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Rapid estimation of the depth and margins of fluorescence targets buried below the tissue surface could improve upon current image-guided surgery techniques for tumor resection.We describe algorithms and instrumentation that permit rapid estimation of the depth and transverse margins of fluorescence target(s) in turbid media; the work aims to introduce, experimentally demonstrate, and characterize the methodology.Spatial frequency domain fluorescence diffuse optical tomography (SFD-FDOT) technique is adapted for rapid and computationally inexpensive estimation of fluorophore target depth and lateral margins. The algorithm utilizes the variation of diffuse fluorescence intensity with respect to spatial-modulation-frequency to compute target depth. The lateral margins are determined via analytical inversion of the data using depth information obtained from the first step. We characterize method performance using fluorescent contrast targets embedded in tissue-simulating phantoms.Single and multiple targets with significant lateral size were imaged at varying depths as deep as 1 cm. Phantom data analysis showed good depth-sensitivity, and the reconstructed transverse margins were mostly within ∼30 % error from true margins.The study suggests that the rapid SFD-FDOT approach could be useful in resection surgery and, more broadly, as a first step in more rigorous SFD-FDOT reconstructions. The experiments permit evaluation of current limitations.

This guest editorial introduces the Special Section on Metabolic Imaging and Spectroscopy: Britton Chance 105th Birthday Commemorative.

Diffuse optical tomography has demonstrated significant potential for clinical utility in the diagnosis and prognosis of breast cancer, and its use in combination with other structural imaging modalities improves lesion localization and the quantification of functional tissue properties. Here, we introduce a hybrid diffuse optical imaging system that operates concurrently with magnetic resonance imaging (MRI) in the imaging suite, utilizing commercially available MR surface coils. The instrument acquires both continuous-wave and time-domain diffuse optical data in the parallel-plate geometry, permitting both absolute assignment of tissue optical properties and three-dimensional tomography; moreover, the instrument is designed to incorporate diffuse correlation spectroscopic measurements for probing tissue blood flow. The instrument is described in detail here. Image reconstructions of a tissue phantom are presented as an initial indicator of the system’s ability to accurately reconstruct optical properties and the concrete benefits of the spatial constraints provided by concurrent MRI. Last, we briefly discuss how various data combinations that the instrument could facilitate, including tissue perfusion, can enable more comprehensive assessment of lesion physiology.

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 [Formula: see text]-score normalization to healthy tissue, produced models with robust predictions. Notably, logistic regression based on [Formula: see text]-score normalization using only tissue oxygen saturation ([Formula: see text]) measured within 10 days of the initial therapy dose was found to be a significant predictor of pCR ([Formula: see text]; 95% CI: 0.82 to 1). This observation suggests that patients who show rapid convergence of tumor tissue [Formula: see text] to surrounding tissue [Formula: see text] 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.

The prevention and treatment of spinal cord injury are focused upon the maintenance of spinal cord blood flow, yet no technology exists to monitor spinal cord ischemia. We recently demonstrated continuous monitoring of spinal cord ischemia with diffuse correlation and optical spectroscopies using an optical probe. Prior to clinical translation of this technology, it is critically important to demonstrate the safety profile of spinal cord exposure to the required light. To our knowledge, this is the first report of in situ safety testing of such a monitor. We expose the spinal cord to laser light utilizing a custom fiber-optic epidural probe in a survival surgery model (11 adult Dorset sheep). We compare the tissue illumination from our instrument with the American National Standards Institute maximum permissible exposures. We experimentally evaluate neurological and pathological outcomes of the irradiated sheep associated with prolonged exposure to the laser source and evaluate heating in ex vivo spinal cord samples. Spinal cord tissue was exposed to light levels at [Formula: see text] the maximum permissible exposure for the eye and [Formula: see text] for the skin. Multidisciplinary testing revealed no functional neurological sequelae, histopathologic evidence of laser-related injury to the spinal cord, or significant temperature changes in ex vivo samples. Low tissue irradiance and the lack of neurological, pathological, and temperature changes upon prolonged exposure to the laser source offer evidence that spinal cord tissues can be monitored safely with near-infrared optical probes placed within the epidural space.

