Diffuse Optical Spectroscopic Imaging Research Articles

Changes in the tumor oxygenation but not in the tumor volume and tumor vascularization reflect early response of breast cancer to neoadjuvant chemotherapy

BackgroundBreast cancer neoadjuvant chemotherapy (NACT) allows for assessing tumor sensitivity to systemic treatment, planning adjuvant treatment and follow-up. However, a sufficiently large number of patients fail to achieve the desired level of pathological tumor response while optimal early response assessment methods have not been established now. In our study, we simultaneously assessed the early chemotherapy-induced changes in the tumor volume by ultrasound (US), the tumor oxygenation by diffuse optical spectroscopy imaging (DOSI), and the state of the tumor vascular bed by Doppler US to elaborate the predictive criteria of breast tumor response to treatment.MethodsA total of 133 patients with a confirmed diagnosis of invasive breast cancer stage II to III admitted to NACT following definitive breast surgery were enrolled, of those 103 were included in the final analysis. Tumor oxygenation by DOSI, tumor volume by US, and tumor vascularization by Doppler US were determined before the first and second cycle of NACT. After NACT completion, patients underwent surgery followed by pathological examination and assessment of the pathological tumor response. On the basis of these, data regression predictive models were created.ResultsWe observed changes in all three parameters 3 weeks after the start of the treatment. However, a high predictive potential for early assessment of tumor sensitivity to NACT demonstrated only the level of oxygenation, ΔStO2, (ρ = 0.802, p ≤ 0.01). The regression model predicts the tumor response with a high probability of a correct conclusion (89.3%). The “Tumor volume” model and the “Vascularization index” model did not accurately predict the absence of a pathological tumor response to treatment (60.9% and 58.7%, respectively), while predicting a positive response to treatment was relatively better (78.9% and 75.4%, respectively).ConclusionsDiffuse optical spectroscopy imaging appeared to be a robust tool for early predicting breast cancer response to chemotherapy. It may help identify patients who need additional molecular genetic study of the tumor in order to find the source of resistance to treatment, as well as to correct the treatment regimen.

Diffuse optical spectroscopic method for tissue and body composition assessment.

.SignificanceGrowing levels of obesity and metabolic syndrome have driven demand for more advanced forms of body composition assessment. While various techniques exist to measure body composition, devices are typically expensive and not portable, involve radiation [in the case of dual-energy x-ray absorptiometry (DXA)], and are limited to analysis of adiposity while metabolic information from blood supply and oxygenation are not considered.AimWe evaluate whether diffuse optical spectroscopic imaging (DOSI) can be used to predict site-specific adiposity and percent fat (whole body) while simultaneously providing information about local tissue hemoglobin levels and oxygenation.ApproachDOSI measures of tissue composition in gastrocnemius, quadriceps, abdomen, and biceps, DXA whole-body composition, and ultrasound-derived skin and adipose tissue thickness (SATT) in the quadriceps were obtained from 99 individuals aged 7 to 34 years old.ResultsVarious DOSI-derived parameters were correlated with SATT and an optical method is proposed for estimating SATT using a newly defined parameter, the optical fat fraction (OFF), which considers all parameters that correlate with SATT. Broadband absorption and scattering spectra from study participants with the thinnest () and thickest SATT (), representing best estimates for pure in vivo lean and fatty tissue, respectively, are reported. Finally, a trained prediction model is developed which allows DOSI assessment of OFF to predict DXA body-fat percentage, demonstrating that DOSI can be used to quantify body composition.ConclusionsThis study shows that DOSI can be used to assess the adiposity of specific tissues or the entire human body, and the OFF parameter is defined for corroboration and further evaluation in future research.

Multi-modal diffuse optical spectroscopy for high-speed monitoring and wide-area mapping of tissue optical properties and hemodynamics.

