Nishanth Krishnamurthy

Broadband Optical Mammography: Chromophore Concentration and Hemoglobin Saturation Contrast in Breast Cancer

This study reports the optical characterization and quantitative oximetry of human breast cancer using spectrally-resolved images collected with a broadband, continuous-wave optical mammography instrument. On twenty-six cancer patients, we collected two-dimensional optical mammograms and created maps of the concentrations of hemoglobin, water, and lipids, as well as the oxygen saturation of hemoglobin. For each cancerous breast, we analyzed the difference between the tumor region (as identified by x-ray and optical mammography) and the remainder of breast tissue. With respect to the surrounding tissue, we found that cancer regions have significantly higher concentrations of total hemoglobin (+2.4±0.4 μM) and water (+7±1% v/v), and significantly lower lipid concentration (8±2% v/v) and oxygen saturation of hemoglobin (5±1%). We also found a significant correlation between the tumor optical contrast and the grade of breast cancer as quantified by the Nottingham histologic score; this demonstrates how optical signatures may be representative of metabolic and morphological features, as well as the aggressive potential of the tumor.

Optical Mammography in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy: Individual Clinical Response Index

RATIONALE AND OBJECTIVES We present an optical mammography study that aims to develop quantitative measures of pathologic response to neoadjuvant chemotherapy (NAC) in patients with breast cancer. Such quantitative measures are based on the concentrations of oxyhemoglobin ([HbO2]), deoxyhemoglobin ([Hb]), total hemoglobin ([HbT]), and hemoglobin saturation (SO2) in breast tissue at the tumor location and at sequential time points during chemotherapy. MATERIALS AND METHODS Continuous-wave, spectrally resolved optical mammography was performed in transmission and parallel-plate geometry on 10 patients before treatment initiation and at each NAC administration (mean number of optical mammography sessions: 12, range: 7-18). Data on two patients were discarded for technical reasons. The patients were categorized as responders (R, >50% decrease in tumor size), or nonresponders (NR, <50% decrease in tumor size) based on imaging and histopathology results. RESULTS At 50% completion of the NAC regimen (therapy midpoint), R (6/8) demonstrated significant decreases in SO2 (-27% ± 4%) and [HbT] (-35 ± 4 µM) at the tumor location with respect to baseline values. By contrast, NR (2/8) showed nonsignificant changes in SO2 and [HbT] at therapy midpoint. We introduce a cumulative response index as a quantitative measure of the individual patients response to therapy. At therapy midpoint, the SO2-based cumulative response index had a sensitivity of 100% and a specificity of 100% for the identification of R. CONCLUSIONS These results show that optical mammography is a promising tool to assess individual response to NAC at therapy midpoint to guide further decision making for neoadjuvant therapy.

Optical mammography: bilateral breast symmetry in hemoglobin saturation maps

Abstract. We present a study of the bilateral symmetry of human breast hemoglobin saturation maps measured with a broadband optical mammography instrument. We have imaged 21 patients with unilateral breast cancer, 32 patients with unilateral benign lesions, and 27 healthy patients. An image registration process was applied to the bilateral hemoglobin saturation (SO2) images by assigning each pixel to the low, middle, or high range of SO2 values, where the thresholds for the categories were the 15th and 85th percentiles of the individual saturation range. The Dice coefficient, which is a measure of similarity, was calculated for each patient’s pair of right and left breast SO2 images. The invasive cancer patients were found to have an average Dice coefficient value of 0.55±0.07, which was significantly lower than the benign and healthy groups (0.61±0.11 and 0.62±0.12, respectively). Although differences were seen in a group analysis, the healthy patient Dice coefficients spanned a wide range, limiting the diagnostic capabilities of this SO2 symmetry analysis on an individual basis. Our results suggest that for assessing the SO2 contrast of breast lesions, it may be better to select a reference tissue in the ipsilateral rather than the contralateral breast.

Broadband optical mammography: Breast tissue thickness compensation algorithm

We present a method to compensate for breast tissue thickness variability in broadband, continuous-wave, parallel plate optical mammography. Tissue thickness information is relevant for the recovery of chromophore concentrations within the breast using continuous-wave, diffusion-based models that assume the breast to be in slab geometry. This method compensates for the discrepancy between the actual phantom or breast shape and the models assumed slab geometry by approximating the thickness of the probed tissue volume. In this work, we applied our tissue thickness compensation algorithm on a breast shaped, homogeneous, tissue-mimicking phantom. Using the thickness found from our algorithm (referred to as our “estimated thickness”) as an input into a continuous-wave, diffusion based model, we recovered the absorption coefficient throughout all scanned pixels in the phantom and found an overall deviation of 12% from the true absorption coefficient. By using the known phantom thickness, we found a strong shape bias within the absorption coefficient recovery and a larger overall deviation of 29%. To test the algorithm on in vivo measurements, we applied this tissue thickness compensation method to a human breast cancer optical mammogram scan. Since the exact thickness of the breast at each pixel is unknown, we compared these results to when a uniform breast thickness is assumed and found a drastic improvement of cancer visualization. This method allows for parallel plate, continuous-wave optical imaging to compensate for the tissue thickness variability at each scanned pixel when modeling the breast data in slab geometry. This compensated thickness is needed as an input to the model in order to accurately map the breast chromophore concentrations and enhance the image contrast of cancer.

