I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy.

I-SPY 2 (investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2) is a process targeting the rapid, focused clinical development of paired oncologic therapies and biomarkers. The framework is an adaptive phase II clinical trial design in the neoadjuvant setting for women with locally advanced breast cancer. I-SPY 2 is a collaborative effort among academic investigators, the National Cancer Institute, the US Food and Drug Administration, and the pharmaceutical and biotechnology industries under the auspices of the Foundation for the National Institutes of Health Biomarkers Consortium.

MRI methods for evaluating the effects of tyrosine kinase inhibitor administration used to enhance chemotherapy efficiency in a breast tumor xenograft model.

PURPOSE: To evaluate whether quantitative MRI parameters are sensitive to the effects of the tyrosine kinase inhibitor gefitinib and can discriminate between two different treatment protocols. MATERIALS AND METHODS: Untreated mice with BT474 breast tumor xenografts were characterized in a preliminary study. Subsequently, tumor volume, apparent diffusion coefficient (ADC), transendothelial permeability (K(ps)), and fractional plasma volume (fPV) were measured in three groups of mice receiving: 1) control vehicle for 10 days, or gefitinib as 2) a single daily dose for 10 days or 3) a 2-day pulsed dose. RESULTS: Gefitinib treatment resulted in significant tumor growth inhibition (pulsed: 439 +/- 93; daily: 404 +/- 53; control: 891 +/- 174 mm(3), P < 0.050) and lower cell density (pulsed: 0.15 +/- 0.01, daily: 0.17 +/- 0.01, control: 0.24 +/- 0.01, P < 0.050) after 9 days. Tumor ADC increased in treated groups but decreased in controls (P > 0.050). Tumor K(ps) decreased with pulsed treatment but rebounded afterwards and increased with daily treatment (P > 0.050). Tumor fPV increased in both treated groups, decreasing afterwards with pulsed treatment (P > 0.050). CONCLUSION: Quantitative MRI can provide a sensitive measure of gefitinib-induced tumor changes, potentially distinguish between treatment regimens, and may be useful for determining optimal treatment scheduling for enhancing chemotherapy delivery.

Menstrual cycle variation of apparent diffusion coefficients measured in the normal breast using MRI.

Recent investigations have shown that tumors may be distinguished from benign lesions in the breast based on differences in apparent diffusion coefficient (ADC) values. The goal of this study was to assess the magnitude of normal variations in the measured ADC of breast parenchyma during the menstrual cycle. Eight healthy female subjects were scanned once a week for 4 weeks, using a diffusion-weighted single-shot fast spin-echo (DW-SSFSE) sequence. The ADC of breast fibroglandular tissue was calculated for each woman at each time point. Results showed a trend of decreased ADC during the second week of the cycle, and increased ADC during the final week. However, no significant influence of menstrual cycle on breast ADC values was identified. The results of this study show that the normal fluctuation of breast ADC is relatively small, and the coefficient of variation was determined to be 5.5% for our group of volunteers during a menstrual cycle. Nonetheless, breast diffusion measurements for tumor differentiation and evaluation of treatment response should be interpreted with consideration of normal variability.

Vascularity assessment of breast lesions with gadolinium-enhanced MR imaging.

Gadolinium-enhanced MR imaging of the breast can be used to characterize both tumor morphology and vascularity. An empirical three-point method using high resolution three-dimensional MR imaging that combines high spatial resolution with an estimate of tumor pharmacokinetics is described. This technique appears to improve diagnostic specificity of breast MR imaging and may provide a noninvasive method of tumor characterization of prognostic value.

Challenges to interpretation of breast MRI.

This review describes the current knowledge and challenges of lesion interpretation with MRI of the breast according to different image interpretation strategies. Particular emphasis is given to patient- and tumor-related factors that influence image interpretation. The impacts of the menstrual cycle, prior surgery, radiation therapy, and chemotherapy are summarized. Particular enhancement features of ductal carcinoma in situ (DCIS) or invasive lobular carcinoma are described. Finally, an adequate diagnosis at MRI of the breast should take into account the results of the patient's history, physical examination, and all imaging tests performed before MRI. J. Magn. Reson. Imaging 2001;13:821-829.

Development, standardization, and testing of a lexicon for reporting contrast-enhanced breast magnetic resonance imaging studies.

