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Oxygen sensing with light has been developing for many decades using injectable molecules called Oxyphors, which are pegylated, dendrimer-encapsulated metalloporphyrins that have a phosphorescence emission lifetime that is a direct reporter of the local oxygen partial pressure (pO2). In recent years, the ability to image this emission from tissue with Cherenkov light excitation during high-energy X-ray-based radiation therapy has been shown and developed for research studies. The main value of this type of lifetime-based pO2 sensing, termed Cherenkov-Excited Luminescence Imaging (CELI) is in its ability to image values of pO2 from within the tissue during radiation therapy using tracers that are systemic and biologically compatible. Spatial mapping of pO2 can realized either as surface imaging or deep tissue tomography through a few centimeters. The spatial resolution is radiation dose-dependent but can be near 0.1 mm, based upon radiation doses expected in a fractionated treatment plan. When imaging tumors with a broad beam irradiation, histograms of pO2 values across the surface have been demonstrated illustrating microscopic sensitivity to the ranges of oxygen levels present, and the ability to track these microscopic histograms during daily fractionated radiation therapy is possible. The pO2 distributions provide for sensitivity to the hypoxic fraction of the tumor—a unique capability of oxygen imaging that has microscopic spatial sampling. Comparisons of the CELI pO2 method to other oxygen-sensing methods, as well as the ability to use the CELI technique as a tool to examine the optimization of radiation therapy treatment technique is ongoing.

A new low-cost imaging system has been developed for MRI-guided Near-Infrared Spectral Tomography (MRI-NIRST) for breast cancer detection. In this new system, 8 flexible sensing strips with 4 source fibers and 4 photodetectors will be applied directly to the breast, from nipple towards chest-wall, to cover the entire breast. For each source illumination, data will be collected at 32 detector locations. The feasibility of this new imaging system was demonstrated using 3D simulation breast phantoms that created from real breast MR images. Our results indicated that total hemoglobin in a tumor smaller than 1 mm could be recovered with this system.

We examine the relative merits of wide-field, sub-diffuse light scatter imaging and micro-computed tomography for visualizing breast tumor heterogeneity. A large dataset of breast tumor slices was imaged using both modalities, and image data were spatially co-registered with histopathological images to facilitate direct comparisons in feature visualization between tissue types, including normal, benign, and malignant tissues, and microcalcifications. Mechanisms of scatter for the two modalities are discussed and related to the features detected by each modality.

The most common treatment for early-stage breast cancer involves breast-conserving surgery (BCS), which is a local resection of malignant tissue. BCS success relies on the presence of healthy tissue margins surrounding each resection. However, approximately 20% of BCS patients require follow-up surgery to remove residual tumor. Micro-computed tomography and optical structured light imaging were investigated for intraoperative margin assessment. Specimens were imaged immediately after resection and before surgical inking, and image data were compared to postoperative histopathology. The study demonstrated the feasibility of imaging during BCS and generated a baseline multimodal dataset of whole BCS resections, including positive margin signatures.

Background Roughly 23% of breast conserving surgery (BCS) patients undergo a second re-excision procedure due to pathologically positive surgical margins. We investigated the feasibility and potential value of micro-Computed Tomography (micro-CT) as a surgical margin guidance tool during BCS. Methods A cohort of 32 BCS specimens was prospectively imaged with a pre-clinical micro-CT system upon arrival in the surgical pathology laboratory. Reconstructed micro-CT scans were evaluated retrospectively by an experienced breast radiologist, who provided binary determinations whether lesions extended to the specimen margin. These readings were then compared to the final pathological diagnosis and to 2D specimen radiography readings. Results Of the 32 specimens imaged, 28 had malignant and four had benign pathological diagnoses. Overall five (four malignant, one benign) of the 32 specimens had lesion tissue extending to the margin. For all 32 specimens, micro-CT reconstructions were calculated (

An approach using direct regularization from co-registered dynamic contrast enhanced magnetic reson- ance images was used to reconstruct near-infrared spectral tomography patient images, which does not need image segmentation. 20 patients with mammography/ultrasound confirmed breast abnormalities were involved in this paper, and the resulting images indicated that tumor total hemoglobin concentration contrast differentiated malignant from benign cases (p-value = 0.021). The approach prod- uced reconstructed images, which significantly reduced surface artifacts near the source-detector locations (p-value = 4.16e-6).

Integration of magnetic resonance imaging (MRI) and near-infrared spectral tomography (NIRST) has yielded promising diagnostic performance for breast imaging in the past. This study focused on whether MRI-guided NIRST can quantify hemoglobin concentration using only continuous wave (CW) measurements. Patients were classified into four breast density groups based on their MRIs. Optical scattering properties were assigned based on average values obtained from these density groups, and MRI-guided NIRST images were reconstructed from calibrated CW data. Total hemoglobin (HbT) contrast between suspected lesions and surrounding normal tissue was used as an indicator of the malignancy. Results obtained from simulations and twenty-four patient cases indicate that the diagnostic power when using only CW data to differentiate malignant from benign abnormalities is similar to that obtained from combined frequency domain (FD) and CW data. These findings suggest that eliminating FD detection to reduce the cost and complexity of MRI-guided NIRST is possible.

