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Purpose: The authors introduce a state-of-the-art all-optical clinical diffuse optical tomography (DOT) imaging instrument which collects spatially dense, multispectral, frequency-domain breast data in the parallel-plate geometry. Methods: The instrument utilizes a CCD-based heterodyne detection scheme that permits massively parallel detection of diffuse photon density wave amplitude and phase for a large number of source–detector pairs (106). The stand-alone clinical DOT instrument thus offers high spatial resolution with reduced crosstalk between absorption and scattering. Other novel features include a fringe profilometry system for breast boundary segmentation, real-time data normalization, and a patient bed design which permits both axial and sagittal breast measurements. Results: The authors validated the instrument using tissue simulating phantoms with two different chromophore-containing targets and one scattering target. The authors also demonstrated the instrument in a case study breast cancer patient; the reconstructed 3D image of endogenous chromophores and scattering gave tumor localization in agreement with MRI. Conclusions: Imaging with a novel parallel-plate DOT breast imager that employs highly parallel, high-resolution CCD detection in the frequency-domain was demonstrated.

The authors introduce a state-of-the-art all-optical clinical diffuse optical tomography (DOT) imaging instrument which collects spatially dense, multispectral, frequency-domain breast data in the parallel-plate geometry.The instrument utilizes a CCD-based heterodyne detection scheme that permits massively parallel detection of diffuse photon density wave amplitude and phase for a large number of source-detector pairs (10(6)). The stand-alone clinical DOT instrument thus offers high spatial resolution with reduced crosstalk between absorption and scattering. Other novel features include a fringe profilometry system for breast boundary segmentation, real-time data normalization, and a patient bed design which permits both axial and sagittal breast measurements.The authors validated the instrument using tissue simulating phantoms with two different chromophore-containing targets and one scattering target. The authors also demonstrated the instrument in a case study breast cancer patient; the reconstructed 3D image of endogenous chromophores and scattering gave tumor localization in agreement with MRI.Imaging with a novel parallel-plate DOT breast imager that employs highly parallel, high-resolution CCD detection in the frequency-domain was demonstrated.

Diffuse optical imaging (DOI) is a noninvasive optical technique that employs near-infrared (NIR) light to quantitatively characterize the optical properties of thick tissues. Although NIR methods were first applied to breast transillumination (also called diaphanography) nearly 80 years ago, quantitative DOI methods employing time- or frequency-domain photon migration technologies have only recently been used for breast imaging (i.e., since the mid-1990s). In this review, the state of the art in DOI for breast cancer is outlined and a multi-institutional Network for Translational Research in Optical Imaging (NTROI) is described, which has been formed by the National Cancer Institute to advance diffuse optical spectroscopy and imaging (DOSI) for the purpose of improving breast cancer detection and clinical management. DOSI employs broadband technology both in near-infrared spectral and temporal signal domains in order to separate absorption from scattering and quantify uptake of multiple molecular probes based on absorption or fluorescence contrast. Additional dimensionality in the data is provided by integrating and co-registering the functional information of DOSI with x-ray mammography and magnetic resonance imaging (MRI), which provide structural information or vascular flow information, respectively. Factors affecting DOSI performance, such as intrinsic and extrinsic contrast mechanisms, quantitation of biochemical components, image formation/visualization, and multimodality co-registration are under investigation in the ongoing research NTROI sites. One of the goals is to develop standardized DOSI platforms that can be used as stand-alone devices or in conjunction with MRI, mammography, or ultrasound. This broad-based, multidisciplinary effort is expected to provide new insight regarding the origins of breast disease and practical approaches for addressing several key challenges in breast cancer, including: Detecting disease in mammographically dense tissue, distinguishing between malignant and benign lesions, and understanding the impact of neoadjuvant chemotherapies.

We acquire and compare three-dimensional tomographic breast images of three females with suspicious masses using diffuse optical tomography (DOT) and positron emission tomography (PET). Co-registration of DOT and PET images was facilitated by a mutual information maximization algorithm. We also compared DOT and whole-body PET images of 14 patients with breast abnormalities. Positive correlations were found between total hemoglobin concentration and tissue scattering measured by DOT, and fluorodeoxyglucose (18F-FDG) uptake. In light of these observations, we suggest potential benefits of combining both PET and DOT for characterization of breast lesions.

