Diffusion MRI signal cumulants and hepatocyte microstructure at fixed diffusion time: Insights from simulations, 9.4T imaging, and histology.

PURPOSE: Relationships between diffusion-weighted MRI signals and hepatocyte microstructure were investigated to inform liver diffusion MRI modeling, focusing on the following question: Can cell size and diffusivity be estimated at fixed diffusion time, realistic SNR, and negligible contribution from extracellular/extravascular water and exchange? METHODS: Monte Carlo simulations were performed within synthetic hepatocytes for varying cell size/diffusivity L / D0 , and clinical protocols (single diffusion encoding; maximum b-value: {1000, 1500, 2000} s/mm2 ; 5 unique gradient duration/separation pairs; SNR = { ∞ , 100, 80, 40, 20}), accounting for heterogeneity in (D0,L) and perfusion contamination. Diffusion ( D ) and kurtosis ( K ) coefficients were calculated, and relationships between (D0,L) and (D,K) were visualized. Functions mapping (D,K) to (D0,L) were computed to predict unseen (D0,L) values, tested for their ability to classify discrete cell-size contrasts, and deployed on 9.4T ex vivo MRI-histology data of fixed mouse livers RESULTS: Relationships between (D,K) and (D0,L) are complex and depend on the diffusion encoding. Functions mapping D,K to (D0,L) captures salient characteristics of D0(D,K) and L(D,K) dependencies. Mappings are not always accurate, but they enable just under 70% accuracy in a three-class cell-size classification task (for SNR = 20, bmax = 1500 s/mm2 , δ = 20 ms, and Δ = 75 ms). MRI detects cell-size contrasts in the mouse livers that are confirmed by histology, but overestimates the largest cell sizes. CONCLUSION: Salient information about liver cell size and diffusivity may be retrieved from minimal diffusion encodings at fixed diffusion time, in experimental conditions and pathological scenarios for which extracellular, extravascular water and exchange are negligible.

Minimizing acquisition-related radiomics variability by image resampling and batch effect correction to allow for large-scale data analysis.

OBJECTIVE: To identify CT-acquisition parameters accounting for radiomics variability and to develop a post-acquisition CT-image correction method to reduce variability and improve radiomics classification in both phantom and clinical applications. METHODS: CT-acquisition protocols were prospectively tested in a phantom. The multi-centric retrospective clinical study included CT scans of patients with colorectal/renal cancer liver metastases. Ninety-three radiomics features of first order and texture were extracted. Intraclass correlation coefficients (ICCs) between CT-acquisition protocols were evaluated to define sources of variability. Voxel size, ComBat, and singular value decomposition (SVD) compensation methods were explored for reducing the radiomics variability. The number of robust features was compared before and after correction using two-proportion z test. The radiomics classification accuracy (K-means purity) was assessed before and after ComBat- and SVD-based correction. RESULTS: Fifty-three acquisition protocols in 13 tissue densities were analyzed. Ninety-seven liver metastases from 43 patients with CT from two vendors were included. Pixel size, reconstruction slice spacing, convolution kernel, and acquisition slice thickness are relevant sources of radiomics variability with a percentage of robust features lower than 80%. Resampling to isometric voxels increased the number of robust features when images were acquired with different pixel sizes (p < 0.05). SVD-based for thickness correction and ComBat correction for thickness and combined thickness-kernel increased the number of reproducible features (p < 0.05). ComBat showed the highest improvement of radiomics-based classification in both the phantom and clinical applications (K-means purity 65.98 vs 73.20). CONCLUSION: CT-image post-acquisition processing and radiomics normalization by means of batch effect correction allow for standardization of large-scale data analysis and improve the classification accuracy. KEY POINTS: • The voxel size (accounting for the pixel size and slice spacing), slice thickness, and convolution kernel are relevant sources of CT-radiomics variability. • Voxel size resampling increased the mean percentage of robust CT-radiomics features from 59.50 to 89.25% when comparing CT scans acquired with different pixel sizes and from 71.62 to 82.58% when the scans were acquired with different slice spacings. • ComBat batch effect correction reduced the CT-radiomics variability secondary to the slice thickness and convolution kernel, improving the capacity of CT-radiomics to differentiate tissues (in the phantom application) and the primary tumor type from liver metastases (in the clinical application).

