Racial Disparities and Other Socioeconomic Predictors of Mortality in Acute Pulmonary Embolism Treatment from the National Inpatient Sample.

PURPOSE: To explore the significance of socioeconomic factors such as race and ethnicity as predictors of mortality in sub-massive and massive acute pulmonary embolism (PE). MATERIALS AND METHODS: Hospitalizations aged > 18 years with acute, non-septic PE from 2016 to 2019 were identified in the National Inpatient Sample and divided into IR (CDT and thrombectomy) and non-IR (tPA) treatments. Statistical analyses calculated significant odds ratios via 95% confidence intervals. The primary outcome of interest was mortality rate. Comorbidities affecting mortality were examined secondarily. RESULTS: Non-Hispanic (NH) Black, Hispanic, and Asian/Pacific Islander patients were significantly less likely to undergo an IR procedure for acute, non-septic PE compared to White patients (NH Black 0.83 [0.76 - 0.90], p<0.05; Hispanic 0.78 [0.68 - 0.89], p=0.06; Asian/Pacific Islander 0.71 [0.51 - 0.98], p=0.72; OR [95% CI]); however, these differences were eliminated when propensity score matching for age, biological sex, and primary insurance-type or primary insurance-type alone. NH Black patients were significantly more likely than White patients to die regardless of undergoing non-IR or an IR treatment. Overall risk of death was 41% higher for NH Black patients compared to White patients (RR [95% CI] 1.41 [1.24 - 1.60], p<0.001). CONCLUSION: NH Black patients have a higher risk of mortality from acute, non-septic PE than White patients. Independent of race, undergoing IR management for acute, non-septic pulmonary embolisms was associated with a lower mortality rate. Matching for primary insurance-type eliminates difference in mortality between races suggest socioeconomic status (SES) may determine outcomes in acute PE.

Fast ICCD-based temperature modulated fluorescence tomography.

Fluorescence tomography (FT) has become a powerful preclinical imaging modality with a great potential for several clinical applications. Although it has superior sensitivity and utilizes low-cost instrumentation, the highly scattering nature of bio-tissue makes FT in thick samples challenging, resulting in poor resolution and low quantitative accuracy. To overcome the limitations of FT, we previously introduced a novel method, termed temperature modulated fluorescence tomography (TMFT), which is based on two key elements: (1) temperature-sensitive fluorescent agents (ThermoDots) and (2) high-intensity focused ultrasound (HIFU). The fluorescence emission of ThermoDots increases up to hundredfold with only several degree temperature elevation. The exceptional and reversible response of these ThermoDots enables their modulation, which effectively allows their localization using the HIFU. Their localization is then used as functional a priori during the FT image reconstruction process to resolve their distribution with higher spatial resolution. The last version of the TMFT system was based on a cooled CCD camera utilizing a step-and-shoot mode, which necessitated long total imaging time only for a small selected region of interest (ROI). In this paper, we present the latest version of our TMFT technology, which uses a much faster continuous HIFU scanning mode based on an intensified CCD (ICCD) camera. This new, to the best of our knowledge, version can capture the whole field-of-view (FOV) of 50×30m m 2 at once and reduces the total imaging time down to 30 min, while preserving the same high resolution (∼1.3m m) and superior quantitative accuracy (<7% error) as the previous versions. Therefore, this new method is an important step toward utilization of TMFT for preclinical imaging.

Monitoring Distribution of the Therapeutic Agent Dimethyl Sulfoxide via Solvatochromic Shift of Albumin-Bound Indocyanine Green.

We recently developed a novel hyperspectral excitation-resolved near-infrared fluorescence imaging system (HER-NIRF) based on a continuous-wave wavelength-swept laser. In this study, this technique is applied to measure the distribution of the therapeutic agent dimethyl sulfoxide (DMSO) by utilizing solvatochromic shift in the spectral profile of albumin-bound Indocyanine green (ICG). Using wide-field imaging in turbid media, complex dynamics of albumin-bound ICG are measured in mixtures of dimethyl sulfoxide (DMSO) and water. Phantom experiments are conducted to evaluate the performance of the HER-NIRF system. The results show that the distribution of DMSO can be visualized in the wide-field reflection geometry. One of the main purposes of the DMSO is to act as a carrier for other drugs, enhancing their effects by facilitating skin penetration. Understanding the solubility and permeability of drugs in vivo is very important in drug discovery and development. Hence, this HER-NIRF technique has great potential to advance the utilization of the therapeutic agent DMSO by mapping its distribution via the solvatochromic shift of ICG. By customizing the operational wavelength range, this system can be applied to any other fluorophores in the near-infrared region and utilized for a wide variety of drug delivery studies.

