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Introduction: Nationally, 25% to 50% of patients undergoing lumpectomy for local management of breast cancer require a secondary excision because of the persistence of residual tumor. Intraoperative assessment of specimen margins by frozen-section analysis is not widely adopted in breast-conserving surgery. Here, a new approach to wide-field optical imaging of breast pathology in situ was tested to determine whether the system could accurately discriminate cancer from benign tissues before routine pathological processing.Methods: Spatial frequency domain imaging (SFDI) was used to quantify near-infrared (NIR) optical parameters at the surface of 47 lumpectomy tissue specimens. Spatial frequency and wavelength-dependent reflectance spectra were parameterized with matched simulations of light transport. Spectral images were co-registered to histopathology in adjacent, stained sections of the tissue, cut in the geometry imaged in situ. A supervised classifier and feature-selection algorithm were implemented to automate discrimination of breast pathologies and to rank the contribution of each parameter to a diagnosis.Results: Spectral parameters distinguished all pathology subtypes with 82% accuracy and benign (fibrocystic disease, fibroadenoma) from malignant (DCIS, invasive cancer, and partially treated invasive cancer after neoadjuvant chemotherapy) pathologies with 88% accuracy, high specificity (93%), and reasonable sensitivity (79%). Although spectral absorption and scattering features were essential components of the discriminant classifier, scattering exhibited lower variance and contributed most to tissue-type separation. The scattering slope was sensitive to stromal and epithelial distributions measured with quantitative immunohistochemistry.Conclusions: SFDI is a new quantitative imaging technique that renders a specific tissue-type diagnosis. Its combination of planar sampling and frequency-dependent depth sensing is clinically pragmatic and appropriate for breast surgical-margin assessment. This study is the first to apply SFDI to pathology discrimination in surgical breast tissues. It represents an important step toward imaging surgical specimens immediately ex vivo to reduce the high rate of secondary excisions associated with breast lumpectomy procedures. © 2013 Laughney et al.; licensee BioMed Central Ltd.

Spatial frequency domain imaging of 5-aminolevulinic acid induced protoporphyrin IX was used to recover absorption, scattering, and fluorescence properties of glioblastoma multiforme in tissue-simulating phantoms and in vivo in a mouse model. © 2012.

Significance: ALA-PpIX and second-window indocyanine green (ICG) have been studied widely for guiding the resection of high-grade gliomas. These agents have different mechanisms of action and uptake characteristics, which can affect their performance as surgical guidance agents. Elucidating these differences in animal models that approach the size and anatomy of the human brain would help guide the use of these agents. Herein, we report on the use of a new pig glioma model and fluorescence cryotomography to evaluate the 3D distributions of both agents throughout the whole brain., Aim: We aim to assess and compare the 3D spatial distributions of ALA-PpIX and second-window ICG in a glioma-bearing pig brain using fluorescence cryotomography., Approach: A glioma was induced in the brain of a transgenic Oncopig via adeno-associated virus delivery of Cre-recombinase plasmids. After tumor induction, the pro-drug 5-ALA and ICG were administered to the animal 3 and 24 h prior to brain harvest, respectively. The harvested brain was imaged using fluorescence cryotomography. The fluorescence distributions of both agents were evaluated in 3D in the whole brain using various spatial distribution and contrast performance metrics., Results: Significant differences in the spatial distributions of both agents were observed. Indocyanine green accumulated within the tumor core, whereas ALA-PpIX appeared more toward the tumor periphery. Both ALA-PpIX and second-window ICG provided elevated tumor-to-background contrast (13 and 23, respectively)., Conclusions: This study is the first to demonstrate the use of a new glioma model and large-specimen fluorescence cryotomography to evaluate and compare imaging agent distribution at high resolution in 3D., (© 2024 The Authors.)

ABY-029, an anti-epidermal growth factor receptor (EGFR) Affibody® molecule conjugated to IRDye 800CW, recently underwent first-in-human testing in soft-tissue sarcoma (STS). FDA Exploratory Investigational New Drug status was obtained for the Phase 0 clinical trial in which study objectives were to determine whether biological variance ratio (BVR) of 10 was achievable, fluorescence intensity correlated with EGFR expression, and doses were well tolerated. Patients (N=12) with STS were recruited based on positive EGFR immunohistochemical staining of diagnostic biopsies. ABY-029 was administered at micro- (30 nanomole, n=3), medium (90 nanomole, n=3), or high dose (171 nanomole, n=6), 1-3 hours prior to surgery. Following tumor resection, ex vivo tissue was imaged to determine mean fluorescence intensity (MFI), BVR, and other contrast measures. EGFR expression was correlated with immunohistochemistry. For micro-, medium, and high doses, mean BVR (SD) in cross-sectional slices were 4 (4), 10 (6), and 7 (8), respectively, for the whole tumor region and 6 (5), 13 (11), and 8 (6), respectively, for pathology-confirmed regions-of-interest. Strong linear correlations were found between all ABY-029 contrast metrics and total EGFR (r≥0.86, p<0.029) in cross-sectional tissue slices, and MFI and EGFR percent area (r=0.63, p<0.0001) in excised region-of-interest tissue sections. No ABY-029 related adverse events were observed. When administered above the microdose, ABY-029 demonstrated high correlation to EGFR expression and contrast values that were encouraging for translation to clinical practice. Contrast was similar to those observed with antibody agents, but with substantially reduced imaging-to-resection time, and no drug-related adverse events.

Objective: To develop a novel Magnetic Resonance Imaging (MRI)-guided Near-Infrared Spectroscopic Tomography (MRg-NIRST) imaging system with an MRI-compatible breast optical interface for breast imaging.

Imaging of tumor-specific fluorescent contrast agents to guide tumor removal has been shown to improve outcomes and is now standard practice for some neurosurgical procedures. However, many agents require administration hours before surgery, a practical challenge, and may exhibit inconsistent concordance with contrast-enhanced MRI (CE-MRI), the current standard for diagnosing and guiding glioma removal. A fluorescent agent that accurately marks tumor shortly after administration and is otherwise similar to CE-MRI would help overcome these shortcomings. Methods: We used whole-body 3-D fluorescence cryo-imaging and co-registered CE-MRI volumes to evaluate several fluorescent contrast agent candidates for diagnostic performance and concordance with CE-MRI. Mice with brain tumors were administered a cocktail of fluorescent agent candidates and a MRI contrast agent, and then imaged with MRI and fluorescence cryo-imaging at several timepoints after administration. The high-resolution 3-D cryo-imaging volumes of the fluorescent agents were used to determine diagnostic performance metrics and correlation with CE-MRI. Results: While all agents showed positive metrics, one agent, tetramethylrhodamine conjugated to a small polyethylene glycol chain (TMR-PEG1k), outperformed the others, exhibiting minimal normal brain signal, high tumor-to-background-ratio, diagnostic accuracy, and cross-correlation to CE-MRI at all post-administration timepoints (10-90 min) and tumor lines examined. Conclusion: These favorable properties establish TMR-PEG1k as a promising candidate for surgical guidance., Competing Interests: Competing Interests: DWR, KDP, SCD are inventors on intellectual property of technologies related to fluorescence-guided surgery. DWR, KDP are involved with InSight Surgical Technologies, Inc, a startup company working to commercialize technology related to fluorescence-guided surgery., (© The author(s).)

Magnetic resonance elastography (MRE) is a promising neuroimaging technique to probe tissue microstructure, which has revealed widespread softening with loss of structural integrity in the aging brain. Traditional MRE approaches assume mechanical isotropy. However, white matter is known to be anisotropic from aligned, myelinated axonal bundles, which can lead to uncertainty in mechanical property estimates in these areas when using isotropic MRE. Recent advances in anisotropic MRE now allow for estimation of shear and tensile anisotropy, along with substrate shear modulus, in white matter tracts. The objective of this study was to investigate age-related differences in anisotropic mechanical properties in human brain white matter tracts for the first time. Anisotropic mechanical properties in all tracts were found to be significantly lower in older adults compared to young adults, with average property differences ranging between 0.028-0.107 for shear anisotropy and between 0.139-0.347 for tensile anisotropy. Stiffness perpendicular to the axonal fiber direction was also significantly lower in older age, but only in certain tracts. When compared with fractional anisotropy measures from diffusion tensor imaging, we found that anisotropic MRE measures provided additional, complementary information in describing differences between the white matter integrity of young and older populations. Anisotropic MRE provides a new tool for studying white matter structural integrity in aging and neurodegeneration.