Imaging Cherenkov emission during radiation therapy cancer treatments can provide a real-time, non-contact sampling of the entire dose field. The emitted Cherenkov signal generated is proportional to deposited dose, however, it is affected by attenuation from the intrinsic tissue optical properties of the patient, which in breast, ranges from primarily adipose to fibroglandular tissue. Patients being treated with whole-breast X-ray radiotherapy (n = 13) were imaged for 108 total fractions, to establish correction factors from the linear relationships between Cherenkov light and CT number (HU). This study elucidates this relationship in vivo, and a correction factor approach is used to scale each image to improve the linear correlation between Cherenkov emission intensity and dose (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$R_{6X}^2 = 0.85,\,R_{10X}^2 = 0.95$$\end{document}R6X2=0.85,R10X2=0.95). This study provides a major step towards direct quantitative radiation dose imaging in humans by utilizing non-contact camera sensing of Cherenkov emission during the radiation therapy treatment., Imaging Cherenkov emission during radiotherapy can provide information on the delivered radiation dose, but is attenuated by optical properties of the tissue. Here the authors derive a correction factor applicable to breast X-ray radiotherapy in human subjects to improve the correlation between Cherenkov emission intensity and dose.

Purpose The purpose of this study was to demonstrate high resolution optical luminescence sensing, referred to as Cherenkov excited luminescence scanning imaging (CELSI), could be achieved during a standard dynamic treatment plan for a whole breast radiotherapy geometry. Methods The treatment plan beams induce Cherenkov light within tissue, and this excitation projects through the beam trajectory across the medium, inducing luminescence where there can be molecular reporter. Broad beams generally produce higher signal but low spatial resolution, yet for dynamic plans the scanning of the multileaf collimator allows for a beam-narrowing strategy by recursively temporal differencing each of the Cherenkov images and associated luminescence images. Then reconstruction from each of these size-reduced beamlets defined by the differenced Cherenkov images provides a well-conditioned matrix inversion, where the spatial frequencies are limited by the higher signal-to-noise ratio beamlets. A built-in stepwise convergence relies on stepwise beam size reduction, which is associated with a widening of the bandwidth of Cherenkov spatial frequency and resultant increase in spatial resolution. For the phantom experiments, europium nanoparticles were used as luminescent probes and embedded at depths ranging from 3 to 8 mm. An intensity modulated radiotherapy (IMRT) plan was used to test this. Results The Cherenkov images spatially guided where the luminescence was measured from, providing high lateral resolution, and iterative reconstruction convergence showed that optimization of the initial and stopping beamlet widths could be achieved with 15 and 4.5 mm, respectively, using a luminescence imaging frame rate of 5/s. With the IMRT breast plan, the original lateral resolution was improved 2X, that is, 0.08-0.24 mm for target depths of 3-8 mm. In comparison, a dynamic wedge (DW) plan showed an inferior image fidelity, with relative contrast recovery decreasing from 0.86 to 0.79. The methodology was applied to a three-dimensional dataset to reconstruct Cherenkov excited luminescence intensity distributions showing volumetric recovery of a 0.5 mm diameter object composed of 0.5 μM luminescent microbeads. Conclusions High resolution CELSI was achieved with a clinical breast external beam radiotherapy (EBRT) plan. It is anticipated that this method can allow visualization and localization for luminescence/fluorescence tagged vasculature, lymph nodes, or superficial tagged regions with most dynamic treatment plans.

Luminescence molecular tomography with Cherenkov excitation offers the ability to non-invasively image and quantify temporal changes in fluorescence throughout the body, and then further realize tumor localization. This can be done in radiotherapy to determine the response to treatment in fractionated therapy. To obtain high signal-to-background or signal-to-noise ratio measurement, it is critical to know the best post time point of in-vivo agent-based molecular imaging, which could account on a high signal ratio of target to skin (TSR). For this purpose, ex-vivo murine experiments were performed to quantify the biokinetics and biodistribution of the major organs, plasma, tumor, and skin.

Cherenkov-excited luminescence scanned imaging (CELSI) is achieved with a clinical linear accelerator during External Beam Radiotherapy, to map out molecular luminescence intensity or lifetime in tissue. In order to realize a deeper imaging depth with a reasonable spatial resolution in CELSI, we optimized the original scanning procedure to complete this in a similar way to x-ray computed tomography and with image reconstruction from Maximum-likelihood expectation maximization and multi-pinhole irradiation for parallelization. Resolution phantom studies showed that a 0.3 mm diameter capillary tube containing 0.01 nM luminescent nanospheres could be recognized at a depth of 21 mm into tissue-like media. Small animal imaging with a 1 mm diameter cylindrical target demonstrated that fast 3D data acquisition can be achieved by this multi-pinhole collimator approach to image high resolution luminescence through a whole animal.

Implementing image-guidance for diffuse optical tomographic imaging involves reducing the spatial optical parameter space within the discrete tissue types being estimated. This makes the inverse problem overdetermined which indicates that the required number of measurements could be less than all available measurements. In this work, we propose a data-optimization approach to curtail the algorithmic complexity and implicitly reconstruct optical absorption image based on direct sensitivity approach. The performance of the proposed method was validated using numerical and gelatin phantom data indicating that this perturbation-like approach can quantify embedded regions with good accuracy and is free of bias errors associated with regularization approaches. The testing of the algorithm on human data of fast pulsatile NIR imaging in breast tissue showed that fast updates are possible and the required number of measurements is equal to discrete tissue types. The proposed method offers high level of measurement optimization for the dynamic imaging, compared to traditional methods of full iterative regularized tomography or recently proposed data resolution-based methods.