Surgery is the most effective method to cure patients with solid tumors, and 50% of all cancer patients undergo resection. Local recurrences are due to tumor cells remaining in the wound, thus we explore near-infrared (NIR) fluorescence spectroscopy and imaging to identify residual cancer cells after surgery. Fifteen canines and two human patients with spontaneously occurring sarcomas underwent intraoperative imaging. During the operation, the wounds were interrogated with NIR fluorescence imaging and spectroscopy. NIR monitoring identified the presence or absence of residual tumor cells after surgery in 14/15 canines with a mean fluorescence signal-to-background ratio (SBR) of ∼16. Ten animals showed no residual tumor cells in the wound bed (mean SBR1-year follow-up. In five animals, the mean SBR of the wound was >15, and histopathology confirmed tumor cells in the postsurgical wound in four/five canines. In the human pilot study, neither patient had residual tumor cells in the wound bed, and both remain disease free at >1.5-year follow up. Intraoperative NIR fluorescence imaging and spectroscopy identifies residual tumor cells in surgical wounds. These observations suggest that NIR imaging techniques may improve tumor resection during cancer operations.

Diffuse optical tomography (DOT) has been employed to derive spatial maps of physiologically important chromophores in the human breast, but the fidelity of these images is often compromised by boundary effects such as those due to the chest wall. We explore the image quality in fast, data-intensive analytic and algebraic linear DOT reconstructions of phantoms with subcentimeter target features and large absorptive regions mimicking the chest wall. Experiments demonstrate that the chest wall phantom can introduce severe image artifacts. We then show how these artifacts can be mitigated by exclusion of data affected by the chest wall. We also introduce and demonstrate a linear algebraic reconstruction method well suited for very large data sets in the presence of a chest wall.

f ICFO-Institut de Ciencies Fotoniques, Mediterranean Technology Park, 08860 Castelldefels (Barcelona), Spain Abstract. Weinvestigateandassesstheutilityofasimpleschemeforcontinuousabsolutebloodflowmonitoring based on diffuse correlation spectroscopy (DCS). The scheme calibrates DCS using venous-occlusion diffuse optical spectroscopy (VO-DOS) measurements of arm muscle tissue at a single time-point. A calibration coef- ficient(γ)forthearmisdetermined,permittingconversionofDCSbloodflowindicestoabsolutebloodflowunits, andastudyofhealthyadults(N ¼ 10)iscarriedouttoascertainthevariabilityof γ.TheaverageDCScalibration coefficient for the right (i.e., dominant) arm was γ ¼ð 1.24 � 0.15Þ × 10 8 ðmL · 100 mL −1 ·m in −1 Þ∕ðcm 2 ∕sÞ. However,variabilitycanbesignificantandisapparentinoursite-to-siteandday-to-dayrepeatedmeasurements. The peak hyperemic blood flow overshoot relative to baseline resting flow was also studied following arm-cuff ischemia; excellent agreement between VO-DOS and DCS was found (R 2 ¼ 0.95, slope ¼ 0.94 � 0.07, mean difference ¼ −0.10 � 0.45). Finally, we show that incorporation of subject-specific absolute optical prop- erties significantly improves blood flow calibration accuracy. © 2015 Society of Photo-Optical Instrumentation Engineers (SPIE)

We employ a hybrid diffuse correlation spec- troscopy DCS and near-infrared spectroscopy NIRS monitor for neonates with congenital heart disease n=33. The NIRS-DCS device measured changes during hypercapnia of oxyhemoglobin, deoxyhemoglobin, and total hemoglobin concentrations; cerebral blood flow rCBFDCS; and oxygen metabolism rCMRO2. Concur- rent measurements with arterial spin-labeled magnetic resonance imaging rCBFASL-MRI, n=12 cross-validate rCBFDCS against rCBFASL-MRI, showing good agreement R=0.7, p=0.01. The study demonstrates use of NIRS- DCS on a critically ill neonatal population, and the results indicate that the optical technology is a promising clinical method for monitoring this population. © 2010 Society of Photo