Purpose: ABY-029, an epidermal growth factor receptor (EGFR)-targeted, synthetic Affibody peptide labeled with a near-infrared fluorophore, is under investigation for fluorescence-guided surgery of sarcomas. To date, studies using ABY-029 have occurred in tumors naïve to chemotherapy (CTx) and radiation therapy (RTx), although these neoadjuvant therapies are frequently used for sarcoma treatment in humans. The goal of this study was to evaluate the impact of CTx and RTx on tumor EGFR expression and ABY-029 fluorescence of human soft-tissue sarcoma xenografts in a murine model., Procedures: Immunodeficient mice (n = 98) were divided into five sarcoma xenograft groups and three treatment groups - CTx only, RTx only, and CTx followed by RTx, plus controls. Four hours post-injection of ABY-029, animals were sacrificed followed by immediate fluorescence imaging of ex vivo adipose, muscle, nerve, and tumor tissues. Histological hematoxylin and eosin staining confirmed tumor type, and immunohistochemistry staining determined EGFR, cluster of differentiation 31 (CD31), and smooth muscle actin (SMA) expression levels. Correlation analysis (Pearson's correlation coefficients, r) and linear regression (unstandardized coefficient estimates, B) were used to determine statistical relationships in molecular expression and tissue fluorescence between xenografts and treatment groups., Results: Neoadjuvant therapies had no broad impact on EGFR expression (|B|≤ 7.0, p ≥ 0.4) or on mean tissue fluorescence (any tissue type, (|B|≤ 2329.0, p ≥ 0.1). Mean tumor fluorescence was significantly related to EGFR expression (r = 0.26, p = 0.01), as expected., Conclusion: Results suggest that ABY-029 as an EGFR-targeted, fluorescent probe is not negatively impacted by neoadjuvant soft-tissue sarcoma therapies, although validation in humans is required., (© 2023. The Author(s), under exclusive licence to World Molecular Imaging Society.)

Pharmacokinetics and biodistribution studies are essential for characterizing fluorescent agents in vivo . However, few simple methods based on fluorescence imaging are available that account for tissue optical properties and sample volume differences. We describe a method for simultaneously quantifying mean fluorescence intensity of whole blood and homogenized tissues in glass capillary tubes for two fluorescent agents, ABY-029 and IRDye 680LT, using wide-field imaging and tissue-specific calibration curves. All calibration curves demonstrated a high degree of linearity with mean R 2  = 0.99 ± 0.01 and RMSE = 0.12 ± 0.04. However, differences between linear regressions indicate that tissue-specific calibration curves are required for accurate concentration recovery. The lower limit of quantification (LLOQ) for all samples tested was determined to be < 0.3 nM for ABY-029 and < 0.4 nM for IRDye 680LT., Competing Interests: ABY-029 was produced under a National Cancer Institute funded academic-industrial partnership between Dartmouth College, Affibody Medical AB, and LI-COR Biosciences, Inc., (© 2024 Optica Publishing Group.)

The last decade has seen a large growth in fluorescence-guided surgery (FGS) imaging and interventions. With the increasing number of clinical specialties implementing FGS, the range of systems with radically different physical designs, image processing approaches, and performance requirements is expanding. This variety of systems makes it nearly impossible to specify uniform performance goals, yet at the same time, utilization of different devices in new clinical procedures and trials indicates some need for common knowledge bases and a quality assessment paradigm to ensure that effective translation and use occurs. It is feasible to identify key fundamental image quality characteristics and corresponding objective test methods that should be determined such that there are consistent conventions across a variety of FGS devices. This report outlines test methods, tissue simulating phantoms and suggested guidelines, as well as personnel needs and professional knowledge bases that can be established. This report frames the issues with guidance and feedback from related societies and agencies having vested interest in the outcome, coming from an independent scientific group formed from academics and international federal agencies for the establishment of these professional guidelines., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Guided surgery has demonstrated significant improvements in patient outcomes in some disease processes. Interest in this field has led to substantial growth in the technologies under investigation. Most likely no single technology will prove to be "best," and combinations of macro- and microscale guidance-using radiological imaging navigation, probes (activatable, perfusion, and molecular-targeted; large- and small-molecule), autofluorescence, tissue intrinsic optical properties, bioimpedance, and other characteristics-will offer patients and surgeons the greatest opportunity for high-success/low-morbidity medical interventions. Problems are arising, however, from the lack of valid testing formats; surgical training simulators suffer the same problems. Small animal models do not accurately recreate human anatomy, especially in terms of tissue volume. Large animal models are expensive and have difficulty replicating many pathological states, particularly when molecular specificity for individual cancers is required. Furthermore, the sheer number of technologies and the potential for synergistic combination leads to exponential growth of testing requirements that is unrealistic for in vivo testing. Therefore, critical need exists to expand the ex vivo/in vitro testing platforms available to investigators and, once validated, a need to increase the acceptance of these methods for funding and regulatory endpoints. Herein is a review of the available ex vivo/in vitro testing formats for guided surgery, a review of their advantages/disadvantages, and consideration for how our field may safely and more swiftly move forward through stronger adoption of these testing and validation methods.

Background: Glioblastoma is the most common primary malignant and treatment-resistant human brain tumor. Rodent models have played an important role in understanding brain cancer biology and treatment. However, due to their small cranium and tumor volume mismatch, relative to human disease, they have been less useful for translational studies. Therefore, development of a consistent and simple large animal glioma xenograft model would have significant translational benefits., Methods: Immunosuppression was induced in twelve standard Yucatan minipigs. 3 pigs received cyclosporine only, while 9 pigs received a combined regimen including cyclosporine (55 mg/kg q12 h), prednisone (25 mg, q24 h) and mycophenolate (500 mg q24 h). U87 cells (2 × 10 6 ) were stereotactically implanted into the left frontal cortex. The implanted brains were imaged by MRI for monitoring. In a separate study, tumors were grown in 5 additional pigs using the combined regimen, and pigs underwent tumor resection with intra-operative image updating to determine if the xenograft model could accurately capture the spatial tumor resection challenges seen in humans., Results: Tumors were successfully implanted and grown in 11 pigs. One animal in cyclosporine only group failed to show clinical tumor growth. Clinical tumor growth, assessed by MRI, progressed slowly over the first 10 days, then rapidly over the next 10 days. The average tumor growth latency period was 20 days. Animals were monitored twice daily and detailed records were kept throughout the experimental period. Pigs were sacrificed humanely when the tumor reached 1 - 2 cm. Some pigs experienced decreased appetite and activity, however none required premature euthanasia. In the image updating study, all five pigs demonstrated brain shift after craniotomy, consistent with what is observed in humans. Intraoperative image updating was able to accurately capture and correct for this shift in all five pigs., Conclusion: This report demonstrates the development and use of a human intracranial glioma model in an immunosuppressed, but nongenetically modified pig. While the immunosuppression of the model may limit its utility in certain studies, the model does overcome several limitations of small animal or genetically modified models. For instance, we demonstrate use of this model for guiding surgical resection with intraoperative image-updating technologies. We further report use of a surrogate extracranial tumor that indicates growth of the intracranial tumor, allowing for relative growth assessment without radiological imaging., Competing Interests: Declaration of competing interest The authors have no conflict of interest to report., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Fluorescence cryo-imaging is a high-resolution optical imaging technique that produces 3-D whole-body biodistributions of fluorescent molecules within an animal specimen. To accomplish this, animal specimens are administered a fluorescent molecule or reporter and are frozen to be autonomously sectioned and imaged at a temperature of -20°C or below. Thus, to apply this technique effectively, administered fluorescent molecules should be relatively invariant to low temperature conditions for cryo-imaging and ideally the fluorescence intensity should be stable and consistent in both physiological and cryo-imaging conditions. Herein, we assessed the mean fluorescence intensity of 11 fluorescent contrast agents as they are frozen in a tissue-simulating phantom experiment and show an example of a tested fluorescent contrast agent in a cryo-imaged whole pig brain. Most fluorescent contrast agents were stable within ~25% except for FITC and PEGylated FITC derivatives, which showed a dramatic decrease in fluorescence intensity when frozen.

