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.
Background
Roughly 23% of breast conserving surgery (BCS) patients undergo a second re-excision procedure due to pathologically positive surgical margins. We investigated the feasibility and ...potential value of micro-Computed Tomography (micro-CT) as a surgical margin guidance tool during BCS.
Methods
A cohort of 32 BCS specimens was prospectively imaged with a pre-clinical micro-CT system upon arrival in the surgical pathology laboratory. Reconstructed micro-CT scans were evaluated retrospectively by an experienced breast radiologist, who provided binary determinations whether lesions extended to the specimen margin. These readings were then compared to the final pathological diagnosis and to 2D specimen radiography readings.
Results
Of the 32 specimens imaged, 28 had malignant and four had benign pathological diagnoses. Overall five (four malignant, one benign) of the 32 specimens had lesion tissue extending to the margin. For all 32 specimens, micro-CT reconstructions were calculated (< 4 min. acquisition + reconstruction time) and each specimen was volumetrically analyzed by a radiologist. Of the 28 malignant specimen readings, 18 matched the final pathological diagnosis 64%, 95 CI (47%–81%), with a negative predictive value of 89% 95 CI (74%–96%). Micro-CT readings revealed changes in the tumor location and margin status as compared to single-projection radiography readings.
Conclusions
Micro-CT scanning of BCS specimens enabled margin status assessment over the entirety of the surgical surface in a clinically relevant time frame, provided additional spatial information over single-projection radiography, and may be a potentially useful BCS guidance tool.
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.
Remote ischemic preconditioning (RIPC) induced by transient limb ischemia releases a dialysable circulating protective factor that reduces ischemia-reperfusion injury. Exercise performance in highly ...trained athletes is limited by tissue hypoxemia and acidosis, which may therefore represent a type of ischemia-reperfusion stress modifiable by RIPC.
National-level swimmers, 13-27 yr, were randomized to RIPC (four cycles of 5-min arm ischemia/5-min reperfusion) or a low-pressure control procedure, with crossover. In study 1, subjects (n=16) performed two incremental submaximal swimming tests with measurement of swimming velocity, blood lactate, and HR. For study 2, subjects (n=18) performed two maximal competitive swims (time trials). To examine possible mechanisms, blood samples taken before and after RIPC were dialysed and used to perfuse mouse hearts (n=10) in a Langendorff preparation. Infarct sizes were compared with dialysate obtained from nonathletic controls. RIPC released a protective factor into the bloodstream, which reduced infarct size in mice (P<0.05 for controls and swimmers). There was no statistically significant difference between the effect of RIPC and the low-pressure control protocol on submaximal exercise performance. However, RIPC was associated with a mean improvement of maximal swim time for 100 m of 0.7 s (P=0.04), an improvement in swim time relative to personal best time (-1.1%, P=0.02), and a significant improvement in average International Swimming Federation points (+22 points, P=0.01).
RIPC improves maximal performance in highly trained swimmers. This simple technique may be applicable to other sports and, more importantly, to other clinical syndromes in which exercise tolerance is limited by tissue hypoxemia or ischemia.
Abstract
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.
A multimodal micro-computed tomography (CT) and multi-spectral structured light imaging (SLI) system is introduced and systematically analyzed to test its feasibility to aid in margin delineation ...during breast conserving surgery (BCS). Phantom analysis of the micro-CT yielded a signal-to-noise ratio of 34, a contrast of 1.64, and a minimum detectable resolution of 240 μm for a 1.2 min scan. The SLI system, spanning wavelengths 490 nm to 800 nm and spatial frequencies up to 1.37 mm−1, was evaluated with aqueous tissue simulating phantoms having variations in particle size distribution, scatter density, and blood volume fraction. The reduced scattering coefficient, μs′ and phase function parameter, γ, were accurately recovered over all wavelengths independent of blood volume fractions from 0% to 4%, assuming a flat sample geometry perpendicular to the imaging plane. The resolution of the optical system was tested with a step phantom, from which the modulation transfer function was calculated yielding a maximum resolution of 3.78 cycles per mm. The three dimensional spatial co-registration between the CT and optical imaging space was tested and shown to be accurate within 0.7 mm. A freshly resected breast specimen, with lobular carcinoma, fibrocystic disease, and adipose, was imaged with the system. The micro-CT provided visualization of the tumor mass and its spiculations, and SLI yielded superficial quantification of light scattering parameters for the malignant and benign tissue types. These results appear to be the first demonstration of SLI combined with standard medical tomography for imaging excised tumor specimens. While further investigations are needed to determine and test the spectral, spatial, and CT features required to classify tissue, this study demonstrates the ability of multimodal CT/SLI to quantify, visualize, and spatially navigate breast tumor specimens, which could potentially aid in the assessment of tumor margin status during BCS.