Cherenkov-excited luminescence scanned imaging (CELSI) has been proposed for radiation-dose determination in medical physics due to its high spatial-resolution over centimeters of tissue. However, dense line-scanning illumination in typical CELSI is time-cost owing to the mechanical movement of the leaves in multi leaf collimator (MLC), resulting into increased radiation exposure. As a result, a scanningless Cherenkov luminescence imaging modality is herein proposed through structuring epi-illumination with MLC-based Hadamard-patterns, which utilizes a reduced radiation does by limiting illumination patterns, extremely shortening the sampling process. In order to effectively reconstruct unknowns from the resultant underdetermined linear system with sparse samplings, a compressed sensing-based reconstruction methodology with l1-norm regularization is adopted. Numerical and phantom experiments show that the proposed methodology achieves the same image quality as the traditional CELSI does.

Purpose: To test the use of a three-dimensional (3D) optical cone beam computed tomography reconstruction algorithm, for estimation of the imparted 3D dose distribution from megavoltage photon beams in a water tank for quality assurance, by imaging the induced Cherenkov-excited fluorescence (CEF). Methods: An intensified charge-coupled device coupled to a standard nontelecentric camera lens was used to tomographically acquire two-dimensional (2D) projection images of CEF from a complex multileaf collimator (MLC) shaped 6 MV linear accelerator x-ray photon beam operating at a dose rate of 600 MU/min. The resulting projections were used to reconstruct the 3D CEF light distribution, a potential surrogate of imparted dose, using a Feldkamp–Davis–Kress cone beam back reconstruction algorithm. Finally, the reconstructed light distributions were compared to the expected dose values from one-dimensional diode scans, 2D film measurements, and the 3D distribution generated from the clinical Varian ECLIPSE treatment planning system using a gamma index analysis. A Monte Carlo derived correction was applied to the Cherenkov reconstructions to account for beam hardening artifacts. Results: 3D light volumes were successfully reconstructed over a 400 × 400 × 350 mm3 volume at a resolution of 1 mm. The Cherenkov reconstructions showed agreement with all comparative methods and were also able to recover both inter- and intra-MLC leaf leakage. Based upon a 3%/3 mm criterion, the experimental Cherenkov light measurements showed an 83%–99% pass fraction depending on the chosen threshold dose. Conclusions: The results from this study demonstrate the use of optical cone beam computed tomography using CEF for the profiling of the imparted dose distribution from large area megavoltage photon beams in water.

A multimodal micro-computed tomography (CT) and multi-spectral structured light imaging (SLI) system is introduced and systematically analyzed to test its feasibility to aid in margin delineation during breast conserving surgery (BCS). Phantom analysis of the micro-CT yielded a signal-to-noise ratio of 34, a contrast of 1.64, and a minimum detectable resolution of 240 μm for a 1.2 min scan. The SLI system, spanning wavelengths 490 nm to 800 nm and spatial frequencies up to 1.37 [Formula: see text], was evaluated with aqueous tissue simulating phantoms having variations in particle size distribution, scatter density, and blood volume fraction. The reduced scattering coefficient, [Formula: see text] and phase function parameter, γ, were accurately recovered over all wavelengths independent of blood volume fractions from 0% to 4%, assuming a flat sample geometry perpendicular to the imaging plane. The resolution of the optical system was tested with a step phantom, from which the modulation transfer function was calculated yielding a maximum resolution of 3.78 cycles per mm. The three dimensional spatial co-registration between the CT and optical imaging space was tested and shown to be accurate within 0.7 mm. A freshly resected breast specimen, with lobular carcinoma, fibrocystic disease, and adipose, was imaged with the system. The micro-CT provided visualization of the tumor mass and its spiculations, and SLI yielded superficial quantification of light scattering parameters for the malignant and benign tissue types. These results appear to be the first demonstration of SLI combined with standard medical tomography for imaging excised tumor specimens. While further investigations are needed to determine and test the spectral, spatial, and CT features required to classify tissue, this study demonstrates the ability of multimodal CT/SLI to quantify, visualize, and spatially navigate breast tumor specimens, which could potentially aid in the assessment of tumor margin status during BCS.

Background While dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) is recognized as the most sensitive examination for breast cancer detection, it has a substantial false positive rate and gadolinium (Gd) contrast agents are not universally well tolerated. As a result, alternatives to diagnosing breast cancer based on endogenous contrast are of growing interest. In this study, endogenous near-infrared spectral tomography (NIRST) guided by T2 MRI was evaluated to explore whether the combined imaging modality, which does not require contrast injection or involve ionizing radiation, can achieve acceptable diagnostic performance. Methods Twenty-four subjects—16 with pathologically confirmed malignancy and 8 with benign abnormalities—were simultaneously imaged with MRI and NIRST prior to definitive pathological diagnosis. MRIs were evaluated independently by three breast radiologists blinded to the pathological results. Optical image reconstructions were constrained by grayscale values in the T2 MRI. MRI and NIRST images were used, alone and in combination, to estimate the diagnostic performance of the data. Outcomes were compared to DCE results. Results Sensitivity, specificity, accuracy, and area under the curve (AUC) of noncontrast MRI when combined with T2-guided NIRST were 94%, 100%, 96%, and 0.95, respectively, whereas these values were 94%, 63%, 88%, and 0.81 for DCE MRI alone, and 88%, 88%, 88%, and 0.94 when DCE-guided NIRST was added. Conclusion In this study, the overall accuracy of imaging diagnosis improved to 96% when T2-guided NIRST was added to noncontrast MRI alone, relative to 88% for DCE MRI, suggesting that similar or better diagnostic accuracy can be achieved without requiring a contrast agent. Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0902-x) contains supplementary material, which is available to authorized users.

