Tissue oxygen saturation predicts response to breast cancer neoadjuvant chemotherapy within 10 days of treatment.

Ideally, neoadjuvant chemotherapy (NAC) assessment should predict pathologic complete response (pCR), a surrogate clinical endpoint for 5-year survival, as early as possible during typical 3- to 6-month breast cancer treatments. We introduce and demonstrate an approach for predicting pCR within 10 days of initiating NAC. The method uses a bedside diffuse optical spectroscopic imaging (DOSI) technology and logistic regression modeling. Tumor and normal tissue physiological properties were measured longitudinally throughout the course of NAC in 33 patients enrolled in the American College of Radiology Imaging Network multicenter breast cancer DOSI trial (ACRIN-6691). An image analysis scheme, employing z-score normalization to healthy tissue, produced models with robust predictions. Notably, logistic regression based on z-score normalization using only tissue oxygen saturation (StO2) measured within 10 days of the initial therapy dose was found to be a significant predictor of pCR (AUC = 0.92; 95% CI: 0.82 to 1). This observation suggests that patients who show rapid convergence of tumor tissue StO2 to surrounding tissue StO2 are more likely to achieve pCR. This early predictor of pCR occurs prior to reductions in tumor size and could enable dynamic feedback for optimization of chemotherapy strategies in breast cancer.

Vertical-cavity surface-emitting laser sources for gigahertz-bandwidth, multiwavelength frequency-domain photon migration.

Frequency-domain photon migration (FDPM) uses modulated laser light to measure the bulk optical properties of turbid media and is increasingly applied for noninvasive functional medical imaging in the near-infrared. Although semiconductor edge-emitting laser diodes have been traditionally used as miniature light sources for this application, we show that vertical-cavity surface-emitting lasers (VCSELs) exhibit output power and modulation performance characteristics suitable for FDPM measurements of tissue optical properties at modulation frequencies exceeding 1 GHz. We also show that an array of multiple VCSEL devices can be coherently modulated at frequencies suitable for FDPM and can improve optical power. In addition, their small size and simple packaging make them an attractive choice as components in wearable sensors and clinical FDPM-based optical spectroscopy systems. We demonstrate the benefits of VCSEL technology by fabricating and testing a unique, compact VCSEL-based optical probe with an integrated avalanche photodiode. We demonstrate sensitivity of the VCSEL-based probe to subcutaneous tissue hemodynamics that was induced during an arterial cuff occlusion of the upper arm in a human subject.

Predicting Responses to Neoadjuvant Chemotherapy in Breast Cancer: ACRIN 6691 Trial of Diffuse Optical Spectroscopic Imaging.

The prospective multicenter ACRIN 6691 trial was designed to evaluate whether changes from baseline to mid-therapy in a diffuse optical spectroscopic imaging (DOSI)-derived imaging endpoint, the tissue optical index (TOI), predict pathologic complete response (pCR) in women undergoing breast cancer neoadjuvant chemotherapy (NAC). DOSI instruments were constructed at the University of California, Irvine (Irvine, CA), and delivered to six institutions where 60 subjects with newly diagnosed breast tumors (at least 2 cm in the longest dimension) were enrolled over a 2-year period. Bedside DOSI images of the tissue concentrations of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctHbO2), water (ctH2O), lipid, and TOI (ctHHb × ctH2O/lipid) were acquired on both breasts up to four times during NAC treatment: baseline, 1-week, mid-point, and completion. Of the 34 subjects (mean age 48.4 ± 10.7 years) with complete, evaluable data from both normal and tumor-containing breast, 10 (29%) achieved pCR as determined by central pathology review. The percent change in tumor-to-normal TOI ratio (%TOITN) from baseline to mid-therapy ranged from -82% to 321%, with a median of -36%. Using pCR as the reference standard and ROC curve methodology, %TOITN AUC was 0.60 (95% CI, 0.39-0.81). In the cohort of 17 patients with baseline tumor oxygen saturation (%StO2) greater than the 77% population median, %TOITN AUC improved to 0.83 (95% CI, 0.63-1.00). We conclude that the combination of baseline functional properties and dynamic optical response shows promise for clinical outcome prediction. Cancer Res; 76(20); 5933-44. ©2016 AACR.

Near-Infrared Optical Imaging for Diagnosis of Maxillary Sinusitis.