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

We combine diffuse optical spectroscopy DOS and dif- fuse correlation spectroscopy DCS to noninvasively monitor early hemodynamic response to neoadjuvant chemotherapy in a breast cancer patient. The potential for early treatment monitoring is dem- onstrated. Within the first week of treatment day 7 DOS revealed significant changes in tumor/normal contrast compared to pretreat- ment day 0 tissue concentrations of deoxyhemoglobin rctHHbT/N =69±21%, oxyhemoglobin rctO2HbT/N=73±25%, total hemo- globin rctTHbT/N=72±17%, and lipid concentration rctLipidT/N =116±13%. Similarly, DCS found significant changes in tumor/ normal blood flow contrast rBFT/N=75±7%on day 7 with respect to day 0. Our observations suggest the combination of DCS and DOS enhances treatment monitoring compared to either technique alone. The hybrid approach also enables construction of indices reflecting tissue metabolic rate of oxygen, which may provide new insights about therapy mechanisms. © 2007 Society of Photo-Optical Instrumentation Engi

We present a novel methodology for combining breast image data obtained at different times, in different geometries, and by different techniques. We combine data based on diffuse optical tomography (DOT) and magnetic resonance imaging (MRI). The software platform integrates advanced multimodal registration and segmentation algorithms, requires minimal user experience, and employs computationally efficient techniques. The resulting superposed 3-D tomographs facilitate tissue analyses based on structural and functional data derived from both modalities, and readily permit enhancement of DOT data reconstruction using MRI-derived a-priori structural information. We demonstrate the multimodal registration method using a simulated phantom, and we present initial patient studies that confirm that tumorous regions in a patient breast found by both imaging modalities exhibit significantly higher total hemoglobin concentration (THC) than surrounding normal tissues. The average THC in the tumorous regions is one to three standard deviations larger than the overall breast average THC for all patients.

We have employed near-infrared optical methods to mea- sure noninvasively the dynamics of muscle blood flow and oxygen saturation (StO2) during cuff occlusion and plantar flexion exercise. Relative muscle oxygen consumption (rVO2) was also computed from these data. Diffuse correlation spectroscopy provides information about blood flow, and diffuse reflectance spectroscopy provides infor- mation about blood oxygenation. Ten healthy subjects and one pa- tient with peripheral arterial disease (PAD) were studied during 3-min arterial cuff occlusion of arm and leg, and during 1-min plantar flex- ion exercise. Signals from different layers (cutaneous tissues and muscles) during cuff occlusion were differentiated, revealing strong hemodynamic responses from muscle layers. During exercise in healthy legs, the observed ;4.7 fold increase in relative blood flow (rBF) was significantly lower than the corresponding increase in rVO2 (;7 fold). The magnitudes of rBF and rVO2 during exercise in the PAD patient were ;1/2 of the healthy controls, and the StO2 recovery time was twice that of the controls. The hybrid instrument improves upon current technologies for measuring muscle responses by simul- taneously measuring rBF and StO2 . The instrument thus provides a method for evaluation of microcirculation and muscle metabolism in patients with vascular diseases. © 2005 Society of Photo-Optical Instrumentation

We compared light-induced fluorescence (LIF) to nominal injected drug dose for predicting the depth of necrosis response to photodynamic therapy (PDT) in a murine tumor model. Mice were implanted with radiation-induced fibrosarcoma (RIF) and were in- jected with 0, 5, or 10 mg/kg Photofrin. 630-nm light (30 J/cm 2 ,7 5 mW/cm 2 ) was delivered to the tumor after 24 hours. Fluorescence emission (l excitation5545 nm, l emission5628 nm) from the tumor was measured. The LIF data had less scatter than injected drug dose, and was found to be at least as good as an injected drug dose for predict- ing the depth of necrosis after PDT. Our observations provide further evidence that fluorescence spectroscopy can be used to quantify tis- sue photosensitizer uptake and to predict PDT tissue damage. © 2003

