Dynamic Diffuse Optical Tomography for Monitoring Neoadjuvant Chemotherapy in Patients with Breast Cancer.

Purpose To identify dynamic optical imaging features that associate with the degree of pathologic response in patients with breast cancer during neoadjuvant chemotherapy (NAC). Materials and Methods Of 40 patients with breast cancer who participated in a longitudinal study between June 2011 and March 2016, 34 completed the study. There were 13 patients who obtained a pathologic complete response (pCR) and 21 patients who did not obtain a pCR. Imaging data from six subjects were excluded from the study because either the patients dropped out of the study before it was finished or there was an instrumentation malfunction. Two weeks into the treatment regimen, three-dimensional images of both breasts during a breath hold were acquired by using dynamic diffuse optical tomography. Features from the breath-hold traces were used to distinguish between response groups. Receiver operating characteristic (ROC) curves and sensitivity analysis were used to determine the degree of association with 5-month treatment outcome. Results An ROC curve analysis showed that this method could identify patients with a pCR with a positive predictive value of 70.6% (12 of 17), a negative predictive value of 94.1% (16 of 17), a sensitivity of 92.3% (12 of 13), a specificity of 76.2% (16 of 21), and an area under the ROC curve of 0.85. Conclusion Several dynamic optical imaging features obtained within 2 weeks of NAC initiation were identified that showed statistically significant differences between patients with pCR and patients without pCR as determined 5 months after treatment initiation. If confirmed in a larger cohort prospective study, these dynamic imaging features may be used to predict treatment outcome as early as 2 weeks after treatment initiation. © RSNA, 2018 Online supplemental material is available for this article.

Diffuse optical tomography changes correlate with residual cancer burden after neoadjuvant chemotherapy in breast cancer patients.

PURPOSE: Breast cancer (BC) patients who achieve a favorable residual cancer burden (RCB) after neoadjuvant chemotherapy (NACT) have an improved recurrence-free survival. Those who have an unfavorable RCB will have gone through months of ineffective chemotherapy. No ideal method exists to predict a favorable RCB early during NACT. Diffuse optical tomography (DOT) is a novel imaging modality that uses near-infrared light to assess hemoglobin concentrations within breast tumors. We hypothesized that the 2-week percent change in DOT-measured hemoglobin concentrations would associate with RCB. METHODS: We conducted an observational study of 40 women with stage II-IIIC BC who received standard NACT. DOT imaging was performed at baseline and 2 weeks after treatment initiation. We evaluated the associations between the RCB index (continuous measure), class (categorical 0, I, II, III), and response (RCB class 0/I = favorable, RCB class II/III = unfavorable) with changes in DOT-measured hemoglobin concentrations. RESULTS: The RCB index correlated significantly with the 2-week percent change in oxyhemoglobin [HbO2] (r = 0.5, p = 0.003), deoxyhemoglobin [Hb] (r = 0.37, p = 0.03), and total hemoglobin concentrations [HbT] (r = 0.5, p = 0.003). The RCB class and response significantly associated with the 2-week percent change in [HbO2] (p ≤ 0.01) and [HbT] (p ≤ 0.02). [HbT] 2-week percent change had sensitivity, specificity, positive, and negative predictive values for a favorable RCB response of 86.7, 68.4, 68.4, and 86.7%, respectively. CONCLUSION: The 2-week percent change in DOT-measured hemoglobin concentrations was associated with the RCB index, class, and response. DOT may help guide NACT for women with BC.

3D Visualisation of Navigation Catheters for Endovascular Procedures Using a 3D Hub and Fiber Optic RealShape Technology: Phantom Study Results.