Computed tomography (CT) is the current gold standard imaging for chronic rhinosinusitis (CRS) but is limited by cost, risk of radiation, and difficulty of being performed in the typical outpatient primary care setting. We describe the novel use of a low-cost, handheld technology to deliver an intraoral near-infrared (NIR) wavelength light to optically image the maxillary sinuses. Digital images were collected for subjects presenting with sinus disease using an intraoral NIR light source for transillumination of the maxillary sinuses, captured by a modified digital single-lens reflex camera. Light intensity contrasts were enhanced using computer analysis and subsequently compared to CT findings. NIR illumination produced unique patterns reflecting different disease states: normal sinus anatomy, mild sinus disease and/or mucosal thickening, and complete opacification of the sinus. Current results suggest that NIR imaging may facilitate the diagnosis of sinusitis in the outpatient setting with minimal cost and no radiation exposure.

Monte Carlo modeling of light propagation in the human head for applications in sinus imaging.

Sinus blockages are a common reason for physician visits, affecting one out of seven people in the United States, and often require medical treatment. Diagnosis in the primary care setting is challenging because symptom criteria (via detailed clinical history) plus objective imaging [computed tomography (CT) or endoscopy] are recommended. Unfortunately, neither option is routinely available in primary care. We previously demonstrated that low-cost near-infrared (NIR) transillumination correlates with the bulk findings of sinus opacity measured by CT. We have upgraded the technology, but questions of source optimization, anatomical influence, and detection limits remain. In order to begin addressing these questions, we have modeled NIR light propagation inside a three-dimensional adult human head constructed via CT images using a mesh-based Monte Carlo algorithm (MMCLAB). In this application, the sinus itself, which when healthy is a void region (e.g., nonscattering), is the region of interest. We characterize the changes in detected intensity due to clear (i.e., healthy) versus blocked sinuses and the effect of illumination patterns. We ran simulations for two clinical cases and compared simulations with measurements. The simulations presented herein serve as a proof of concept that this approach could be used to understand contrast mechanisms and limitations of NIR sinus imaging.

Effect of blood flow restriction on tissue oxygenation during knee extension.

PURPOSE: Time-resolved near-infrared spectroscopy was used to quantify tissue oxy- and deoxyhemoglobin concentrations ([HbO2] and [HbR]) and O2 saturation (stO2) in the oblique fibers of the vastus medialis muscle and brain prefrontal cortex during knee extension with and without blood flow restriction (BFR). METHODS: Six young healthy males performed three sets of knee extensions on a dynamometer (50% one-repetition maximum) separated by 90-s rest periods in three conditions: 1) until fatigue without BFR (fatigue), 2) until fatigue with BFR (100 mm Hg cuff constriction around thigh (BFR)), 3) same number of repetitions from condition 2 without BFR (matched). Each condition was performed on a separate visit. RESULTS: BFR was associated with higher [HbR] at the oblique fibers of the vastus medialis muscle (rest 1: 57.8 (BFR) vs 35.0 µM (matched); P < 0.0001) and a significantly lower stO2 during recovery periods between sets (7.5%-11.2 % lower than non-BFR conditions for rest 1 and 2, P < 0.0001). Using a piecewise linear spline method, a spike in [HbR] was observed before the onset of HbR clearance during recovery, causing HbR clearance to begin at a higher concentration (81 (BFR) vs 62 µM (matched), P = 0.029). [HbO2] kinetics during recovery were also affected by BFR, with longer duration (BFR, 51 s; matched, 31 s; P = 0.047) but lower rate of increase (BFR, 58 µM·min; matched, 89 µM·min; P = 0.004) during recovery. In the prefrontal cortex, BFR was associated with increased [HbR], diminished increase in [HbO2], and higher subjective exertion. CONCLUSIONS: These findings yield insight into possible physiological mechanisms of BFR and suggest a role of time-resolved near-infrared spectroscopy in monitoring and optimization of BFR exercise on an individual basis.

Assessing tumor contrast in radiographically dense breast tissue using Diffuse Optical Spectroscopic Imaging (DOSI).

