MR histology reveals tissue features beneath heterogeneous MRI signal in genetically engineered mouse models of sarcoma.

Purpose: To identify significant relationships between quantitative cytometric tissue features and quantitative MR (qMRI) intratumorally in preclinical undifferentiated pleomorphic sarcomas (UPS). Materials and methods: In a prospective study of genetically engineered mouse models of UPS, we registered imaging libraries consisting of matched multi-contrast in vivo MRI, three-dimensional (3D) multi-contrast high-resolution ex vivo MR histology (MRH), and two-dimensional (2D) tissue slides. From digitized histology we generated quantitative cytometric feature maps from whole-slide automated nuclear segmentation. We automatically segmented intratumoral regions of distinct qMRI values and measured corresponding cytometric features. Linear regression analysis was performed to compare intratumoral qMRI and tissue cytometric features, and results were corrected for multiple comparisons. Linear correlations between qMRI and cytometric features with p values of <0.05 after correction for multiple comparisons were considered significant. Results: Three features correlated with ex vivo apparent diffusion coefficient (ADC), and no features correlated with in vivo ADC. Six features demonstrated significant linear relationships with ex vivo T2*, and fifteen features correlated significantly with in vivo T2*. In both cases, nuclear Haralick texture features were the most prevalent type of feature correlated with T2*. A small group of nuclear topology features also correlated with one or both T2* contrasts, and positive trends were seen between T2* and nuclear size metrics. Conclusion: Registered multi-parametric imaging datasets can identify quantitative tissue features which contribute to UPS MR signal. T2* may provide quantitative information about nuclear morphology and pleomorphism, adding histological insights to radiological interpretation of UPS.

High-resolution hybrid micro-CT imaging pipeline for mouse brain region segmentation and volumetric morphometry.

BACKGROUND: Brain region segmentation and morphometry in humanized apolipoprotein E (APOE) mouse models with a human NOS2 background (HN) contribute to Alzheimer's disease (AD) research by demonstrating how various risk factors affect the brain. Photon-counting detector (PCD) micro-CT provides faster scan times than MRI, with superior contrast and spatial resolution to energy-integrating detector (EID) micro-CT. This paper presents a pipeline for mouse brain imaging, segmentation, and morphometry from PCD micro-CT. METHODS: We used brains of 26 mice from 3 genotypes (APOE22HN, APOE33HN, APOE44HN). The pipeline included PCD and EID micro-CT scanning, hybrid (PCD and EID) iterative reconstruction, and brain region segmentation using the Small Animal Multivariate Brain Analysis (SAMBA) tool. We applied SAMBA to transfer brain region labels from our new PCD CT atlas to individual PCD brains via diffeomorphic registration. Region-based and voxel-based analyses were used for comparisons by genotype and sex. RESULTS: Together, PCD and EID scanning take ~5 hours to produce images with a voxel size of 22 µm, which is faster than MRI protocols for mouse brain morphometry with voxel size above 40 µm. Hybrid iterative reconstruction generates PCD images with minimal artifacts and higher spatial resolution and contrast than EID images. Our PCD atlas is qualitatively and quantitatively similar to the prior MRI atlas and successfully transfers labels to PCD brains in SAMBA. Male and female mice had significant volume differences in 26 regions, including parts of the entorhinal cortex and cingulate cortex. APOE22HN brains were larger than APOE44HN brains in clusters from the hippocampus, a region where atrophy is associated with AD. CONCLUSIONS: This work establishes a pipeline for mouse brain analysis using PCD CT, from staining to imaging and labeling brain images. Our results validate the effectiveness of the approach, setting a foundation for research on AD mouse models while reducing scanning durations.

Advanced photon counting CT imaging pipeline for cardiac phenotyping of apolipoprotein E mouse models.

