Irving N. Weinberg

High-Resolution Fluorodeoxyglucose Positron Emission Tomography with Compression (“Positron Emission Mammography”) is Highly Accurate in Depicting Primary Breast Cancer

Abstract:  We sought to prospectively assess the diagnostic performance of a high‐resolution positron emission tomography (PET) scanner using mild breast compression (positron emission mammography [PEM]). Data were collected on concomitant medical conditions to assess potential confounding factors. At four centers, 94 consecutive women with known breast cancer or suspicious breast lesions received 18F‐fluorodeoxyglucose (FDG) intravenously, followed by PEM scans. Readers were provided clinical histories and x‐ray mammograms (when available). After excluding inevaluable cases and two cases of lymphoma, PEM readings were correlated with histopathology for 92 lesions in 77 women: 77 index lesions (42 malignant), 3 ipsilateral lesions (3 malignant), and 12 contralateral lesions (3 malignant). Of 48 cancers, 16 (33%) were clinically evident; 11 (23%) were ductal carcinoma in situ (DCIS), and 37 (77%) were invasive (30 ductal, 4 lobular, and 3 mixed; median size 21 mm). PEM depicted 10 of 11 (91%) DCIS and 33 of 37 (89%) invasive cancers. PEM was positive in 1 of 2 T1a tumors, 4 of 6 T1b tumors, 7 of 7 T1c tumors, and 4 of 4 cases where tumor size was not available (e.g., no surgical follow‐up). PEM sensitivity for detecting cancer was 90%, specificity 86%, positive predictive value (PPV) 88%, negative predictive value (NPV) 88%, accuracy 88%, and area under the receiver‐operating characteristic curve (Az) 0.918. In three patients, cancer foci were identified only on PEM, significantly changing patient management. Excluding eight diabetic subjects and eight subjects whose lesions were characterized as clearly benign with conventional imaging, PEM sensitivity was 91%, specificity 93%, PPV 95%, NPV 88%, accuracy 92%, and Az 0.949 when interpreted with mammographic and clinical findings. FDG PEM has high diagnostic accuracy for breast lesions, including DCIS. 

Preliminary results for positron emission mammography: real-time functional breast imaging in a conventional mammography gantry

In order to optimally integrate radiotracer breast imaging within the breast clinic, anatomy and pathology should be easily correlated with functional nuclear medicine breast images. As a first step in the development of a hybrid functional/anatomic breast imaging platform with biopsy capability, a conventional X-ray mammography gantry was modified to image the compressed breast with positron emitters. Phantom studies with the positron emission mammography (PEM) device showed that a 1-cc hot spot could be detected within 5 min. A preliminary clinical trial demonstrated in vivo visualization of primary breast cancer within 4 min. For sites where positron-emitting radionuclides are available, PEM promises to achieve low-cost directed functional examination of breast abnormalities, with the potential for achieving X-ray correlation and image-guided biopsy.

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.

Tc-99m Sestamibi Scintimammography for the Evaluation of Breast Masses in Patients with Radiographically Dense Breasts.

Abstract: The objective of this study was to evaluate the usefulness of technetium‐99m sestamibi (MIBI) scintimammography for the diagnosis of breast cancer in patients with palpable breast masses that cannot be adequately evaluated by mammography due to the presence of radiographically dense breasts. At 5 minutes after intravenous injection of MIBI, scintimammograms were obtained in 80 patients who had grade 3 or 4 glandular density on mammograms and a palpable breast mass. Excisional biopsy or FNA biopsy was obtained in 68 lesions in 67 patients. Scintimammography (22 true positive, 4 false positive, 41 true negative, 1 false negative) resulted in a sensitivity of 95.6%, specificity 91.1%, positive predictive value 84.6%, and negative predictive value 97.6%. Mammography (19 true positive, 21 false positive, 24 true negative, 4 false negative) resulted in a sensitivity of 73.9%, specificity 53.3%, positive predictive value 44.7%, and negative predictive value 80%. MIBI scintimammography has a higher sensitivity and specificity than mammography in patients with radiographically dense breasts. It is useful as an adjunct to mammography in those patients with radiographically dense breasts for the characterization of palpable masses. Although sensitivity of mammography in this cohort was high, its specificity was significantly lower than scintimammography. If validated in prospective studies it could provide a safe way of avoiding a breast biopsy in patients with benign findings on clinical exam, mammography, and needle aspiration cytology.

Method for Combined FDG‐PET and Radiographic Imaging of Primary Breast Cancers

Abstract: The purpose of the study was to demonstrate the feasibility of a hybrid functional/anatomic breast imaging platform with biopsy capability for facilitating lesion detection and diagnosis. This platform consists of an investigative dedicated positron emission mammography (PEM) device mounted on a stereotactic X‐ray mammography system, permitting sequential acquisition of mammographic and emission images during a single breast compression. There is automatic coregistration of images from both modalities, and these results can be successfully correlated with histopathologic findings. The potential utility of functional images correlated to anatomic images would include noninvasively detecting clinically and radiographically occult cancers, assessing response to therapy, discriminating between benign and malignant breast masses, and ultimately reducing the number of invasive and costly surgical interventions. A spot‐digital mammogram and subsequent PEM image, collected over a 4‐minute period, were obtained in a single patient with the breast in compression after intravenous injection of (F‐18)‐2‐deoxy‐2‐fluoro‐D‐glucose (FDG) at the time of stereotactic biopsy. The authors conclude that FDG‐based lesion localization information may be combined with the lesion X‐ray attenuation characteristics using this common imaging platform.

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.