Roberta DiFlorio-Alexander

In vivo quantitative imaging of normal and cancerous breast tissue using broadband diffuse optical tomography

PURPOSE A NIR tomography system that combines frequency domain (FD) and continuous wave (CW) measurements was used to image normal and malignant breast tissues. METHODS FD acquisitions were confined to wavelengths less than 850 nm because of detector limitations, whereas light from longer wavelengths (up to 948 nm) was measured in CW mode with CCD-coupled spectrometer detection. The two data sets were combined and processed in a single spectrally constrained reconstruction to map concentrations of hemoglobin, water, and lipid, as well as scattering parameters in the breast. RESULTS Chromophore concentrations were imaged in the breasts of nine asymptomatic volunteers to evaluate their intrasubject and intersubject variability. Normal subject data showed physiologically expected trends. Images from three cancer patients indicate that the added CW data is critical to recovering the expected increases in water and decreases in lipid content within malignancies. Contrasts of 1.5 to twofold in hemoglobin and water values were found in cancers. CONCLUSIONS In vivo breast imaging with instrumentation that combines FD and CW NIR data acquisition in a single spectral reconstruction produces more accurate hemoglobin, water, and lipid results relative to FD data alone.

Predicting Breast Tumor Response to Neoadjuvant Chemotherapy with Diffuse Optical Spectroscopic Tomography prior to Treatment

Purpose: To determine whether pretreatment biomarkers obtained from diffuse optical spectroscopic tomographic (DOST) imaging predicts breast tumor response to neoadjuvant chemotherapy (NAC), which would have value to potentially eliminate delays in prescribing definitive local regional therapy that may occur from a standard complete 6- to 8-month course of NAC. Experimental Design: Nineteen patients undergoing NAC were imaged with DOST before, during, and after treatment. The DOST images of total hemoglobin concentration (HbT), tissue oxygen saturation (StO2), and water (H2O) fraction at different time points have been used for testing the abilities of differentiating patients having pathologic complete response (pCR) versus pathologic incomplete response (pIR). Results: Significant differences (P < 0.001, AUC = 1.0) were found between pCR patients versus pIR in outcome, based on the percentage change in tumor HbT within the first cycle of treatment. In addition, pretreatment tumor HbT (pretreatment HbT) relative to the contralateral breast was statistically significant (P = 0.01, AUC = 0.92) in differentiating pCR from pIR. Conclusions: This is the first clinical evidence that DOST HbT may differentiate the two groups with predictive significance based on data acquired before NAC even begins. The study also demonstrates the potential of accelerating the validation of optimal NAC regimens through future randomized clinical trials by reducing the number of patients required and the length of time they need to be followed by using a validated imaging surrogate as an outcome measure. Clin Cancer Res; 20(23); 6006–15. ©2014 AACR.

Adaptable Near-Infrared Spectroscopy Fiber Array for Improved Coupling to Different Breast Sizes During Clinical MRI

RATIONALE AND OBJECTIVES Near-infrared spectroscopy (NIRS) of breast can provide functional information on the vascular and structural compartments of tissues in regions identified during simultaneous magnetic resonance imaging (MRI). NIRS can be acquired during dynamic contrast-enhanced MRI (DCE-MRI) to accomplish image-guided spectroscopy of the enhancing regions, potentially increasing the diagnostic specificity of the examination and reducing the number of biopsies performed as a result of inconclusive MRI breast imaging studies. MATERIALS AND METHODS We combine synergistic attributes of concurrent DCE-MRI and NIRS with a new design of the clinical NIRS breast interface that couples to a standard MR breast coil and allows imaging of variable breast sizes. Spectral information from healthy volunteers and cancer patients is recovered, providing molecular information in regions defined by the segmented MR image volume. RESULTS The new coupling system significantly improves examination utility by allowing improved coupling of the NIR fibers to breasts of all cup sizes and lesion locations. This improvement is demonstrated over a range of breast sizes (cup size A through D) and normal tissue heterogeneity using a group of eight healthy volunteers and two cancer patients. Lesions located in the axillary region and medial-posterior breast are now accessible to NIRS optodes. Reconstructed images were found to have biologically plausible hemoglobin content, oxygen saturation, and water and lipid fractions. CONCLUSIONS In summary, a new NIRS/MRI breast interface was developed to accommodate the variation in breast sizes and lesion locations that can be expected in clinical practice. DCE-MRI-guided NIRS quantifies total hemoglobin, oxygenation, and scattering in MR-enhancing regions, increasing the diagnostic information acquired from MR examinations.