.Significance: Diffuse optical spectroscopic imaging (DOSI) is a versatile technology sensitive to changes in tissue composition and hemodynamics and has been used for a wide variety of clinical applications. Specific applications have prompted the development of versions of the DOSI technology to fit specific clinical needs. This work describes the development and characterization of a multi-modal DOSI (MM-DOSI) system that can acquire metabolic, compositional, and pulsatile information at multiple penetration depths in a single hardware platform. Additionally, a 3D tracking system is integrated with MM-DOSI, which enables registration of the acquired data to the physical imaging area.Aim: We demonstrate imaging, layered compositional analysis, and metabolism tracking capabilities using a single MM-DOSI system on optical phantoms as well as in vivo human tissue.Approach: We characterize system performance with a silicone phantom containing an embedded object. To demonstrate multi-layer sensitivity, we imaged human calf tissue with a 4.8-mm skin-adipose thickness. Human thenar tissue was also measured using a combined broadband DOSI and continuous-wave near-infrared spectroscopy method ( acquisition rate).Results: High-resolution optical property maps of absorption () and reduced scattering () were recovered on the phantom by capturing over 1000 measurement points in under 5 minutes. On human calf tissue, we show two probing depth layers have significantly different () total-hemo/myoglobin and composition. On thenar tissue, we calculate tissue arterial oxygen saturation, venous oxygen saturation, and tissue metabolic rate of oxygen consumption during baseline and after release of an arterial occlusion.Conclusions: The MM-DOSI can switch between collection of broadband spectra, high-resolution images, or multi-depth hemodynamics without any hardware reconfiguration. We conclude that MM-DOSI enables acquisition of high resolution, multi-modal data consolidated in a single platform, which can provide a more comprehensive understanding of tissue hemodynamics and composition for a wide range of clinical applications.

Real-Time Handheld Probe Tracking and Image Formation Using Digital Frequency-Domain Diffuse Optical Spectroscopy.

Frequency-domain diffuse optical spectroscopic imaging (FD-DOS) is a non-invasive method for measuring absolute concentrations of tissue chromophores such as oxy- and deoxy-hemoglobin in vivo. The utility of FD-DOS for clinical applications such as monitoring chemotherapy response in breast cancer has previously been demonstrated, but challenges for further clinical translation, such as slow acquisition speed and lack of user feedback, remain. Here, we propose a new high speed FD-DOS instrument that allows users to freely acquire measurements over the tissue surface, and is capable of rapidly imaging large volumes of tissue. We utilize 3D monocular probe tracking combined with custom digital FD-DOS hardware and a high-speed data processing pipeline for the instrument. Results are displayed during scanning over the surface of the sample using a probabilistic Monte Carlo light propagation model. We show this instrument can measure absorption and scattering coefficients with an error of 7% and 1% respectively, with 0.7 mm positional accuracy. We demonstrate the equivalence of our visualization methodology with a standard interpolation approach, and demonstrate two proof-of-concept in vivo results showing superficial vasculature in the human forearm and surface contrast in a healthy human breast. Our new FD-DOS system is able to compute chromophore concentrations in real-time (1.5 Hz) in vivo. This method has the potential to improve the quality of FD-DOS image scans while reducing measurement times for a variety of clinical applications.

Breast cancer differential diagnosis using diffuse optical spectroscopic imaging and regression with z-score normalized data.