Bioluminescence tomography (BLT) provides fundamental insight into biological processes in vivo. To fully realize its potential, it is important to develop image reconstruction algorithms that accurately visualize and quantify the bioluminescence signals taking advantage of limited boundary measurements. In this study, a new two-step reconstruction method for BLT is developed by taking advantage of the sparse a priori information of the light emission using multispectral measurements. The first step infers a wavelength-dependent prior by using all multi-wavelength measurements. The second step reconstructs the source distribution based on this developed prior. Simulation, phantom and in vivo results were performed to assess and compare the accuracy and the computational efficiency of this algorithm with conventional sparsity-promoting BLT reconstruction algorithms, and results indicate that the position errors are reduced from a few millimeters down to sub-millimeter, and reconstruction time is reduced by three orders of magnitude in most cases, to just under a few seconds. The recovery of single objects and multiple (two and three) small objects are simulated, and the recovery of images of a mouse phantom and an experimental animal with an existing luminescent source in the abdomen is demonstrated. Matlab code is available at https://github.com/jinchaofeng/code/tree/master.

The parametric image of Volume Transfer Coefficient (Ktrans) in MRI has been used to guide image reconstruction of Near-Infrared Spectral Tomography (NIRST). The image reconstruction used direct regularization, in which no segmentation has been involved. A total of 24 patients were involved in this study and the reconstructed results show that the tumor total hemoglobin (HbT) contrast could be used to differentiate the malignant from the benign cases (p-value= 0.018). The addition of the MRI information allows more accurate and definitive HbT values from the NIRST.

A portable, 12-wavelength hybrid frequency domain (FD) and continuous wave (CW) near-infrared spectral tomography (NIRST) system was developed for efficient characterization of breast cancer in a clinical oncology setting. Two sets of three FD and three CW measurements were acquired simultaneously. The imaging time was reduced from 90 to 55 seconds with a new gain adjustment scheme of the optical detector. The study of integrating this system into the workflow of clinical oncology practice is ongoing.

A tomographic reconstruction algorithm for Cherenkov-excited luminescence scanned imaging (CELSI) is proposed and demonstrated for the first time, to reconstruct distributions of luminescent source. Coupled continuous wave (CW) diffusion equations are used to model luminescent photon propagation in biological tissues. The CELSI reconstruction was achieved by minimizing the difference between measured and computed data based on Tikhonov regularization technique. The feasibility and effectiveness of the algorithm were tested with numerical simulations on noisy data. In addition, comparisons between conventional diffuse optical fluorescence tomography (DOFT) and CELSI were also performed. Contrast-detail analysis was also used to evaluate the imaging performance of CELSI.

Megavoltage radiation beams used in External Beam Radiotherapy (EBRT) generate Cherenkov light emission in tissues and equivalent phantoms. This optical emission was utilized to excite an oxygen-sensitive phosphorescent probe, PtG4, which has been developed specifically for NIR lifetime-based sensing of the partial pressure of oxygen (pO2). Phosphorescence emission, at different time points with respect to the excitation pulse, was acquired by an intensifier-gated CCD camera synchronized with radiation pulses delivered by a medical linear accelerator. The pO2 distribution was tomographically recovered in a tissue-equivalent phantom during EBRT with multiple beams targeted from different angles at a tumor-like anomaly. The reconstructions were tested in two different phantoms that have fully oxygenated background, to compare a fully oxygenated and a fully deoxygenated inclusion. To simulate a realistic situation of EBRT, where the size and location of the tumor is well known, spatial information of a prescribed region was utilized in the recovery estimation. The phantom results show that region-averaged pO2 values were recovered successfully, differentiating aerated and deoxygenated inclusions. Finally, a simulation study was performed showing that pO2 in human brain tumors can be measured to within 15 mmHg for edge depths less than 10-20 mm using the Cherenkov Excited Phosphorescence Oxygen imaging (CEPhOx) method and PtG4 as a probe. This technique could allow non-invasive monitoring of pO2 in tumors during the normal process of EBRT, where beams are generally delivered from multiple angles or arcs during each treatment fraction.

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.

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.