We employ diffuse optical tomography (DOT) to track treatment progress in a female subject presenting with locally advanced invasive carcinoma of the breast during neoadjuvant chemotherapy. Three-dimensional images of total hemoglobin concentration and scattering identified the tumor. Our measurements reveal tumor shrinkage during the course of chemotherapy, in reasonable agreement with magnetic resonance images of the same subject. A decrease in total hemoglobin concentration contrast between tumor and normal tissue was also observed over time. The results demonstrate the potential of DOT for measuring physiological parameters of breast lesions during chemotherapy.

Purpose: To investigate the variation in blood flow during PDT and to determine the oxygen supplying rate, g, to refine the empirical macroscopic model. Methods: RIF tumors were propagated in female C3H mice by injecting cell suspension at a concentration of 1×106 cells/ml on the shoulder region. Photosensitizer(e.g., HPPH) was injected into the mice through tail vein at a concentration of 0.25 mg/kg when the tumors grew to ∼6 mm in diameter and depth. Temporal changes of tissue oxygen concentration were recorded prior, during and post PDT treatment using OxyLite single-channel tissue pO2 monitor(OXFORD OPTRONIX). [3O2] was approximated by multiplying the measured pO2 with 3O2 solubility in tissue(1.295 µM/mmHg). The experimental [3O2] profile were compared with those simulated with the macroscopic model with and without considering the blood flow changes. The dynamical change of blood flow during PDT was simulated by making parameter g to be time dependent, in which the g function was obtained from Photofrin-mediated PDT in RIF tumors. The relative blood flow changes in the tumors prior, during and post PDT treatment were measured using diffuse correlation spectroscopy (DCS) in a non-contact configuration. Results: Both macroscopic models, with and without blood flow changes, show reasonably good agreement with the experimental [3O2] measurements. However, a rapid increase in the measured [3O2] between 700–1200s during PDT treatment could not be simulated with our empirical models. As blood flow is the direct measure of tissue oxygen supply and different photosensitizers might impact the blood flow differently, detailed studies are essential to investigate the variation in blood flow changes and the impact on the [3O2] consumption using different photosensitizers. Conclusion: DCS can be used to monitor relative blood flow noninvasively. The continuous input of oxygen supply rate is essential to refine our empirical macroscopic model to better predict PDT treatment outcome.

Computer aided detection (CAD) data analysis procedures are introduced and applied to derive composite diffuse optical tomography (DOT) signatures of malignancy in human breast tissue. In contrast to previous optical mammography analysis schemes, the new statistical approach utilizes optical property distributions across multiple subjects and across the many voxels of each subject. The methodology is tested in a population of 35 biopsy-confirmed malignant lesions.DOT CAD employs multiparameter, multivoxel, multisubject measurements to derive a simple function that transforms DOT images of tissue chromophores and scattering into a probability of malignancy tomogram. The formalism incorporates both intrasubject spatial heterogeneity and intersubject distributions of physiological properties derived from a population of cancercontaining breasts (the training set). A weighted combination of physiological parameters from the training set define a malignancy parameter (M), with the weighting factors optimized by logistic regression to separate training-set cancer voxels from training-set healthy voxels. The utility of M is examined, employing 3D DOT images from an additional subjects (the test set).Initial results confirm that the automated technique can produce tomograms that distinguish healthy from malignant tissue. When compared to a gold standard tissue segmentation, this protocol produced an average true positive rate (sensitivity) of 89% and a true negative rate (specificity) of 94% using an empirically chosen probability threshold.This study suggests that the automated multisubject, multivoxel, multiparameter statistical analysis of diffuse optical data is potentially quite useful, producing tomograms that distinguish healthy from malignant tissue. This type of data analysis may also prove useful for suppression of image artifacts.