.Significance: Current imaging paradigms for differential diagnosis of suspicious breast lesions suffer from high false positive rates that force patients to undergo unnecessary biopsies. Diffuse optical spectroscopic imaging (DOSI) noninvasively probes functional hemodynamic and compositional parameters in deep tissue and has been shown to be sensitive to contrast between normal and malignant tissues.Aim: DOSI methods are under investigation as an adjunct to mammography and ultrasound that could reduce false positive rates and unnecessary biopsies, particularly in radiographically dense breasts.Methods: We performed a retrospective analysis of 212 subjects with suspicious breast lesions who underwent DOSI imaging. Physiological tissue parameters were -score normalized to the patient’s contralateral breast tissue and input to univariate logistic regression models to discriminate between malignant tumors and the surrounding normal tissue. The models were then used to differentiate malignant lesions from benign lesions.Results: Models incorporating several individual hemodynamic parameters were able to accurately distinguish malignant tumors from both the surrounding background tissue and benign lesions with area under the curve (AUC) . -score normalization improved the discriminatory ability and calibration of these predictive models relative to unnormalized or ratio-normalized data.Conclusions: Findings from a large subject population study show how DOSI data normalization that accounts for normal tissue heterogeneity and quantitative statistical regression approaches can be combined to improve the ability of DOSI to diagnose malignant lesions. This improved diagnostic accuracy, combined with the modality’s inherent logistical advantages of portability, low cost, and nonionizing radiation, could position DOSI as an effective adjunct modality that could be used to reduce the number of unnecessary invasive biopsies.

Characterization of bony anatomic regions in pediatric and adult healthy volunteers using diffuse optical spectroscopic imaging.

.Significance: Diffuse optical spectroscopic imaging (DOSI) measures quantitative functional and molecular information in thick tissue in a noninvasive manner using near-infrared light. DOSI may be useful for diagnosis and prognosis of bone pathologies including osteosarcoma and Ewing’s sarcoma, but little is currently known about DOSI-derived parameters in bony anatomic locations where this disease occurs.Aim: Our goal is to quantify the optical characteristics and chromophore content of bony anatomic locations of healthy volunteers and assess differences due to anatomic region, age, sex, ethnicity, race, and body fat.Approach: Fifty-five healthy volunteers aged 4 to 72 were enrolled in the study. The optical properties and quantitative tissue concentrations of oxyhemoglobin, deoxyhemoglobin, water, and lipids were assessed at the distal humerus, distal femur, and proximal tibia. Body fat was assessed using skinfold calipers. One volunteer underwent a more comprehensive body scan from neck to foot to explore chromophore distributions within an individual. Regression analysis was used to identify the most important sources of variation in the measured data set.Results: Statistical differences between bony locations were found for scattering, water, and lipids, but not for hemoglobin. All chromophores had statistical differences with sex, but there were no significant age-related correlations. Regression analysis revealed that body fat measured with skinfold calipers was the most important predictor of oxy-, deoxy-, total hemoglobin, and lipids. Hemoglobin and lipid levels were highly correlated () over the subject population and within the single-subject body scan.Conclusions: DOSI can successfully measure bony anatomic sites where osteosarcomas and Ewing’s sarcomas commonly occur. Future studies of bone pathology using DOSI should account for the variation caused by anatomic region, sex, race and ethnicity, and body fat as these cause substantial variations in DOSI-derived metrics.

Diffuse optical spectroscopic imaging reveals distinct early breast tumor hemodynamic responses to metronomic and maximum tolerated dose regimens

BackgroundBreast cancer patients with early-stage disease are increasingly administered neoadjuvant chemotherapy (NAC) to downstage their tumors prior to surgery. In this setting, approximately 31% of patients fail to respond to therapy. This demonstrates the need for techniques capable of providing personalized feedback about treatment response at the earliest stages of therapy to identify patients likely to benefit from changing treatment. Diffuse optical spectroscopic imaging (DOSI) has emerged as a promising functional imaging technique for NAC monitoring. DOSI uses non-ionizing near-infrared light to provide non-invasive measures of absolute concentrations of tissue chromophores such as oxyhemoglobin. In 2011, we reported a new DOSI prognostic marker, oxyhemoglobin flare: a transient increase in oxyhemoglobin capable of discriminating NAC responders within the first day of treatment. In this follow-up study, DOSI was used to confirm the presence of the flare as well as to investigate whether DOSI markers of NAC response are regimen dependent.MethodsThis dual-center study examined 54 breast tumors receiving NAC measured with DOSI before therapy and the first week following chemotherapy administration. Patients were treated with either a standard of care maximum tolerated dose (MTD) regimen or an investigational metronomic (MET) regimen. Changes in tumor chromophores were tracked throughout the first week and compared to pathologic response and treatment regimen at specific days utilizing generalized estimating equations (GEE).ResultsWithin patients receiving MTD therapy, the oxyhemoglobin flare was confirmed as a prognostic DOSI marker for response appearing as soon as day 1 with post hoc GEE analysis demonstrating a difference of 48.77% between responders and non-responders (p < 0.0001). Flare was not observed in patients receiving MET therapy. Within all responding patients, the specific treatment was a significant predictor of day 1 changes in oxyhemoglobin, showing a difference of 39.45% (p = 0.0010) between patients receiving MTD and MET regimens.ConclusionsDOSI optical biomarkers are differentially sensitive to MTD and MET regimens at early timepoints suggesting the specific treatment regimen should be considered in future DOSI studies. Additionally, DOSI may help to identify regimen-specific responses in a more personalized manner, potentially providing critical feedback necessary to implement adaptive changes to the treatment strategy.