BACKGROUND: Cardiovascular disease (CVD) is associated with the apolipoprotein E (APOE) gene and lipid metabolism. This study aimed to develop an imaging-based pipeline to comprehensively assess cardiac structure and function in mouse models expressing different APOE genotypes using photon-counting computed tomography (PCCT). METHODS: 123 mice grouped based on APOE genotype (APOE2, APOE3, APOE4, APOE knockout (KO)), gender, human NOS2 factor, and diet (control or high fat) were used in this study. The pipeline included PCCT imaging on a custom-built system with contrast-enhanced in vivo imaging and intrinsic cardiac gating, spectral and temporal iterative reconstruction, spectral decomposition, and deep learning cardiac segmentation. Statistical analysis evaluated genotype, diet, sex, and body weight effects on cardiac measurements. RESULTS: Our results showed that PCCT offered high quality imaging with reduced noise. Material decomposition enabled separation of calcified plaques from iodine enhanced blood in APOE KO mice. Deep learning-based segmentation showed good performance with Dice scores of 0.91 for CT-based segmentation and 0.89 for iodine map-based segmentation. Genotype-specific differences were observed in left ventricular volumes, heart rate, stroke volume, ejection fraction, and cardiac index. Statistically significant differences were found between control and high fat diets for APOE2 and APOE4 genotypes in heart rate and stroke volume. Sex and weight were also significant predictors of cardiac measurements. The inclusion of the human NOS2 gene modulated these effects. CONCLUSIONS: This study demonstrates the potential of PCCT in assessing cardiac structure and function in mouse models of CVD which can help in understanding the interplay between genetic factors, diet, and cardiovascular health.

Leveraging 3D Bioprinting and Photon-Counting Computed Tomography to Enable Noninvasive Quantitative Tracking of Multifunctional Tissue Engineered Constructs.

3D bioprinting is revolutionizing the fields of personalized and precision medicine by enabling the manufacturing of bioartificial implants that recapitulate the structural and functional characteristics of native tissues. However, the lack of quantitative and noninvasive techniques to longitudinally track the function of implants has hampered clinical applications of bioprinted scaffolds. In this study, multimaterial 3D bioprinting, engineered nanoparticles (NPs), and spectral photon-counting computed tomography (PCCT) technologies are integrated for the aim of developing a new precision medicine approach to custom-engineer scaffolds with traceability. Multiple CT-visible hydrogel-based bioinks, containing distinct molecular (iodine and gadolinium) and NP (iodine-loaded liposome, gold, methacrylated gold (AuMA), and Gd2 O3 ) contrast agents, are used to bioprint scaffolds with varying geometries at adequate fidelity levels. In vitro release studies, together with printing fidelity, mechanical, and biocompatibility tests identified AuMA and Gd2 O3 NPs as optimal reagents to track bioprinted constructs. Spectral PCCT imaging of scaffolds in vitro and subcutaneous implants in mice enabled noninvasive material discrimination and contrast agent quantification. Together, these results establish a novel theranostic platform with high precision, tunability, throughput, and reproducibility and open new prospects for a broad range of applications in the field of precision and personalized regenerative medicine.

A Deep Learning Approach for Rapid and Generalizable Denoising of Photon-Counting Micro-CT Images.

Photon-counting CT (PCCT) is powerful for spectral imaging and material decomposition but produces noisy weighted filtered backprojection (wFBP) reconstructions. Although iterative reconstruction effectively denoises these images, it requires extensive computation time. To overcome this limitation, we propose a deep learning (DL) model, UnetU, which quickly estimates iterative reconstruction from wFBP. Utilizing a 2D U-net convolutional neural network (CNN) with a custom loss function and transformation of wFBP, UnetU promotes accurate material decomposition across various photon-counting detector (PCD) energy threshold settings. UnetU outperformed multi-energy non-local means (ME NLM) and a conventional denoising CNN called UnetwFBP in terms of root mean square error (RMSE) in test set reconstructions and their respective matrix inversion material decompositions. Qualitative results in reconstruction and material decomposition domains revealed that UnetU is the best approximation of iterative reconstruction. In reconstructions with varying undersampling factors from a high dose ex vivo scan, UnetU consistently gave higher structural similarity (SSIM) and peak signal-to-noise ratio (PSNR) to the fully sampled iterative reconstruction than ME NLM and UnetwFBP. This research demonstrates UnetU's potential as a fast (i.e., 15 times faster than iterative reconstruction) and generalizable approach for PCCT denoising, holding promise for advancing preclinical PCCT research.

MCR toolkit: A GPU-based toolkit for multi-channel reconstruction of preclinical and clinical x-ray CT data.