This PDF file contains the editorial “Guest Editorial: Special Issue Celebrating Britton Chance” for JBO Vol. 5 Issue 02

We describe an approach that combines clinical ultrasound and photon migration techniques to enhance the sensitivity and information content of diffuse optical tomography. Measurements were performed on a postmenopausal woman with a single 1.8 x 0.9 cm malignant ductal carcinoma in situ approximately 7.4 mm beneath the skin surface (UCI IRB protocol 95-563). The ultrasound-derived information about tumor geometry enabled us to segment the breast tissue into tumor and background regions. Optical data was obtained with a multifrequency, multiwavelength hand-held frequency-domain photon migration backscattering probe. The optical properties of the tumor and background were then computed using the ultrasound-derived geometrical constraints. An iterative perturbative approach, using parallel processing, provided quantitative information about scattering and absorption simultaneously with the ability to incorporate and resolve complex boundary conditions and geometries. A three to four fold increase in the tumor absorption coefficient and nearly 50% reduction in scattering coefficient relative to background was observed (lambda = 674, 782, 803, and 849 nm). Calculations of the mean physiological parameters reveal fourfold greater tumor total hemoglobin concentration [Hbtot] than normal breast (67 microM vs 16 microM) and tumor hemoglobin oxygen saturation (SOx) values of 63% (vs 73% and 68% in the region surrounding the tumor and the opposite normal tissue, respectively). Comparison of semi-infinite to heterogeneous models shows superior tumor/background contrast for the latter in both absorption and scattering. Sensitivity studies assessing the impact of tumor size and refractive index assumptions, as well as scan direction, demonstrate modest effects on recovered properties.

Transcranial magnetic stimulation (TMS) modulates processing in the human brain and is therefore of interest as a treatment modality for neurologic conditions. During TMS administration, an electric current passing through a coil on the scalp creates a rapidly varying magnetic field that induces currents in the cerebral cortex. The effects of low-frequency (1 Hz), repetitive TMS (rTMS) on motor cortex cerebral blood flow (CBF) and tissue oxy- genation in seven healthy adults, during/after 20 min stimulation, is reported. Noninvasive optical methods are employed: diffuse correlation spectroscopy (DCS) for blood flow and diffuse optical spectroscopy (DOS) for hemo- globin concentrations. A significant increase in median CBF (33%) on the side ipsilateral to stimulation was observed during rTMS and persisted after discontinuation. The measured hemodynamic parameter variations enabled computation of relative changes in cerebral metabolic rate of oxygen consumption during rTMS, which increased significantly (28%) in the stimulated hemisphere. By contrast, hemodynamic changes from base- line were not observed contralateral to rTMS administration (all parameters, p> 0.29). In total, these findings pro- vide new information about hemodynamic/metabolic responses to low-frequency rTMS and, importantly, demonstrate the feasibility of DCS/DOS for noninvasive monitoring of TMS-induced physiologic effects. © 2013

Peripheral artery disease (PAD) is a common condition with high morbidity. While measurement of tissue oxygen saturation (S(t)O(2)) has been demonstrated, this is the first study to assess both S(t)O(2) and relative blood flow (rBF) in the extremities of PAD patients. Diffuse optics is employed to measure hemodynamic response to treadmill and pedal exercises in 31 healthy controls and 26 patients. For S(t)O(2), mild and moderate/severe PAD groups show pronounced differences compared with controls. Pre-exercise mean S(t)O(2) is lower in PAD groups by 9.3% to 10.6% compared with means of 63.5% to 66.2% in controls. For pedal, relative rate of return of S(t)O(2) to baseline is more rapid in controls (p0.05). Patterns of rBF also differ among groups. After both exercises, rBF tend to occur at depressed levels among severe PAD patients compared with healthy (p0.05); post-treadmill, rBF tend to occur at elevated levels among healthy compared with severe PAD patients (p0.05). Additionally, relative rate of return to baseline S(t)O(2) is more rapid among subjects with reduced levels of depression in rBF (p = 0.041), even after adjustment for ankle brachial index. This suggests a physiologic connection between rBF and oxygenation that can be measured using diffuse optics, and potentially employed as an evaluative tool in further studies.