Abstract 1408: Diffuse optical spectroscopic imaging reveals regimen-dependent changes in breast tumors throughout neoadjuvant chemotherapy

Abstract Diffuse Optical Spectroscopic Imaging (DOSI) is a non-invasive near-infrared imaging modality than can provide label-free functional and metabolic information about breast tumors, probing depths up to several centimeters. Previous work has shown that DOSI has prognostic value for pathological response at key timepoints during neoadjuvant (presurgical) chemotherapy (NAC), including baseline, 24 hours after the first infusion, week 1, and at the midpoint of therapy. To date there have been almost no reports on how specific NAC regimens affect the prognostic capability of DOSI. Here we present a large multi-center DOSI dataset consisting of 54 breast tumors and 313 unique measurements taken across three timepoints during NAC: Baseline, week 1, and midpoint of treatment. We will show for the first time that the manifestation of DOSI response parameters (oxyhemoglobin, de-oxyhemoglobin, water, and lipid) is highly dependent on the specific NAC regimen used. Subjects were treated with either a Maximum Tolerated Dose (MTD) regimen, in which a higher dose is administered less frequently, or a Metronomic (MET) regimen, in which a smaller dose is given more frequently. MTD regimen of cytotoxic agents has traditionally been the most effective method to treat breast cancer as it aims to kill the maximum amount of tumor cells before regrowth. MET administration of cytotoxic therapies has shown antiangiogenic properties aiming to limit toxic side effects and drug resistance, while potentially inducing tumor dormancy and immunomodulation. Subjects treated with MTD regimen and also responding to this treatment exhibited an oxyhemoglobin flare in the first day of NAC. In contrast, subjects treated with MET presented only small fluctuations in oxyhemoglobin throughout the first week of NAC. The oxyhemoglobin flare has been theorized to be induced by an inflammatory effect significant for cell death, which could be in response to specifically the MTD regimen and its higher dosing. This study indicates that the specific regimen must be considered when using DOSI for NAC monitoring. It also suggests DOSI may provide biological insight into the regimen-specific mechanisms of action. Citation Format: Anup Tank, Hannah Peterson, Vivian Pera, Syeda Tabassum, Naomi Ko, Anais Leproux, Bruce Tromberg, Darren Roblyer. Diffuse optical spectroscopic imaging reveals regimen-dependent changes in breast tumors throughout neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1408.

Diffuse optical spectroscopic imaging for the investigation of human lactation physiology: a case study on mammary involution.