BACKGROUND: The advancement of x-ray CT into the domains of photon counting spectral imaging and dynamic cardiac and perfusion imaging has created many new challenges and opportunities for clinicians and researchers. To address challenges such as dose constraints and scanning times while capitalizing on opportunities such as multi-contrast imaging and low-dose coronary angiography, these multi-channel imaging applications require a new generation of CT reconstruction tools. These new tools should exploit the relationships between imaging channels during reconstruction to set new image quality standards while serving as a platform for direct translation between the preclinical and clinical domains. PURPOSE: We outline and demonstrate a new Multi-Channel Reconstruction (MCR) Toolkit for GPU-based analytical and iterative reconstruction of preclinical and clinical multi-energy and dynamic x-ray CT data. To promote open science, open-source distribution of the Toolkit will coincide with the release of this publication (GPL v3; gitlab.oit.duke.edu/dpc18/mcr-toolkit-public). METHODS: The MCR Toolkit source code is implemented in C/C++ and NVIDIA's CUDA GPU programming interface, with scripting support from MATLAB and Python. The Toolkit implements matched, separable footprint CT reconstruction operators for projection and backprojection in two geometries: planar, cone-beam CT (CBCT) and 3rd generation, cylindrical multi-detector row CT (MDCT). Analytical reconstruction is performed using filtered backprojection (FBP) for circular CBCT, weighted FBP (WFBP) for helical CBCT, and cone-parallel projection rebinning followed by WFBP for MDCT. Arbitrary combinations of energy and temporal channels are iteratively reconstructed under a generalized multi-channel signal model for joint reconstruction. We solve this generalized model algebraically using the split Bregman optimization method and the BiCGSTAB(l) linear solver interchangeably for both CBCT and MDCT data. Rank-sparse kernel regression (RSKR) and patch-based singular value thresholding (pSVT) are used to regularize the energy and time dimensions, respectively. Under a Gaussian noise model, regularization parameters are estimated automatically from the input data, dramatically reducing algorithm complexity for end users. Multi-GPU parallelization of the reconstruction operators is supported to manage reconstruction times. RESULTS: Denoising with RSKR and pSVT and post-reconstruction material decomposition are illustrated with preclinical and clinical cardiac photon-counting (PC)CT data. A digital MOBY mouse phantom with cardiac motion is used to illustrate single energy (SE), multi-energy (ME), time resolved (TR), and combined multi-energy and time-resolved (METR) helical, CBCT reconstruction. A fixed set of projection data is used across all reconstruction cases to demonstrate the Toolkit's robustness to increasing data dimensionality. Identical reconstruction code is applied to in vivo cardiac PCCT data acquired in a mouse model of atherosclerosis (METR). Clinical cardiac CT reconstruction is illustrated using the XCAT phantom and the DukeSim CT simulator, while dual-source, dual-energy CT reconstruction is illustrated for data acquired with a Siemens Flash scanner. Benchmarking results with NVIDIA RTX 8000 GPU hardware demonstrate 61%-99% efficiency in scaling computation from one to four GPUs for these reconstruction problems. CONCLUSIONS: The MCR Toolkit provides a robust solution for temporal and spectral x-ray CT reconstruction problems and was built from the ground up to facilitate translation of CT research and development between preclinical and clinical applications.

Co-Clinical Imaging Metadata Information (CIMI) for Cancer Research to Promote Open Science, Standardization, and Reproducibility in Preclinical Imaging.

Preclinical imaging is a critical component in translational research with significant complexities in workflow and site differences in deployment. Importantly, the National Cancer Institute's (NCI) precision medicine initiative emphasizes the use of translational co-clinical oncology models to address the biological and molecular bases of cancer prevention and treatment. The use of oncology models, such as patient-derived tumor xenografts (PDX) and genetically engineered mouse models (GEMMs), has ushered in an era of co-clinical trials by which preclinical studies can inform clinical trials and protocols, thus bridging the translational divide in cancer research. Similarly, preclinical imaging fills a translational gap as an enabling technology for translational imaging research. Unlike clinical imaging, where equipment manufacturers strive to meet standards in practice at clinical sites, standards are neither fully developed nor implemented in preclinical imaging. This fundamentally limits the collection and reporting of metadata to qualify preclinical imaging studies, thereby hindering open science and impacting the reproducibility of co-clinical imaging research. To begin to address these issues, the NCI co-clinical imaging research program (CIRP) conducted a survey to identify metadata requirements for reproducible quantitative co-clinical imaging. The enclosed consensus-based report summarizes co-clinical imaging metadata information (CIMI) to support quantitative co-clinical imaging research with broad implications for capturing co-clinical data, enabling interoperability and data sharing, as well as potentially leading to updates to the preclinical Digital Imaging and Communications in Medicine (DICOM) standard.

An Online Repository for Pre-Clinical Imaging Protocols (PIPs).