Identification of Precise 3D CT Radiomics for Habitat Computation by Machine Learning in Cancer.

Purpose To identify precise three-dimensional radiomics features in CT images that enable computation of stable and biologically meaningful habitats with machine learning for cancer heterogeneity assessment. Materials and Methods This retrospective study included 2436 liver or lung lesions from 605 CT scans (November 2010-December 2021) in 331 patients with cancer (mean age, 64.5 years ± 10.1 [SD]; 185 male patients). Three-dimensional radiomics were computed from original and perturbed (simulated retest) images with different combinations of feature computation kernel radius and bin size. The lower 95% confidence limit (LCL) of the intraclass correlation coefficient (ICC) was used to measure repeatability and reproducibility. Precise features were identified by combining repeatability and reproducibility results (LCL of ICC ≥ 0.50). Habitats were obtained with Gaussian mixture models in original and perturbed data using precise radiomics features and compared with habitats obtained using all features. The Dice similarity coefficient (DSC) was used to assess habitat stability. Biologic correlates of CT habitats were explored in a case study, with a cohort of 13 patients with CT, multiparametric MRI, and tumor biopsies. Results Three-dimensional radiomics showed poor repeatability (LCL of ICC: median [IQR], 0.442 [0.312-0.516]) and poor reproducibility against kernel radius (LCL of ICC: median [IQR], 0.440 [0.33-0.526]) but excellent reproducibility against bin size (LCL of ICC: median [IQR], 0.929 [0.853-0.988]). Twenty-six radiomics features were precise, differing in lung and liver lesions. Habitats obtained with precise features (DSC: median [IQR], 0.601 [0.494-0.712] and 0.651 [0.52-0.784] for lung and liver lesions, respectively) were more stable than those obtained with all features (DSC: median [IQR], 0.532 [0.424-0.637] and 0.587 [0.465-0.703] for lung and liver lesions, respectively; P < .001). In the case study, CT habitats correlated quantitatively and qualitatively with heterogeneity observed in multiparametric MRI habitats and histology. Conclusion Precise three-dimensional radiomics features were identified on CT images that enabled tumor heterogeneity assessment through stable tumor habitat computation. Keywords: CT, Diffusion-weighted Imaging, Dynamic Contrast-enhanced MRI, MRI, Radiomics, Unsupervised Learning, Oncology, Liver, Lung Supplemental material is available for this article. © RSNA, 2024 See also the commentary by Sagreiya in this issue.

Radiomic Signatures Associated with CD8+ Tumour-Infiltrating Lymphocytes: A Systematic Review and Quality Assessment Study.

The tumour immune microenvironment influences the efficacy of immune checkpoint inhibitors. Within this microenvironment are CD8-expressing tumour-infiltrating lymphocytes (CD8+ TILs), which are an important mediator and marker of anti-tumour response. In practice, the assessment of CD8+ TILs via tissue sampling involves logistical challenges. Radiomics, the high-throughput extraction of features from medical images, may offer a novel and non-invasive alternative. We performed a systematic review of the available literature reporting radiomic signatures associated with CD8+ TILs. We also aimed to evaluate the methodological quality of the identified studies using the Radiomics Quality Score (RQS) tool, and the risk of bias and applicability with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Articles were searched from inception until 31 December 2021, in three electronic databases, and screened against eligibility criteria. Twenty-seven articles were included. A wide variety of cancers have been studied. The reported radiomic signatures were heterogeneous, with very limited reproducibility between studies of the same cancer group. The overall quality of studies was found to be less than desirable (mean RQS = 33.3%), indicating a need for technical maturation. Some potential avenues for further investigation are also discussed.

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer.

Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFV600E colorectal cancer (mCRCBRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCBRAF-V600E treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12-0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10-0.71; P = 0.008), in patients with MSS-RNF43mutated versus MSS-RNF43wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCBRAF-V600E tumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients.