Optically derived tissue properties across a range of breast densities and the effects of breast compression on estimates of hemoglobin, oxygen metabolism, and water and lipid concentrations were obtained from a coregistered imaging system that integrates near-infrared spectral tomography (NIRST) with digital breast tomosynthesis (DBT). Image data were analyzed from 27 women who underwent four IRB approved NIRST/DBT exams that included fully and mildly compressed breast acquisitions in two projections—craniocaudal (CC) and mediolateral-oblique (MLO)—and generated four data sets per patient (full and moderate compression in CC and MLO views). Breast density was correlated with HbT (r=0.64, p=0.001), water (r=0.62, p=0.003), and lipid concentrations (r=?0.74, p

Purpose: Design optimization and phantom validation of an integrated digital breast tomosynthesis (DBT) and near-infrared spectral tomography (NIRST) system targeting improvement in sensitivity and specificity of breast cancer detection is presented. Factors affecting instrumentation design include minimization of cost, complexity, and examination time while maintaining high fidelity NIRST measurements with sufficient information to recover accurate optical property maps. Methods: Reconstructed DBT slices from eight patients with abnormal mammograms provided anatomical information for the NIRST simulations. A limited frequency domain (FD) and extensive continuous wave (CW) NIRST system was modeled. The FD components provided tissue scattering estimations used in the reconstruction of the CW data. Scattering estimates were perturbed to study the effects on hemoglobin recovery. Breast mimicking agar phantoms with inclusions were imaged using the combined DBT/NIRST system for comparison with simulation results. Results: Patient simulations derived from DBT images show successful reconstruction of both normal and malignant lesions in the breast. They also demonstrate the importance of accurately quantifying tissue scattering. Specifically, 20% errors in optical scattering resulted in 22.6% or 35.1% error in quantification of total hemoglobin concentrations, depending on whether scattering was over- or underestimated, respectively. Limited frequency-domain optical signal sampling provided two regions scattering estimates (for fat and fibroglandular tissues) that led to hemoglobin concentrations that reduced the error in the tumor region by 31% relative to when a single estimate of optical scattering was used throughout the breast volume of interest. Acquiring frequency-domain data with six wavelengths instead of three did not significantly improve the hemoglobin concentration estimates. Simulation results were confirmed through experiments in two-region breast mimicking gelatin phantoms. Conclusions: Accurate characterization of scattering is necessary for quantification of hemoglobin. Based on this study, a system design is described to optimally combine breast tomosynthesis with NIRST.

Near-infrared spectroscopy (NIRS) of tissue provides quantification of absorbers, scattering and luminescent agents in bulk tissue through the use of measurement data and assumptions. Prior knowledge can be critical about things such as (i) the tissue shape and/or structure, (ii) spectral constituents, (iii) limits on parameters, (iv) demographic or biomarker data, and (v) biophysical models of the temporal signal shapes. A general framework of NIRS imaging with prior information is presented, showing that prior information datasets could be incorporated at any step in the NIRS process, with the general workflow being: (i) data acquisition, (ii) pre-processing, (iii) forward model, (iv) inversion/reconstruction, (v) post-processing, and (vi) interpretation/diagnosis. Most of the development in NIRS has used ad hoc or empirical implementations of prior information such as pre-measured absorber or fluorophore spectra, or tissue shapes as estimated by additional imaging tools. A comprehensive analysis would examine what prior information maximizes the accuracy in recovery and value for medical diagnosis, when implemented at separate stages of the NIRS sequence. Individual applications of prior information can show increases in accuracy or improved ability to estimate biochemical features of tissue, while other approaches may not. Most beneficial inclusion of prior information has been in the inversion/reconstruction process, because it solves the mathematical intractability. However, it is not clear that this is always the most beneficial stage.

A near-infrared (NIR) tomography system with spectrally-encoded sources in two wavelength bands was built to quantify the temporal oxyhemoglobin and deoxyhemoglobin contrast in breast tissue at a 20 Hz bandwidth. The system was integrated into a 3 T magnetic resonance (MR) imaging system through a customized breast coil interface for simultaneous optical and MRI acquisition. In this configuration, the MR images provide breast tissue structural information for NIR spectroscopy of adipose and fibro-glandular tissue in breast. Spectral characterization performance of the NIR system was verified through dynamic phantom experiments. Normal human subjects were imaged with finger pulse oximeter (PO) plethysmogram synchronized to the NIR system to provide a frequency-locked reference. Both the raw data from the NIR system and the recovered absorption coefficients of the breast at two wavelengths showed the same frequency of about 1.3 Hz as the PO output. The frequency lock-in approach provided a practical platform for MR-localized recovery of small pulsatile variations of oxyhemoglobin and deoxyhemoglobin in the breast, which are related to the heartbeat and vascular resistance of the tissue.

Purpose: A NIRtomography 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 spectralreconstruction produces more accurate hemoglobin, water, and lipid results relative to FD data alone.

e12655Background: NIRST provides biophysical data including oxy- and deoxy-hemoglobin, water, lipid, and scatter components, useful in distinguishing cancer from normal breast tissue. Unlike anatom...

Fluorescence sampling of cellular function is widely used in all aspects of biology, allowing the visualization of cellular and sub-cellular biological processes with spatial resolutions in the range from nanometers up to centimeters. Imaging of fluorescence in vivo has become the most commonly used radiological tool in all pre-clinical work. In the last decade, full-body pre-clinical imaging systems have emerged with a wide range of utilities and niche application areas. The range of fluorescent probes that can be excited in the visible to near-infrared part of the electromagnetic spectrum continues to expand, with the most value for in vivo use being beyond the 630 nm wavelength, because the absorption of light sharply decreases. Whole-body in vivo fluorescence imaging has not yet reached a state of maturity that allows its routine use in the scope of large-scale pre-clinical studies. This is in part due to an incomplete understanding of what the actual fundamental capabilities and limitations of this imaging modality are. However, progress is continuously being made in research laboratories pushing the limits of the approach to consistently improve its performance in terms of spatial resolution, sensitivity and quantification. This paper reviews this imaging technology with a particular emphasis on its potential uses and limitations, the required instrumentation, and the possible imaging geometries and applications. A detailed account of the main commercially available systems is provided as well as some perspective relating to the future of the technology development. Although the vast majority of applications of in vivo small animal imaging are based on epi-illumination planar imaging, the future success of the method relies heavily on the design of novel imaging systems based on state-of-the-art optical technology used in conjunction with high spatial resolution structural modalities such as MRI, CT or ultra-sound.