.Relatively few imaging and sensing technologies are employed to study human lactation physiology. In particular, human mammary development during pregnancy as well as mammary involution after lactation have been poorly described, despite their importance for breast cancer diagnosis and treatment during these phases. Our case study shows the potential of diffuse optical spectroscopic imaging (DOSI) to uniquely study the spatiotemporal changes in mammary tissue composition during the involution of the lactating breast toward its pre-pregnant state. At nine time intervals over a period of eight months after the cessation of breastfeeding, we reconstructed 2-D maps of mammary water content, lipid content, total hemoglobin (THb) concentration, oxygen saturation (), and tissue optical scattering. Mammary lipid content in the nonareolar region showed a significant relative increase of 59%, whereas water content and THb concentration showed a significant relative decrease of 50% and 48%, respectively. Significant changes were also found in and tissue optical scattering. Our findings are consistent with the gradual replacement of fibroglandular tissue by adipose tissue and vascular regression during mammary involution. Moreover, our data provide unique insight into the dynamics of breast tissue composition and demonstrate the effectiveness of DOSI as a technique to study human lactation physiology.

Monocular 3D Probe Tracking for Generating Sub-Surface Optical Property Maps From Diffuse Optical Spectroscopic Imaging.

Diffuse optical spectroscopic imaging (DOSI) is a promising biophotonic technology for clinical tissue assessment, but is currently hampered by difficult wide area assessment. A co-integrative optical imaging system is proposed for dense sub-surface optical property spatial assessment. The proposed system fuses a co-aligned set of camera frames and diffuse optical spectroscopy measurements to generate spatial sub-surface optical property maps. A 3D rigid body motion estimation model was developed by fitting automatically detected target features to an a priori geometric model using a single overhead camera. Point-wise optical properties were measured across the tissue using frequency domain photon migration DOSI. The 3D probe trajectory and temporal optical property data were fused to generate 2D spatial optical property maps, which were projected onto the tissue image using pre-calibrated camera parameters. The system demonstrated sub-millimeter positional accuracy (error 0.24 ± 0.35mm) across different probe speeds (1.0-3.8cm/s), and displacement accuracy in overhead ([Formula: see text]mm) and tilted (0.51 ± 0.51mm) camera orientations. Unstructured scans on a tumor inclusion phantom showed strong contrast under different probe paths, and significant ( ) changes in optical properties in an in vivo leg cuff occlusion protocol with spatial anatomy localization. The proposed co-integrative optical imaging system generated dense sub-surface optical property distributions across wide tissue areas with sub-millimeter accuracy at different probe speeds and trajectories, and does not require pre-planned probe route for tissue assessment. This system provides a valuable tool for real-time non-invasive tissue health and cancer screening, and enables longitudinal disease progression assessment through unstructured probe-based optical tissue assessment.

Linearized reconstruction for diffuse optical spectroscopic imaging

In this paper, we present a novel reconstruction method for diffuse optical spectroscopic imaging with a commonly used tissue model of optical absorption and scattering. It is based on linearization and group sparsity, which allows the diffusion coefficient and absorption coefficient to be recovered simultaneously, provided that their spectral profiles are incoherent and a sufficient number of wavelengths are judiciously taken for the measurements. We also discuss the reconstruction for an imperfectly known boundary and show that, with multi-wavelength data, the method can reduce the influence of modelling errors and still recover the absorption coefficient. Extensive numerical experiments are presented to support our analysis.

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

In vivo, noninvasive functional measurements of bone sarcoma using diffuse optical spectroscopic imaging.

Diffuse optical spectroscopic imaging (DOSI) is an emerging near-infrared imaging technique that noninvasively measures quantitative functional information in thick tissue. This study aimed to assess the feasibility of using DOSI to measure optical contrast from bone sarcomas. These tumors are rare and pose technical and practical challenges for DOSI measurements due to the varied anatomic locations and tissue depths of presentation. Six subjects were enrolled in the study. One subject was unable to be measured due to tissue contact sensitivity. For the five remaining subjects, the signal-to-noise ratio, imaging depth, optical properties, and quantitative tissue concentrations of oxyhemoglobin, deoxyhemoglobin, water, and lipids from tumor and contralateral normal tissues were assessed. Statistical differences between tumor and contralateral normal tissue were found in chromophore concentrations and optical properties for four subjects. Low signal-to-noise was encountered during several subject's measurements, suggesting increased detector sensitivity will help to optimize DOSI for this patient population going forward. This study demonstrates that DOSI is capable of measuring optical properties and obtaining functional information in bone sarcomas. In the future, DOSI may provide a means to stratify treatment groups and monitor chemotherapy response for this disease.