Background: Accuracy of electrode placement for deep brain stimulation (DBS) is critical to achieving desired surgical outcomes and impacts the efficacy of treating neurodegenerative diseases. Intraoperative brain shift degrades the accuracy of surgical navigation based on preoperative images., Purpose: We extended a model-based image updating scheme to address intraoperative brain shift in DBS surgery and improved its accuracy in deep brain., Methods: We evaluated 10 patients, retrospectively, who underwent bilateral DBS surgery and classified them into groups of large and small deformation based on a 2 mm subsurface movement threshold and brain shift index of 5%. In each case, sparse brain deformation data were used to estimate whole brain displacements and deform preoperative CT (preCT) to generate updated CT (uCT). Accuracy of uCT was assessed using target registration errors (TREs) at the Anterior Commissure (AC), Posterior Commissure (PC), and four calcification points in the sub-ventricular area by comparing their locations in uCT with their ground truth counterparts in postoperative CT (postCT)., Results: In the large deformation group, TREs were reduced from 2.5 mm in preCT to 1.2 mm in uCT (53% compensation); in the small deformation group, errors were reduced from 1.25 to 0.74 mm (41%). Average reduction of TREs at AC, PC and pineal gland were significant, statistically (p ⩽ 0.01)., Conclusions: With more rigorous validation of model results, this study confirms the feasibility of improving the accuracy of model-based image updating in compensating for intraoperative brain shift during DBS procedures by assimilating deep brain sparse data., (© 2023 American Association of Physicists in Medicine.)

Purpose: The aim of this study is to investigate whether near-infrared spectral tomography (NIRST) might serve as a reliable prognostic tool to predict residual cancer burden (RCB) in patients with breast cancer undergoing neoadjuvant chemotherapy (NAC) based upon early treatment response measurements., Experimental Design: A total of thirty-five patients with breast cancer receiving NAC were included in this study. NIRST imaging was performed at multiple time points, including: before treatment, at end of the first cycle, at the mid-point, and post-NAC treatments. From reconstructed NIRST images, average values of total hemoglobin (HbT) were obtained for both the tumor region and contralateral breast at each time point. RCB scores/classes were assessed by a pathologist using histologic slides of the surgical specimen obtained after completing NAC. Logistic regression of the normalized early percentage change of HbT in the tumor region (ΔHbT%) was used to predict RCB and determine its significance as an indicator for differentiating cases within each RCB class., Results: The ΔHbT% at the end of the first cycle, as compared with pretreatment levels, showed excellent prognostic capability in differentiating RCB-0 from RCB-I/II/III or RCB-II from RCB-0/I/III (P < 0.001). Corresponding area under the curve (AUC) values for these comparisons were 0.97 and 0.94, and accuracy values were 0.90 and 0.83, respectively., Conclusions: NIRST holds promise as a potential clinical tool that can be seamlessly integrated into existing clinical workflow within the infusion suite. By providing early assessment of RCB, NIRST has potential to improve breast cancer patient management strategies., (©2023 American Association for Cancer Research.)

Background: Breast-conserving surgery (BCS) is an integral component of early-stage breast cancer treatment, but costly reexcision procedures are common due to the high prevalence of cancer-positive margins on primary resections. A need exists to develop and evaluate improved methods of margin assessment to detect positive margins intraoperatively., Methods: A prospective trial was conducted through which micro-computed tomography (micro-CT) with radiological interpretation by three independent readers was evaluated for BCS margin assessment. Results were compared to standard-of-care intraoperative margin assessment (i.e., specimen palpation and radiography [abbreviated SIA]) for detecting cancer-positive margins., Results: Six hundred margins from 100 patients were analyzed. Twenty-one margins in 14 patients were pathologically positive. On analysis at the specimen-level, SIA yielded a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 42.9%, 76.7%, 23.1%, and 89.2%, respectively. SIA correctly identified six of 14 margin-positive cases with a 23.5% false positive rate (FPR). Micro-CT readers achieved sensitivity, specificity, PPV, and NPV ranges of 35.7-50.0%, 55.8-68.6%, 15.6-15.8%, and 86.8-87.3%, respectively. Micro-CT readers correctly identified five to seven of 14 margin-positive cases with an FPR range of 31.4-44.2%. If micro-CT scanning had been combined with SIA, up to three additional margin-positive specimens would have been identified., Discussion: Micro-CT identified a similar proportion of margin-positive cases as standard specimen palpation and radiography, but due to difficulty distinguishing between radiodense fibroglandular tissue and cancer, resulted in a higher proportion of false positive margin assessments., (© 2023. Society of Surgical Oncology.)

Significance: Tissue phantoms that mimic the optical and radiologic properties of human or animal tissue play an important role in the development, characterization, and evaluation of imaging systems. Phantoms that are easily produced and stable for longitudinal studies are highly desirable., Aim: A new type of long-lasting phantom was developed with commercially available materials and was assessed for fabrication ease, stability, and optical property control. Magnetic resonance imaging (MRI) and x-ray computed tomography (CT) contrast properties were also evaluated., Approach: A systematic investigation of relationships between concentrations of skin-like pigments and composite optical properties was conducted to realize optical property phantoms in the red and near-infrared (NIR) wavelength range that also offered contrast for CT and MRI., Results: Phantom fabrication time was < 1    h and did not involve any heating or cooling processes. Changes in optical properties were < 2 % over a 12-month period. Phantom optical and spectral features were similar to human soft tissue over the red to NIR wavelength ranges. Pigments used in the study also had CT and MRI contrasts for multimodality imaging studies., Conclusions: The phantoms described here mimic optical properties of soft tissue and are suitable for multimodality imaging studies involving CT or MRI without adding secondary contrast agents., (© 2023 The Authors.)

Hyperspectral imaging and spectral analysis quantifies fluorophore concentration during fluorescence-guided surgery 1-6 . However, acquisition of the multiple wavelengths required to implement these methods can be time-consuming and hinder surgical workflow. To this end, a snapshot hyperspectral imaging system capable of acquiring 64 channels of spectral data simultaneously was developed for rapid hyperspectral imaging during neurosurgery. The system uses a birefringent spectral demultiplexer to split incoming light and redirect wavelengths to different sections of a large format microscope sensor. Its configuration achieves high optical throughput, accepts unpolarized input light and exceeds channel count of prior image-replicating imaging spectrometers by 4-fold. Tissue-simulating phantoms consisting of serial dilutions of the fluorescent agent characterize system linearity and sensitivity, and comparisons to performance of a liquid crystal tunable filter based hyperspectral imaging device are favorable. The new instrument showed comparable, if not improved, sensitivity at low fluorophore concentrations; yet, acquired wide-field images at more than 70-fold increase in frame rate. Image data acquired in the operating room during human brain tumor resection confirm these findings. The new device is an important advance in achieving real-time quantitative imaging of fluorophore concentration for guiding surgery., (© 2023. The Author(s).)

Background: Imaging-based navigation technologies require static referencing between the target anatomy and the optical sensors. Imaging-based navigation is therefore well suited to operations involving bony anatomy; however, these technologies have not translated to soft-tissue surgery. We sought to determine if fluorescence imaging complement conventional, radiological imaging-based navigation to guide the dissection of soft-tissue phantom tumors., Methods: Using a human tissue-simulating model, we created tumor phantoms with physiologically accurate optical density and contrast concentrations. Phantoms were dissected using all possible combinations of computed tomography (CT), magnetic resonance, and fluorescence imaging; controls were included. The data were margin accuracy, margin status, tumor spatial alignment, and dissection duration., Results: Margin accuracy was higher for combined navigation modalities compared to individual navigation modalities, and accuracy was highest with combined CT and fluorescence navigation (p = 0.045). Margin status improved with combined CT and fluorescence imaging., Conclusions: At present, imaging-based navigation has limited application in guiding soft-tissue tumor operations due to its inability to compensate for positional changes during surgery. This study indicates that fluorescence guidance enhances the accuracy of imaging-based navigation and may be best viewed as a synergistic technology, rather than a competing one., (© 2022 Wiley Periodicals LLC.)