INTRODUCTION: Radiographic density adversely affects the performance of X-ray mammography and can be particularly problematic in younger and high-risk women. Because of this limitation, there is significant ongoing effort to develop alternative cancer screening and detection strategies for this population. This pilot study evaluates the potential of Diffuse Optical Spectroscopic Imaging (DOSI) to image known tumors in dense breast tissue. METHODS: We performed a retrospective analysis on 24 radiographically dense breast cancer subjects measured with DOSI over a four-year period (Breast Imaging Reporting and Data System - BI-RADS, category 3 and 4, average age = 39 ± 7.6, average maximum size 31 ± 1 7 mm). Two previously-described DOSI contrast functions, the tissue optical index (TOI) and the specific tumor component (STC), which are based upon the concentrations and spectral signatures of hemoglobin, water and lipids, respectively, were used to form 2D optical images of breast tumors. RESULTS: Using TOI and STC, 21 out of 24 breast tumors were found to be statistically different from the surrounding highly vascularized dense tissue and to be distinguishable from the areolar region. For these patients, the tumor to normal contrast was 2.6 ± 1.2 (range 1.3 to 5.5) and 10.0 ± 7.5 (range 3.3 to 26.4) for TOI and STC, respectively. STC images were particularly useful in eliminating metabolic background from the retroareolar region which led to identification of two out of four retroareolar tumors. CONCLUSIONS: Using both the abundance and the disposition of the tissue chromophores recovered from the DOSI measurements, we were able to observe tumor contrast relative to dense breast tissue. These preliminary results suggest that DOSI spectral characterization strategies may provide new information content that could help imaging breast tumors in radiographically dense tissue and in particular in the areolar complex.

Optical imaging correlates with magnetic resonance imaging breast density and reveals composition changes during neoadjuvant chemotherapy.

INTRODUCTION: In addition to being a risk factor for breast cancer, breast density has been hypothesized to be a surrogate biomarker for predicting response to endocrine-based chemotherapies. The purpose of this study was to evaluate whether a noninvasive bedside scanner based on diffuse optical spectroscopic imaging (DOSI) provides quantitative metrics to measure and track changes in breast tissue composition and density. To access a broad range of densities in a limited patient population, we performed optical measurements on the contralateral normal breast of patients before and during neoadjuvant chemotherapy (NAC). In this work, DOSI parameters, including tissue hemoglobin, water, and lipid concentrations, were obtained and correlated with magnetic resonance imaging (MRI)-measured fibroglandular tissue density. We evaluated how DOSI could be used to assess breast density while gaining new insight into the impact of chemotherapy on breast tissue. METHODS: This was a retrospective study of 28 volunteers undergoing NAC treatment for breast cancer. Both 3.0-T MRI and broadband DOSI (650 to 1,000 nm) were obtained from the contralateral normal breast before and during NAC. Longitudinal DOSI measurements were used to calculate breast tissue concentrations of oxygenated and deoxygenated hemoglobin, water, and lipid. These values were compared with MRI-measured fibroglandular density before and during therapy. RESULTS: Water (r = 0.843; P < 0.001), deoxyhemoglobin (r = 0.785; P = 0.003), and lipid (r = -0.707; P = 0.010) concentration measured with DOSI correlated strongly with MRI-measured density before therapy. Mean DOSI parameters differed significantly between pre- and postmenopausal subjects at baseline (water, P < 0.001; deoxyhemoglobin, P = 0.024; lipid, P = 0.006). During NAC treatment measured at about 90 days, significant reductions were observed in oxyhemoglobin for pre- (-20.0%; 95% confidence interval (CI), -32.7 to -7.4) and postmenopausal subjects (-20.1%; 95% CI, -31.4 to -8.8), and water concentration for premenopausal subjects (-11.9%; 95% CI, -17.1 to -6.7) compared with baseline. Lipid increased slightly in premenopausal subjects (3.8%; 95% CI, 1.1 to 6.5), and water increased slightly in postmenopausal subjects (4.4%; 95% CI, 0.1 to 8.6). Percentage change in water at the end of therapy compared with baseline correlated strongly with percentage change in MRI-measured density (r = 0.864; P = 0.012). CONCLUSIONS: DOSI functional measurements correlate with MRI fibroglandular density, both before therapy and during NAC. Although from a limited patient dataset, these results suggest that DOSI may provide new functional indices of density based on hemoglobin and water that could be used at the bedside to assess response to therapy and evaluate disease risk.

Molecular imaging of water binding state and diffusion in breast cancer using diffuse optical spectroscopy and diffusion weighted MRI.