Measurements of coherent hemodynamics to enrich the physiological information provided by near-infrared spectroscopy (NIRS) and functional MRI

Hemodynamic-based neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and near-infrared spectroscopy (NIRS) sense hemoglobin concentration in cerebral tissue. The local concentration of hemoglobin, which is differentiated into oxy- and deoxy-hemoglobin by NIRS, features spontaneous oscillations over time scales of 10-100 s in response to a number of local and systemic physiological processes. If one of such processes becomes the dominant source of cerebral hemodynamics, there is a high coherence between this process and the associated hemodynamics. In this work, we report a method to identify such conditions of coherent hemodynamics, which may be exploited to study and quantify microvasculature and microcirculation properties. We discuss how a critical value of significant coherence may depend on the specific data collection scheme (for example, the total acquisition time) and the nature of the hemodynamic data (in particular, oxy- and deoxy-hemoglobin concentrations measured with NIRS show an intrinsic level of correlation that must be taken into account). A frequency-resolved study of coherent hemodynamics is the basis for the new technique of coherent hemodynamics spectroscopy (CHS), which aims to provide measures of cerebral blood flow and cerebral autoregulation. While these concepts apply in principle to both fMRI and NIRS data, in this article we focus on NIRS data.

Individual response to neoadjuvant chemotherapy assessed with optical mammography in patients with breast cancer

We report an optical mammography study on eight patients with breast cancer who underwent neoadjuvant chemotherapy. Of these eight patients, six were responders (tumor size decreased by more than 50%) and two were nonresponders (tumor size decreased by less than 50%). The goals of this study are (1) to characterize the temporal evolution of the hemoglobin concentration ([HbT]) and saturation (SO2) in breast tissue during the course of treatment in responders and non-responders, and (2) to define a quantitative index that is capable of identifying responders and nonresponders during treatment. We found that both [HbT] and SO2 decreased by a greater amount in responders than in non-responders during therapy. This result applied to both cancerous and healthy breast, but the discrimination of responders and non-responders was more significant with SO2 measurements in the cancerous breast. A cumulative response index defined in terms of SO2 measurements in the cancerous breast achieved a 100% sensitivity and 100% specificity for the identification of responders and non-responders at therapy midpoint. These results confirm the potential of optical mammography in assessing response to neoadjuvant chemotherapy during treatment, thus offering the opportunity to consider alternative options to ineffective treatment regimens.

Broadband optical mammography instrument for depth-resolved imaging and local dynamic measurements

We present a continuous-wave instrument for non-invasive diffuse optical imaging of the breast in a parallel-plate transmission geometry. The instrument measures continuous spectra in the wavelength range 650-1000 nm, with an intensity noise level <1.5% and a spatial sampling rate of 5 points/cm in the x- and y-directions. We collect the optical transmission at four locations, one collinear and three offset with respect to the illumination optical fiber, to recover the depth of optical inhomogeneities in the tissue. We imaged a tissue-like, breast shaped, silicone phantom (6 cm thick) with two embedded absorbing structures: a black circle (1.7 cm in diameter) and a black stripe (3 mm wide), designed to mimic a tumor and a blood vessel, respectively. The use of a spatially multiplexed detection scheme allows for the generation of on-axis and off-axis projection images simultaneously, as opposed to requiring multiple scans, thus decreasing scan-time and motion artifacts. This technique localizes detected inhomogeneities in 3D and accurately assigns their depth to within 1 mm in the ideal conditions of otherwise homogeneous tissue-like phantoms. We also measured induced hemodynamic changes in the breast of a healthy human subject at a selected location (no scanning). We applied a cyclic, arterial blood pressure perturbation by alternating inflation (to a pressure of 200 mmHg) and deflation of a pneumatic cuff around the subjects thigh at a frequency of 0.05 Hz, and measured oscillations with amplitudes up to 1 μM and 0.2 μM in the tissue concentrations of oxyhemoglobin and deoxyhemoglobin, respectively. These hemodynamic oscillations provide information about the vascular structure and functional integrity in tissue, and may be used to assess healthy or abnormal perfusion in a clinical setting.

Optical Mammography: Imaging breast cancer response to neoadjuvant chemotherapy

Optical mammograms were obtained on 7 patients undergoing neoadjuvant chemotherapy. When therapy was 30% complete, patients achieving a high pathologic response had a lower oxy-hemoglobin decrease compared to those with extensive disease remaining.

Optical mammography instrument for broadband spectral imaging with depth discrimination

We are developing a new instrument for diffuse optical mammography in parallel plate geometry that operates over a broad spectral range of 600-1000 nm, features a scan time of 1-2 min, and allows for dynamic measurements at a selected region of interest. Furthermore, this new instrument is capable of depth discrimination of optical inhomogeneities embedded in the examined tissue by using multiple off-axis detection fibers. Using a solid silicone phantoms, mimicking breast tissue with 39 mm thickness, we demonstrate the capability of this instrument to recover the depth of blood-vessel-like structures to within ~2 mm. Additionally, we demonstrate the capability of this instrument to perform dynamic optical measurements with a temporal sampling rate as high as 20 Hz. We describe our plans to integrate this rich spectral, spatial, and temporal information into a single instrument for translation into clinical measurements on breast cancer patients.

3D parameter reconstruction in hyperspectral diffuse optical tomography

The imaging of shape perturbation and chromophore concentration using Diffuse Optical Tomography (DOT) data can be mathematically described as an ill-posed and non-linear inverse problem. The reconstruction algorithm for hyperspectral data using a linearized Born model is prohibitively expensive, both in terms of computation and memory. We model the shape of the perturbation using parametric level-set approach (PaLS). We discuss novel computational strategies for reducing the computational cost based on a Krylov subspace approach for parameteric linear systems and a compression strategy for the parameter-to-observation map. We will demonstrate the validity of our approach by comparison with experiments.