Providing method descriptions that are more detailed than currently available in typical peer reviewed journals has been identified as an actionable area for improvement. In the biochemical and cell biology space, this need has been met through the creation of new journals focused on detailed protocols and materials sourcing. However, this format is not well suited for capturing instrument validation, detailed imaging protocols, and extensive statistical analysis. Furthermore, the need for additional information must be counterbalanced by the additional time burden placed upon researchers who may be already overtasked. To address these competing issues, this white paper describes protocol templates for positron emission tomography (PET), X-ray computed tomography (CT), and magnetic resonance imaging (MRI) that can be leveraged by the broad community of quantitative imaging experts to write and self-publish protocols in protocols.io. Similar to the Structured Transparent Accessible Reproducible (STAR) or Journal of Visualized Experiments (JoVE) articles, authors are encouraged to publish peer reviewed papers and then to submit more detailed experimental protocols using this template to the online resource. Such protocols should be easy to use, readily accessible, readily searchable, considered open access, enable community feedback, editable, and citable by the author.

Evaluation of the impact of a novel denoising algorithm on image quality in dual-energy abdominal CT of obese patients.

OBJECTIVES: Evaluate a novel algorithm for noise reduction in obese patients using dual-source dual-energy (DE) CT imaging. METHODS: Seventy-nine patients with contrast-enhanced abdominal imaging (54 women; age: 58 ± 14 years; BMI: 39 ± 5 kg/m2, range: 35-62 kg/m2) from seven DECT (SOMATOM Flash or Force) were retrospectively included (01/2019-12/2020). Image domain data were reconstructed with the standard clinical algorithm (ADMIRE/SAFIRE 2), and denoised with a comparison (ME-NLM) and a test algorithm (rank-sparse kernel regression). Contrast-to-noise ratio (CNR) was calculated. Four blinded readers evaluated the same original and denoised images (0 (worst)-100 (best)) in randomized order for perceived image noise, quality, and their comfort making a diagnosis from a table of 80 options. Comparisons between algorithms were performed using paired t-tests and mixed-effects linear modeling. RESULTS: Average CNR was 5.0 ± 1.9 (original), 31.1 ± 10.3 (comparison; p < 0.001), and 8.9 ± 2.9 (test; p < 0.001). Readers were in good to moderate agreement over perceived image noise (ICC: 0.83), image quality (ICC: 0.71), and diagnostic comfort (ICC: 0.6). Diagnostic accuracy was low across algorithms (accuracy: 66, 63, and 67% (original, comparison, test)). The noise received a mean score of 54, 84, and 66 (p < 0.05); image quality 59, 61, and 65; and the diagnostic comfort 63, 68, and 68, respectively. Quality and comfort scores were not statistically significantly different between algorithms. CONCLUSIONS: The test algorithm produces quantitatively higher image quality than current standard and existing denoising algorithms in obese patients imaged with DECT and readers show a preference for it. CLINICAL RELEVANCE STATEMENT: Accurate diagnosis on CT imaging of obese patients is challenging and denoising algorithms can increase the diagnostic comfort and quantitative image quality. This could lead to better clinical reads. KEY POINTS: • Improving image quality in DECT imaging of obese patients is important for accurate and confident clinical reads, which may be aided by novel denoising algorithms using image domain data. • Accurate diagnosis on CT imaging of obese patients is especially challenging and denoising algorithms can increase quantitative and qualitative image quality. • Image domain algorithms can generalize well and can be implemented at other institutions.

Animal Models and Their Role in Imaging-Assisted Co-Clinical Trials.

The availability of high-fidelity animal models for oncology research has grown enormously in recent years, enabling preclinical studies relevant to prevention, diagnosis, and treatment of cancer to be undertaken. This has led to increased opportunities to conduct co-clinical trials, which are studies on patients that are carried out parallel to or sequentially with animal models of cancer that mirror the biology of the patients' tumors. Patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM) are considered to be the models that best represent human disease and have high translational value. Notably, one element of co-clinical trials that still needs significant optimization is quantitative imaging. The National Cancer Institute has organized a Co-Clinical Imaging Resource Program (CIRP) network to establish best practices for co-clinical imaging and to optimize translational quantitative imaging methodologies. This overview describes the ten co-clinical trials of investigators from eleven institutions who are currently supported by the CIRP initiative and are members of the Animal Models and Co-clinical Trials (AMCT) Working Group. Each team describes their corresponding clinical trial, type of cancer targeted, rationale for choice of animal models, therapy, and imaging modalities. The strengths and weaknesses of the co-clinical trial design and the challenges encountered are considered. The rich research resources generated by the members of the AMCT Working Group will benefit the broad research community and improve the quality and translational impact of imaging in co-clinical trials.

Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma.