Tissue water content and molecular microenvironment can provide important intrinsic contrast for cancer imaging. In this work, we examine the relationship between water optical spectroscopic features related to binding state and magnetic resonance imaging (MRI)-measured water diffusion dynamics. Broadband diffuse optical spectroscopic imaging (DOSI) and MR images were obtained from eight patients with locally-advanced infiltrating ductal carcinomas (tumor size=5.5 ± 3.2 cm). A DOSI-derived bound water index (BWI) was compared to the apparent diffusion coefficient (ADC) of diffusion weighted (DW) MRI. BWI and ADC were positively correlated (R=0.90, p-value=0.003) and BWI and ADC both decreased as the bulk water content increased (R=-0.81 and -0.89, respectively). BWI correlated inversely with tumor size (R=-0.85, p-value=0.008). Our results suggest underlying sensitivity differences between BWI and ADC to water in different tissue compartments (e.g., extracellular vs cellular). These data highlight the potential complementary role of DOSI and DW-MRI in providing detailed information on the molecular disposition of water in breast tumors. Because DOSI is a portable technology that can be used at the bedside, BWI may provide a low-cost measure of tissue water properties related to breast cancer biology.

Diffuse optical imaging using spatially and temporally modulated light.

The authors describe the development of diffuse optical imaging (DOI) technologies, specifically the use of spatial and temporal modulation to control near infrared light propagation in thick tissues. We present theory and methods of DOI focusing on model-based techniques for quantitative, in vivo measurements of endogenous tissue absorption and scattering properties. We specifically emphasize the common conceptual framework of the scalar photon density wave for both temporal and spatial frequency-domain approaches. After presenting the history, theoretical foundation, and instrumentation related to these methods, we provide a brief review of clinical and preclinical applications from our research as well as our outlook on the future of DOI technology.

Tissue phantoms in multicenter clinical trials for diffuse optical technologies.

Tissue simulating phantoms are an important part of instrumentation validation, standardization/training and clinical translation. Properly used, phantoms form the backbone of sound quality control procedures. We describe the development and testing of a series of optically turbid phantoms used in a multi-center American College of Radiology Imaging Network (ACRIN) clinical trial of Diffuse Optical Spectroscopic Imaging (DOSI). The ACRIN trial is designed to measure the response of breast tumors to neoadjuvant chemotherapy. Phantom measurements are used to determine absolute instrument response functions during each measurement session and assess both long and short-term operator and instrument reliability.

Head-up tilt and hyperventilation produce similar changes in cerebral oxygenation and blood volume: an observational comparison study using frequency-domain near-infrared spectroscopy.

PURPOSE: During anesthesia, maneuvers which cause the least disturbance of cerebral oxygenation with the greatest decrease in intracranial pressure would be most beneficial to patients with intracranial hypertension. Both head-up tilt (HUT) and hyperventilation are used to decrease brain bulk, and both may be associated with decreases in cerebral oxygenation. In this observational study, our null hypothesis was that the impact of HUT and hyperventilation on cerebral tissue oxygen saturation (SctO2) and cerebral blood volume (CBV) are comparable. METHODS: Surgical patients without neurological disease were anesthetized with propofol-remifentanil. Before the start of surgery, frequency-domain near-infrared spectroscopy was used to measure SctO2 and CBV at the supine position, at the 30° head-up and head-down positions, as well as during hypoventilation and hyperventilation. RESULTS: Thirty-three patients were studied. Both HUT and hyperventilation induced small decreases in SctO2 [3.5 (2.6)%; P < 0.001 and 3.0 (1.8)%; P < 0.001, respectively] and in CBV [0.05 (0.07) mL x 100 g(-1); P < 0.001 and 0.06 (0.05) mL x 100 g(-1); P < 0.001, respectively]. There were no differences between HUT to 30° and hyperventilation to an end-tidal carbon dioxide (ETCO2) of 25 mmHg (from 45 mmHg) in both SctO2 (P = 0.3) and CBV (P = 0.4). DISCUSSION: The small but statistically significant decreases in both SctO2 and CBV caused by HUT and hyperventilation are comparable. There was no correlation between the decreases in SctO2 and CBV and the decreases in blood pressure and cardiac output during head-up and head-down tilts. However, the decreases in both SctO2 and CBV correlate with the decreases in ETCO2 during ventilation adjustment.