The purpose of this study was to develop, standardize, and test reproducibility of a lexicon for reporting contrast-enhanced breast magnetic resonance imaging (MRI) examinations. To standardize breast MRI lesion description and reporting, seven radiologists with extensive breast MRI experience developed consensus on technical detail, clinical history, and terminology reporting to describe kinetic and architectural features of lesions detected on contrast-enhanced breast MR images. This lexicon adapted American College of Radiology Breast Imaging and Data Reporting System terminology for breast MRI reporting, including recommendations for reporting clinical history, technical parameters for breast MRI, descriptions for general breast composition, morphologic and kinetic characteristics of mass lesions or regions of abnormal enhancement, and overall impression and management recommendations. To test morphology reproducibility, seven radiologists assessed morphology characteristics of 85 contrast-enhanced breast MRI studies. Data from each independent reader were used to compute weighted and unweighted kappa (kappa) statistics for interobserver agreement among readers. The MR lexicon differentiates two lesion types, mass and non-mass-like enhancement based on morphology and geographical distribution, with descriptors of shape, margin, and internal enhancement. Lexicon testing showed substantial agreement for breast density (kappa = 0.63) and moderate agreement for lesion type (kappa = 0.57), mass margins (kappa = 0.55), and mass shape (kappa = 0.42). Agreement was fair for internal enhancement characteristics. Unweighted kappa statistics showed highest agreement for the terms dense in the breast composition category, mass in lesion type, spiculated and smooth in mass margins, irregular in mass shape, and both dark septations and rim enhancement for internal enhancement characteristics within a mass. The newly developed breast MR lexicon demonstrated moderate interobserver agreement. While breast density and lesion type appear reproducible, other terms require further refinement and testing to lead to a uniform standard language and reporting system for breast MRI. J. Magn. Reson. Imaging 2001;13:889-895.

MR imaging of the breast in patients with positive margins after lumpectomy: influence of the time interval between lumpectomy and MR imaging.

OBJECTIVE: Postsurgical contrast enhancement resulting from inflammatory changes at the site of surgery limits the accuracy of MR imaging of the breast in diagnosing residual breast cancer. This study was undertaken to evaluate the influence of the time interval between lumpectomy and MR imaging on the diagnosis of residual breast cancer. MATERIALS AND METHODS: Sixty-eight patients who had undergone excisional biopsy with positive resection margins underwent MR imaging for evaluation of residual breast cancer and possible breast conservation. Patients were retrospectively stratified according to the time interval between lumpectomy and MR imaging. Dynamic and morphologic enhancement features were used for lesion characterization. Imaging findings were correlated with results of histopathology. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for patients waiting 7, 14, 21, 28, 35, and 42 days after initial surgery before undergoing MR imaging of the breast. RESULTS: The time interval between lumpectomy and MR imaging of the breast had the greatest influence on the specificity and negative predictive value of MR imaging, increasing progressively over time. A plateau of highest values of 75% specificity and 86% negative predictive value was reached at 28 and 35 days after surgery, respectively. Although the sensitivity and positive predictive value showed smaller variations over time, peak values of 95% sensitivity and 92% positive predictive value were obtained at 35 and 28 days after surgery, respectively. CONCLUSION: We recommend scheduling patients with positive resection margins no earlier than 28 days after initial surgery for evaluation of residual cancer using MR imaging of the breast.

Dynamic high-spatial-resolution MR imaging of suspicious breast lesions: diagnostic criteria and interobserver variability.

OBJECTIVE: Our study was undertaken to develop diagnostic rules and to assess the reproducibility of dynamic and morphologic parameters for the characterization of suspicious breast lesions using dynamic high-spatial-resolution MR imaging. MATERIALS AND METHODS: Fifty-seven patients with suspicious mammographic or palpable findings underwent preoperative contrast-enhanced MR imaging of the breast using a three-time-point method of acquisition. Each lesion was prospectively analyzed by two independent radiologists for morphologic and visual dynamic enhancement characteristics. A classification and regression tree was used to examine the optimal order, cutoff points, and combination of imaging parameters to build a diagnostic rule separating benign from malignant lesions using histopathology findings as the standard of reference. Kappa statistics were used to determine observer variability. RESULTS: Among 23 benign and 34 malignant lesions (12 invasive, three ductal carcinoma in situ, and 19 mixed cancer), margin morphology (p = 0.001) and enhancement pattern (p = 0.001) were the most significant MR imaging findings for lesion characterization. Focal mass lesions were classified as malignant when spiculated margins or both the washout enhancement pattern and "nonsmooth" margins were present. Interobserver agreement was almost perfect for washout pattern and substantial for margin assessment. In the limited population tested retrospectively, the diagnostic rule yielded a sensitivity and positive predictive value of 97% each and a specificity and negative predictive value of 96% each. CONCLUSION: The washout enhancement pattern combined with lesion margin assessment on dynamic contrast-enhanced high-resolution MR imaging of the breast allows reproducible lesion characterization and may be a highly specific diagnostic tool.

Semi-automated analysis for MRI of breast tumors.

Magnetic resonance imaging (MRI) techniques have the potential to greatly improve breast cancer detection, diagnosis, and treatment. Currently, a major problem associated with breast MRI is the overwhelming amount of data acquired during an exam, and the time-intensive analysis required to evaluate the images. We have developed a software platform for semi-automated analysis to assess both the tumor extent and overall grade or severity based on our diagnostic criteria. In a test subset of over 50 patients, the automated program produced results more accurate overall than those measurements taken manually, with a reduction in time for analysis from approximately 45 minutes down to 5 minutes per patient study.

