Radio-Pathomic Maps of Cell Density Identify Brain Tumor Invasion beyond Traditional MRI-Defined Margins.

BACKGROUND AND PURPOSE: Currently, contrast-enhancing margins on T1WI are used to guide treatment of gliomas, yet tumor invasion beyond the contrast-enhancing region is a known confounding factor. Therefore, this study used postmortem tissue samples aligned with clinically acquired MRIs to quantify the relationship between intensity values and cellularity as well as to develop a radio-pathomic model to predict cellularity using MR imaging data. MATERIALS AND METHODS: This single-institution study used 93 samples collected at postmortem examination from 44 patients with brain cancer. Tissue samples were processed, stained with H&E, and digitized for nuclei segmentation and cell density calculation. Pre- and postgadolinium contrast T1WI, T2 FLAIR, and ADC images were collected from each patient's final acquisition before death. In-house software was used to align tissue samples to the FLAIR image via manually defined control points. Mixed-effects models were used to assess the relationship between single-image intensity and cellularity for each image. An ensemble learner was trained to predict cellularity using 5 × 5 voxel tiles from each image, with a two-thirds to one-third train-test split for validation. RESULTS: Single-image analyses found subtle associations between image intensity and cellularity, with a less pronounced relationship in patients with glioblastoma. The radio-pathomic model accurately predicted cellularity in the test set (root mean squared error = 1015 cells/mm2) and identified regions of hypercellularity beyond the contrast-enhancing region. CONCLUSIONS: A radio-pathomic model for cellularity trained with tissue samples acquired at postmortem examination is able to identify regions of hypercellular tumor beyond traditional imaging signatures.

Quantitative Evaluation of Bone Microstructure using High-Resolution Extremity Cone-Beam CT with a CMOS Detector.

PURPOSE: A high-resolution cone-beam CT (CBCT) system for extremity imaging has been developed using a custom complementary metal-oxide-semiconductor (CMOS) x-ray detector. The system has spatial resolution capability beyond that of recently introduced clinical orthopedic CBCT. We evaluate performance of this new scanner in quantifying trabecular microstructure in subchondral bone of the knee. METHODS: The high-resolution scanner uses the same mechanical platform as the commercially available Carestream OnSight 3D extremity CBCT, but replaces the conventional amorphous silicon flat-panel detector (a-Si:H FPD with 0.137 mm pixels and a ~0.7 mm thick scintillator) with a Dalsa Xineos3030 CMOS detector (0.1 mm pixels and a custom 0.4 mm scintillator). The CMOS system demonstrates ~40% improved spatial resolution (FWHM of a ~0.1 mm tungsten wire) and ~4× faster scan time than FPD-based extremity CBCT (FPD-CBCT). To investigate potential benefits of this enhanced spatial resolution in quantitative assessment of bone microstructure, 26 trabecular core samples were obtained from four cadaveric tibias and imaged using FPD-CBCT (75 µm voxels), CMOS-CBCT (75 µm voxels), and reference micro-CT (µCT, 15 µm voxels). CBCT bone segmentations were obtained using local Bernsen's thresholding combined with global histogram-based pre-thresholding; µCT segmentation involved Otsu's method. Measurements of trabecular thickness (Tb.Th), spacing (Tb.Sp), number (Tb.N) and bone volume (BV/TV) were performed in registered regions of interest in the segmented CBCT and µCT reconstructions. RESULTS: CMOS-CBCT achieved noticeably improved delineation of trabecular detail compared to FPD-CBCT. Correlations with reference µCT for metrics of bone microstructure were better for CMOS-CBCT than FPD-CBCT, in particular for Tb.Th (increase in Pearson correlation from 0.84 with FPD-CBCT to 0.96 with CMOS-CBCT) and Tb.Sp (increase from 0.80 to 0.85). This improved quantitative performance of CMOS-CBCT is accompanied by a reduction in scan time, from ~60 sec for a clinical high resolution protocol on FPD-CBCT to ~17 sec for CMOS-CBCT. CONCLUSION: The CMOS-based extremity CBCT prototype achieves improved performance in quantification of bone microstructure, while retaining other diagnostic capabilities of its FPD-based precursor, including weight-bearing imaging. The new system offers a promising platform for quantitative imaging of skeletal health in osteoporosis and osteoarthritis.

Coupled Active Shape Models for Automated Segmentation and Landmark Localization in High-Resolution CT of the Foot and Ankle.