Analysis of MRI parameters together with NIRS values (n=28 subjects) shows that the combinations of Ktrans with either HbT or TOI have high diagnostic accuracy, increasing AUC values to 93-94% and specificity up to 100%.

Multi-parameter functional image guidance is demonstrated to regularize NIRS tomography with MRI dynamic contrast and water diffusion. The approach shows increased contrast in the tumors from 1.76 to 2.23, relative to a regular MRI guidance approach.

Analysis of breast DCE-MR and NIR tomography imaging of 17 NAC patients showed combined pre-TX contrast intensity and HbT were statistically significant in differentiating the patients with versus without complete pathological response (AUC=0.94).

Results of simulation and patient image reconstructions showed that a distance-constrained direct regularization can improve MRI guided near-infrared breast image quality in terms of less artifacts and higher HbT contrast of the tumor to normal tissue.

Cherenkov light emission occurs when high energy radiation (E>220keV) travels through tissue. This optical signal is used for molecular tracer imaging, radiation dose imaging, or molecular sensing in vivo. Human and animal studies are demonstrated.

Imaging of oxygen saturation provides a spatial map of the tissue metabolic activity and has potential in diagnosis and treatment monitoring of breast cancer. Oxygen-saturation imaging is possible through near-infrared (NIR) tomography, but has low signal-to-noise ratio (SNR). This can be augmented by using NIR tomography as an add-on to MRI. Presented are results from a free-standing NIR system and a hybrid MR-guided system for breast imaging. In results from imaging 60 healthy volunteers in the initial NIR system, oxygen saturation was a significant discriminator between the BIRADS classifications of adipose tissue, heterogeneously dense, and extremely dense tissue. By using the MR-guided NIR system, more accurate tissue-specific data were obtained on adipose and fibroglandular volumes, with 11 healthy volunteers. In these data, oxygen saturation in the adipose tissue correlated with percentage of adipose tissue. In two case studies of infiltrating ductal carcinomas, oxygen saturation was reduced at the site of the tumor, as compared with the surrounding healthy tissue, agreeing with conventional thought that hypoxia exists in larger solid tumors. The MRI-guided NIR images of oxygen saturation provide higher resolution and superior SNR and will likely be used in the future to study and characterize specific tissue volumes.

Purpose: The purpose of this study was to determine the diagnostically most important molecular biomarkers quantified by magnetic resonance-guided (MR) near-infrared spectral tomography (NIRST) that distinguish malignant breast lesions from benign abnormalities when combined with outcomes from clinical breast MRI. Experimental Design: The study was HIPAA compliant and approved by the Dartmouth Institutional Review Board, the NIH, the United States State Department, and Xijing Hospital. MR-guided NIRST evaluated hemoglobin, water, and lipid content in regions of interest defined by concurrent dynamic contrast-enhanced MRI (DCE-MRI) in the breast. MRI plus NIRST was performed in 44 subjects (median age, 46, age range, 20–81 years), 28 of whom had subsequent malignant pathologic diagnoses, and 16 had benign conditions. A subset of 30 subject examinations yielded optical data that met minimum sensitivity requirements to the suspicious lesion and were included in the analyses of diagnostic performance. Results: In the subset of 30 subject examinations meeting minimum optical data sensitivity criterion, the MR-guided NIRST separated malignant from benign lesions using total hemoglobin (HbT; P < 0.01) and tissue optical index (TOI; P < 0.001). Combined MRI plus TOI data caused one false positive and 1 false negative, and produced the best diagnostic performance, yielding an AUC of 0.95, sensitivity of 95%, specificity of 89%, positive predictive value of 95%, and negative predictive value of 89%, respectively. Conclusions: MRI plus NIRST results correlated well with histopathologic diagnoses and could provide additional information to reduce the number of MRI-directed biopsies. Clin Cancer Res; 21(17); 3906–12. ©2015 AACR.

An optimized approach to nonlinear iterative reconstruction of magnetic resonance imaging (MRI)-guided near-infrared spectral tomography (NIRST) images was developed using an L-curve-based algorithm for the choice of regularization parameter. This approach was applied to clinical exam data to maximize the reconstructed values differentiating malignant and benign lesions. MRI/NIRST data from 25 patients with abnormal breast readings (BI-RADS category 4-5) were analyzed using this optimal regularization methodology, and the results showed enhanced p values and area under the curve (AUC) for the task of differentiating malignant from benign lesions. Of the four absorption parameters and two scatter parameters, the most significant differences for benign versus malignant were total hemoglobin (HbT) and tissue optical index (TOI) with p values = 0.01 and 0.001, and AUC values = 0.79 and 0.94, respectively, in terms of HbT and TOI. This dramatically improved the values relative to fixed regularization (p value = 0.02 and 0.003; AUC = 0.75 and 0.83) showing that more differentiation was possible with the optimal method. Through a combination of both biomarkers, HbT and TOI, the AUC increased from 82.9% (fixed regulation = 0.1) to 94.3% (optimal method).