Robust imaging habitat computation using voxel-wise radiomics features.

Tumor heterogeneity has been postulated as a hallmark of treatment resistance and a cure constraint in cancer patients. Conventional quantitative medical imaging (radiomics) can be extended to computing voxel-wise features and aggregating tumor subregions with similar radiological phenotypes (imaging habitats) to elucidate the distribution of tumor heterogeneity within and among tumors. Despite the promising applications of imaging habitats, they may be affected by variability of radiomics features, preventing comparison and generalization of imaging habitats techniques. We performed a comprehensive repeatability and reproducibility analysis of voxel-wise radiomics features in more than 500 lung cancer patients with computed tomography (CT) images and demonstrated the effect of voxel-wise radiomics variability on imaging habitats computation in 30 lung cancer patients with test-retest images. Repeatable voxel-wise features characterized texture heterogeneity and were reproducible regardless of the applied feature extraction parameters. Imaging habitats computed using robust radiomics features were more stable than those computed using all features in test-retest CTs from the same patient. Nine voxel-wise radiomics features (joint energy, joint entropy, sum entropy, maximum probability, difference entropy, Imc1, Imc2, Idn and Idmn) were repeatable and reproducible. This supports their application for computing imaging habitats in lung tumors towards the discovery of previously unseen tumor heterogeneity and the development of novel non-invasive imaging biomarkers for precision medicine.

Feasibility of online IMPT adaptation using fast, automatic and robust dose restoration.

Intensity-modulated proton therapy (IMPT) offers excellent dose conformity and healthy tissue sparing, but it can be substantially compromised in the presence of anatomical changes. A major dosimetric effect is caused by density changes, which alter the planned proton range in the patient. Three different methods, which automatically restore an IMPT plan dose on a daily CT image were implemented and compared: (1) simple dose restoration (DR) using optimization objectives of the initial plan, (2) voxel-wise dose restoration (vDR), and (3) isodose volume dose restoration (iDR). Dose restorations were calculated for three different clinical cases, selected to test different capabilities of the restoration methods: large range adaptation, complex dose distributions and robust re-optimization. All dose restorations were obtained in less than 5 min, without manual adjustments of the optimization settings. The evaluation of initial plans on repeated CTs showed large dose distortions, which were substantially reduced after restoration. In general, all dose restoration methods improved DVH-based scores in propagated target volumes and OARs. Analysis of local dose differences showed that, although all dose restorations performed similarly in high dose regions, iDR restored the initial dose with higher precision and accuracy in the whole patient anatomy. Median dose errors decreased from 13.55 Gy in distorted plan to 9.75 Gy (vDR), 6.2 Gy (DR) and 4.3 Gy (iDR). High quality dose restoration is essential to minimize or eventually by-pass the physician approval of the restored plan, as long as dose stability can be assumed. Motion (as well as setup and range uncertainties) can be taken into account by including robust optimization in the dose restoration. Restoring clinically-approved dose distribution on repeated CTs does not require new ROI segmentation and is compatible with an online adaptive workflow.

Advanced treatment planning using direct 4D optimisation for pencil-beam scanned particle therapy.

We report on development of a new four-dimensional (4D) optimisation approach for scanned proton beams, which incorporates both irregular motion patterns and the delivery dynamics of the treatment machine into the plan optimiser. Furthermore, we assess the effectiveness of this technique to reduce dose to critical structures in proximity to moving targets, while maintaining effective target dose homogeneity and coverage. The proposed approach has been tested using both a simulated phantom and a clinical liver cancer case, and allows for realistic 4D calculations and optimisation using irregular breathing patterns extracted from e.g. 4DCT-MRI (4D computed tomography-magnetic resonance imaging). 4D dose distributions resulting from our 4D optimisation can achieve almost the same quality as static plans, independent of the studied geometry/anatomy or selected motion (regular and irregular). Additionally, current implementation of the 4D optimisation approach requires less than 3 min to find the solution for a single field planned on 4DCT of a liver cancer patient. Although 4D optimisation allows for realistic calculations using irregular breathing patterns, it is very sensitive to variations from the planned motion. Based on a sensitivity analysis, target dose homogeneity comparable to static plans (D5-D95 <5%) has been found only for differences in amplitude of up to 1 mm, for changes in respiratory phase <200 ms and for changes in the breathing period of <20 ms in comparison to the motions used during optimisation. As such, methods to robustly deliver 4D optimised plans employing 4D intensity-modulated delivery are discussed.