Background: Fluorescence molecular imaging using ABY-029, an epidermal growth factor receptor (EGFR)-targeted, synthetic Affibody peptide labeled with a near-infrared fluorophore, is under investigation for surgical guidance during head and neck squamous cell carcinoma (HNSCC) resection. However, tumor-to-normal tissue contrast is confounded by intrinsic physiological limitations of heterogeneous EGFR expression and non-specific agent uptake., Objective: In this preliminary study, radiomic analysis was applied to optical ABY-029 fluorescence image data for HNSCC tissue classification through an approach termed "optomics." Optomics was employed to improve tumor identification by leveraging textural pattern differences in EGFR expression conveyed by fluorescence. The study objective was to compare the performance of conventional fluorescence intensity thresholding and optomics for binary classification of malignant vs. non-malignant HNSCC tissues., Materials and Methods: Fluorescence image data collected through a Phase 0 clinical trial of ABY-029 involved a total of 20,073 sub-image patches (size of 1.8 × 1.8 mm 2 ) extracted from 24 bread-loafed slices of HNSCC surgical resections originating from 12 patients who were stratified into three dose groups (30, 90, and 171 nanomoles). Each dose group was randomly partitioned on the specimen-level 75%/25% into training/testing sets, then all training and testing sets were aggregated. A total of 1,472 standardized radiomic features were extracted from each patch and evaluated by minimum redundancy maximum relevance feature selection, and 25 top-ranked features were used to train a support vector machine (SVM) classifier. Predictive performance of the SVM classifier was compared to fluorescence intensity thresholding for classifying testing set image patches with histologically confirmed malignancy status., Results: Optomics provided consistent improvement in prediction accuracy and false positive rate (FPR) and similar false negative rate (FNR) on all testing set slices, irrespective of dose, compared to fluorescence intensity thresholding (mean accuracies of 89% vs. 81%, P  = 0.0072; mean FPRs of 12% vs. 21%, P  = 0.0035; and mean FNRs of 13% vs. 17%, P  = 0.35)., Conclusions: Optomics outperformed conventional fluorescence intensity thresholding for tumor identification using sub-image patches as the unit of analysis. Optomics mitigate diagnostic uncertainties introduced through physiological variability, imaging agent dose, and inter-specimen biases of fluorescence molecular imaging by probing textural image information. This preliminary study provides a proof-of-concept that applying radiomics to fluorescence molecular imaging data offers a promising image analysis technique for cancer detection in fluorescence-guided surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Chen, Streeter, Hunt, Sardar, Gunn, Tafe, Paydarfar, Pogue, Paulsen and Samkoe.)

Objective . In vivo imaging assessments of skeletal muscle structure and function allow for longitudinal quantification of tissue health. Magnetic resonance elastography (MRE) non-invasively quantifies tissue mechanical properties, allowing for evaluation of skeletal muscle biomechanics in response to loading, creating a better understanding of muscle functional health. Approach . In this study, we analyze the anisotropic mechanical response of calf muscles using MRE with a transversely isotropic, nonlinear inversion algorithm (TI-NLI) to investigate the role of muscle fiber stiffening under load. We estimate anisotropic material parameters including fiber shear stiffness (μ1), substrate shear stiffness (μ2), shear anisotropy (ϕ), and tensile anisotropy (ζ) of the gastrocnemius muscle in response to both passive and active tension. Main results . In passive tension, we found a significant increase inμ1,ϕ,andζwith increasing muscle length. While in active tension, we observed increasingμ2and decreasingϕandζduring active dorsiflexion and plantarflexion-indicating less anisotropy-with greater effects when the muscles act as agonist. Significance . The study demonstrates the ability of this anisotropic MRE method to capture the multifaceted mechanical response of skeletal muscle to tissue loading from muscle lengthening and contraction., (© 2023 Institute of Physics and Engineering in Medicine.)

Accelerating innovation in the space of fluorescence imaging for surgical applications has increased interest in safely and expediently advancing these technologies to clinic through Food and Drug Administration-(FDA-) compliant trials. Conventional metrics for early phase trials include drug safety, tolerability, dosing, and pharmacokinetics. Most procedural imaging technologies rely on administration of an exogenous fluorophore and concurrent use of an imaging system; both of which must receive FDA approval to proceed to clinic. Because fluorophores are classified as medical imaging agents, criteria for establishing dose are different, and arguably more complicated, than therapeutic drugs. Since no therapeutic effect is desired, medical imaging agents are ideally administered at the lowest dose that achieves adequate target differentiation. Because procedural imaging modalities are intended to enhance and/or ease proceduralists' identification or assessment of tissues, beneficial effects of these technologies may manifest in the form of qualitative endpoints such as: 1) confidence; 2) decision-making; and 3) satisfaction with the specified procedure. Due to the rapid expansion of medical imaging technologies, we believe that our field requires standardized criteria to evaluate existing and emerging technologies objectively so that both quantitative and qualitative aspects of their use may be measured and useful comparisons to assess their relative value may occur. Here, we present a 15-item consensus-based survey instrument to assess the utility of novel imaging technologies from the proceduralist's standpoint.

Purpose: We have developed a fully 3D data acquisition system for microwave breast imaging which can operate simultaneously inside a magnetic resonance imaging (MRI). MRI is used regularly for breast imaging to distinguish tumors from normal tissue. It generally has poor specificity unless used with a gadolinium contrast agent. Microwave imaging could fill this need because of the good endogenous tumor:normal tissue property contrast, especially in light of safety concerns for gadolinium. The antenna array consists of 16 monopole antennas positioned in a horizontal circle surrounding the breast which can then be moved vertically for 3D coverage of the breast. The tank system materials were chosen to minimize artifacts in the MR image within the specific shared imaging zone. The support rods are stainless steel, albeit positioned sufficiently far from the imaging target to have little effect. The mechanical motion parts are all 3D printed plastic. Unlike many conventional antennas, the monopoles consist of just the center conductor and insulator of the coaxial cable, making it one of the least possible metallic structures., Methods: Data were acquired both inside and outside of the MR bore to confirm that the MR bore did not have adverse effects on the microwave imaging process. The imaging tank was filled with a mixture of glycerin and water to both provide a reasonable property match to the phantom and to highly attenuate the fields which also acted to suppress multi-path signals. Microwave images were reconstructed using our Gauss-Newton scheme combined with a log transformation for a more linear convergence. MR images were also acquired to assess the effects of the microwave tank structures on the imaging., Results: The microwave measurement data were acquired in log magnitude and phase format at 200 MHz increments from 700-1900 MHz. Each antenna acted sequentially as a transmitter while the complement of 15 acted as a receiver. The single frequency images were reconstructed using a Gauss-Newton iterative technique with a standard log transformation to linearize the process. The data showed that the signal strengths were between 7-10 dB lower for the case when the array was inside the MRI versus when not. Notwithstanding, the image quality was still high because of the significant signal to noise ratio. The reconstructed images in both situations demonstrated good 3D object recovery of the vertically size and shaped varying object. The MR images were not adversely affected by the presence of antennas or feed structures., Conclusions: We have demonstrated that our technique can recover high-quality images of a 3D varying object within an MRI system. Compatibility issues have been addressed for both the microwave and MRI systems. The reduced SNR for the case operating in the MRI did not adversely affect the images. To the best of our knowledge, this is the first example of a microwave imaging system operating in an MRI with full 3D volumetric capability., (© 2022 American Association of Physicists in Medicine.)