A portable hybrid frequency domain (FD)-continuous wave (CW) Near-Infrared spectroscopy NIRS system has been developed for quantifying changes in total hemoglobin, oxygen saturation and water content in the breast during neoadjuvant chemotherapy. Simultaneous acquisition of two sets of 3 FD channels and 3 CW channels could be completed within 1 min. System calibration and homogeneous phantom measurement show phase variation less than 3% when PMT gain from 0.7 to 1.1 was used. The study of integrating this system into the workflow of clinical oncology practice is ongoing.

Magnetic resonance (MR)-guided near-infrared spectral tomography was developed and used to image adipose and fibroglandular breast tissue of 11 normal female subjects, recruited under an institutional review board-approved protocol. Images of hemoglobin, oxygen saturation, water fraction, and subcellular scattering were reconstructed and show that fibroglandular fractions of both blood and water are higher than in adipose tissue. Variation in adipose and fibroglandular tissue composition between individuals was not significantly different across the scattered and dense breast categories. Combined MR and near-infrared tomography provides fundamental molecular information about these tissue types with resolution governed by MR T1 images.

Materials and Methods. A new spectral reconstruction method that is considered to provide the most accurate estimates of hemoglobin level, oxygen saturation, water fraction, scattering power, and amplitude was used to assess healthy breast tissue imaged in vivo by means of NIR tomography. The approach directly recovers functional parameters with inherent inclusion of spectral behavior enforced through the incorporation of a priori model assumptions. Sixty subjects were imaged by using a frequency-domain instrument followed by spectral image reconstruction and statistical analysis for significant correlations. Results. The new analysis shows statistically significant inverse correlations between body mass index and breast total hemoglobin and water fractions. Water fraction also correlated inversely with age and separated certain categories of breast density. Average scatter power was indicative of breast radiographic density composition, whereas scatter amplitude varied inversely with breast diameter. Total hemoglobin correlated with water fraction, whereas water correlated with scatter power. Conclusion. The changes observed here are attributable to volume fraction alterations and provide some of the most comprehensive data on breast composition variations with demographic factors.

Multi-wavelength Near-Infrared (NIR) Tomography was utilized in this study to non-invasively quantify physiological parameters of breast tumors using direct spectral reconstruction. Frequency domain NIR measurements were incorporated with a new spectrally constrained direct chromophore and scattering image reconstruction algorithm, which was validated in simulations and experimental phantoms. Images of total hemoglobin, oxygen saturation, water, and scatter parameters were obtained with higher accuracy than previously reported. Using this spectral approach, in vivo NIR images are presented and interpreted through a series of case studies (n=6 subjects) having differing abnormalities. The corresponding mammograms and ultrasound images are also evaluated. Three of six cases were malignant (infiltrating ductal carcinomas) and showed higher hemoglobin (34–86% increase), a reduction in oxygen saturation, an increase in water content as well as scatter changes relative to surrounding normal tissue. Three of six cases were benign, two of which were diagnosed with fibrocystic disease and showed a dominant contrast in water, consistent with fluid filled cysts. Scatter amplitude was the main source of contrast in the volunteer with the benign condition fibrosis, which typically contains denser collagen tissue. The changes monitored correspond to physiological changes associated with angiogenesis, hypoxia and cell proliferation anticipated in cancers. These changes represent potential diagnostic indicators, which can be assessed to characterize breast tumors.

The design and implementation of a multispectral, frequency-domain near infrared tomography system is outlined, which operates in a MRI magnet for utilization of MR-guided image reconstruction of tissue optical properties. Using long silica optical fiber bundles, measurements of light transmission through up to 12 cm of female breast tissue can be acquired simultaneously with MRI scans. The NIR system utilizes six optical wavelengths from 660 to 850 nm using intensity modulated diode lasers nominally working at 100 MHz. Photomultiplier tube detector gain levels are electronically controlled on a time scale of 200 ms, thereby allowing rapid switching of the source to locations around the tissue. There are no moving parts in the detection channels and for each source position, 15 PMTs operating in parallel allow sensitivity down to 0.5 pW/cm2 at the tissue surface. Images of breast tissue optical absorption and reduced scattering coefficients are obtained using a Newton-type reconstruction algorithm to solv...

Near-infrared (NIR) tomography is a technique used to measure light propagation through tissue and generate images of internal optical property distributions from boundary measurements. Most popular applications have concentrated on female breast imaging, neonatal and adult head imaging, as well as muscle and small animal studies. In most instances a highly scattering medium with a homogeneous refractive index is assumed throughout the imaging domain. Using these assumptions, it is possible to simplify the model to the diffusion approximation. However, biological tissue contains regions of varying optical absorption and scatter, as well as varying refractive index. In this work, we introduce an internal boundary constraint in the finite element method approach to modelling light propagation through tissue that accounts for regions of different refractive indices. We have compared the results to data from a Monte Carlo simulation and show that for a simple two-layered slab model of varying refractive index, the phase of the measured reflectance data is significantly altered by the variation in internal refractive index, whereas the amplitude data are affected only slightly.