Multiwavelength photo-magnetic imaging algorithm improved for direct chromophore concentration recovery using spectral constraints.

Multiwavelength photo-magnetic imaging (PMI) is a novel combination of diffuse optics and magnetic resonance imaging, to the best of our knowledge, that yields tissue chromophore concentration maps with high resolution and quantitative accuracy. Here, we present the first experimental results, to the best of our knowledge, obtained using a spectrally constrained PMI image reconstruction method, where chromophore concentration maps are directly recovered, unlike the conventional two-step approach that requires an intermediate step of reconstructing wavelength-dependent absorption coefficient maps. The imposition of the prior spectral information into the PMI inverse problem improves the reconstructed image quality and allows recovery of highly quantitative concentration maps, which are crucial for effective cancer detection and characterization. The obtained results demonstrate the higher performance of the direct reconstruction method. Indeed, the reconstructed concentration maps are not only of higher quality but also obtained approximately 2 times faster than the conventional method.

Multi-Wavelength Photo-Magnetic Imaging System for Photothermal Therapy Guidance.

BACKGROUND AND OBJECTIVES: In photothermal therapy, cancerous tissue is treated by the heat generated from absorbed light energy. For effective photothermal therapy, the parameters affecting the induced temperature should be determined before the treatment by modeling the increase in temperature via numerical simulations. However, accurate simulations can only be achieved when utilizing the accurate optical, thermal, and physiological properties of the treated tissue. Here, we propose a multi-wavelength photo-magnetic imaging (PMI) technique that provides quantitative and spatially resolved tissue optical absorption maps at any wavelength within the near-infrared (NIR) window to assist accurate photothermal therapy planning. STUDY DESIGN/MATERIALS AND METHODS: The study was conducted using our recently developed multi-wavelength PMI system, which operates at four laser wavelengths (760, 808, 860, and 980 nm). An agar tissue-simulating phantom containing water, lipid, and ink was illuminated using these wavelengths, and the slight internal laser-induced temperature rise was measured using magnetic resonance thermometry (MRT). The phantom optical absorption was recovered at the used wavelengths using our dedicated PMI image reconstruction algorithm. These absorption maps were then used to resolve the concentration of the tissue chromophores, and thus deduce its optical absorption spectrum in the NIR region based on the Beer-Lambert law. RESULTS: The optical absorption of the phantom was successfully recovered at the used four wavelengths with an average error of ~1.9%. The recovered absorption coefficient was then used to simulate temperature variations inside the phantom. A comparison between the modeled temperature maps and the MRT measured ones showed that these maps are in a good agreement with an average pseudo R2 statistic of 0.992. These absorption values were used to successfully recover the concentration of the used chromophores. Finally, these concentrations are used to accurately calculate the total absorption spectrum of the phantom in the NIR spectral window with an average error as low as ~2.3%. CONCLUSIONS: Multi-wavelength PMI demonstrated a great ability to assess the distribution of tissue chromophores, thus providing its total absorption at any wavelength within the NIR spectral range. Therefore, applications of photothermal therapy applied at NIR wavelengths can benefit from the absorption spectrum recovered by PMI to determine important parameters such as laser power as well as the laser exposure time needed to attain a specific increase in temperature prior to treatment. Lasers Surg. Med. 00:00-00, 2020. © 2020 Wiley Periodicals LLC.

Ex vivo validation of photo-magnetic imaging.

We recently introduced a new high-resolution diffuse optical imaging technique termed photo-magnetic imaging (PMI), which utilizes magnetic resonance thermometry (MRT) to monitor the 3D temperature distribution induced in a medium illuminated with a near-infrared light. The spatiotemporal temperature distribution due to light absorption can be accurately estimated using a combined photon propagation and heat diffusion model. High-resolution optical absorption images are then obtained by iteratively minimizing the error between the measured and modeled temperature distributions. We have previously demonstrated the feasibility of PMI with experimental studies using tissue simulating agarose phantoms. In this Letter, we present the preliminary ex vivo PMI results obtained with a chicken breast sample. Similarly to the results obtained on phantoms, the reconstructed images reveal that PMI can quantitatively resolve an inclusion with a 3 mm diameter embedded deep in a biological tissue sample with only 10% error. These encouraging results demonstrate the high performance of PMI in ex vivo biological tissue and its potential for in vivo imaging.