Objective: Fiber Optic RealShape (FORS) is a new technology that visualises the full three dimensional (3D) shape of guidewires using an optical fibre embedded in the device. Co-registering FORS guidewires with anatomical images, such as a digital subtraction angiography (DSA), provides anatomical context for navigating these devices during endovascular procedures. The objective of this study was to demonstrate the feasibility and usability of visualising compatible conventional navigation catheters, together with the FORS guidewire, in phantom with a new 3D Hub technology and to understand potential clinical benefits. Methods: The accuracy of localising the 3D Hub and catheter in relation to the FORS guidewire, was evaluated using a translation stage test setup and a retrospective analysis of prior clinical data. Catheter visualisation accuracy and navigation success was assessed in a phantom study where 15 interventionists navigated devices to three pre-defined targets in an abdominal aortic phantom using an Xray or computed tomography angiography (CTA) roadmap. Additionally, the interventionists were surveyed about the usability and potential benefits of the 3D Hub. Results: The location of the 3D Hub and catheter along the FORS guidewire was detected correctly 96.59% of the time. During the phantom study, all 15 interventionists successfully reached the target locations 100% of the time and the error in catheter visualisation was 0.69 mm. The interventionists agreed or strongly agreed that the 3D Hub was easy to use and the greatest potential clinical benefit over FORS is in offering interventionists choice over which catheter they used. Conclusion: This set of studies has shown that FORS guided catheter visualisation, enabled by a 3D Hub, is accurate and easy to use in a phantom setting. Further evaluation is needed to understand the benefits and limitations of the 3D Hub technology during endovascular procedures.

Optical biomarkers for breast cancer derived from dynamic diffuse optical tomography.

Diffuse optical tomography (DOT) is a noninvasive, nonionizing imaging modality that uses near-infrared light to visualize optically relevant chromophores. A recently developed dynamic DOT imaging system enables the study of hemodynamic effects in the breast during a breath-hold. Dynamic DOT imaging was performed in a total of 21 subjects (age 54±10 years) including 3 healthy subjects and 18 subjects with benign (n=8) and malignant (n=14) masses. Three-dimensional time-series images of the percentage change in oxygenated and deoxygenated hemoglobin concentrations ([HbO2] and [Hb]) from baseline are obtained over the course of a breath-hold. At a time point of 15 s following the end of the breath-hold, [Hb] in healthy breasts has returned to near-baseline values (1.6%±0.5%), while tumor-bearing breasts have increased levels of [Hb] (6.8%±3.6%, p<0.01). Further, healthy subjects have a higher correlation between the breasts over the course of the breath-hold as compared with the subjects with breast cancer (healthy: 0.96±0.02; benign: 0.89±0.02; malignant: 0.78±0.23, p<0.05). Therefore this study shows that dynamic features extracted from DOT measurements can differentiate healthy and diseased breast tissues. These features provide a physiologic method for identifying breast cancer without the need for ionizing radiation.

Dynamic diffuse optical tomography imaging of peripheral arterial disease.

Peripheral arterial disease (PAD) is the narrowing of arteries due to plaque accumulation in the vascular walls. This leads to insufficient blood supply to the extremities and can ultimately cause cell death. Currently available methods are ineffective in diagnosing PAD in patients with calcified arteries, such as those with diabetes. In this paper we investigate the potential of dynamic diffuse optical tomography (DDOT) as an alternative way to assess PAD in the lower extremities. DDOT is a non-invasive, non-ionizing imaging modality that uses near-infrared light to create spatio-temporal maps of oxy- and deoxy-hemoglobin in tissue. We present three case studies in which we used DDOT to visualize vascular perfusion of a healthy volunteer, a PAD patient and a diabetic PAD patient with calcified arteries. These preliminary results show significant differences in DDOT time-traces and images between all three cases, underscoring the potential of DDOT as a new diagnostic tool.

Monitoring early tumor response to drug therapy with diffuse optical tomography.

Although anti-angiogenic agents have shown promise as cancer therapeutics, their efficacy varies between tumor types and individual patients. Providing patient-specific metrics through rapid noninvasive imaging can help tailor drug treatment by optimizing dosages, timing of drug cycles, and duration of therapy-thereby reducing toxicity and cost and improving patient outcome. Diffuse optical tomography (DOT) is a noninvasive three-dimensional imaging modality that has been shown to capture physiologic changes in tumors through visualization of oxygenated, deoxygenated, and total hemoglobin concentrations, using non-ionizing radiation with near-infrared light. We employed a small animal model to ascertain if tumor response to bevacizumab (BV), an anti-angiogenic agent that targets vascular endothelial growth factor (VEGF), could be detected at early time points using DOT. We detected a significant decrease in total hemoglobin levels as soon as one day after BV treatment in responder xenograft tumors (SK-NEP-1), but not in SK-NEP-1 control tumors or in non-responder control or BV-treated NGP tumors. These results are confirmed by magnetic resonance imaging T2 relaxometry and lectin perfusion studies. Noninvasive DOT imaging may allow for earlier and more effective control of anti-angiogenic therapy.