This study aims to investigate whether adding neoadjuvant radiotherapy (RT), anti-programmed cell death protein-1 (PD-1) antibody (anti-PD-1), or RT + anti-PD-1 to surgical resection improves disease-free survival for mice with soft tissue sarcomas (STS). We generated a high mutational load primary mouse model of STS by intramuscular injection of adenovirus expressing Cas9 and guide RNA targeting Trp53 and intramuscular injection of 3-methylcholanthrene (MCA) into the gastrocnemius muscle of wild-type mice (p53/MCA model). We randomized tumor-bearing mice to receive isotype control or anti-PD-1 antibody with or without radiotherapy (20 Gy), followed by hind limb amputation. We used micro-CT to detect lung metastases with high spatial resolution, which was confirmed by histology. We investigated whether sarcoma metastasis was regulated by immunosurveillance by lymphocytes or tumor cell-intrinsic mechanisms. Compared with surgery with isotype control antibody, the combination of anti-PD-1, radiotherapy, and surgery improved local recurrence-free survival (P = 0.035) and disease-free survival (P = 0.005), but not metastasis-free survival. Mice treated with radiotherapy, but not anti-PD-1, showed significantly improved local recurrence-free survival and metastasis-free survival over surgery alone (P = 0.043 and P = 0.007, respectively). The overall metastasis rate was low (∼12%) in the p53/MCA sarcoma model, which limited the power to detect further improvement in metastasis-free survival with addition of anti-PD-1 therapy. Tail vein injections of sarcoma cells into immunocompetent mice suggested that impaired metastasis was due to inability of sarcoma cells to grow in the lungs rather than a consequence of immunosurveillance. In conclusion, neoadjuvant radiotherapy improves metastasis-free survival after surgery in a primary model of STS.

Feature attention graph neural network for estimating brain age and identifying important neural connections in mouse models of genetic risk for Alzheimer's disease.

Alzheimer's disease (AD) remains one of the most extensively researched neurodegenerative disorders due to its widespread prevalence and complex risk factors. Age is a crucial risk factor for AD, which can be estimated by the disparity between physiological age and estimated brain age. To model AD risk more effectively, integrating biological, genetic, and cognitive markers is essential. Here, we utilized mouse models expressing the major APOE human alleles and human nitric oxide synthase 2 to replicate genetic risk for AD and a humanized innate immune response. We estimated brain age employing a multivariate dataset that includes brain connectomes, APOE genotype, subject traits such as age and sex, and behavioral data. Our methodology used Feature Attention Graph Neural Networks (FAGNN) for integrating different data types. Behavioral data were processed with a 2D Convolutional Neural Network (CNN), subject traits with a 1D CNN, brain connectomes through a Graph Neural Network using quadrant attention module. The model yielded a mean absolute error for age prediction of 31.85 days, with a root mean squared error of 41.84 days, outperforming other, reduced models. In addition, FAGNN identified key brain connections involved in the aging process. The highest weights were assigned to the connections between cingulum and corpus callosum, striatum, hippocampus, thalamus, hypothalamus, cerebellum, and piriform cortex. Our study demonstrates the feasibility of predicting brain age in models of aging and genetic risk for AD. To verify the validity of our findings, we compared Fractional Anisotropy (FA) along the tracts of regions with the highest connectivity, the Return-to-Origin Probability (RTOP), Return-to-Plane Probability (RTPP), and Return-to-Axis Probability (RTAP), which showed significant differences between young, middle-aged, and old age groups. Younger mice exhibited higher FA, RTOP, RTAP, and RTPP compared to older groups in the selected connections, suggesting that degradation of white matter tracts plays a critical role in aging and for FAGNN's selections. Our analysis suggests a potential neuroprotective role of APOE2, relative to APOE3 and APOE4, where APOE2 appears to mitigate age-related changes. Our findings highlighted a complex interplay of genetics and brain aging in the context of AD risk modeling.

Automated multimodal segmentation of acute ischemic stroke lesions on clinical MR images.