Remote positioning optical breast magnetic resonance coil for slice-selection during image-guided near-infrared spectroscopy of breast cancer

The design and testing of a pneumatic optical positioning interface produced with the goal of improving fiber positioning in magnetic resonance (MR)-guided diffuse spectral imaging of breast cancer is presented. The system was created for vertical positioning of optical fibers inside the MR bore during a patient exam to target suspicious lesions with MR scans for reference and collect multiple planes of optical data. The interface includes new fiber plates for mechanical and optical coupling to the breast, and was tested in phantoms and human imaging. Reconstructions with data taken in the new interface show acceptable linearity over different absorber concentrations (residual norm = 0.067), and exhibit good contrast recovery at different imaging planes, which is consistent with previous work. An example of human breast imaging through the new interface is shown and a discussion of how it compares to other patient interfaces for breast imaging is presented. Design goals of increasing the available degrees of freedom for fiber positioning while maintaining good patient-fiber contact and comfort were accomplished. This interface allows improved volumetric imaging with interactive and accurate slice selection to quantify targeted suspicious lesions.

Real-Time Electrical Impedance Variations in Women With and Without Breast Cancer

The chaotic vascular network surrounding malignant tumors leads to pulsatile blood flow patterns that differ from those in benign regions of the breast. This study aimed to determine if high-speed electrical impedance tomography (EIT) is able to detect conductivity changes associated with cyclic blood-volume changes and to gauge the potential of using these signatures to differentiate malignant from benign regions within the breast. EIT imaging of pulsating latex membranes submerged in saline baths provided initial validation of its use for tracking temporally varying conductivities. Nineteen women (10 with cancer, nine without) were imaged with EIT over the course of several heartbeats in synchrony with pulse-oximetry acquisition. Eight parameters (rs, φ(rt,max), rt,max, Plow:full, Phigh:full, Plow:high) relating the conductivity images and pulse-oximeter signatures were extracted and used as a means of comparing malignant and benign regions of the breast. Significant differences between malignant and benign regions of interest were noted in seven of the eight parameters. The maximum correlation between conductivity and pulse-oximeter signals, rt,max, was observed to be the optimal discriminating parameter with a receiver operating characteristic area under the curve of 0.8 and a specificity of 81% at a sensitivity of 77%. Assessing the dynamic conductivity of breast may provide additional clinical utility to that of standard imaging modalities, but further investigation is necessary to better understand the biophysical mechanisms leading to the observed conductivity changes.

Breast MRI-detected cystic apocrine metaplasia: imaging features with microvessel analysis and histologic correlation.

OBJECTIVE The purpose of this article is to characterize the histologic vascular features and distinguishing MRI features of cystic apocrine metaplasia to better understand imaging-pathology concordance. MATERIALS AND METHODS Retrospective review of 261 consecutive MRI-guided biopsy cases was performed. Pathology results were reviewed for all biopsies; cystic apocrine metaplasia was identified as the predominant finding in 19 cases (7%). CD31 immunohistochemistry was subsequently performed on the most representative block of cystic apocrine metaplasia, and microvasculature was evaluated using computer-assisted image analysis. The contrast-enhanced MRI examinations correlating with the cystic apocrine metaplasia cases were independently reviewed by two radiologists specializing in breast imaging; lesions were analyzed for morphologic, kinetic, and T2 characteristics. RESULTS On MRI review, 17 of 19 (89%) lesions were 10 mm or smaller. Washout kinetics were present in 11 of 19 (58%) lesions, and 14 of 19 (74%) lesions were at least partially hyperintense on T2-weighted sequences relative to adjacent glandular tissue. Cystic apocrine metaplasia had a higher percentage area (mean, 4.1%) of CD31-immunostained microvessels compared with background fibroglandular tissue (mean, 1.2%). CONCLUSION Cystic apocrine metaplasia should be considered in the differential diagnosis of a T2-hyperintense enhancing focus or subcentimeter smoothly marginated mass, even if associated with washout kinetics. Cystic apocrine metaplasia contains a statistically significant increase in microvessel area compared with background fibroglandular tissue and fat and, therefore, may be considered a concordant result for this set of imaging findings.

Portable, parallel 9-wavelength near-infrared spectral tomography (NIRST) system for efficient characterization of breast cancer within the clinical oncology infusion suite.