Impact of contralateral and ipsilateral reference tissue selection on self-referencing differential spectroscopy for breast cancer detection.

We previously developed a self-referencing differential spectroscopic (SRDS) method to detect lesions by identifying a spectroscopic biomarker of breast cancer, i.e., the specific tumor component (STC). The SRDS method is based on the assumption of the exclusive presence of this spectroscopic biomaker in malignant disease. Although clinical results using this method have already been published, the dependence of the STC spectra on the choice of reference tissue has not yet been addressed. In this study, we explore the impact of the selection of the reference region size and location on the STC spectrum in 10 subjects with malignant breast tumors. Referencing from both contralateral and ipsilateral sides was performed. Regardless of the referencing, we are able to obtain consistent high contrast images of malignant lesions using the STC with less than 13% deviation. These results suggest that the STC measurements are independent of any type, location, and amount of normal breast tissue used for referencing. This confirms the initial assumption of the SRDS analysis, that there are specific tumor components in cancer that do not exist in normal tissue. This also indicates that bilateral measurements are not required for lesion identification using the STC method.

Diffuse optical spectroscopic imaging correlates with final pathological response in breast cancer neoadjuvant chemotherapy.

Diffuse optical spectroscopic imaging (DOSI) non-invasively and quantitatively measures tissue haemoglobin, water and lipid. Pilot studies in small groups of patients demonstrate that DOSI may be useful for longitudinal monitoring and predicting breast cancer neoadjuvant chemotherapy pathological response. This study evaluates the performance of a bedside DOSI platform in 34 breast cancer patients followed for several months. DOSI optical endpoints obtained at multiple timepoints are compared with final pathological response. Thirty-six stage II/III breast cancers (34 patients) were measured in vivo with DOSI prior to, in the middle of and after the completion of pre-surgical neoadjuvant chemotherapy. Cancer therapies ranged from standard anthracyclines to targeted therapies. Changes in DOSI-measured parameters at each timepoint were compared against final surgical pathology. Absolute changes in the tumour-to-normal (T/N) ratio of tissue deoxyhaemoglobin concentration (ctHHb) and relative changes in the T/N ratio of a tissue optical index (TOI) were most sensitive and correlate to pathological response. Changes in ctHHb and TOI were significantly different between tumours that achieved pathological complete response (pCR) versus non-pCR. By therapy midpoint, mean TOI-T/N changes were 47±8 versus 20±5 per cent for pCR versus non-pCR subjects, respectively (Z=0.011). Changes in ctHHb and TOI scaled significantly with the degree of pathological response (non-, partial and complete). DOSI measurements of TOI separated pCR from non-pCR by therapy midpoint regardless of drug or dosing strategy. This approach is well suited to monitoring breast tumour response and may provide feedback for optimizing therapeutic outcomes and minimizing side-effects.

Frequent optical imaging during breast cancer neoadjuvant chemotherapy reveals dynamic tumor physiology in an individual patient.

RATIONALE AND OBJECTIVES: Imaging tumor response to neoadjuvant chemotherapy in vivo offers unique opportunities for patient care and clinical decision-making. Detailed imaging studies may allow oncologists to optimize therapeutic drug type and dose based on individual patient response. Most radiologic methods are used sparingly because of cost; thus, important functional information about tumor response dynamics may be missed. In addition, current clinical standards are based on determining tumor size changes; thus, standard anatomic imaging may be insensitive to early or frequent biochemical responses. Because optical methods provide functional imaging end points, our objective is to develop a low-barrier-to-access bedside approach that can be used for frequent, functional assessment of dynamic tumor physiology in individual patients. MATERIALS AND METHODS: Diffuse Optical Spectroscopic Imaging (DOSI) is a noninvasive, bedside functional imaging technique that quantifies the concentration and molecular state of tissue hemoglobin, water, and lipid. Pilot clinical studies have shown that DOSI may be a useful tool for quantifying neoadjuvant chemotherapy response, typically by comparing the degree of change in tumor water and deoxy-hemoglobin concentration before and after therapy. Patient responses at 1 week and mid-therapy have been used to predict clinical outcome. In this report, we assess the potential value of frequent DOSI monitoring by performing measurements on 19 different days in a 51-year-old subject with infiltrating ductal carcinoma (initial tumor size 60 x 27 mm) who received neoadjuvant chemotherapy (anthracyclines and bevacizumab) over an 18-week period. RESULTS: A composite index, the Tissue Optical Index (TOI), showed a significant ( approximately 50%) decrease over the nearly 18 weeks of chemotherapy. Tumor response was sensitive to the type of chemotherapy agent, and functional indices fluctuated in a manner consistent with dynamic tumor physiology. Final pathology revealed 4 mm of residual disease, which was detectible by DOSI at the conclusion of chemotherapy before surgery. CONCLUSION: This case study suggests that DOSI may be a bedside-capable tool for frequent longitudinal monitoring of therapeutic functional response to neoadjuvant chemotherapy.