Magnetic resonance (MR) imaging (MRI) is commonly used to diagnose, assess and monitor stroke. Accurate and timely segmentation of stroke lesions provides the anatomico-structural information that can aid physicians in predicting prognosis, as well as in decision making and triaging for various rehabilitation strategies. To segment stroke lesions, MR protocols, including diffusion-weighted imaging (DWI) and T2-weighted fluid attenuated inversion recovery (FLAIR) are often utilized. These imaging sequences are usually acquired with different spatial resolutions due to time constraints. Within the same image, voxels may be anisotropic, with reduced resolution along slice direction for diffusion scans in particular. In this study, we evaluate the ability of 2D and 3D U-Net Convolutional Neural Network (CNN) architectures to segment ischemic stroke lesions using single contrast (DWI) and dual contrast images (T2w FLAIR and DWI). The predicted segmentations correlate with post-stroke motor outcome measured by the National Institutes of Health Stroke Scale (NIHSS) and Fugl-Meyer Upper Extremity (FM-UE) index based on the lesion loads overlapping the corticospinal tracts (CST), which is a neural substrate for motor movement and function. Although the four methods performed similarly, the 2D multimodal U-Net achieved the best results with a mean Dice of 0.737 (95% CI: 0.705, 0.769) and a relatively high correlation between the weighted lesion load and the NIHSS scores (both at baseline and at 90 days). A monotonically constrained quintic polynomial regression yielded R2 = 0.784 and 0.875 for weighted lesion load versus baseline and 90-Days NIHSS respectively, and better corrected Akaike information criterion (AICc) scores than those of the linear regression. In addition, using the quintic polynomial regression model to regress the weighted lesion load to the 90-Days FM-UE score results in an R2 of 0.570 with a better AICc score than that of the linear regression. Our results suggest that the multi-contrast information enhanced the accuracy of the segmentation and the prediction accuracy for upper extremity motor outcomes. Expanding the training dataset to include different types of stroke lesions and more data points will help add a temporal longitudinal aspect and increase the accuracy. Furthermore, adding patient-specific data may improve the inference about the relationship between imaging metrics and functional outcomes.

Material decomposition from photon-counting CT using a convolutional neural network and energy-integrating CT training labels.

Objective.Photon-counting CT (PCCT) has better dose efficiency and spectral resolution than energy-integrating CT, which is advantageous for material decomposition. Unfortunately, the accuracy of PCCT-based material decomposition is limited due to spectral distortions in the photon-counting detector (PCD).Approach.In this work, we demonstrate a deep learning (DL) approach that compensates for spectral distortions in the PCD and improves accuracy in material decomposition by using decomposition maps provided by high-dose multi-energy-integrating detector (EID) data as training labels. We use a 3D U-net architecture and compare networks with PCD filtered back projection (FBP) reconstruction (FBP2Decomp), PCD iterative reconstruction (Iter2Decomp), and PCD decomposition (Decomp2Decomp) as the input.Main results.We found that our Iter2Decomp approach performs best, but DL outperforms matrix inversion decomposition regardless of the input. Compared to PCD matrix inversion decomposition, Iter2Decomp gives 27.50% lower root mean squared error (RMSE) in the iodine (I) map and 59.87% lower RMSE in the photoelectric effect (PE) map. In addition, it increases the structural similarity (SSIM) by 1.92%, 6.05%, and 9.33% in the I, Compton scattering (CS), and PE maps, respectively. When taking measurements from iodine and calcium vials, Iter2Decomp provides excellent agreement with multi-EID decomposition. One limitation is some blurring caused by our DL approach, with a decrease from 1.98 line pairs/mm at 50% modulation transfer function (MTF) with PCD matrix inversion decomposition to 1.75 line pairs/mm at 50% MTF when using Iter2Decomp.Significance.Overall, this work demonstrates that our DL approach with high-dose multi-EID derived decomposition labels is effective at generating more accurate material maps from PCD data. More accurate preclinical spectral PCCT imaging such as this could serve for developing nanoparticles that show promise in the field of theranostics (therapy and diagnostics).

Photon Counting CT and Radiomic Analysis Enables Differentiation of Tumors Based on Lymphocyte Burden.

The purpose of this study was to investigate if radiomic analysis based on spectral micro-CT with nanoparticle contrast-enhancement can differentiate tumors based on lymphocyte burden. High mutational load transplant soft tissue sarcomas were initiated in Rag2+/- and Rag2-/- mice to model varying lymphocyte burden. Mice received radiation therapy (20 Gy) to the tumor-bearing hind limb and were injected with a liposomal iodinated contrast agent. Five days later, animals underwent conventional micro-CT imaging using an energy integrating detector (EID) and spectral micro-CT imaging using a photon-counting detector (PCD). Tumor volumes and iodine uptakes were measured. The radiomic features (RF) were grouped into feature-spaces corresponding to EID, PCD, and spectral decomposition images. The RFs were ranked to reduce redundancy and increase relevance based on TL burden. A stratified repeated cross validation strategy was used to assess separation using a logistic regression classifier. Tumor iodine concentration was the only significantly different conventional tumor metric between Rag2+/- (TLs present) and Rag2-/- (TL-deficient) tumors. The RFs further enabled differentiation between Rag2+/- and Rag2-/- tumors. The PCD-derived RFs provided the highest accuracy (0.68) followed by decomposition-derived RFs (0.60) and the EID-derived RFs (0.58). Such non-invasive approaches could aid in tumor stratification for cancer therapy studies.