Magnetic particle spectroscopy (MPS) in the Brownian relaxation regime, also termed magnetic spectroscopy of Brownian motion (MSB), can detect and quantitate very low, sub-nanomolar concentrations of molecular biomarkers. MPS/MSB uses the harmonics of the magnetization induced by a small, low-frequency oscillating magnetic field to provide quantitative information about the magnetic nanoparticles' (mNPs') microenvironment. A key application uses antibody-coated mNPs to produce biomarker-mediated aggregation that can be detected using MPS/MSB. However, relaxation changes can also be caused by viscosity changes. To address this challenge, we propose a metric that can distinguish between aggregation and viscosity. Viscosity changes scale the MPS/MSB harmonic ratios with a constant multiplier across all applied field frequencies. The change in viscosity is exactly equal to the multiplier with generality, avoiding the need to understand the signal explicitly. This simple scaling relationship is violated when particles aggregate. Instead, a separate multiplier must be used for each frequency. The standard deviation of the multipliers over frequency defines a metric isolating viscosity (zero standard deviation) from aggregation (non-zero standard deviation). It increases monotonically with biomarker concentration. We modeled aggregation and simulated the MPS/MSB signal changes resulting from aggregation and viscosity changes. MPS/MSB signal changes were also measured experimentally using 100 nm iron-oxide mNPs in solutions with different viscosities (modulated by glycerol concentration) and with different levels of aggregation (modulated by concanavalin A linker concentrations). Experimental and simulation results confirmed that viscosity changes produced small changes in the standard deviation and aggregation produced larger values of standard deviation. This work overcomes a key barrier to using MPS/MSB to detect biomarkers in vivo with variable tissue viscosity.

Background: Evaluate whether the Breast Cancer Locator™ (BCL), a novel guidance system based on supine MRI images, can be safely and effectively deployed by several surgeons at multiple sites., Methods: Patients with palpable breast cancer underwent supine MRI at their local institution. A three dimensional (3D) digital image of the tumor in the breast was derived from supine MRI images and used to generate 1) an interactive 3D virtual image of the tumor in the breast (Visualizer) and 2) a plastic bra-like form that allowed the surgeon to place a central wire and bracketing wires in the breast (BCL). The primary objective was to determine the proportion of patients who had the central localization wire deployed within the cancer on specimen mammogram., Results: Fourteen patients were enrolled at 4 different sites by 6 surgeons. BCLs were successfully manufactured for all patients. The central wire was deployed within the tumor on specimen mammogram in 12 of the 13 patients who had a central wire placed (92%). The cancer was excised with negative margins in 14/14 cases (100%). No adverse events occurred., Conclusions: Supine MRI image acquisition was accomplished successfully across multiple sites. Multiple surgeons utilized the BCL system to localize cancers accurately and safely., Competing Interests: Declaration of competing interest Drs. Barth, Krishnaswamy and Paulsen have ownership interest in CairnSurgical, Inc and are listed on patents relevant to the Breast Cancer Locator guidance system., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Breast-conserving surgery requires that resection margins be cancer-free, but re-excision rates due to positive margins have remained near 20% for much of the last decade with high variability between surgical centers. Recent studies have demonstrated that volumetric X-ray imaging improves margin assessment over standard techniques, given the speed of image reconstruction and full three-dimensional sensing of all margins. Deep learning approaches for automated analysis of volumetric medical image data are gaining traction and could play an important role streamlining the clinical workflow for intra-surgical specimen imaging. X-ray imaging systems currently deployed in clinical studies suffer from poor tumor-to-fibroglandular tissue contrast, motivating the development of adjuvant tools that could potentially complement volumetric X-ray scanning and further improve the future of intra-surgical margin assessment by real-time augmented guidance for the surgeon., Competing Interests: Declaration of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SSS, KDP, and BWP have a patent pending (US Application No.: 17/076,788) related to this study. BWP is President and Co-Founder of DoseOptics, LLC. KDP is Co-Founder of CairnSurgical, Inc. Authors in their roles in the medical industry did not impact this article. BH did not disclose any competing interests.

Change in vertebral position between preoperative imaging and the surgical procedure reduces the accuracy of image-guided spinal surgery, requiring repeated imaging and surgical field registration, a process that takes time and exposes patients to additional radiation. We developed a handheld, camera-based, deformable registration system (intraoperative stereovision, iSV) to register the surgical field automatically and compensate for spinal motion during surgery without further radiation exposure., Methods: We measured motion-induced errors in image-guided lumbar pedicle screw placement in 6 whole-pig cadavers using state-of-the-art commercial spine navigation (StealthStation; Medtronic) and iSV registration that compensates for intraoperative vertebral motion. We induced spinal motion by using preoperative computed tomography (pCT) of the lumbar spine performed in the supine position with accentuated lordosis and performing surgery with the animal in the prone position. StealthStation registration of pCT occurred using metallic fiducial markers implanted in each vertebra, and iSV data were acquired to perform a deformable registration between pCT and the surgical field. Sixty-eight pedicle screws were placed in 6 whole-pig cadavers using iSV and StealthStation registrations in random order of vertebral level, relying only on image guidance without invoking the surgeon's judgment. The position of each pedicle screw was assessed with post-procedure CT and confirmed via anatomical dissection. Registration errors were assessed on the basis of implanted fiducials., Results: The frequency and severity of pedicle screw perforation were lower for iSV registration compared with StealthStation (97% versus 68% with Grade 0 medial perforation for iSV and StealthStation, respectively). Severe perforation occurred only with StealthStation (18% versus 0% for iSV). The overall time required for iSV registration (computational efficiency) was ∼10 to 15 minutes and was comparable with StealthStation registration (∼10 min). The mean target registration error was smaller for iSV relative to StealthStation (2.81 ± 0.91 versus 8.37 ± 1.76 mm)., Conclusions: Pedicle screw placement was more accurate with iSV registration compared with state-of-the-art commercial navigation based on preoperative CT when alignment of the spine changed during surgery., Clinical Relevance: The iSV system compensated for intervertebral motion, which obviated the need for repeated vertebral registration while providing efficient, accurate, radiation-free navigation during open spinal surgery., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSOA/A365)., (Copyright © 2022 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

Non-invasive near-infrared spectral tomography (NIRST) can incorporate the structural information provided by simultaneous magnetic resonance imaging (MRI), and this has significantly improved the images obtained of tissue function. However, the process of MRI guidance in NIRST has been time consuming because of the needs for tissue-type segmentation and forward diffuse modeling of light propagation. To overcome these problems, a reconstruction algorithm for MRI-guided NIRST based on deep learning is proposed and validated by simulation and real patient imaging data for breast cancer characterization. In this approach, diffused optical signals and MRI images were both used as the input to the neural network, and simultaneously recovered the concentrations of oxy-hemoglobin, deoxy-hemoglobin, and water via end-to-end training by using 20,000 sets of computer-generated simulation phantoms. The simulation phantom studies showed that the quality of the reconstructed images was improved, compared to that obtained by other existing reconstruction methods. Reconstructed patient images show that the well-trained neural network with only simulation data sets can be directly used for differentiating malignant from benign breast tumors., Competing Interests: Disclosures. The authors declare no conflicts of interest.

Magnetic resonance elastography (MRE) is an MRI technique for imaging the mechanical properties of brain in vivo, and has shown differences in properties between neuroanatomical regions and sensitivity to aging, neurological disorders, and normal brain function. Past MRE studies investigating these properties have typically assumed the brain is mechanically isotropic, though the aligned fibers of white matter suggest an anisotropic material model should be considered for more accurate parameter estimation. Here we used a transversely isotropic, nonlinear inversion algorithm (TI-NLI) and multiexcitation MRE to estimate the anisotropic material parameters of individual white matter tracts in healthy young adults. We found significant differences between individual tracts for three recovered anisotropic parameters: substrate shear stiffness, μ (range: 2.57 - 3.02 kPa), shear anisotropy, ϕ (range: -0.026 - 0.164), and tensile anisotropy, ζ (range: 0.559 - 1.049). Additionally, we demonstrated the repeatability of these parameter estimates in terms of lower variability of repeated measures in a single subject relative to variability in our sample population. Further, we observed significant differences in anisotropic mechanical properties between segments of the corpus callosum (genu, body, and splenium), which is expected based on differences in axonal microstructure. This study shows the ability of MRE with TI-NLI to estimate anisotropic mechanical properties of white matter and presents reference properties for tracts throughout the healthy brain., Competing Interests: Conflict of Interest The authors have no conflicts of interest related to this work.