Noninvasive optical imaging of resistance training adaptations in human muscle.

.A quantitative and dynamic analysis of skeletal muscle structure and function can guide training protocols and optimize interventions for rehabilitation and disease. While technologies exist to measure body composition, techniques are still needed for quantitative, long-term functional imaging of muscle at the bedside. We evaluate whether diffuse optical spectroscopic imaging (DOSI) can be used for long-term assessment of resistance training (RT). DOSI measures of tissue composition were obtained from 12 adults before and after 5 weeks of training and compared to lean mass fraction (LMF) from dual-energy X-ray absorptiometry (DXA). Significant correlations were detected between DXA LMF and DOSI-measured oxy-hemo/myoglobin, deoxy-hemo/myoglobin, total-hemo/myoglobin, water, and lipid. RT-induced increases of in oxy-hemo/myoglobin (, ) and total-hemo/myoglobin (, ) from the medial gastrocnemius were detected with DOSI and accompanied by increases in lean soft tissue mass (, ) and increases in 1 rep-max strength (, ). DOSI measures of vascular and/or muscle changes combined with correlations between DOSI and DXA suggest that quantitative diffuse optical methods can be used to evaluate body composition, provide feedback on long-term interventions, and generate new insight into training-induced muscle adaptations.

Freehand diffuse optical spectroscopy imaging for intraoperative identification of major venous and arterial vessels underlying peritoneal fat: an in vivo demonstration in a pig model.

Inadvertent injury to important anatomic structures is a significant risk in minimally invasive surgery (MIS) that potentially requires conversion to an open procedure, which results in increased morbidity and mortality. Surgeons operating minimal-invasively currently do not have an easy-to-use, real-time device to aid in intraoperative identification of important anatomic structures that underlie tissue planes. We demonstrate freehand diffuse optical spectroscopy (DOS) imaging for intraoperatively identifying major underlying veins and arteries. An applicator probe that can be affixed to and detached from an 8-mm laparoscopic instrument has been developed. The 10-mm DOS source-detector separation renders sampling of tissue heterogeneities a few millimeters deep. DOS spectra acquired consecutively during freehand movement of the applicator probe on the tissue surface are displayed as a temporal and spectral image to assist in spatially resolved identification of the underlying structures. Open surgery identifications of the vena cava and aorta underlying peritoneal fat of ∼4 mm in thickness using the applicator probe under room light were demonstrated repeatedly in multiple pigs in vivo.

Bevacizumab Induces Acute Hypoxia and Cancer Progression in Patients with Refractory Breast Cancer: Multimodal Functional Imaging and Multiplex Cytokine Analysis

Purpose: Bevacizumab, an antibody against endothelial growth factor, is a key but controversial drug in the treatment of metastatic breast cancer. We, therefore, aimed to determine the intrinsic resistance to bevacizumab at the physiologic and molecular levels in advanced breast cancer using PET, dynamic contrast-enhanced MRI, diffuse optical spectroscopic imaging (DOSI), and multiplex cytokine assays.Experimental Design: In total, 28 patients diagnosed with advanced stage III/IV breast cancer receiving single-agent bevacizumab for 1 week followed by paclitaxel combined with bevacizumab underwent 18F-fluorodeoxyglucose (FDG)-PET, 18F-fluoromisonidazole (FMISO)-PET, and MRI at both baseline and two courses after treatment initiation. Hemodynamic measurement using DOSI and blood sample collection were performed at baseline and multiple times during the first week after the initiation of single-agent bevacizumab. We distinguished nonresponders from responders by serial FDG-PET based on their glycolytic changes to chemotherapy.Results: Nonresponders showed significantly higher hypoxic activity on FMISO-PET and less tumor shrinkage than responders. Hemodynamic parameters showed higher tumor blood volume and a remarkable decrease in the tissue oxygen level in nonresponders compared with responders after the infusion of single-agent bevacizumab. Multiplex cytokine assays revealed increased plasma levels of both proangiogenic and hypoxia-related inflammatory cytokines in nonresponders and decreased levels in responders.Conclusions: Nonresponders exhibited a higher degree of angiogenesis with more severe hypoxia than responders during bevacizumab treatment. These findings demonstrated that the addition of bevacizumab to paclitaxel treatment under hypoxic conditions could be ineffective and may result in acute hypoxia and increased cytokine secretion associated with cancer progression. Clin Cancer Res; 23(19); 5769-78. ©2017 AACR.

