Diffuse optical imaging (DOI) may be a beneficial diagnostic method for women with mammographically dense breast tissue. In order to evaluate the utility of DOI, we are developing broadband diffuse optical spectroscopy (DOS) to characterize the functional origins of optical signals in breast cancer patients. Broadband DOS combines multifrequency intensity-modulated and continuous-wave near-infrared light to quantify tissue absorption and scattering spectra from 650 to 1000 nm. Values of intrinsic physiological properties (oxy- and deoxy-hemoglobin, water, lipid, and scatter power) derived from absorption and scattering spectra provide detailed information on breast physiology. We present the results of clinical studies of 58 stage II/III malignant breast tumors using a noninvasive, handheld, broadband DOS probe. On average, eight positions were scanned over tumor and contralateral normal breast for each subject. Intrinsic physiological properties were statistically significantly different for malignant vs. normal tissues for all subjects, without patient age or tumor size/type stratification. Breast tissues containing malignant tumors displayed reduced lipid content ( approximately 20%) and increased water, deoxy-, and oxy-hemoglobin (>50% each) compared to normal breast tissues. Functional perturbations by the tumor were significantly larger than functional variations in normal tissues. A tissue optical index (TOI) derived from intrinsic physiological properties yielded an average two-fold contrast difference between malignant tumors and intrinsic tissue properties. Our results demonstrate that intrinsic optical signals can be influenced by functional perturbations characteristic of malignant transformation; cellular metabolism, extracellular matrix composition, and angiogenesis. Our findings further underscore the importance of broadband measurements and patient age stratification in breast cancer DOI.

Diffuse optical spectroscopy (DOS) and imaging are emerging diagnostic techniques that quantitatively measure the concentration of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctO 2Hb), water (ctH 2O), and lipid in cm-thick tissues. In early-stage clinical studies, diffuse optical imaging and DOS have been used to characterize breast tumor biochemical composition and monitor therapeutic response in stage II/III neoadjuvant chemotherapy patients. We investigated whether DOS measurements obtained before and 1 week into a 3-month adriamycin/cytoxan neoadjuvant chemotherapy regimen can predict final, postsurgical pathological response. Baseline DOS measurements of 11 patients before therapy revealed significant increases in tumor ctHHb, ctO 2Hb, ctH 2O, and spectral scattering slope, and decreases in bulk lipids, relative to normal breast tissue. Tumor concentrations of ctHHb, ctO 2Hb, and ctH2O dropped 27 ؎ 15%, 33 ؎ 7%, and 11 ؎ 15%, respectively, within 1 week (6.5 ؎ 1.4 days) of the first treatment for pathology-confirmed responders (n ‫؍‬ 6), whereas nonresponders (n ‫؍‬ 5) and normal side controls showed no significant changes in these parameters. The best single predictor of therapeutic response 1 week posttreatment was ctHHb (83% sensitivity, 100% specificity), while discrimination analysis based on combined ctHHb and ctH 2O changes classified responders vs. nonresponders with 100% sensitivity and specificity. In addition, the pretreatment tumor-to-normal ctO 2Hb ratio was significantly higher in responders (2.82 ؎ 0.44) vs. nonresponders (1.82 ؎ 0.49). These results highlight DOS sensitivity to tumor cellular metabolism and biochemical composition and demonstrate its potential for predicting and monitoring an individual's response to treatment.diffuse optical imaging ͉ frequency-domain photon migration ͉ near-infrared ͉ tissue spectroscopy ͉ translational research O ptimal management locally advanced breast cancer (LABC) remains a complex therapeutic problem (1). LABC represents 5-20% of all newly diagnosed breast cancers in the United States with a higher incidence in medically underserved areas (2). Treatment for LABC has evolved from radical mastectomy to preoperative neoadjuvant chemotherapy followed by mastectomy or breast conservation therapy (3). Despite aggressive local therapy, long-term patient survival is still poor. LABC remains controversial because of uncertainties in determining the optimal intensity and duration of neoadjuvant chemotherapy and evaluating therapeutic response (2, 4, 5).Neoadjuvant chemotherapy response is determined by serial physical examination, mammography and/or ultrasound. Complete pathological response (cPR) is an important therapeutic endpoint that is a surrogate for eradicating micrometastases, and strongly correlates with patient survival (6). Thus one goal of neoadjuvant chemotherapy monitoring is to determine early when a patient will demonstrate cPR. Many studies revealed significant discrepancies between clinical response assessments and final pathology (7-9).A rece...