A combined magnetic resonance and near-infrared (MRI-NIR) imaging modality can potentially yield high resolution maps of optical properties from noninvasive simultaneous measurement. The main disadvantage of near-infrared (NIR) tomography lies in the low spatial resolution resulting from the highly scattering nature of tissue for these wavelengths. MRI has achieved high resolution, but suffers from low specificity. In this study, NIR image reconstruction algorithms that incorporate a priori structural information provided by MRI are investigated in an attempt to optimize recovery of a simulated optical property distribution. The effect of high levels of tissue heterogeneity are evaluated to determine the limitations of incorporating prior information into a realistic set of patient breast images. We assume absorption coefficient (/spl mu//sub a/) variations near /spl plusmn/40%, and transport scattering coefficient (/spl mu//sub s//sup //) variations near /spl plusmn/20%, in a coronal breast MRI geometry. Changes in tissue pathology due to tumor growth can be observed with NIR tompgraphy, and so the goal here is to determine how best to quantify these tumor-based contrast regions within the presence of high tissue heterogeneity. By applying knowledge of tissue's layered structure in reconstruction through various constraints in the iterative algorithm, quantitative recovery of the tumor optical properties improves from 69% to 74%, and localization improves as well. However, only when the true heterogeneity of the tissue distribution was included was accurate quantification of the tumor region possible. Using a good initial guess of /spl mu//sub a/ and /spl mu//sub s//sup //, derived from the regional structure of the model, quantification of the region reaches 99% of the true value, and spatial resolution retains a similar value to the original MRI image.

For pt. I see ibid., vol. 21, no. 7, p. 755-63 (2002). Image error analysis of a diffuse near-infrared tomography (NIR) system has been carried out on simulated data using a statistical approach described in pt. I of this paper (Pogue et al., 2002). The methodology is used here with experimental data acquired on phantoms with a prototype imaging system intended for characterizing breast tissue. Results show that imaging performance is not limited by random measurement error, but rather by calibration issues. The image error over the entire field of view is generally not minimized when an accurate homogeneous estimate of the phantom properties is available; however, local image error over a target region of interest (ROI) is reduced. The image reconstruction process which includes a Levenberg-Marquardt style regularization provides good minimization of the objective function, yet its reduction is not always correlated with an overall image error decrease. Minimization of the bias in an ROI which contains localized changes in the optical properties can be achieved through five to nine iterations of the algorithm. Precalibration of the algorithm through statistical evaluation of phantom studies may provide a better measure of the image accuracy than that implied by minimization of the standard objective function.

Near-infrared (NIR) diffuse tomography is an emerging method for imaging the interior of tissues to quantify concentrations of hemoglobin and exogenous chromophores non-invasively in vivo. It often exploits an optical diffusion model-based image reconstruction algorithm to estimate spatial property values from measurements of the light flux at the surface of the tissue. In this study, mean-squared error (MSE) over the image is used to evaluate methods for regularizing the ill-posed inverse image reconstruction problem in NIR tomography. Estimates of image bias and image standard deviation were calculated based upon 100 repeated reconstructions of a test image with randomly distributed noise added to the light flux measurements. It was observed that the bias error dominates at high regularization parameter values while variance dominates as the algorithm is allowed to approach the optimal solution. This optimum does not necessarily correspond to the minimum projection error solution, but typically requires further iteration with a decreasing regularization parameter to reach the lowest image error. Increasing measurement noise causes a need to constrain the minimum regularization parameter to higher values in order to achieve a minimum in the overall image MSE.

A portable near infrared spectral tomography (NIRST) system was adapted for breast cancer detection and treatment monitoring with improved speed of acquisition for parallel 12 wavelengths of parallel frequency-domain (FD) and continuous-wavelength (CW) measurement. Using a novel gain adjustment scheme in the Photomultiplier Tube detectors (PMTs), the data acquisition time for simultaneous acquisition involving three FD and three CW wavelengths, has been reduced from 90 to 55 seconds, while signal variation was also reduced from 2.1% to 1.1%. Tomographic images of breast collagen content have been recovered for the first time, and image reconstruction approaches with and without collagen content included have been validated in simulation studies and normal subject exams. Simulations indicate that including collagen content into the reconstruction procedure can significantly reduce the overestimation in total hemoglobin, water and lipid by 8.9μM, 1.8% and 15.8%, respectively, and underestimates in oxygen saturation by 9.5%, given an average 10% background collagen content. A breast cancer patient with invasive ductal carcinoma was imaged and the reconstructed images show that the recovered tumor/background contrast in total hemoglobin increased from 1.5 to 1.7 when collagen was included in reconstruction.

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.

In this study, data from breast MRI-guided near infrared spectroscopy (NIRS) exams delivered to 44 patients scheduled for surgical resection (ending in 16 benign and 28 malignant diagnoses) were analyzed using a spatial sensitivity metric to quantify the adequacy of the optical measurements for interrogating the tumor region of interest, as derived from the concurrent MRI scan. Along with positional sensitivity, the incorporation of spectral priors and the selection of an appropriate regularization parameter in the image reconstruction were considered, and found to influence the diagnostic accuracy of the recovered images. Once optimized, the MRI/NIRS data was able to differentiate the malignant from benign lesions through both total hemoglobin (p = 0.0037) and tissue optical index (p = 0.00019), but required the relative spatial sensitivity of the optical measurement data to each lesion to be above 1%. Spectral constraints implemented during the reconstruction were required to obtain statistically significant diagnostic information from images of H2O, lipids, and Tissue Optical Index (TOI). These results confirm the need for optical systems that have homogenous spatial coverage of the breast while still being able to accommodate the normal range of breast sizes.