As rapidly accelerating technology, fluorescence guided surgery (FGS) has the potential to place molecular information directly into the surgeon's field of view by imaging administered fluorescent contrast agents in real time, circumnavigating pre-operative MR registration challenges with brain deformation. The most successful implementation of FGS is 5-ALA-PpIX guided glioma resection which has been linked to improved patient outcomes. While FGS may offer direct in-field guidance, fluorescent contrast agent distributions are not as familiar to the surgical community as Gd-MRI uptake, and may provide discordant information from previous Gd-MRI guidance. Thus, a method to assess and validate consistency between fluorescence-labeled tumor regions and Gd-enhanced tumor regions could aid in understanding the correlation between optical agent fluorescence and Gd-enhancement. Herein, we present an approach for comparing whole-brain fluorescence biodistributions with Gd-enhancement patterns on a voxel-by-voxel basis using co-registered fluorescent cryo-volumes and Gd-MRI volumes. In this initial study, a porcine-human glioma xenograft model was administered 5-ALA-PpIX, imaged with MRI, and euthanized 22 hours following 5-ALA administration. Following euthanization, the extracted brain was imaged with the cryo-macrotome system. After image processing steps and non-rigid, point-based registration, the fluorescence cryo-volume and Gd-MRI volume were compared for similarity metrics including: image similarity, tumor shape similarity, and classification similarity. This study serves as a proof-of-principle in validating our screening approach for quantitatively comparing 3D biodistributions between optical agents and Gd-based agents.

Curative surgery for other many cancers requires that the tumor be removed with a zone of normal tissue surrounding the tumor with 'negative' margins. Sarcomas, cancers of the bones, muscles, and fat, require WLE for cure. Unfortunately, 'positive' margins occur in 20-25% of sarcoma surgeries, associated with cancer recurrence and reduced survival. Our group successfully tested a small-molecule fluorophore (ABY-029) in sarcomas that targets the epidermal growth factor receptor. We sought to evaluate human sarcoma xenografts for epidermal growth factor receptor expression and binding of ABY-029 with and without exposure to standard presurgical chemotherapy and radiation. We inoculated groups of 24 NSG mice with five cell lines (120 mice total). Eight mice from each cell line received: 1) radiation alone; 2) chemotherapy alone; or 3) chemotherapy and radiation. We administered ABY-029 2-4 hours before surgery. Tumor and biopsy portions of background tissues were removed. All tissues were imaged on a LI-COR Odyssey and processed in pathology. There were no significant reductions in epidermal growth factor receptor expression or in ABY-029-mediated fluorescence in tumors exposed to chemotherapy, radiation, or both. fluorescence-guided surgery demonstrates strong promise to improve curative surgical cancer care, particularly for sarcomas where the positive margin rate is substantial. Fluorophore performance must be evaluated under circumstances that duplicate accurately the biological milieu relevant to a particular cancer. This work shows that human sarcoma xenografts subjected to standard therapies do not demonstrate a change in epidermal growth factor receptor expression or in epidermal growth factor receptor-targeted fluorescence, thereby indicating that epidermal growth factor receptor-targeted fluorescence-guided surgery should be feasible under normal therapeutic conditions in the clinic.

Integration of magnetic resonance imaging (MRI) and near-infrared spectral tomography (NIRST) has yielded promising diagnostic performance for breast imaging in the past. This study focused on whether MRI-guided NIRST can quantify hemoglobin concentration using only continuous wave (CW) measurements. Patients were classified into four breast density groups based on their MRIs. Optical scattering properties were assigned based on average values obtained from these density groups, and MRI-guided NIRST images were reconstructed from calibrated CW data. Total hemoglobin (HbT) contrast between suspected lesions and surrounding normal tissue was used as an indicator of the malignancy. Results obtained from simulations and twenty-four patient cases indicate that the diagnostic power when using only CW data to differentiate malignant from benign abnormalities is similar to that obtained from combined frequency domain (FD) and CW data. These findings suggest that eliminating FD detection to reduce the cost and complexity of MRI-guided NIRST is possible., Competing Interests: The authors declare no conflicts of interest., (© 2021 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

High positive margin rates in oncologic breast-conserving surgery are a pressing clinical problem. Volumetric X-ray scanning is emerging as a powerful ex vivo specimen imaging technique for analyzing resection margins, but X-rays lack contrast between non-malignant and malignant fibrous tissues. In this study, combined micro-CT and wide-field optical image radiomics were developed to classify malignancy of breast cancer tissues, demonstrating that X-ray/optical radiomics improve malignancy classification. Ninety-two standardized features were extracted from co-registered micro-CT and optical spatial frequency domain imaging samples extracted from 54 breast tumors exhibiting seven tissue subtypes confirmed by microscopic histological analysis. Multimodal feature sets improved classification performance versus micro-CT alone when adipose samples were included (AUC = 0.88 vs. 0.90; p-value = 3.65e-11) and excluded, focusing the classification task on exclusively non-malignant fibrous versus malignant tissues (AUC = 0.78 vs. 0.85; p-value = 9.33e-14). Extending the radiomics approach to high-dimensional optical data-termed "optomics" in this study-offers a promising optical image analysis technique for cancer detection. Radiomic feature data and classification source code are publicly available., (© 2021. The Author(s).)

Is it possible to find deterministic relationships between optical measurements and pathophysiology in an unsupervised manner and based on data alone? Optical property quantification is a rapidly growing biomedical imaging technique for characterizing biological tissues that shows promise in a range of clinical applications, such as intraoperative breast-conserving surgery margin assessment. However, translating tissue optical properties to clinical pathology information is still a cumbersome problem due to, amongst other things, inter- and intrapatient variability, calibration, and ultimately the nonlinear behavior of light in turbid media. These challenges limit the ability of standard statistical methods to generate a simple model of pathology, requiring more advanced algorithms. We present a data-driven, nonlinear model of breast cancer pathology for real-time margin assessment of resected samples using optical properties derived from spatial frequency domain imaging data. A series of deep neural network models are employed to obtain sets of latent embeddings that relate optical data signatures to the underlying tissue pathology in a tractable manner. These self-explanatory models can translate absorption and scattering properties measured from pathology, while also being able to synthesize new data. The method was tested on a total of 70 resected breast tissue samples containing 137 regions of interest, achieving rapid optical property modeling with errors only limited by current semi-empirical models, allowing for mass sample synthesis and providing a systematic understanding of dataset properties, paving the way for deep automated margin assessment algorithms using structured light imaging or, in principle, any other optical imaging technique seeking modeling. Code is available.

In patients undergoing breast-conserving surgery (BCS), the rate of re-excision procedures to remove residual tumor left behind after initial resection can be high. Projection radiography, and recently, volumetric x-ray imaging are used to assess margin adequacy, but x-ray imaging lacks contrast between healthy, abnormal benign, and malignant fibrous tissues important for surgical decision making. The purpose of this study was to compare micro-CT and optical scatter imagery of surgical breast specimens and to demonstrate enhanced contrast-to intra-tumoral morphologies and tumor boundary features revealed by optical scatter imaging. A total of 57 breast tumor slices from 57 patients were imaged ex vivo by spatially co-registered micro-CT and optical scatter scanning. Optical scatter exhibited greater similarity with micro-CT in 89% (51/57) of specimens versus diffuse white light (DWL) luminance using mutual information (mean ± standard deviation of 0.48 ± 0.21 versus 0.24 ± 0.12; p  < 0.001) and in 81% (46/57) of specimens using the Sørensen-Dice coefficient (0.48 ± 0.21 versus 0.33 ± 0.18; p  < 0.001). The coefficient of variation (CV) quantified the feature content in each image. Optical scatter exhibited the highest CV in every specimen (optical scatter: 0.70 ± 0.17; diffuse luminance: 0.24 ± 01; micro-CT: 0.15 ± 0.03 for micro-CT; p  < 0.001). Optical scatter also exhibited the highest contrast ratios across representative tumor boundaries with adjacent healthy/benign fibrous tissues (1.5-3.7 for optical scatter; 1.0-1.1 for diffuse luminance; 1.0-1.1 for micro-CT). The two main findings from this study were: first, optical scatter contrast was in general similar to the radiological view of the tissue relative to DWL imaging; and second, optical scatter revealed additional features associated with fibrous tissue structures of similar radiodensity that may be relevant to diagnosis. The value of micro-CT lies in its rapid three-dimensional scanning of specimen morphology, and combined with optical scatter imaging with sensitivity to fibrous surface tissues, may be an attractive solution for margin assessment during BCS., (© 2021 Institute of Physics and Engineering in Medicine.)