Feasibility study of high spatial resolution multimodality fluorescence tomography in ex vivo biological tissue.

Previously, we demonstrated that temperature-modulated fluorescence tomography (TM-FT) could provide fluorescence images with high quantitative accuracy and the spatial resolution of focused ultrasound. TM-FT is based on scanning the focused ultrasound across the medium to activate temperature-reversible fluorescent nanoprobes (ThermoDots). This technique can resolve small fluorescent targets located several centimeters deep in turbid media with millimeter resolution. Our past studies with this multimodality technique used agar phantoms, which could not represent the true heterogeneous nature of the acoustic and optical properties of biological tissue. In this work, we report the results of the first TM-FT study performed on ex vivo chicken breast tissue. In order to improve the spatial resolution of this technique, diffuse optical tomography is also used to better estimate the optical property maps of the tissue, which is utilized as functional a priori for the TM-FT reconstruction algorithm. These ex vivo results show that TM-FT can accurately recover the concentration and position of a 1.5 mm×5 mm inclusion filled with ThermoDots. Since the inclusion is embedded 2 cm deep in the chicken breast sample, these results demonstrate the great potential of TM-FT for future in vivo small animal imaging.

Breast density quantification using structured-light-based diffuse optical tomography simulations.

We present the feasibility of structured-light-based diffuse optical tomography (DOT) to quantify the breast density with an extensive simulation study. This study is performed on multiple numerical breast phantoms built from magnetic resonance imaging (MRI) images. These phantoms represent realistic tissue morphologies and are given typical breast optical properties. First, synthetic data are simulated at five wavelengths using our structured-light-based DOT forward problem. Afterwards, the inverse problem is solved to obtain the absorption images and subsequently the chromophore concentration maps. Parameters, such as segmented volumes and mean concentrations, are extracted from these maps and used in a regression model to estimate the percent breast densities. These estimations are correlated with the true values from MRI, r=0.97, showing that our new technique is promising in measuring breast density.

Experimental evaluation of the resolution and quantitative accuracy of temperature-modulated fluorescence tomography.

Previously, we reported on the spatial resolution and quantitative accuracy of temperature-modulated fluorescence tomography (TM-FT) using simulation studies. TM-FT is a novel fully integrated multimodality imaging technique that combines fluorescence diffuse optical tomography (FT) with focused ultrasound. Utilizing unique thermo-reversible fluorescent nanocapsules (ThermoDots), TM-FT provides high-resolution cross-sectional fluorescence images in thick tissue (up to 6 cm). Focused ultrasound and temperature-sensitive ThermoDots are combined to provide accurate localization of these fluorescent probes and functional a priori information to constrain the conventional FT reconstruction algorithm. Our previous simulation studies evaluated the performance of TM-FT using synthetic phantoms with multiple fluorescence targets of various sizes located at different depths. In this follow-up work, we perform experimental studies to evaluate the performance of this hybrid imaging system, in particular, the effect of size, depth, and concentration of the fluorescence target. While FT alone is unable to accurately locate and resolve the fluorophore target in many cases, TM-FT is able to resolve the size and concentration of the ThermoDots within a thick turbid medium with high accuracy for all cases. The maximum error in the recovered ThermoDots concentration and target sizes with TM-FT are 12% and 25%, respectively.

Comprehensive analytical model for CW laser induced heat in turbid media.

In this work, we present a new analytical approach to model continuous wave laser induced temperature in highly homogeneous turbid media. First, the diffusion equation is used to model light transport and a comprehensive solution is derived analytically by obtaining a special Greens' function. Next, the time-dependent bio-heat equation is used to describe the induced heat increase and propagation within the medium. The bio-heat equation is solved analytically utilizing the separation of variables technique. Our theoretical model is successfully validated using numerical simulations and experimental studies with agarose phantoms and ex-vivo chicken breast samples. The encouraging results show that our method can be implemented as a simulation tool to determine important laser parameters that govern the magnitude of temperature rise within homogenous biological tissue or organs.

