David R. Busch

Differentiation of benign and malignant breast tumors by in-vivo three-dimensional parallel-plate diffuse optical tomography

We have developed a novel parallel-plate diffuse optical tomography (DOT) system for three-dimensional in vivo imaging of human breast tumor based on large optical data sets. Images of oxy-, deoxy-, and total hemoglobin concentration as well as blood oxygen saturation and tissue scattering were reconstructed. Tumor margins were derived using the optical data with guidance from radiology reports and magnetic resonance imaging. Tumor-to-normal ratios of these endogenous physiological parameters and an optical index were computed for 51 biopsy-proven lesions from 47 subjects. Malignant cancers (N=41) showed statistically significant higher total hemoglobin, oxy-hemoglobin concentration, and scattering compared to normal tissue. Furthermore, malignant lesions exhibited a twofold average increase in optical index. The influence of core biopsy on DOT results was also explored; the difference between the malignant group measured before core biopsy and the group measured more than 1 week after core biopsy was not significant. Benign tumors (N=10) did not exhibit statistical significance in the tumor-to-normal ratios of any parameter. Optical index and tumor-to-normal ratios of total hemoglobin, oxy-hemoglobin concentration, and scattering exhibited high area under the receiver operating characteristic curve values from 0.90 to 0.99, suggesting good discriminatory power. The data demonstrate that benign and malignant lesions can be distinguished by quantitative three-dimensional DOT.

Time to surgery and preoperative cerebral hemodynamics predict postoperative white matter injury in neonates with hypoplastic left heart syndrome

OBJECTIVE Hypoxic-ischemic white mater brain injury commonly occurs in neonates with hypoplastic left heart syndrome (HLHS). Approximately one half of HLHS survivors will exhibit neurobehavioral symptoms believed to be associated with this injury, although the exact timing of the injury is unknown. METHODS Neonates with HLHS were recruited for pre- and postoperative monitoring of cerebral oxygen saturation, cerebral oxygen extraction fraction, and cerebral blood flow using 2 noninvasive optical-based techniques: diffuse optical spectroscopy and diffuse correlation spectroscopy. Anatomic magnetic resonance imaging was performed before and approximately 1 week after surgery to quantify the extent and timing of the acquired white matter injury. The risk factors for developing new or worsened white matter injury were assessed using uni- and multivariate logistic regression. RESULTS A total of 37 neonates with HLHS were studied. On univariate analysis, neonates who developed a large volume of new, or worsened, postoperative white matter injury had a significantly longer time to surgery (P=.0003). In a multivariate model, a longer time between birth and surgery, delayed sternal closure, and greater preoperative cerebral blood flow were predictors of postoperative white matter injury. Additionally, a longer time to surgery and greater preoperative cerebral blood flow on the morning of surgery correlated with lower cerebral oxygen saturation (P=.03 and P=.05, respectively) and greater oxygen extraction fraction (P=.05 for both). CONCLUSIONS A longer time to surgery was associated with new postoperative white matter injury in otherwise healthy neonates with HLHS. The results suggest that earlier Norwood palliation might decrease the likelihood of acquiring postoperative white matter injury.

Modified Beer-Lambert law for blood flow

We develop and validate a Modified Beer-Lambert law for blood flow based on diffuse correlation spectroscopy (DCS) measurements. The new formulation enables blood flow monitoring from temporal intensity autocorrelation function data taken at single or multiple delay-times. Consequentially, the speed of the optical blood flow measurement can be substantially increased. The scheme facilitates blood flow monitoring of highly scattering tissues in geometries wherein light propagation is diffusive or non-diffusive, and it is particularly well-suited for utilization with pressure measurement paradigms that employ differential flow signals to reduce contributions of superficial tissues.

Influence of probe pressure on the diffuse correlation spectroscopy blood flow signal: extra-cerebral contributions

A pilot study explores relative contributions of extra-cerebral (scalp/skull) versus brain (cerebral) tissues to the blood flow index determined by diffuse correlation spectroscopy (DCS). Microvascular DCS flow measurements were made on the head during baseline and breath-holding/hyperventilation tasks, both with and without pressure. Baseline (resting) data enabled estimation of extra-cerebral flow signals and their pressure dependencies. A simple two-component model was used to derive baseline and activated cerebral blood flow (CBF) signals, and the DCS flow indices were also cross-correlated with concurrent Transcranial Doppler Ultrasound (TCD) blood velocity measurements. The study suggests new pressure-dependent experimental paradigms for elucidation of blood flow contributions from extra-cerebral and cerebral tissues.