Imaging breast cancer chemotherapy response with light. Commentary on Soliman et al., p. 2605.

Diffuse optical spectroscopy (DOS), which is used to image tumor metabolic response to neoadjuvant chemotherapy (NAC), shows large changes in tumor functional parameters with significant reductions in oxy- and deoxyhemoglobin for responders versus nonresponders. Although investigational, DOS may provide a cost-effective, risk-free method for optimizing NAC drug and dosing strategies for individual patients.

Parametric Diffuse Optical Imaging in Reflectance Geometry.

Diffuse optical imaging (DOI) is a model-based technique used for noninvasive characterization of subsurface tissue function and structure. Compared to more common transmission geometries, reflectance DOI has the advantage of being portable and easily implemented in a clinical setting. However, reflectance measurements are generally not compatible with conventional DOI image reconstruction methods because they typically provide a limited number of unique tissue views. In this paper, we describe a fast and reliable DOI image reconstruction method based on parameterization of tissue and tumor optical contrast, using physiological a priori knowledge. The reconstruction method is formulated within the general Bayesian inversion framework and is capable of handling both model and measurement errors. Simulations are carried out to illustrate the application of this approach, using a limited number of source-detector combinations. It is also shown that parametric reflectance DOI is robust to model misspecifications and measurement noise.

Characterization of metabolic differences between benign and malignant tumors: high-spectral-resolution diffuse optical spectroscopy.

PURPOSE: To develop a near-infrared spectroscopic method to identify breast cancer biomarkers and to retrospectively determine if benign and malignant breast lesions could be distinguished by using this method. MATERIALS AND METHODS: The study was HIPAA compliant and was approved by the university institutional review board. Written informed consent was obtained. By using self-referencing differential spectroscopy (SRDS) analysis, the existence of specific spectroscopic signatures of breast lesions on images acquired by using diffuse optical spectroscopy imaging in the wavelength range (650-1000 nm) was established. The SRDS method was tested in 60 subjects (mean age, 38 years; age range, 22-74 years). There were 17 patients with benign breast tumors and 22 patients with malignant breast tumors. There were 21 control subjects. RESULTS: Discrimination analysis helped separate malignant from benign tumors. A total of 40 lesions (22 malignant and 18 benign) were analyzed. Twenty were true-positive lesions, 17 were true-negative lesions, one was a false-positive lesion, and two were false-negative lesions (sensitivity, 91% [20 of 22]; specificity, 94% [17 of 18]; positive predictive value, 95% [20 of 21]; and negative predictive value, 89% [17 of 19]). CONCLUSION: The SRDS method revealed localized tumor biomarkers specific to pathologic state.

Assessing the spatial extent of breast tumor intrinsic optical contrast using ultrasound and diffuse optical spectroscopy.

Little is known about the relationship between anatomic and functional contrast derived from intrinsic optical signals. In order to address this relationship, finite-element (FEM) forward simulations were compared to diffuse optical spectroscopy (DOS) reflectance measurements obtained from 10 breast tumor patients. Clinical ultrasound images were used to estimate anatomical tumor size and depth for the FEM simulations. Actual DOS-measured tumor absorption could not be matched by forward model simulations when tumor size was constrained to match ultrasound dimensions. However, agreement was achieved when the lesion was viewed as a distribution of optical properties (i.e., an extended target). This result suggests that the spatial extent of optical contrast in breast tumors may be significantly greater than anatomical dimensions reported by standard imaging modalities. Analysis indicates that invasive breast tumors with anatomical dimensions of 1 cm may still be detectable at depths of 30 mm or more (the center of the lesion to the surface of tissue) using DOS in a reflectance geometry.

Assessing the future of diffuse optical imaging technologies for breast cancer management.

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.