Implementation of a new scanning method for high-resolution fluorescence tomography using thermo-sensitive fluorescent agents.

Conventional fluorescence tomography provides images of the distribution of fluorescent agents within highly scattering media, but suffers from poor spatial resolution. Previously, we introduced a new method termed "temperature-modulated fluorescence tomography" (TM-FT) that generates fluorescence images with high spatial resolution. TM-FT first uses focused ultrasound to locate the distribution of temperature-sensitive fluorescence probes. Afterward, this a priori information is utilized to improve the performance of the inverse solver for conventional fluorescence tomography and reveal quantitatively accurate fluorophore concentration maps. However, the disadvantage of this novel method is the long data acquisition time as the ultrasound beam was scanned in a step-and-shoot mode. In this Letter, we present a new, fast scanning method that reduces the imaging time 40 fold. By continuously scanning the ultrasound beam over a 50 mm by 25 mm field-of-view, high-resolution fluorescence images are obtained in less than 29 min, which is critical for in vivo small animal imaging.

Simulation-based evaluation of the resolution and quantitative accuracy of temperature-modulated fluorescence tomography.

Conventional fluorescence tomography (FT) can recover the distribution of fluorescent agents within a highly scattering medium. However, poor spatial resolution remains its foremost limitation. Previously, we introduced a new fluorescence imaging technique termed "temperature-modulated fluorescence tomography" (TM-FT), which provides high-resolution images of fluorophore distribution. TM-FT is a multimodality technique that combines fluorescence imaging with focused ultrasound to locate thermo-sensitive fluorescence probes using a priori spatial information to drastically improve the resolution of conventional FT. In this paper, we present an extensive simulation study to evaluate the performance of the TM-FT technique on complex phantoms with multiple fluorescent targets of various sizes located at different depths. In addition, the performance of the TM-FT is tested in the presence of background fluorescence. The results obtained using our new method are systematically compared with those obtained with the conventional FT. Overall, TM-FT provides higher resolution and superior quantitative accuracy, making it an ideal candidate for in vivo preclinical and clinical imaging. For example, a 4 mm diameter inclusion positioned in the middle of a synthetic slab geometry phantom (D:40 mm×W:100 mm) is recovered as an elongated object in the conventional FT (x=4.5 mm; y=10.4 mm), while TM-FT recovers it successfully in both directions (x=3.8 mm; y=4.6 mm). As a result, the quantitative accuracy of the TM-FT is superior because it recovers the concentration of the agent with a 22% error, which is in contrast with the 83% error of the conventional FT.

Gold nanoparticle-mediated photothermal therapy guidance with multi-wavelength photomagnetic imaging.

Difficulty in heating tumors with high spatial selectivity while protecting surrounding healthy tissues from thermal harm is a challenge for cancer photothermal treatment (PTT). To mitigate this problem, PTT mediated by photothermal agents (PTAs) has been established as a potential therapeutic technique to boost selectivity and reduce damage to surrounding healthy tissues. Various gold nanoparticles (AuNP) have been effectively utilized as PTAs, mainly using strategies to target cancerous tissue and increase selective thermal damage. Meanwhile, imaging can be used in tandem to monitor the AuNP distribution and guide the PTT. Mainly, the parameters impacting the induced temperature can be determined using simulation tools before treatment for effective PTT. However, accurate simulations can only be performed if the amount of AuNPs accumulated in the tumor is known. This study introduces Photo-Magnetic Imaging (PMI), which can appropriately recover the AuNP concentration to guide the PTT. Using multi-wavelength measurements, PMI can provide AuNP concentration based on their distinct absorption spectra. Tissue-simulating phantom studies are conducted to demonstrate the potential of PMI in recovering AuNP concentration for PTT planning. The recovered AuNP concentration is used to model the temperature increase accurately in a small inclusion representing tumor using a multiphysics solver that takes into account the light propagation and heat diffusion in turbid media.

Self-Guided Algorithm for Fast Image Reconstruction in Photo-Magnetic Imaging: Artificial Intelligence-Assisted Approach.