Diffuse correlation spectroscopy (DCS) is a novel optical technique that appears to be an excellent tool for assessing cerebral blood flow in a continuous and non-invasive manner at the bedside. We present new clinical validation of the DCS methodology by demonstrating strong agreement between DCS indices of relative cerebral blood flow and indices based on phase-encoded velocity mapping magnetic resonance imaging (VENC MRI) of relative blood flow in the jugular veins and superior vena cava. Data were acquired from 46 children with single ventricle cardiac lesions during a hypercapnia intervention. Significant increases in cerebral blood flow, measured both by DCS and by VENC MRI, as well as significant increases in oxyhemoglobin concentration, and total hemoglobin concentration, were observed during hypercapnia. Comparison of blood flow changes measured by VENC MRI in the jugular veins and by DCS revealed a strong linear relationship, R ¼ 0.88, p < 0.001, slope ¼ 0.91 � 0.07. Similar correlations were observed between DCS and VENC MRI in the superior vena cava, R ¼ 0.77, slope ¼ 0.99 � 0.12, p < 0.001. The relationship between VENC MRI in the aorta and DCS, a negative control, was weakly correlated, R ¼ 0.46, slope ¼ 1.77 � 0.45, p < 0.001. © 2012 Society of Photo-Optical Instru

We used a nonimpact inertial rotational model of a closed head injury in neonatal piglets to simulate the conditions following traumatic brain injury in infants. Diffuse optical techniques, including diffuse reflectance spectroscopy and diffuse correlation spectroscopy (DCS), were used to measure cerebral blood oxygenation and blood flow continuously and noninvasively before injury and up to 6 h after the injury. The DCS measurements of relative cerebral blood flow were validated against the fluorescent microsphere method. A strong linear correlation was observed between the two techniques (R = 0.89, p < 0.00001). Injury-induced cerebral hemodynamic changes were quantified, and significant changes were found in oxy- and deoxy-hemoglobin concentrations, total hemoglobin concentration, blood oxygen saturation, and cerebral blood flow after the injury. The diffuse optical measurements were robust and also correlated well with recordings of vital physiological parameters over the 6-h monitoring period, such as mean arterial blood pressure, arterial oxygen saturation, and heart rate. Finally, the diffuse optical techniques demonstrated sensitivity to dynamic physiological events, such as apnea, cardiac arrest, and hypertonic saline infusion. In total, the investigation corraborates potential of the optical methods for bedside monitoring of pediatric and adult human patients in the neurointensive care unit.

Near-infrared diffuse reflectance spectroscopy DRS has been used to noninvasively monitor optical properties during photo- dynamic therapy PDT. This technique has been extensively vali- dated in tissue phantoms; however, validation in patients has been limited. This pilot study compares blood oxygenation and photosen- sitizer tissue uptake measured by multiwavelength DRS with ex vivo assays of the hypoxia marker, 2-2-nitroimida-zol-1H-yl-N- 2,2,3,3,3-pentafluoropropylacetamide EF5, and the photosensitizer motexafin lutetium, MLu from tissues at the same tumor site of three tumors in two patients with intra-abdominal cancers. Similar in vivo and ex vivo measurements of MLu concentration are carried out in murine radiation-induced fibrosarcoma RIF tumors n=9. The se- lection of optimal DRS wavelength range and source-detector separa- tions is discussed and implemented, and the association between in vivo and ex vivo measurements is examined. The results demon- strate a negative correlation between blood oxygen saturation StO2 and EF5 binding, consistent with published relationships between EF5 binding and electrode measured pO2, and between electrode mea- sured pO2 and StO2. A tight correspondence is observed between in vivo DRS and ex vivo measured MLu concentration in the RIF tumors; similar data are positively correlated in the human intraperitoneal tu- mors. These results further demonstrate the potential of in vivo DRS measurements in clinical PDT. © 2007 Society of Photo-Optical Instrumentation