Background Immunosuppressive drugs such as tacrolimus have revolutionized our ability to transplant organs between individuals. Tacrolimus acts systemically to suppress the activity of T-cells within ...and around transplanted organs. However, tacrolimus also suppresses T-cell function in the skin, contributing to a high incidence of skin cancer and associated mortality and morbidity in solid organ transplant recipients. Here, we aimed to identify a compound capable of re-establishing antitumor T-cell control in the skin despite the presence of tacrolimus. Methods In this study, we performed time-resolved fluorescence resonance energy transfer to identify molecules capable of antagonizing the interaction between tacrolimus and FKBP12. The capacity of these molecules to rescue mouse and human T-cell function in the presence of tacrolimus was determined in vitro, and the antitumor effect of the lead compound, Q-2361, was assessed in “regressor” models of skin cancer in immunosuppressed mice. Systemic CD8 T-cell depletion and analyses of intratumoral T-cell activation markers and effector molecule production were performed to determine the mechanism of tumor rejection. Pharmacokinetic studies of topically applied Q-2361 were performed to assess skin and systemic drug exposure. Results Q-2361 potently blocked the interaction between tacrolimus and FKBP12 and reversed the inhibition of the nuclear factor of activated T cells activation by tacrolimus following T-cell receptor engagement in human Jurkat cells. Q-2361 rescued T-cell function in the presence of tacrolimus, rapamycin, and everolimus. Intratumoral injection of Q-2361-induced tumor regression in mice systemically immune suppressed with tacrolimus. Mechanistically, Q-2361 treatment permitted T-cell activation, proliferation, and effector function within tumors. When CD8 T cells were depleted, Q-2361 could not induce tumor regression. A simple solution-based Q-2361 topical formulation achieved high and sustained residence in the skin with negligible drug in the blood. Conclusions Our findings demonstrate that the local application of Q-2361 permits T-cells to become activated driving tumor rejection in the presence of tacrolimus. The data presented here suggests that topically applied Q-2361 has great potential for the reactivation of T-cells in the skin but not systemically, and therefore represents a promising strategy to prevent or treat skin malignancies in immunosuppressed organ transplant recipients.
To determine whether pretreatment biomarkers obtained from diffuse optical spectroscopic tomographic (DOST) imaging predicts breast tumor response to neoadjuvant chemotherapy (NAC), which would have ...value to potentially eliminate delays in prescribing definitive local regional therapy that may occur from a standard complete 6- to 8-month course of NAC.
Nineteen patients undergoing NAC were imaged with DOST before, during, and after treatment. The DOST images of total hemoglobin concentration (HbT), tissue oxygen saturation (StO2), and water (H2O) fraction at different time points have been used for testing the abilities of differentiating patients having pathologic complete response (pCR) versus pathologic incomplete response (pIR).
Significant differences (P < 0.001, AUC = 1.0) were found between pCR patients versus pIR in outcome, based on the percentage change in tumor HbT within the first cycle of treatment. In addition, pretreatment tumor HbT (pretreatment HbT) relative to the contralateral breast was statistically significant (P = 0.01, AUC = 0.92) in differentiating pCR from pIR.
This is the first clinical evidence that DOST HbT may differentiate the two groups with predictive significance based on data acquired before NAC even begins. The study also demonstrates the potential of accelerating the validation of optimal NAC regimens through future randomized clinical trials by reducing the number of patients required and the length of time they need to be followed by using a validated imaging surrogate as an outcome measure.
Subdiffuse spatial frequency domain imaging (sd-SFDI) data of 42 freshly excised, bread-loafed tumor resections from breast-conserving surgery (BCS) were evaluated using texture analysis and a ...machine learning framework for tissue classification. Resections contained 56 regions of interest (RoIs) determined by expert histopathological analysis. RoIs were coregistered with sd-SFDI data and sampled into ∼4 × 4 mm2 subimage samples of confirmed and homogeneous histological categories. Sd-SFDI reflectance textures were analyzed using gray-level co-occurrence matrix pixel statistics, image primitives, and power spectral density curve parameters. Texture metrics exhibited statistical significance (p-value < 0.05) between three benign and three malignant tissue subtypes. Pairs of benign and malignant subtypes underwent texture-based, binary classification with correlation-based feature selection. Classification performance was evaluated using fivefold cross-validation and feature grid searching. Classification using subdiffuse, monochromatic reflectance (illumination spatial frequency of fx = 1.37 mm − 1, optical wavelength of λ = 490 nm) achieved accuracies ranging from 0.55 (95% CI: 0.41 to 0.69) to 0.95 (95% CI: 0.90 to 1.00) depending on the benign–malignant diagnosis pair. Texture analysis of sd-SFDI data maintains the spatial context within images, is free of light transport model assumptions, and may provide an alternative, computationally efficient approach for wide field-of-view (cm2) BCS tumor margin assessment relative to pixel-based optical scatter or color properties alone.
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