Previously, we introduced photomagnetic imaging (PMI) that synergistically utilizes laser light to slightly elevate the tissue temperature and magnetic resonance thermometry (MRT) to measure the induced temperature. The MRT temperature maps are then converted into absorption maps using a dedicated PMI image reconstruction algorithm. In the MRT maps, the presence of abnormalities such as tumors would create a notable high contrast due to their higher hemoglobin levels. In this study, we present a new artificial intelligence-based image reconstruction algorithm that improves the accuracy and spatial resolution of the recovered absorption maps while reducing the recovery time. Technically, a supervised machine learning approach was used to detect and delineate the boundary of tumors directly from the MRT maps based on their temperature contrast to the background. This information was further utilized as a soft functional a priori in the standard PMI algorithm to enhance the absorption recovery. Our new method was evaluated on a tissue-like phantom with two inclusions representing tumors. The reconstructed absorption map showed that the well-trained neural network not only increased the PMI spatial resolution but also improved the accuracy of the recovered absorption to as low as a 2% percentage error, reduced the artifacts by 15%, and accelerated the image reconstruction process approximately 9-fold.

Development of a preclinical CCD-based temperature modulated fluorescence tomography platform.

In preclinical research, fluorescence molecular tomography (FMT) is the most sensitive imaging modality to interrogate whole-body and provide 3D distribution of fluorescent contract agents. Despite its superior sensitivity, its mediocre spatial-resolution has been the main barrier to its clinical translation. This limitation is mainly due to the high scattering of optical photons in biological tissue together with the limited boundary measurements that lead to an undetermined and ill-posed inverse problem. To overcome the limitations of FMT, we previously introduced a novel method termed, Temperature Modulated Fluorescence Tomography (TMFT). TMFT utilizes thermos-sensitive fluorescent agents (ThermoDots) as a key component and localizes them with high-intensity focused ultrasound (HIFU). Scanning the focused HIFU beam having a diameter Ø = 1.3 mm across the tissue while monitoring the variation in the measured fluorescence signals reveals the position of the ThermoDots with high spatial accuracy. We have formerly built a prototype TMFT system that uses optical fibers for detection. In this paper, we present an upgraded version using a CCD camera-based detection that enables non-contact imaging. In this version, the animal under investigation is placed on an ultrasound transparent membrane, which eliminates the need for its immersion in optical matching fluids that were required by the fiber-based system. This CCD-based system will pave the way for convenient and wide-spread use of TMFT in preclinical research. Its performance validation on phantom studies demonstrates that high spatial-resolution (∼1.3 mm) and quantitative accuracy in recovered fluorophore concentration (<3% error) can be achieved.

Development of a theranostic preclinical fluorescence molecular tomography/cone beam CT-guided irradiator platform.

Image-guided small animal radiation research platforms allow more precise radiation treatment. Commercially available small animal X-ray irradiators are often equipped with a CT/cone-beam CT (CBCT) component for target guidance. Besides having poor soft-tissue contrast, CBCT unfortunately cannot provide molecular information due to its low sensitivity. Hence, there are extensive efforts to incorporate a molecular imaging component besides CBCT on these radiation therapy platforms. As an extension of these efforts, here we present a theranostic fluorescence tomography/CBCT-guided irradiator platform that provides both anatomical and molecular guidance, which can overcome the limitations of stand-alone CBCT. The performance of our hybrid system is validated using both tissue-like phantoms and mice ex vivo. Both studies show that fluorescence tomography can provide much more accurate quantitative results when CBCT-derived structural information is used to constrain the inverse problem. The error in the recovered fluorescence absorbance reduces nearly 10-fold for all cases, from approximately 60% down to 6%. This is very significant since high quantitative accuracy in molecular information is crucial to the correct assessment of the changes in tumor microenvironment related to radiation therapy.

Early assessment of irreversible electroporation ablation outcomes by analyzing MRI texture: preclinical study in an animal model of liver tumor.