Vascularity assessment of breast lesions with gadolinium-enhanced MR imaging.

Gadolinium-enhanced MR imaging techniques can be used to assess both breast tumor morphology and vascularity. Pharmacokinetic models can be used to extract physiological parameters related to tumor vascularity from signal intensity-time curves. This article describes an empirical method, using three-point high resolution MR imaging, that also provides assessment of tumor vascularity. These techniques appear to improve diagnostic specificity of breast MR imaging and provide a noninvasive method for tumor characterization that may have prognostic value.

Technical aspects of breast magnetic resonance imaging.

The appropriate role for magnetic resonance imaging (MRI) as an adjunct technique to mammography in the detection, diagnosis, staging, and therapy management of breast cancer has been the subject of much current research. The clinical application determines the choice of imaging technique. Time restraints due to the rapid kinetics of contrast enhancement require that trade-offs be made between spatial and temporal resolution, with a resulting effect on sensitivity and specificity. This article discusses some general requirements and recommendations for breast MRI techniques, including dedicated radiofrequency coils, pulse sequence specifications and image quality considerations, fat-suppression techniques, methods of contrast administration, and image postprocessing and interpretation.

Imaging techniques for breast MR imaging.

Specialized rf coils and pulse sequence techniques for contrast-enhanced breast imaging have been a focus of recent attention in MR imaging research. The imaging strategies for maximizing sensitivity and specificity involve trade-offs between spatial and temporal resolution. This article discusses these issues and others, such as considerations for coil design, fat suppression, patient positioning, motion artifact reduction, and methods for quantitative measurement of dynamic contrast enhancement.

Impact of section doubling on MR angiography.

To improve the quality of projection angiograms generated from three-dimensional magnetic resonance (MR) angiography data, the authors applied voxel shifting to create intermediate sections ("section doubling") prior to maximum intensity projection. To date, the authors have processed MR angiography studies with and without section doubling in 20 cases. Section doubling resulted in improved vessel contrast and delineation of continuity (especially of small vessels) in all cases.

Oblique reformatting of multislice magnetic resonance images for improved visualization of coronary arteries.

A technique for reformatting multislice magnetic resonance images into arbitrary oblique planes has been developed and implemented on a Toshiba MRT-35 (formerly Diasonics MT/S) imaging system (South San Francisco, CA). This method is designed to allow the user to easily define a new plane by marking with a cursor features of interest on two or three different image levels. These features are combined in the resulting oblique image. The reformatted image can have arbitrary angulation and is created with a pixel dimension equivalent to the original data set. Resolution ranges from the original in-plane resolution to the slice thickness, depending on angulation. An improvement in signal-to-noise ratio results from the effective averaging performed by interpolation. This method is optimally used to correct for small variations in alignment, such as the positioning of the intervertebral disks. It can also be used to generate reformatted images at many different angles from a single multislice data set. This method has been applied to the particular problem of improving the presentation of coronary arteries on a conventional set of multislice spin-echo cardiac images by increasing the visible length of individual coronary segments.

Echo-planar pediatric imager.

Practical constraints make it difficult to build large-aperture echo-planar magnetic resonance (MR) imagers. The implementation of a pediatric imager and its performance are described. Spatial resolution and signal-to-noise levels comparable to those of 1982 state-of-the-art MR imagers have been achieved in imaging times of 0.05-0.15 seconds. T1 and T2 information are obtainable in the echo-planar mode. A major issue is that of chemical-shift displacements.

The value of relaxation times and density measurements in clinical MRI.

The hope that MRI relaxation time signatures would identify tissues, specifically, malignancies, has not been realized. This is due much less to measurement inaccuracies than to a large intrinsic variability and overlaps between malignancies and many benign pathologies. Neither has there been success in predicting relaxation times from basic tissue compositions. Nevertheless, MRI provides a qualitative measure of tissue hydration, and of flow, on the basis of relaxation times. Furthermore, pixel-by-pixel maps of relaxation times have proven useful in understanding the MRI process, in predicting the efficacy of untried techniques, and replace, in many circumstances, the need for acquisition of images with diverse sequencing parameters.

Partial flip angle MR imaging.

Theoretical analysis predicts that performing magnetic resonance (MR) imaging with partial (less than 90 degrees) flip angles can reduce imaging times two- to fourfold when lesions with elevated T1 values are being examined. This time savings occurs because repetition time (TR) is reduced when imaging is performed with partial flips. Partial flip MR imaging can also improve signal-to-noise ratio (S/N) in fast body imaging. For this study, analytical tools were used to predict image contrast and S/N for short TR, partial flip sequences. Experimental implementation of the short TR, partial flip sequences that analytical work had predicted would be optimal supported the analytical predictions and demonstrated their validity. Partial flip MR imaging is applicable to reducing imaging time only when the ratio of signal differences to noise exceeds threshold values in conventional MR images. Partial flip sequences can be used to advantage in MR imaging of both the head and the body, and the observed effects are predictable through theoretical analysis.