Optically Measured Microvascular Blood Flow Contrast of Malignant Breast Tumors

Microvascular blood flow contrast is an important hemodynamic and metabolic parameter with potential to enhance in vivo breast cancer detection and therapy monitoring. Here we report on non-invasive line-scan measurements of malignant breast tumors with a hand-held optical probe in the remission geometry. The probe employs diffuse correlation spectroscopy (DCS), a near-infrared optical method that quantifies deep tissue microvascular blood flow. Tumor-to-normal perfusion ratios are derived from thirty-two human subjects. Mean (95% confidence interval) tumor-to-normal ratio using surrounding normal tissue was 2.25 (1.92–2.63); tumor-to-normal ratio using normal tissues at the corresponding tumor location in the contralateral breast was 2.27 (1.94–2.66), and using normal tissue in the contralateral breast was 2.27 (1.90–2.70). Thus, the mean tumor-to-normal ratios were significantly different from unity irrespective of the normal tissue chosen, implying that tumors have significantly higher blood flow than normal tissues. Therefore, the study demonstrates existence of breast cancer contrast in blood flow measured by DCS. The new, optically accessible cancer contrast holds potential for cancer detection and therapy monitoring applications, and it is likely to be especially useful when combined with diffuse optical spectroscopy/tomography.

Optical malignancy parameters for monitoring progression of breast cancer neoadjuvant chemotherapy

We introduce and demonstrate use of a novel, diffuse optical tomography (DOT) based breast cancer signature for monitoring progression of neoadjuvant chemotherapy. This signature, called probability of malignancy, is obtained by statistical image analysis of total hemoglobin concentration, blood oxygen saturation, and scattering coefficient distributions in the breast tomograms of a training-set population with biopsy-confirmed breast cancers. A pilot clinical investigation adapts this statistical image analysis approach for chemotherapy monitoring of three patients. Though preliminary, the study shows how to use the malignancy parameter for separating responders from partial-responders and demonstrates the potential utility of the methodology compared to traditional DOT quantification schemes.

Computer aided automatic detection of malignant lesions in diffuse optical mammography

PURPOSE 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. METHODS 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). RESULTS 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. CONCLUSIONS 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.

Blood Flow Reduction in Breast Tissue due to Mammographic Compression

RATIONALE AND OBJECTIVES This study measures hemodynamic properties such as blood flow and hemoglobin concentration and oxygenation in the healthy human breast under a wide range of compressive loads. Because many breast-imaging technologies derive contrast from the deformed breast, these load-dependent vascular responses affect contrast agent-enhanced and hemoglobin-based breast imaging. METHODS Diffuse optical and diffuse correlation spectroscopies were used to measure the concentrations of oxygenated and deoxygenated hemoglobin, lipid, water, and microvascular blood flow during axial breast compression in the parallel-plate transmission geometry. RESULTS Significant reductions (P < .01) in total hemoglobin concentration (∼30%), blood oxygenation (∼20%), and blood flow (∼87%) were observed under applied pressures (forces) of up to 30 kPa (120 N) in 15 subjects. Lipid and water concentrations changed <10%. CONCLUSIONS Imaging protocols based on injected contrast agents should account for variation in tissue blood flow due to mammographic compression. Similarly, imaging techniques that depend on endogenous blood contrasts will be affected by breast compression during imaging.

Toward Noninvasive Characterization of Breast Cancer and Cancer Metabolism with Diffuse Optics

We review recent developments in diffuse optical imaging and monitoring of breast cancer, i.e. optical mammography. Optical mammography permits non-invasive, safe and frequent measurement of tissue hemodynamics oxygen metabolism and components (lipids, water, etc.), the development of new compound indices indicative of the risk and malignancy, and holds potential for frequent non-invasive longitudinal monitoring of therapy progression.

Pressure modulation algorithm to separate cerebral hemodynamic signals from extracerebral artifacts.

Abstract. We introduce and validate a pressure measurement paradigm that reduces extracerebral contamination from superficial tissues in optical monitoring of cerebral blood flow with diffuse correlation spectroscopy (DCS). The scheme determines subject-specific contributions of extracerebral and cerebral tissues to the DCS signal by utilizing probe pressure modulation to induce variations in extracerebral blood flow. For analysis, the head is modeled as a two-layer medium and is probed with long and short source-detector separations. Then a combination of pressure modulation and a modified Beer-Lambert law for flow enables experimenters to linearly relate differential DCS signals to cerebral and extracerebral blood flow variation without a priori anatomical information. We demonstrate the algorithm’s ability to isolate cerebral blood flow during a finger-tapping task and during graded scalp ischemia in healthy adults. Finally, we adapt the pressure modulation algorithm to ameliorate extracerebral contamination in monitoring of cerebral blood oxygenation and blood volume by near-infrared spectroscopy.