PURPOSE: We develop an Active Shape Model (ASM) framework for automated bone segmentation and anatomical landmark localization in weight-bearing Cone-Beam CT (CBCT). To achieve a robust shape model fit in narrow joint spaces of the foot (0.5 - 1 mm), a new approach for incorporating proximity constraints in ASM (coupled ASM, cASM) is proposed. METHODS: In cASM, shape models of multiple adjacent foot bones are jointly fit to the CBCT volume. This coupling enables checking for proximity between the evolving shapes to avoid situations where a conventional single-bone ASM might erroneously fit to articular surfaces of neighbouring bones. We used 21 extremity CBCT scans of the weight-bearing foot to compare segmentation and landmark localization accuracy of ASM and cASM in leave-one-out validation. Each scan was used as a test image once; shape models of calcaneus, talus, navicular, and cuboid were built from manual surface segmentations of the remaining 20 scans. The models were augmented with seven anatomical landmarks used for common measurements of foot alignment. The landmarks were identified in the original CBCT volumes and mapped onto mean bone shape surfaces. ASM and cASM were run for 100 iterations, and the number of principal shape components was increased every 10 iterations. Automated landmark localization was achieved by applying known point correspondences between landmark vertices on the mean shape and vertices of the final active shape segmentation of the test image. RESULTS: Root Mean Squared (RMS) error of bone surface segmentation improved from 3.6 mm with conventional ASM to 2.7 mm with cASM. Furthermore, cASM achieved convergence (no change in RMS error with iteration) after ~40 iterations of shape fitting, compared to ~60 iterations for ASM. Distance error in landmark localization was 25% to 55% lower (depending on the landmark) with cASM than with ASM. The importance of using a coupled model is underscored by the finding that cASM detected and corrected collisions between evolving shapes in 50% to 80% (depending on the bone) of shape model fits. CONCLUSION: The proposed cASM framework improves accuracy of shape model fits, especially in complexes of tightly interlocking, articulated joints. The approach enables automated anatomical analysis in volumetric imaging of the foot and ankle, where narrow joint spaces challenge conventional shape models.

Robust Quantitative Assessment of Trabecular Microarchitecture in Extremity Cone-Beam CT Using Optimized Segmentation Algorithms.

PURPOSE: In-vivo evaluation of bone microarchitecture remains challenging because of limited resolution of conventional orthopaedic imaging modalities. We investigate the performance of flat-panel detector extremity Cone-Beam CT (CBCT) in quantitative analysis of trabecular bone. To enable accurate morphometry of fine trabecular bone architecture, advanced CBCT pre-processing and segmentation algorithms are developed. METHODS: The study involved 35 transilliac bone biopsy samples imaged on extremity CBCT (voxel size 75 µm, imaging dose ~13 mGy) and gold standard µCT (voxel size 7.67 µm). CBCT image segmentation was performed using (i) global Otsu's thresholding, (ii) Bernsen's local thresholding, (iii) Bernsen's local thresholding with additional histogram-based global pre-thresholding, and (iv) the same as (iii) but combined with contrast enhancement using a Laplacian Pyramid. Correlations between extremity CBCT with the different segmentation algorithms and gold standard µCT were investigated for measurements of Bone Volume over Total Volume (BV/TV), Trabecular Thickness (Tb.Th), Trabecular Spacing (Tb.Sp), and Trabecular Number (Tb.N). RESULTS: The combination of local thresholding with global pre-thresholding and Laplacian contrast enhancement outperformed other CBCT segmentation methods. Using this optimal segmentation scheme, strong correlation between extremity CBCT and µCT was achieved, with Pearson coefficients of 0.93 for BV/TV, 0.89 for Tb.Th, 0.91 for Tb.Sp, and 0.88 for Tb.N (all results statistically significant). Compared to a simple global CBCT segmentation using Otsu's algorithm, the advanced segmentation method achieved ~20% improvement in the correlation coefficient for Tb.Th and ~50% improvement for Tb.Sp. CONCLUSIONS: Extremity CBCT combined with advanced image pre-processing and segmentation achieves high correlation with gold standard µCT in measurements of trabecular microstructure. This motivates ongoing development of clinical applications of extremity CBCT in in-vivo evaluation of bone health e.g. in early osteoarthritis and osteoporosis.

High-Resolution Extremity Cone-Beam CT with a CMOS Detector: Evaluation of a Clinical Prototype in Quantitative Assessment of Bone Microarchitecture.

PURPOSE: A prototype high-resolution extremity cone-beam CT (CBCT) system based on a CMOS detector was developed to support quantitative in vivo assessment of bone microarchitecture. We compare the performance of CMOS CBCT to an amorphous silicon (a-Si:H) FPD extremity CBCT in imaging of trabecular bone. METHODS: The prototype CMOS-based CBCT involves a DALSA Xineos3030 detector (99 µm pixels) with 400 µm-thick CsI scintillator and a compact 0.3 FS rotating anode x-ray source. We compare the performance of CMOS CBCT to an a-Si:H FPD scanner built on a similar gantry, but using a Varian PaxScan2530 detector with 0.137 mm pixels and a 0.5 FS stationary anode x-ray source. Experimental studies include measurements of Modulation Transfer Function (MTF) for the detectors and in 3D image reconstructions. Image quality in clinical scenarios is evaluated in scans of a cadaver ankle. Metrics of trabecular microarchitecture (BV/TV, Bone Volume/Total Volume, TbSp, Trabecular Spacing, and TbTh, trabecular thickness) are obtained in a human ulna using CMOS CBCT and a-Si:H FPD CBCT and compared to gold standard µCT. RESULTS: The CMOS detector achieves ~40% increase in the f20 value (frequency at which MTF reduces to 0.20) compared to the a-Si:H FPD. In the reconstruction domain, the FWHM of a 127 µm tungsten wire is also improved by ~40%. Reconstructions of a cadaveric ankle reveal enhanced modulation of trabecular structures with the CMOS detector and soft-tissue visibility that is similar to that of the a-Si:H FPD system. Correlations of the metrics of bone microarchitecture with gold-standard µCT are improved with CMOS CBCT: from 0.93 to 0.98 for BV/TV, from 0.49 to 0.74 for TbTh, and from 0.9 to 0.96 for TbSp. CONCLUSION: Adoption of a CMOS detector in extremity CBCT improved spatial resolution and enhanced performance in metrics of bone microarchitecture compared to a conventional a-Si:H FPD. The results support development of clinical applications of CMOS CBCT in quantitative imaging of bone health.

