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.

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.

Overcoming detector limitations of x-ray photon counting for preclinical microcomputed tomography.

Spectral computed tomography (CT) using photon counting detectors (PCDs) can provide accurate tissue composition measurements by utilizing the energy dependence of x-ray attenuation in different materials. PCDs are especially suited for K-edge imaging, revealing the spatial distribution of select imaging probes through quantitative material decomposition. We report on a prototype spectral micro-CT system with a CZT-based PCD (DxRay, Inc.) that has 16 × 16 pixels of 0.5 × 0.5 mm 2 , a thickness of 3 mm, and four energy thresholds. Due to the PCD's limited size ( 8 × 8 mm 2 ), our system uses a translate-rotate projection acquisition strategy to cover a field of view relevant for preclinical imaging ( ∼ 4.5 cm ). Projection corrections were implemented to minimize artifacts associated with dead pixels and projection stitching. A sophisticated iterative algorithm was used to reconstruct both phantom and ex vivo mouse data. To achieve preclinically relevant spatial resolution, we trained a convolutional neural network to perform pan-sharpening between low-resolution PCD data ( 247 - µ m voxels) and high-resolution energy-integrating detector data ( 82 - µ m voxels), recovering a high-resolution estimate of the spectral contrast suitable for material decomposition. Long-term, preclinical spectral CT systems such as ours could serve in the developing field of theranostics (therapy and diagnostics) for cancer research.