A portable near-infrared spectral tomography (NIRST) system was developed with simultaneous frequency domain (FD) and continuous-wave (CW) optical measurements for efficient characterization of breast cancer in a clinical oncology setting. Simultaneous FD and CW recordings were implemented to speed up acquisition to 3 minutes for all 9 wavelengths, spanning a range from 661nm to 1064nm. An adjustable interface was designed to fit various breast sizes and shapes. Spatial images of oxy- and deoxy-hemoglobin, water, lipid, and scattering components were reconstructed using a 2D FEM approach. The system was tested on a group of 10 normal subjects, who were examined bilaterally and the recovered optical images were compared to radiographic breast density. Significantly higher total hemoglobin and water were estimated in the high density relative to low density groups. One patient with invasive ductal carcinoma was also examined and the cancer region was characterized as having a contrast ratio of 1.4 in total hemoglobin and 1.2 in water.

Automatic and robust calibration of optical detector arrays for biomedical diffuse optical spectroscopy

The design and testing of a new, fully automated, calibration approach is described. The process was used to calibrate an image-guided diffuse optical spectroscopy system with 16 photomultiplier tubes (PMTs), but can be extended to any large array of optical detectors and associated imaging geometry. The design goals were accomplished by developing a routine for robust automated calibration of the multi-detector array within 45 minutes. Our process was able to characterize individual detectors to a median norm of the residuals of 0.03 V for amplitude and 4.4 degrees in phase and achieved less than 5% variation between all the detectors at the 95% confidence interval for equivalent measurements. Repeatability of the calibrated data from the imaging system was found to be within 0.05 V for amplitude and 0.2 degrees for phase, and was used to evaluate tissue-simulating phantoms in two separate imaging geometries. Spectroscopic imaging of total hemoglobin concentration was recovered to within 5% of the true value in both cases. Future work will focus on streamlining the technology for use in a clinical setting with expectations of achieving accurate quantification of suspicious lesions in the breast.

Combined Three-Dimensional Magnetic Resonance Guided Optical Spectroscopy for Functional and Molecular Imaging of Human Breast Cancer

Dynamic contrast enhanced magnetic resonance is used to image high-risk patients for breast cancer because of its higher sensitivity to tumors than mammography. We focus on Near Infrared Spectroscopy (NIRS) imaging and Fluorescence Molecular Tomography (FMT), emerging imaging techniques that non-invasively quantify optical properties of total hemoglobin, oxygen saturation, water content, scattering, lipid concentration and endogenous Protoporphyrin IX (PpIX) emission. We present methods on combining the synergistic attributes of DCE-MR, NIRS, and FMT for in-vivo imaging of breast cancer in three dimensions using a custom optical MR breast coil and diffusion based light modeling software, NIRFAST. We present example results from a breast cancer patient. Preliminary results show elevated hemoglobin values and water fraction. Fluorescence values in the tumor region, however, were not always elevated above the surrounding tissue as we had expected. The additional information gained from NIRS and FMT may improve the ability to distinguish between malignant and benign lesions during MR imaging. These dual modality instruments will provide complex anatomical and molecular prognostic information, and may decrease the number of biopsies, thereby improving patient care.

Absolute calibration for complex-geometry biomedical diffuse optical spectroscopy

We have presented methodology to calibrate data in NIRS/MRI imaging versus an absolute reference phantom and results in both phantoms and healthy volunteers. This method directly calibrates data to a diffusion-based model, takes advantage of patient specific geometry from MRI prior information, and generates an initial guess without the need for a large data set. This method of calibration allows for more accurate quantification of total hemoglobin, oxygen saturation, water content, scattering, and lipid concentration as compared with other, slope-based methods. We found the main source of error in the method to be derived from incorrect assignment of reference phantom optical properties rather than initial guess in reconstruction. We also present examples of phantom and breast images from a combined frequency domain and continuous wave MRI-coupled NIRS system. We were able to recover phantom data within 10% of expected contrast and within 10% of the actual value using this method and compare these results with slope-based calibration methods. Finally, we were able to use this technique to calibrate and reconstruct images from healthy volunteers. Representative images are shown and discussion is provided for comparison with existing literature. These methods work towards fully combining the synergistic attributes of MRI and NIRS for in-vivo imaging of breast cancer. Complete software and hardware integration in dual modality instruments is especially important due to the complexity of the technology and success will contribute to complex anatomical and molecular prognostic information that can be readily obtained in clinical use.