High-resolution extremity cone-beam CT with a CMOS detector: Task-based optimization of scintillator thickness.

PURPOSE: CMOS x-ray detectors offer small pixel sizes and low electronic noise that may support the development of novel high-resolution imaging applications of cone-beam CT (CBCT). We investigate the effects of CsI scintillator thickness on the performance of CMOS detectors in high resolution imaging tasks, in particular in quantitative imaging of bone microstructure in extremity CBCT. METHODS: A scintillator thickness-dependent cascaded systems model of CMOS x-ray detectors was developed. Detectability in low-, high- and ultra-high resolution imaging tasks (Gaussian with FWHM of ~250 µm, ~80 µm and ~40 µm, respectively) was studied as a function of scintillator thickness using the theoretical model. Experimental studies were performed on a CBCT test bench equipped with DALSA Xineos3030 CMOS detectors (99 µm pixels) with CsI scintillator thicknesses of 400 µm and 700 µm, and a 0.3 FS compact rotating anode x-ray source. The evaluation involved a radiographic resolution gauge (0.6-5.0 lp/mm), a 127 µm tungsten wire for assessment of 3D resolution, a contrast phantom with tissue-mimicking inserts, and an excised fragment of human tibia for visual assessment of fine trabecular detail. RESULTS: Experimental studies show ~35% improvement in the frequency of 50% MTF modulation when using the 400 µm scintillator compared to the standard nominal CsI thickness of 700 µm. Even though the high-frequency DQE of the two detectors is comparable, theoretical studies show a 14% to 28% increase in detectability index (d'2) of high- and ultrahigh resolution tasks, respectively, for the detector with 400 µm CsI compared to 700 µm CsI. Experiments confirm the theoretical findings, showing improvements with the adoption of 400 µm panel in the visibility of the radiographic pattern (2× improvement in peak-to-through distance at 4.6 lp/mm) and a 12.5% decrease in the FWHM of the tungsten wire. Reconstructions of the tibial plateau reveal enhanced visibility of trabecular structures with the CMOS detector with 400 µm scinitllator. CONCLUSION: Applications on CMOS detectors in high resolution CBCT imaging of trabecular bone will benefit from using a thinner scintillator than the current standard in general radiography. The results support the translation of the CMOS sensor with 400 µm CsI onto the clinical prototype of CMOS-based extremity CBCT.

Atlas-based automatic measurements of the morphology of the tibiofemoral joint.

PURPOSE: Anatomical metrics of the tibiofemoral joint support assessment of joint stability and surgical planning. We propose an automated, atlas-based algorithm to streamline the measurements in 3D images of the joint and reduce user-dependence of the metrics arising from manual identification of the anatomical landmarks. METHODS: The method is initialized with coarse registrations of a set of atlas images to the fixed input image. The initial registrations are then refined separately for the tibia and femur and the best matching atlas is selected. Finally, the anatomical landmarks of the best matching atlas are transformed onto the input image by deforming a surface model of the atlas to fit the shape of the tibial plateau in the input image (a mesh-to-volume registration). We apply the method to weight-bearing volumetric images of the knee obtained from 23 subjects using an extremity cone-beam CT system. Results of the automated algorithm were compared to an expert radiologist for measurements of Static Alignment (SA), Medial Tibial Slope (MTS) and Lateral Tibial Slope (LTS). RESULTS: Intra-reader variability as high as ~10% for LTS and 7% for MTS (ratio of standard deviation to the mean in repeated measurements) was found for expert radiologist, illustrating the potential benefits of an automated approach in improving the precision of the metrics. The proposed method achieved excellent registration of the atlas mesh to the input volumes. The resulting automated measurements yielded high correlations with expert radiologist, as indicated by correlation coefficients of 0.72 for MTS, 0.8 for LTS, and 0.89 for SA. CONCLUSIONS: The automated method for measurement of anatomical metrics of the tibiofemoral joint achieves high correlation with expert radiologist without the need for time consuming and error prone manual selection of landmarks.