Purposes: Accurate and efficient spine registration is crucial to success of spine image guidance. However, changes in spine pose cause intervertebral motion that can lead to significant registration errors. In this study, we develop a geometrical rectification technique via nonlinear principal component analysis (NLPCA) to achieve level-wise vertebral registration that is robust to large changes in spine pose., Methods: We used explanted porcine spines and live pigs to develop and test our technique. Each sample was scanned with preoperative CT (pCT) in an initial pose and rescanned with intraoperative stereovision (iSV) in a different surgical posture. Patient registration rectified arbitrary spinal postures in pCT and iSV into a common, neutral pose through a parameterized moving-frame approach. Topologically encoded depth projection 2D images were then generated to establish invertible point-to-pixel correspondences. Level-wise point correspondences between pCT and iSV vertebral surfaces were generated via 2D image registration. Finally, closed-form vertebral level-wise rigid registration was obtained by directly mapping 3D surface point pairs. Implanted mini-screws were used as fiducial markers to measure registration accuracy., Results: In seven explanted porcine spines and two live animal surgeries (maximum in-spine pose change of 87.5 mm and 32.7 degrees averaged from all spines), average target registration errors (TRE) of 1.70  ±  0.15 mm and 1.85 ± 0.16 mm were achieved, respectively. The automated spine rectification took 3-5 min, followed by an additional 30 secs for depth image projection and level-wise registration., Conclusions: Accuracy and efficiency of the proposed level-wise spine registration support its application in human open spine surgeries. The registration framework, itself, may also be applicable to other intraoperative imaging modalities such as ultrasound and MRI, which may expand utility of the approach in spine registration in general.

Background: Tumors that take up and metabolize 5-aminolevulinic acid emit bright pink fluorescence when illuminated with blue light, aiding surgeons in identifying the margin of resection. The adoption of this method is hindered by the blue light illumination, which is too dim to safely operate under and therefore necessitates switching back and forth from white-light mode. The aim of this study was to examine the addition of an optimized secondary illuminant adapter to improve usability of blue-light mode without degrading tumor contrast., Methods: Color science methods were used to evaluate the color of the secondary illuminant and its impact on color rendering index as well as the tumor-to-background color contrast in data collected from 7 patients with high-grade gliomas (World Health Organization grade III and IV). A secondary illuminant adapter was built to provide 475-600 nm light the intensity of which can be controlled by the surgeon and was evaluated in 2 additional patients., Results: Secondary illuminant color had opposing effects on color rendering index and tumor-to-background color contrast; providing surgeon control of intensity allows this trade-off to be balanced in real time. Demonstration in 2 high-grade glioma cases confirms this, showing that additional visibility adds value when intensity can be controlled by the surgeon., Conclusions: Addition of a secondary illuminant may mitigate surgeon complaints that the operative field is too dark under the blue light illumination required for 5-aminolevulinic acid fluorescence guidance by providing improved color rendering index without completely sacrificing tumor-to-background color contrast., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Rationale and Objectives: Hydrocephalus (HC) is caused by accumulating cerebrospinal fluid resulting in enlarged ventricles and neurological symptoms. HC can be treated via a shunt in a subset of patients; identifying which individuals will respond through noninvasive imaging would avoid complications from unsuccessful treatments. This preliminary work is a longitudinal study applying MR Elastography (MRE) to HC patients with a focus on normal pressure hydrocephalus (NPH)., Materials and Methods: Twenty-two ventriculomegaly patients were imaged and subsequently received a lumbar drain placement for cerebrospinal fluid (CSF) drainage. NPH lumbar drain responders and NPH syndrome nonresponders were categorized by clinical presentation. Displacement images were acquired using intrinsic activation (IA) MRE and poroelastic inversion recovered shear stiffness and hydraulic conductivity values. A stable IA-MRE inversion protocol was developed to produce unique solutions for both recovered properties, independent of initial estimates., Results: Property images showed significantly increased shear modulus (p = 0.003 in periventricular region, p = 0.005 in remaining cerebral tissue) and hydraulic conductivity (p = 0.04 in periventricular region) in ventriculomegaly patients compared to healthy volunteers. Baseline MRE imaging did not detect significant differences between NPH lumbar drain responders and NPH syndrome nonresponders; however, MRE time series analysis demonstrated consistent trends in average poroelastic shear modulus values over the course of the lumbar drain process in responders (initial increase, followed by a later decrease) which did not occur in nonresponders., Conclusion: These findings are indicative of acute mechanical changes in the brain resulting from CSF drainage in NPH patients., (Copyright © 2020 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Magnetic Resonance Elastography allows noninvasive visualization of tissue mechanical properties by measuring the displacements resulting from applied stresses, and fitting a mechanical model. Poroelasticity naturally lends itself to describing tissue - a biphasic medium, consisting of both solid and fluid components. This article reviews the theory of poroelasticity, and shows that the spatial distribution of hydraulic permeability, the ease with which the solid matrix permits the flow of fluid under a pressure gradient, can be faithfully reconstructed without spatial priors in simulated environments. The paper describes an in-house MRE computational platform - a multi-mesh, finite element poroelastic solver coupled to an artificial epistemic agent capable of running Bayesian inference to reconstruct inhomogenous model mechanical property images from measured displacement fields. Building on prior work, the domain of convergence for inference is explored, showing that hydraulic permeabilities over several orders of magnitude can be reconstructed given very little prior knowledge of the true spatial distribution., Competing Interests: Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Standard anatomical atlases are common in neuroimaging because they facilitate data analyses and comparisons across subjects and studies. The purpose of this study was to develop a standardized human brain atlas based on the physical mechanical properties (i.e., tissue viscoelasticity) of brain tissue using magnetic resonance elastography (MRE). MRE is a phase contrast-based MRI method that quantifies tissue viscoelasticity noninvasively and in vivo thus providing a macroscopic representation of the microstructural constituents of soft biological tissue. The development of standardized brain MRE atlases are therefore beneficial for comparing neural tissue integrity across populations. Data from a large number of healthy, young adults from multiple studies collected using common MRE acquisition and analysis protocols were assembled (N = 134; 78F/ 56 M; 18-35 years). Nonlinear image registration methods were applied to normalize viscoelastic property maps (shear stiffness, μ, and damping ratio, ξ) to the MNI152 standard structural template within the spatial coordinates of the ICBM-152. We find that average MRE brain templates contain emerging and symmetrized anatomical detail. Leveraging the substantial amount of data assembled, we illustrate that subcortical gray matter structures, white matter tracts, and regions of the cerebral cortex exhibit differing mechanical characteristics. Moreover, we report sex differences in viscoelasticity for specific neuroanatomical structures, which has implications for understanding patterns of individual differences in health and disease. These atlases provide reference values for clinical investigations as well as novel biophysical signatures of neuroanatomy. The templates are made openly available (github.com/mechneurolab/mre134) to foster collaboration across research institutions and to support robust cross-center comparisons., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

We examine the value of an active line scan with spatial gating for imaging sub-diffuse, wide-field reflectance microtexture. Line scanning combined with spatial gating and linear translation can be used for localized detection of features in the surface layer of a turbid target. The line scan provides broadband spatial frequency modulation, and the spatial gating effectively high-pass filters the reflectance. The major benefit of this approach is that of high dynamic range (70%-90%) signal preservation and high contrast to noise when imaging at high spatial frequencies. Alternative approaches, such as spatial frequency domain imaging, are degraded by low dynamic range in demodulated images, making it nearly impossible to image over a wide field of view at frequencies over 1.5 m m -1 using commercial technology. As such, active line scanning with spatial gating presents as an inherently high sensitivity and high dynamic range method of imaging microscopic scattering features in only the surface layer of a turbid medium.