This pilot study explores the potential of noninvasive diffuse correlation spectroscopy (DCS) and diffuse reflectance spectroscopy (DRS) for monitoring early relative blood flow (rBF), tissue oxygen saturation (StO(2)), and total hemoglobin concentration (THC) responses to chemo-radiation therapy in patients with head and neck tumors. rBF, StO(2), and THC in superficial neck tumor nodes of eight patients are measured before and during the chemo-radiation therapy period. The weekly rBF, StO(2), and THC kinetics exhibit different patterns for different individuals, including significant early blood flow changes during the first two weeks. Averaged blood flow increases (52.7+/-9.7)% in the first week and decreases (42.4+/-7.0)% in the second week. Averaged StO(2) increases from (62.9+/-3.4)% baseline value to (70.4+/-3.2)% at the end of the second week, and averaged THC exhibits a continuous decrease from pretreatment value of (80.7+/-7.0) [microM] to (73.3+/-8.3) [microM] at the end of the second week and to (63.0+/-8.1) [microM] at the end of the fourth week of therapy. These preliminary results suggest daily diffuse-optics-based therapy monitoring is feasible during the first two weeks and may have clinical promise.

We evaluate Photofrin-mediated photodynamic therapy (PDT) in a phase 2 clinical trial as an adjuvant to surgery to treat peritoneal carcinomatosis. We extract tissue optical [reduced scattering (mu(s)'), absorption (mu(a)), and attenuation coefficients (mu(eff))] and physiological [blood oxygen saturation (%S(t)O2), total hemoglobin concentration (THC), and photosensitizer concentration (c(Photofrin))] properties in 12 patients using a diffuse reflectance instrument and algorithms based on the diffusion equation. Before PDT, in normal intraperitoneal tissues %S(t)O2 and THC ranged between 32 to 100% and 19 to 263 microM, respectively; corresponding data from tumor tissues ranged between 11 to 44% and 61 to 224 microM. Tumor %S(t)O2 is significantly lower than oxygenation of normal intraperitoneal tissues in the same patients. The mean (+/-standard error of mean) penetration depth (delta) in millimeters at 630 nm is 4.8(+/-0.6) for small bowel, 5.2 (+/-0.67) for large bowel, 3.39(+/-0.29) for peritoneum, 5.19(+/-1.4) for skin, 1.0(+/-0.1) for liver, and 3.02(+/-0.66) for tumor. c(Photofrin) in micromolars is 4.9(+/-2.3) for small bowel, 4.8(+/-2.3) for large bowel, 3.0 (+/-1.0) for peritoneum, 2.5(+/-0.9) for skin, and 7.4(+/-2.8) for tumor. In all tissues examined, mean c(Photofrin) tends to decrease after PDT, perhaps due to photobleaching. These results provide benchmark in-vivo tissue optical property data, and demonstrate the feasibility of in-situ measurements during clinical PDT treatments.

Decorrelation and depolarization properties of multiply scattering media and tissues in the case of propagation of coherent probe beams are analyzed in terms of photon path distribution. A specific correlation time determining the relationship between correlation and polarization states of scattered optical fields is introduced. Results of correlation and polarization experiments with phantom scatterers (such as water suspensions of polystyrene spheres) and tissues with controlled optical properties (such as the human sclera) are presented. © 1999 Society of Photo-Optical Instrumentation Engineers. [S1083-3668(99)00901-6]