Performance assessment of diffuse optical spectroscopic imaging instruments in a 2-year multicenter breast cancer trial

We present a framework for characterizing the performance of an experimental imaging technology, diffuse optical spectroscopic imaging (DOSI), in a 2-year multicenter American College of Radiology Imaging Network (ACRIN) breast cancer study (ACRIN-6691). DOSI instruments combine broadband frequency-domain photon migration with time-independent near-infrared (650 to 1000 nm) spectroscopy to measure tissue absorption and reduced scattering spectra and tissue hemoglobin, water, and lipid composition. The goal of ACRIN-6691 was to test the effectiveness of optically derived imaging endpoints in predicting the final pathologic response of neoadjuvant chemotherapy (NAC). Sixty patients were enrolled over a 2-year period at participating sites and received multiple DOSI scans prior to and during 3- to 6-month NAC. The impact of three sources of error on accuracy and precision, including different operators, instruments, and calibration standards, was evaluated using a broadband reflectance standard and two different solid tissue-simulating optical phantoms. Instruments showed <0.0010 mm−1 (10.3%) and 0.06 mm−1 (4.7%) deviation in broadband absorption and reduced scattering, respectively, over the 2-year duration of ACRIN-6691. These variations establish a useful performance criterion for assessing instrument stability. The proposed procedures and tests are not limited to DOSI; rather, they are intended to provide methods to characterize performance of any instrument used in translational optical imaging.

Abstract 699: Clinical feasibility of chemotherapy monitoring for bone sarcoma patients with diffuse optical spectroscopic imaging

Abstract Background: Sarcomas account for almost 15% of all childhood cancers and 40-60% of these patients develop locally recurrent or metastatic disease. Currently in many sarcomas, the only clinically accepted prognostic marker in patients with localized disease is the percent of tumor necrosis at the time of surgery. Diffuse Optical Spectroscopic Imaging (DOSI) is an emerging near-infrared (NIR) imaging technique that non-invasively measures quantitative functional information and may provide a new means to monitor and predict chemotherapy response in sarcoma which could impact treatment decisions. Here we evaluate the feasibility of measuring pediatric sarcomas with DOSI. Methods: Patients diagnosed with either Ewing’s Sarcoma or osteosarcoma underwent DOSI measurement at multiple time points during their course of neoadjuvant chemotherapy. A handheld probe was used to take point measurements in a 1 cm spaced grid at tumor and contralateral normal locations. The measurement area was approximately 6 x 7 cm and a single point measurement typically took 15-30 s, which includes the time it takes to position the probe, ensure good contact between the probe and the skin, and acquire data. The optical properties, and absolute concentrations of oxyhemoglobin (ctHbO2), deoxyhemoglobin (ctHb), water (ctH2O), and lipids were compared between tumor and normal measurements. Results: To date, one osteosarcoma and two Ewing’s sarcoma patients have been measured. At baseline and early in treatment, all subjects had a statistical difference in total hemoglobin concentration between the affected and contralateral normal tissues (p &amp;lt; 0.05 for Student’s t-test, Kolmogorov-Smirnov test, and Mann-Whitney rank test). Statistical differences also appeared in oxyhemoglobin, deoxyhemoglobin, oxygen saturation, water, lipids, scattering amplitude, and scattering power although longitudinal trends varied across patients. Conclusions: DOSI can be utilized to measure optical properties and to obtain functional information in bone sarcoma patients. It can detect differences between affected and normal tissue. A better understanding of the optical properties in this patient population is needed. Larger data sets are needed to characterize and quantify sarcoma optical properties and treatment response dynamics, ideally finding a functional biomarker associated with pathologic response. Additional accrual of primary bone sarcoma patients and normal volunteers is ongoing. Citation Format: Hannah M. Peterson, Bang H. Hoang, David Geller, Richard Gorlick, Rui Yang, Jeremy Berger, Janet Tingling, Michael Roth, Jonathan Gill, Darren Roblyer. Clinical feasibility of chemotherapy monitoring for bone sarcoma patients with diffuse optical spectroscopic imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 699. doi:10.1158/1538-7445.AM2017-699