Diffuse optical imaging (DOI) is a noninvasive optical technique that employs near-infrared (NIR) light to quantitatively characterize the optical properties of thick tissues. Although NIR methods were first applied to breast transillumination (also called diaphanography) nearly 80 years ago, quantitative DOI methods employing time- or frequency-domain photon migration technologies have only recently been used for breast imaging (i.e., since the mid-1990s). In this review, the state of the art in DOI for breast cancer is outlined and a multi-institutional Network for Translational Research in Optical Imaging (NTROI) is described, which has been formed by the National Cancer Institute to advance diffuse optical spectroscopy and imaging (DOSI) for the purpose of improving breast cancer detection and clinical management. DOSI employs broadband technology both in near-infrared spectral and temporal signal domains in order to separate absorption from scattering and quantify uptake of multiple molecular probes based on absorption or fluorescence contrast. Additional dimensionality in the data is provided by integrating and co-registering the functional information of DOSI with x-ray mammography and magnetic resonance imaging (MRI), which provide structural information or vascular flow information, respectively. Factors affecting DOSI performance, such as intrinsic and extrinsic contrast mechanisms, quantitation of biochemical components, image formation∕visualization, and multimodality co-registration are under investigation in the ongoing research NTROI sites. One of the goals is to develop standardized DOSI platforms that can be used as stand-alone devices or in conjunction with MRI, mammography, or ultrasound. This broad-based, multidisciplinary effort is expected to provide new insight regarding the origins of breast disease and practical approaches for addressing several key challenges in breast cancer, including: Detecting disease in mammographically dense tissue, distinguishing between malignant and benign lesions, and understanding the impact of neoadjuvant chemotherapies.

We employ diffuse optical tomography (DOT) to track treatment progress in a female subject presenting with locally advanced invasive carcinoma of the breast during neoadjuvant chemotherapy. Three-dimensional images of total hemoglobin concentration and scattering identified the tumor. Our measurements reveal tumor shrinkage during the course of chemotherapy, in reasonable agreement with magnetic resonance images of the same subject. A decrease in total hemoglobin concentration contrast between tumor and normal tissue was also observed over time. The results demonstrate the potential of DOT for measuring physiological parameters of breast lesions during chemotherapy.

We investigate the uptake of a nontargeted contrast agent by breast tumors using a continuous wave diffuse optical tomography apparatus. The instrument operates in the near-infrared spectral window and employs 16 sources and 16 detectors to collect light in parallel on the surface of the tumor-bearing breast (coronal geometry). In our protocol an extrinsic contrast agent, Indocyanine Green (ICG), was injected by bolus. Three clinical scenarios with three different pathologies were investigated. A two-compartment model was used to analyze the pharmacokinetics of ICG and preprocess the data, and diffuse optical tomography was used for imaging. Localization and delineation of the tumor was achieved in good agreement with a priori information. Moreover, different dynamical features were observed for differing pathologies. The malignant cases exhibited slower rate constants (uptake and outflow) compared to healthy tissue. These results provide further evidence that in vivo pharmacokinetics of ICG in breast tumors may be a useful diagnostic tool for differentiation of benign and malignant pathologies.

Three-dimensional diffuse optical tomography (DOT) of breast requires large data sets for even modest resolution (1 cm). We present a hybrid DOT system that combines a limited number of frequency domain (FD) measurements with a large set of continuous wave (cw) measurements. The FD measurements are used to quantitatively determine tissue averaged absorption and scattering coefficients. The larger cw data sets (10(5) measurements) collected with a lens coupled CCD, permit 3D DOT reconstructions of a 1-liter tissue volume. To address the computational complexity of large data sets and 3D volumes we employ finite difference based reconstructions computed in parallel. Tissue phantom measurements evaluate imaging performance. The tests include the following: point spread function measures of resolution, characterization of the size and contrast of single objects, field of view measurements and spectral characterization of constituent concentrations. We also report in vivo measurements. Average tissue optical properties of a healthy breast are used to deduce oxy- and deoxy-hemoglobin concentrations. Differential imaging with a tumor simulating target adhered to the surface of a healthy breast evaluates the influence of physiologic fluctuations on image noise. This tomography system provides robust, quantitative, full 3D image reconstructions with the advantages of high data throughput, single detector-tissue coupling path, and large (1L) imaging domains. In addition, we find that point spread function measurements provide a useful and comprehensive representation of system performance.