Contrast ultrasound imaging for identification of early responder tumor models to anti-angiogenic therapy.

Agents targeting vascular endothelial growth factor (VEGF) have been validated as cancer therapeutics, yet efficacy can differ widely between tumor types and individual patients. In addition, such agents are costly and can have significant toxicities. Rapid noninvasive determination of response could provide significant benefits. We tested if response to the anti-VEGF antibody bevacizumab (BV) could be detected using contrast-enhanced ultrasound imaging (CEUS). We used two xenograft model systems with previously well-characterized responses to VEGF inhibition, a responder (SK-NEP-1) and a non-responder (NGP), and examined perfusion-related parameters. CEUS demonstrated that BV treatment arrested the increase in blood volume in the SK-NEP-1 tumor group only. Molecular imaging of α(V)ß(3) with targeted microbubbles was a more sensitive prognostic indicator of BV efficacy. CEUS using RGD-labeled microbubbles showed a robust decrease in α(V)ß(3) vasculature following BV treatment in SK-NEP-1 tumors. Paralleling these findings, lectin perfusion assays detected a disproportionate pruning of smaller, branch vessels. Therefore, we conclude that the response to BV can be identified soon after initiation of treatment, often within 3 days, by use of CEUS molecular imaging techniques. The use of a noninvasive ultrasound approach may allow for earlier and more effective determination of efficacy of antiangiogenic therapy.

Digital optical tomography system for dynamic breast imaging.

Diffuse optical tomography has shown promising results as a tool for breast cancer screening and monitoring response to chemotherapy. Dynamic imaging of the transient response of the breast to an external stimulus, such as pressure or a respiratory maneuver, can provide additional information that can be used to detect tumors. We present a new digital continuous-wave optical tomography system designed to simultaneously image both breasts at fast frame rates and with a large number of sources and detectors. The system uses a master-slave digital signal processor-based detection architecture to achieve a dynamic range of 160 dB and a frame rate of 1.7 Hz with 32 sources, 64 detectors, and 4 wavelengths per breast. Included is a preliminary study of one healthy patient and two breast cancer patients showing the ability to identify an invasive carcinoma based on the hemodynamic response to a breath hold.

PDE-constrained multispectral imaging of tissue chromophores with the equation of radiative transfer.

We introduce a transport-theory-based PDE-constrained multispectral model for direct imaging of the spatial distributions of chromophores concentrations in biological tissue. The method solves the forward problem (boundary radiance at each wavelength) and the inverse problem (spatial distribution of chromophores concentrations), in an all-at-once manner in the framework of a reduced Hessian sequential quadratic programming method. To illustrate the code's performance, we present numerical and experimental studies involving tumor bearing mice. It is shown that the PDE-constrained multispectral method accelerates the reconstruction process by up to 15 times compared to unconstrained reconstruction algorithms and provides more accurate results as compared to the so-called two-step approach to multi-wavelength imaging.

The design and characterization of a digital optical breast cancer imaging system.

Optical imaging has the potential to play a major role in breast cancer screening and diagnosis due to its ability to image cancer characteristics such as angiogenesis and hypoxia. A promising approach to evaluate and quantify these characteristics is to perform dynamic imaging studies in which one monitors the hemodynamic response to an external stimulus, such as a valsalva maneuver. It has been shown that the response to such stimuli shows MARKED differences between cancerous and healthy tissues. The fast imaging rates and large dynamic range of digital devices makes them ideal for this type of imaging studies. Here we present a digital optical tomography system designed specifically for dynamic breast imaging. The instrument uses laser diodes at 4 different near-infrared wavelengths with 32 sources and 128 silicon photodiode detectors.

Real-time magnetic resonance with physiologic monitoring for improved scan localization.

Imaging of the coronary arteries at diagnostic resolutions is made difficult due to cardiac and respiratory motion during data acquisition. Cardiac gating and respiratory gating or breath holding are effective ways to reduce the effects of motion. The optimal cardiac and respiratory timings vary widely across individuals. This work presents a real-time magnetic resonance imaging approach with physiologic monitoring that can be used to predict the optimal timings on a subject-by-subject basis during a brief real-time prescan. The feasibility of this approach at determining the optimal cardiac trigger delay and respiratory phase is demonstrated.