Longitudinal optical monitoring of blood flow in breast tumors during neoadjuvant chemotherapy

We measure tissue blood flow markers in breast tumors during neoadjuvant chemotherapy and investigate their correlation to pathologic complete response in a pilot longitudinal patient study (n = 4). Tumor blood flow is quantified optically by diffuse correlation spectroscopy (DCS), and tissue optical properties, blood oxygen saturation, and total hemoglobin concentration are derived from concurrent diffuse optical spectroscopic imaging (DOSI). The study represents the first longitudinal DCS measurement of neoadjuvant chemotherapy in humans over the entire course of treatment; it therefore offers a first correlation between DCS flow indices and pathologic complete response. The use of absolute optical properties measured by DOSI facilitates significant improvement of DCS blood flow calculation, which typically assumes optical properties based on literature values. Additionally, the combination of the DCS blood flow index and the tissue oxygen saturation from DOSI permits investigation of tissue oxygen metabolism. Pilot results from four patients suggest that lower blood flow in the lesion-bearing breast is correlated with pathologic complete response. Both absolute lesion blood flow and lesion flow relative to the contralateral breast exhibit potential for characterization of pathological response. This initial demonstration of the combined optical approach for chemotherapy monitoring provides incentive for more comprehensive studies in the future and can help power those investigations.

Sample size and power determination when limited preliminary information is available

BackgroundWe describe a novel strategy for power and sample size determination developed for studies utilizing investigational technologies with limited available preliminary data, specifically of imaging biomarkers. We evaluated diffuse optical spectroscopic imaging (DOSI), an experimental noninvasive imaging technique that may be capable of assessing changes in mammographic density. Because there is significant evidence that tamoxifen treatment is more effective at reducing breast cancer risk when accompanied by a reduction of breast density, we designed a study to assess the changes from baseline in DOSI imaging biomarkers that may reflect fluctuations in breast density in premenopausal women receiving tamoxifen.MethodWhile preliminary data demonstrate that DOSI is sensitive to mammographic density in women about to receive neoadjuvant chemotherapy for breast cancer, there is no information on DOSI in tamoxifen treatment. Since the relationship between magnetic resonance imaging (MRI) and DOSI has been established in previous studies, we developed a statistical simulation approach utilizing information from an investigation of MRI assessment of breast density in 16 women before and after treatment with tamoxifen to estimate the changes in DOSI biomarkers due to tamoxifen.ResultsThree sets of 10,000 pairs of MRI breast density data with correlation coefficients of 0.5, 0.8 and 0.9 were simulated and generated and were used to simulate and generate a corresponding 5,000,000 pairs of DOSI values representing water, ctHHB, and lipid. Minimum sample sizes needed per group for specified clinically-relevant effect sizes were obtained.ConclusionThe simulation techniques we describe can be applied in studies of other experimental technologies to obtain the important preliminary data to inform the power and sample size calculations.