and high magnetic field strengths). To address these requirements we developed software and fast 3D printer technology that automates the design, optimization, and manufacturing of these gradient coils. Our design software applies the principles of 3D printing (rapid prototyping) to control the gradient coil manufacturing process. Our 3D printer is the first printer to combine electrical conductors (e.g. silver) and high-grade electrical insulators (e.g., Kapton) for manufacturing MRI gradient coils. We have applied the additive manufacturing (3D printing) methods to the design and manufacturing of ultra-strong and ultra-fast (rise time ≤ 10 μs) magnetic gradient coils for high-performance magnetic resonance imaging (MRI) systems. Experiments with bi-planar 3D-printed gradient coils installed in a tabletop MRI system (0.34 T) show that we can get images with in-plane resolution of 50 μm and good image signal-to-noise in seconds using fast pulse sequences (fast gradient echo).

Neurostimulation using mechanical motion of magnetic particles wiggled by external oscillating magnetic gradients

Delivery and control of untethered neuronal stimulation devices deep in the brain is currently difficult to perform and control with cell-level spatial resolution, but would be useful in both research and clinical applications. Magnetic particles can be noninvasively delivered with high precision to deep structures through dynamic magnetic inversion. This article demonstrates in an invertebrate animal that neuronal stimulation can be achieved using mechanical vibration of implanted particles, in which the vibration is realized through an externally-applied magnetic field under MRI guidance. Potential eventual applications of the technology include stimulation and modulation of the deep brain or peripheral neurons, using wearable electromagnetic coils for control and activation.

Improvement of energy resolution in Geiger-mode APD arrays using curve-fitting of signal decay

A method is presented to improve the energy resolution of scintillators read out with Geiger-mode avalanche photodiode arrays. The method employs digital signal processing, in which individual decay curves for gamma-ray detection events are digitized and then fitted to analytical functions whose amplitude provides energy information. Simulation studies suggest that after-pulses represent the largest source of energy resolution loss, which can be improved with curve-fitting. An experimental measurement confirmed that energy resolution could be improved with least-square curve-fits to a simple exponential model.