Objective: The efficacy of deep brain stimulation (DBS) depends on accurate placement of electrodes. Although stereotactic frames enable co-registration of image-based surgical planning and the operative field, the accuracy of electrode placement can be degraded by intra-operative brain shift. In this study, we adapted a biomechanical model to estimate whole brain displacements from which we deformed preoperative CT (preCT) to generate an updated CT (uCT) that compensates for brain shift., Methods: We drove the deformation model using displacement data derived from deformation in the frontal cortical surface that occurred during the DBS intervention. We evaluated 15 patients, retrospectively, who underwent bilateral DBS surgery, and assessed the accuracy of uCT in terms of target registration error (TRE) relative to a CT acquired post-placement (postCT). We further divided subjects into large (Group L) and small (Group S) deformation groups based on a TRE threshold of 1.6mm. Anterior commissure (AC), posterior commissure (PC) and pineal gland (PG) were identified on preCT and postCT and used to quantify TREs in preCT and uCT., Results: In the group of large brain deformation, average TREs for uCT were 1.11 ± 0.13 and 1.07 ± 0.38 mm at AC and PC, respectively, compared to 1.85 ± 0.17 and 0.92 ± 0.52 mm for preCT. The model updating approach improved AC localization but did not alter TREs at PC., Conclusion: This preliminary study suggests that our image updating method may compensate for brain shift around surgical targets of importance during DBS surgery, although further investigation is warranted before conclusive evidence will be available., Significance: With further development and evaluation, our model-based image updating method using intraoperative sparse data may compensate for brain shift in DBS surgery efficiently, and have utility in updating targeting coordinates.

Background: Current practices for fluorescence-guided cancer surgery utilize a single fluorescent agent, but homogeneous distribution throughout the tumor is difficult to achieve. We hypothesize that administering a perfusion and a molecular-targeted agent at their optimal administration-to-imaging time will improve whole-tumor contrast., Experimental Design: Mice bearing subcutaneous xenograft human synovial sarcomas were administered indocyanine green (ICG) (3 mg/kg) or ABY-029 (48.7 μg/kg)-an epidermal growth factor receptor-targeted Affibody molecule-alone or in combination. Fluorescence contrast and signal distribution were compared between treatment groups. Two commercial fluorescence imaging systems were tested for simultaneous imaging of ICG and ABY-029., Results: ABY-029 has a moderate positive correlation with viable tumor (ρ = 0.2 ± 0.4), while ICG demonstrated a strong negative correlation (ρ = -0.6 ± 0.1). The contrast-to-variance ratio was highest in the ABY-029 +ICG (2.5 ± 0.8), compared to animals that received ABY-029 (2.3 ± 0.8) or ICG (2.0 ± 0.5) alone. Moreover, the combination of ABY-029 + ICG minimizes the correlation between viable tumor and fluorescence intensity (ρ = -0.1 ± 0.2) indicating the fluorescence signal distribution is more homogeneous throughout the tumor milieu., Conclusion: Dual-agent imaging utilizing a single channel in a commercial fluorescence-guided imaging system tailored for IRDye 800CW is a promising method to increase tumor contrast in a clinical setting., (© 2020 Wiley Periodicals LLC.)

Under physiological conditions biomarker concentrations tend to rise and fall over time e.g. for inflammation. Ex vivo measurements provide a snapshot in time of biomarker concentrations, which is useful, but limited. Approaching real time monitoring of biomarker concentration(s) using a wearable, implantable or injectable in vivo sensor is therefore an appealing target. As an early step towards developing an in vivo biomarker sensor, antibody (AB) tagged magnetic nanoparticles (NPs) are used here to demonstrate the in vitro measurement of ~5 distinct biomarkers with high specificity and sensitivity. In previous work, aptamers were used to target a given biomarker in vitro and generate magnetic clusters that exhibit a characteristic rotational signature quite different from free NPs. Here the method is expanded to detect a much wider range of biomarkers using polyclonal ABs attached to the surface of the NPs. Commercial ABs exist for a wide range of targets allowing accurate and specific concentration measurements for most significant biomarkers. We show sufficient detection sensitivity, using an in-house spectrometer to measure the rotational signatures of the NPs, to assess physiological concentrations of hormones, cytokines and other signaling molecules. Detection limits for biomarkers drawn mainly from pain and inflammation targets were: 10 pM for mouse Granzyme B (mGZM-B), 40 pM for mouse interferon-gamma (mIFN- γ ), 7 pM for mouse interleukin-6 (mIL-6), 40 pM for rat interleukin-6 (rIL-6), 40 pM for mouse vascular endothelial growth factor (mVEGF) and 250 pM for rat calcitonin gene related peptide (rCGRP). Much lower detection limits are certainly possible using improved spectrometers and nanoparticles.

Background: Image guidance in open spinal surgery is compromised by changes in spinal alignment between preoperative images and surgical positioning. We evaluated registration of stereo-views of the surgical field to compensate for vertebral alignment changes., Objective: To assess accuracy and efficiency of an optically tracked hand-held stereovision (HHS) system to acquire images of the exposed spine during surgery., Methods: Standard midline posterior approach exposed L1 to L6 in 6 cadaver porcine spines. Fiducial markers were placed on each vertebra as "ground truth" locations. Spines were positioned supine with accentuated lordosis, and preoperative computed tomography (pCT) was acquired. Spines were re-positioned in a neutral prone posture, and locations of fiducials were acquired with a tracked stylus. Intraoperative stereovision (iSV) images were acquired and 3-dimensional (3D) surfaces of the exposed spine were reconstructed. HHS accuracy was assessed in terms of distances between reconstructed fiducial marker locations and their tracked counterparts. Level-wise registrations aligned pCT with iSV to account for changes in spine posture. Accuracy of updated computed tomography (uCT) was assessed using fiducial markers and other landmarks., Results: Acquisition time for each image pair was <1 s. Mean reconstruction time was <1 s for each image pair using batch processing, and mean accuracy was 1.2 ± 0.6 mm across 6 cases. Mean errors of uCT were 3.1 ± 0.7 and 2.0 ± 0.5 mm on the dorsal and ventral sides, respectively., Conclusion: Results suggest that a portable HHS system offers potential to acquire accurate image data from the surgical field to facilitate surgical navigation during open spine surgery., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Magnetic resonance elastography (MRE) has been developed to noninvasively reconstruct mechanical properties for tissue and tissue-like materials over a frequency range of 10 ~200 Hz. In this work, low frequency (1~1.5 Hz) MRE activations were employed to estimate mechanical property distributions of simulated data and experimental phantoms. Nonlinear inversion (NLI) MRE algorithms based on viscoelastic and poroelastic material models were used to solve the inverse problems and recover images of the shear modulus and hydraulic conductivity. Data from a simulated phantom containing an inclusion with property contrast was carried out to study the feasibility of our low frequency actuated approach. To verify the stability of NLI algorithms for low frequency actuation, different levels of synthetic noise were added to the displacement data. Spatial distributions and property values were recovered well for noise level less than 5%. For the presented experimental phantom reconstructions with regularizations, the computed storage moduli from viscoelastic and poroelastic MRE gave similar results. Contrast was detected between inclusions and background in recovered hydraulic conductivity images. Results and findings confirm the feasibility of future in vivo neuroimaging examinations using natural cerebrovascular pulsations at cardiac frequencies, which can eliminate specialized equipment for high frequency actuation.