Purpose: Diffuse Optical Tomography (DOT) provides multi‐parameter data on metabolic function, however interpretation of these data can be challenging. Computer Aided Detection (CAD) data analysis procedures for DOT are introduced and applied to derive composite signatures of malignancy in human breast tissue. In contrast to previous optical mammographyanalysis schemes, the new statistical approach utilizes distributions of several optical properties across multiple subjects and across the many voxels from each subject. The methodology is tested in a population of biopsy‐confirmed malignant (35) and benign (8) lesions. Methods: DOT CAD employs multi‐parameter, multi‐voxel, multi‐subject measurements to derive a simple function which transforms DOT images of tissue chromophores and scattering into a ‘probability of malignancy’ tomogram. The formalism incorporates both intra‐subject spatial heterogeneity and inter‐subject distributions of physiological properties derived from a population of cancer‐containing breasts. A weighted combination of physiological parameters define a ‘Malignancy Parameter’ (M). Logistic regression is currently utilized for weighting factor optimization. The utility of M is examined, employing 3D DOT images from an additional subject in a leave‐one‐out cross validation procedure. Results: Initial results confirm the automated technique can, without any human intervention, produce tomograms that distinguish healthy from malignant tissue. When compared with a gold standard tissue segmentation, this protocol produced an average true positive rate (sensitivity) of 89% and true negative rate (specificity) of 94% using an empirically chosen probability threshold. Conclusions: This study suggests the automated multi‐subject, multi‐voxel, multi‐parameter statistical analysis of diffuse optical data are potentially quite useful, producing tomograms which distinguish healthy from malignant tissue using the relatively simple logistic regression classifier. This type of data analysis may also prove useful for suppression of image artifacts.

Purpose: Ascertain effects of mammographic compression on microvascular blood flow and thus understand potential confounding factors due to compression on contrast agent distribution. Method and Materials: An X‐ray mammogram simulator was constructed to hold optical fibers for diffuse correlation spectroscopymeasurements of blood flow and diffuse optical spectroscopymeasurements of hemoglobin concentration and oxygenation. 15 healthy subjects were recruited for experiments consisting of 3 serial compression‐release cycles. Results: Small (∼15% or ∼1cm) changes in plate separation resulted in dramatic changes in blood volume (∼47%) and flow (∼65%) in measurements of 15 subjects. However, there was significant inter‐ and intra‐ subject variation in response within the population. Conclusion: The distribution of contrast agents injected during mammographic compression will be affected by the average and inhomogeneous changes in blood flowmeasured in this study. This study is currently being expanded and instrumentation improved to identify the cause of inter‐subject variation in blood flow changes.

Purpose: Improve quantification of Cerebral Metabolic Rate of Oxygen (CMR02) by developing a diffuse optical instrument for use in continuous bedside monitoring of neonatal patients with congenital heart defects. Method and Materials: A compact (17″×l7&″×l4&″) Time‐Domain Diffuse Optical Spectroscopy (TD‐DOS) system has been developed and combined with a Diffuse Correlation Spectroscopy (DCS) system. The TD‐DOS system is composed of 3 lasers (685, 785, and 830 nm), 2 PMTs, 2 time correlated single photon counting(TCSPC) cards, and control electronics; the DCS system consists of 2 long‐coherence length 785nm lasers, 8 photon‐counting APDs, and a customized correlator. TD‐DOS allows absolute measurement of optical scattering and absorption, which permits calculation of absolute values for local hemoglobin concentration and tissue oxygen saturation (StO2); DCS measures relative changes in microvascular blood flow. We approximate CMRO2 changes using a compartmentalized model of the cerebral vasculature and Fick's law. However, this calculation relies upon knowledge of baseline physiological properties, namely, blood oxygen saturation and volume, both obtainable from TD‐DOS. Simultaneously, relative changes in cerebral blood flow will be measured by DCS. Together, these diffuse optical modalities will allow us to calculate CMRO2 based on the individual physiological parameters of each subject. Results: Previous works on neonates with congenital heart defects have utilized instrumentation incapable of measuring absolute optical properties. Calculations of CMRO2 were therefore based upon sparse literature reports of baseline quantities obtained from healthy subjects, who are not representative of our patient population. We will demonstrate an improved quantification of CMRO2 by eliminating the questionable assumptions of blood oxygenation and volume in neonatal brains in favor of direct measurements. Conclusion: By combining TD‐DOS measurements of absolute tissueoptical properties with DCS measurements of relative microvascular blood flow, these TD‐DOS data will permit an improved calculation of CMRO2 by providing individualized baseline values.