OBJECTIVES: Accurate differentiation of temporary vs. permanent changes occurring following irreversible electroporation (IRE) holds immense importance for the early assessment of ablative treatment outcomes. Here, we investigated the benefits of advanced statistical learning models for an immediate evaluation of therapeutic outcomes by interpreting quantitative characteristics captured with conventional MRI. METHODS: The preclinical study integrated twenty-six rabbits with anatomical and perfusion MRI data acquired with a 3T clinical MRI scanner. T1w and T2w MRI data were quantitatively analyzed, and forty-six quantitative features were computed with four feature extraction methods. The candidate key features were determined by graph clustering following the filtering-based feature selection technique, RELIEFF algorithm. Kernel-based support vector machines (SVM) and random forest (RF) classifiers interpreting quantitative features of T1w, T2w, and combination (T1w+T2w) MRI were developed for replicating the underlying characteristics of the tissues to distinguish IRE ablation regions for immediate assessment of treatment response. Accuracy, sensitivity, specificity, and area under the receiver operating characteristics curve were used to evaluate classification performance. RESULTS: Following the analysis of quantitative variables, three features were integrated to develop a SVM classification model, while five features were utilized for generating RF classifiers. SVM classifiers demonstrated detection accuracy of 91.06%, 96.15%, and 98.04% for individual and combination MRI data, respectively. Besides, RF classifiers obtained slightly lower accuracy compared to SVM which were 95.06%, 89.40%, and 94.38% respectively. CONCLUSIONS: Quantitative models integrating structural characteristics of conventional T1w and T2w MRI data with statistical learning techniques identified IRE ablation regions allowing early assessment of treatment status.

Improvement of absorption and scattering discrimination by selection of sensitive points on temporal profile in diffuse optical tomography.

We present a new method allowing the reconstruction of 3D time-domain diffuse optical tomography images, based on the time-dependent diffusion equation and an iterative algorithm (ART) using specific points on the temporal profiles. The first advantage of our method versus the full time-resolved scheme consists in considerably reducing the inverse problem resolution time. Secondly, in the presence of scattering heterogeneities, our method provides images of better quality comparatively to classical methods using full-time data or the first moments of the profiles.

Resolving tissue chromophore concentration at MRI resolution using multi-wavelength photo-magnetic imaging.

Photo-magnetic imaging (PMI) is an emerging optical imaging modality that showed great performance on providing absorption maps with high resolution and quantitative accuracy. As a multi-modality technology, PMI warms up the imaged object using a near infrared laser while temperature variation is measured using magnetic resonance imaging. By probing tissue at multiple wavelengths, concentration of the main tissue chromophores such as oxy- and deoxy-hemoglobin, lipid, and water are obtained then used to derive functional parameters such as total hemoglobin concentration and relative oxygen saturation. In this paper, we present a multi-wavelength PMI system that was custom-built to host five different laser wavelengths. After recovering the high-resolution absorption maps, a least-squared minimization process was used to resolve the different chromophore concentration. The performance of the system was experimentally tested on a phantom with two different dyes. Their concentrations were successfully assessed with high spatial resolution and average accuracy of nearly 80%.

Automated in vivo Assessment of Vascular Response to Radiation using a Hybrid Theranostic X-ray Irradiator/Fluorescence Molecular Imaging System.

Hypofractionated stereotactic body radiotherapy treatments (SBRT) have demonstrated impressive results for the treatment of a variety of solid tumors. The role of tumor supporting vasculature damage in treatment outcome for SBRT has been intensely debated and studied. Fast, non-invasive, longitudinal assessments of tumor vasculature would allow for thorough investigations of vascular changes correlated with SBRT treatment response. In this paper, we present a novel theranostic system which incorporates a fluorescence molecular imager into a commercial, preclinical, microCT-guided, irradiator and was designed to quantify tumor vascular response (TVR) to targeted radiotherapy. This system overcomes the limitations of single-timepoint imaging modalities by longitudinally assessing spatiotemporal differences in intravenously-injected ICG kinetics in tumors before and after high-dose radiation. Changes in ICG kinetics were rapidly quantified by principle component (PC) analysis before and two days after 10 Gy targeted tumor irradiation. A classifier algorithm based on PC data clustering identified pixels with TVR. Results show that two days after treatment, a significant delay in ICG clearance as measured by exponential decay (40.5±16.1% P=0.0405 Paired t-test n=4) was observed. Changes in the mean normalized first and second PC feature pixel values (PC1 & PC2) were found (P=0.0559, 0.0432 paired t-test), suggesting PC based analysis accurately detects changes in ICG kinetics. The PC based classification algorithm yielded spatially-resolved TVR maps. Our first-of-its-kind theranostic system, allowing automated assessment of TVR to SBRT, will be used to better understand the role of tumor perfusion in metastasis and local control.