Detection of Lung Nodules in Micro-CT Imaging Using Deep Learning.

We are developing imaging methods for a co-clinical trial investigating synergy between immunotherapy and radiotherapy. We perform longitudinal micro-computed tomography (micro-CT) of mice to detect lung metastasis after treatment. This work explores deep learning (DL) as a fast approach for automated lung nodule detection. We used data from control mice both with and without primary lung tumors. To augment the number of training sets, we have simulated data using real augmented tumors inserted into micro-CT scans. We employed a convolutional neural network (CNN), trained with four competing types of training data: (1) simulated only, (2) real only, (3) simulated and real, and (4) pretraining on simulated followed with real data. We evaluated our model performance using precision and recall curves, as well as receiver operating curves (ROC) and their area under the curve (AUC). The AUC appears to be almost identical (0.76-0.77) for all four cases. However, the combination of real and synthetic data was shown to improve precision by 8%. Smaller tumors have lower rates of detection than larger ones, with networks trained on real data showing better performance. Our work suggests that DL is a promising approach for fast and relatively accurate detection of lung tumors in mice.

Evaluating renal lesions using deep-learning based extension of dual-energy FoV in dual-source CT-A retrospective pilot study.

PURPOSE: Dual-source (DS) CT, dual-energy (DE) field of view (FoV) is limited to the size of the smaller detector array. The purpose was to establish a deep learning-based approach to DE extrapolation by estimating missing image data using data from both tubes to evaluate renal lesions. METHOD: A DE extrapolation deep-learning (DEEDL) algorithm had been trained on DECT data of 50 patients using a DSCT with DE-FoV = 33 cm (Somatom Flash). Data from 128 patients with known renal lesions falling within DE-FoV was retrospectively collected (100/140 kVp; reference dataset 1). A smaller DE-FoV = 20 cm was simulated excluding the renal lesion of interest (dataset 2) and the DEEDL was applied to this dataset. Output from the DEEDL algorithm was evaluated using ReconCT v14.1 and Syngo.via. Mean attenuation values in lesions on mixed images (HU) were compared calculating the root-mean-squared-error (RMSE) between the datasets using MATLAB R2019a. RESULTS: The DEEDL algorithm performed well reproducing the image data of the kidney lesions (Bosniak 1 and 2: 125, Bosniak 2F: 6, Bosniak 3: 1 and Bosniak 4/(partially) solid: 32) with RSME values of 10.59 HU, 15.7 HU for attenuation, virtual non-contrast, respectively. The measurements performed in dataset 1 and 2 showed strong correlation with linear regression (r2: attenuation = 0.89, VNC = 0.63, iodine = 0.75), lesions were classified as enhancing with an accuracy of 0.91. CONCLUSION: This DEEDL algorithm can be used to reconstruct a full dual-energy FoV from restricted data, enabling reliable HU value measurements in areas not covered by the smaller FoV and evaluation of renal lesions.

Ex Vivo MR Histology and Cytometric Feature Mapping Connect Three-dimensional in Vivo MR Images to Two-dimensional Histopathologic Images of Murine Sarcomas.