ctH 2 O = water concentration; ctHHb = deoxygenated hemoglobin concentration; ctO 2 Hb = oxygenated hemoglobin concentration; ctTHb = total tissue hemoglobin concentration; DOI = diffuse optical imaging; DOS = diffuse optical spectroscopy; MRI = magnetic resonance imaging; NIR = near infrared; stO 2 = tissue hemoglobin oxygenation saturation; TOI = tissue optical index.Available online http://breast-cancer-research.com/content/7/6/279 AbstractDiffuse optical spectroscopy (DOS) and diffuse optical imaging (DOI) are non-invasive diagnostic techniques that employ nearinfrared (NIR) light to quantitatively characterize the optical properties of centimeter-thick, multiple-scattering tissues. Although NIR was first applied to breast diaphanography more than 70 years ago, quantitative optical methods employing time-or frequencydomain 'photon migration' technologies have only recently been used for breast imaging. Because their performance is not limited by mammographic density, optical methods can provide new insight regarding tissue functional changes associated with the appearance, progression, and treatment of breast cancer, particularly for younger women and high-risk subjects who may not benefit from conventional imaging methods. This paper reviews the principles of diffuse optics and describes the development of broadband DOS for quantitatively measuring the optical and physiological properties of thick tissues. Clinical results are shown highlighting the sensitivity of diffuse optics to malignant breast tumors in 12 pre-menopausal subjects ranging in age from 30 to 39 years and a patient undergoing neoadjuvant chemotherapy for locally advanced breast cancer. Significant contrast was observed between normal and tumor regions of tissue for deoxy-hemoglobin (p = 0.005), oxy-hemoglobin (p = 0.002), water (p = 0.014), and lipids (p = 0.0003). Tissue hemoglobin saturation was not found to be a reliable parameter for distinguishing between tumor and normal tissues. Optical data were converted into a tissue optical index that decreased 50% within 1 week in response to neoadjuvant chemotherapy. These results suggest a potential role for diffuse optics as a bedside monitoring tool that could aid the development of new strategies for individualized patient care. IntroductionAlthough mammography is the primary clinical imaging modality used to detect breast cancer, limitations in both sensitivity and specificity, particularly in younger and high-risk women, have led to the development of alternative techniques. Overall, mammography has reduced sensitivity in pre-menopausal women [1] and is not clinically advantageous for women under 35 years of age [2]. A general consensus has emerged that mammography is not recommended for women less than 40 years of age, and in the 40 to 50 year old population there is uncertainly regarding its effectiveness. Additional complications arise due to the fact that in premenopausal women, mammographic density and false negative rates are greater during the luteal versus follicular phase of the...

Approximately 8-20% of breast cancer patients receiving neoadjuvant chemotherapy fail to achieve a measurable response and endure toxic side effects without benefit. Most clinical and imaging measures of response are obtained several weeks after the start of therapy. Here, we report that functional hemodynamic and metabolic information acquired using a noninvasive optical imaging method on the first day after neoadjuvant chemotherapy treatment can discriminate nonresponding from responding patients. Diffuse optical spectroscopic imaging was used to measure absolute concentrations of oxyhemoglobin, deoxyhemoglobin, water, and lipid in tumor and normal breast tissue of 24 tumors in 23 patients with untreated primary breast cancer. Measurements were made before chemotherapy, on day 1 after the first infusion, and frequently during the first week of therapy. Various multidrug, multicycle regimens were used to treat patients. Diffuse optical spectroscopic imaging measurements were compared with final postsurgical pathologic response. A statistically significant increase, or flare, in oxyhemoglobin was observed in partial responding (n = 11) and pathologic complete responding tumors (n = 8) on day 1, whereas nonresponders (n = 5) showed no flare and a subsequent decrease in oxyhemoglobin on day 1. Oxyhemoglobin flare on day 1 was adequate to discriminate nonresponding tumors from responding tumors. Very early measures of chemotherapy response are clinically convenient and offer the potential to alter treatment strategies, resulting in improved patient outcomes.in vivo imaging | near-infrared | diffuse optics | tissue spectroscopy | therapeutic monitoring