Purpose To establish a platform for quantitative tissue-based interpretation of cytoarchitecture features from tumor MRI measurements. Materials and Methods In a pilot preclinical study, multicontrast in vivo MRI of murine soft-tissue sarcomas in 10 mice, followed by ex vivo MRI of fixed tissues (termed MR histology), was performed. Paraffin-embedded limb cross-sections were stained with hematoxylin-eosin, digitized, and registered with MRI. Registration was assessed by using binarized tumor maps and Dice similarity coefficients (DSCs). Quantitative cytometric feature maps from histologic slides were derived by using nuclear segmentation and compared with registered MRI, including apparent diffusion coefficients and transverse relaxation times as affected by magnetic field heterogeneity (T2* maps). Cytometric features were compared with each MR image individually by using simple linear regression analysis to identify the features of interest, and the goodness of fit was assessed on the basis of R2 values. Results Registration of MR images to histopathologic slide images resulted in mean DSCs of 0.912 for ex vivo MR histology and 0.881 for in vivo MRI. Triplicate repeats showed high registration repeatability (mean DSC, >0.9). Whole-slide nuclear segmentations were automated to detect nuclei on histopathologic slides (DSC = 0.8), and feature maps were generated for correlative analysis with MR images. Notable trends were observed between cell density and in vivo apparent diffusion coefficients (best line fit: R2 = 0.96, P < .001). Multiple cytoarchitectural features exhibited linear relationships with in vivo T2* maps, including nuclear circularity (best line fit: R2 = 0.99, P < .001) and variance in nuclear circularity (best line fit: R2 = 0.98, P < .001). Conclusion An infrastructure for registering and quantitatively comparing in vivo tumor MRI with traditional histologic analysis was successfully implemented in a preclinical pilot study of soft-tissue sarcomas. Keywords: MRI, Pathology, Animal Studies, Tissue Characterization Supplemental material is available for this article. © RSNA, 2021.

Characterization of cardiovascular injury in mice following partial-heart irradiation with clinically relevant dose and fractionation.

BACKGROUND AND PURPOSE: Late cardiac toxicity is a major side effect of radiation therapy (RT) for breast cancer. We developed and characterized a mouse model of radiation-induced heart disease that mimics the dose, fractionation, and beam arrangement of left breast and chest wall RT. MATERIAL AND METHODS: Female wild-type (C57BL6/J) and atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice (on a C57BL/6J background) on regular chow were treated with 2 Gy × 25 fractions of partial-heart irradiation via opposed tangential beams to the left chest wall. The changes in myocardial perfusion and cardiac function of C57BL/6J mice were examined by single-photon emission computed tomography (SPECT) and echocardiography, respectively. In addition to SPECT and echocardiography, the formation of calcified plaques and changes in cardiac function of ApoE-/- mice were examined by dual-energy microCT (DE-CT) and pressure-volume (PV) loop analysis, respectively. The development of myocardial fibrosis was examined by histopathology. RESULTS: Compared to unirradiated controls, irradiated C57BL/6J mice showed no significant changes by SPECT or echocardiography up to 18 months after 2 Gy × 25 partial-heart irradiation even though irradiated mice exhibited a modest increase in myocardial fibrosis. For ApoE-/- mice, 2 Gy × 25 partial-heart irradiation did not cause significant changes by SPECT, DE-CT, or echocardiography. However, PV loop analysis revealed a significant decrease in load-dependent systolic and diastolic function measures including cardiac output, dV/dtmax and dV/dt min 12 months after RT. CONCLUSIONS: Following clinically relevant doses of partial-heart irradiation in C57BL/6J and ApoE-/- mice, assessment with noninvasive imaging modalities such as echocardiography, SPECT, and DE-CT yielded no evidence of decreased myocardial perfusion and cardiac dysfunction related to RT. However, invasive hemodynamic assessment with PV loop analysis indicated subtle, but significant, changes in cardiac function of irradiated ApoE-/- mice. PV loop analysis may be useful for future preclinical studies of radiation-induced heart disease, especially if subtle changes in cardiac function are expected.

Co-Clinical Imaging Resource Program (CIRP): Bridging the Translational Divide to Advance Precision Medicine.

The National Institutes of Health's (National Cancer Institute) precision medicine initiative emphasizes the biological and molecular bases for cancer prevention and treatment. Importantly, it addresses the need for consistency in preclinical and clinical research. To overcome the translational gap in cancer treatment and prevention, the cancer research community has been transitioning toward using animal models that more fatefully recapitulate human tumor biology. There is a growing need to develop best practices in translational research, including imaging research, to better inform therapeutic choices and decision-making. Therefore, the National Cancer Institute has recently launched the Co-Clinical Imaging Research Resource Program (CIRP). Its overarching mission is to advance the practice of precision medicine by establishing consensus-based best practices for co-clinical imaging research by developing optimized state-of-the-art translational quantitative imaging methodologies to enable disease detection, risk stratification, and assessment/prediction of response to therapy. In this communication, we discuss our involvement in the CIRP, detailing key considerations including animal model selection, co-clinical study design, need for standardization of co-clinical instruments, and harmonization of preclinical and clinical quantitative imaging pipelines. An underlying emphasis in the program is to develop best practices toward reproducible, repeatable, and precise quantitative imaging biomarkers for use in translational cancer imaging and therapy. We will conclude with our thoughts on informatics needs to enable collaborative and open science research to advance precision medicine.