The impact of breathing guidance and prospective gating during thoracic 4DCT imaging: an XCAT study utilizing lung cancer patient motion.

Two interventions to overcome the deleterious impact irregular breathing has on thoracic-abdominal 4D computed tomography (4DCT) are (1) facilitating regular breathing using audiovisual biofeedback (AVB), and (2) prospective respiratory gating of the 4DCT scan based on the real-time respiratory motion. The purpose of this study was to compare the impact of AVB and gating on 4DCT imaging using the 4D eXtended cardiac torso (XCAT) phantom driven by patient breathing patterns. We obtained simultaneous measurements of chest and abdominal walls, thoracic diaphragm, and tumor motion from 6 lung cancer patients under two breathing conditions: (1) AVB, and (2) free breathing. The XCAT phantom was used to simulate 4DCT acquisitions in cine and respiratory gated modes. 4DCT image quality was quantified by artefact detection (NCCdiff), mean square error (MSE), and Dice similarity coefficient of lung and tumor volumes (DSClung, DSCtumor). 4DCT acquisition times and imaging dose were recorded. In cine mode, AVB improved NCCdiff, MSE, DSClung, and DSCtumor by 20% (p = 0.008), 23% (p < 0.001), 0.5% (p < 0.001), and 4.0% (p < 0.003), respectively. In respiratory gated mode, AVB improved NCCdiff, MSE, and DSClung by 29% (p < 0.001), 34% (p < 0.001), 0.4% (p < 0.001), respectively. AVB increased the cine acquisitions by 15 s and reduced respiratory gated acquisitions by 31 s. AVB increased imaging dose in cine mode by 10%. This was the first study to quantify the impact of breathing guidance and respiratory gating on 4DCT imaging. With the exception of DSCtumor in respiratory gated mode, AVB significantly improved 4DCT image analysis metrics in both cine and respiratory gated modes over free breathing. The results demonstrate that AVB and respiratory-gating can be beneficial interventions to improve 4DCT for cancer radiation therapy, with the biggest gains achieved when these interventions are used simultaneously.

Four-Dimensional Dose Reconstruction for Scanned Proton Therapy Using Liver 4DCT-MRI.

PURPOSE: Four-dimensional computed tomography-magnetic resonance imaging (4DCT-MRI) is an image-processing technique for simulating many 4DCT data sets from a static reference CT and motions extracted from 4DMRI studies performed using either volunteers or patients. In this work, different motion extraction approaches were tested using 6 liver cases, and a detailed comparison between 4DCT-MRI and 4DCT was performed. METHODS AND MATERIALS: 4DCT-MRI has been generated using 2 approaches. The first approach used motion extracted from 4DMRI as being "most similar" to that of 4DCT from the same patient (subject-specific), and the second approach used the most similar motion obtained from a motion library derived from 4DMRI liver studies of 13 healthy volunteers (population-based). The resulting 4DCT-MRI and 4DCTs were compared using scanned proton 4D dose calculations (4DDC). RESULTS: Dosimetric analysis showed that 93% ± 8% of points inside the clinical target volume (CTV) agreed between 4DCT and subject-specific 4DCT-MRI (gamma analysis: 3%/3 mm). The population-based approach however showed lower dosimetric agreement with only 79% ± 14% points in the CTV reaching the 3%/3 mm criteria. CONCLUSIONS: 4D CT-MRI extends the capabilities of motion modeling for dose calculations by accounting for realistic and variable motion patterns, which can be directly employed in clinical research studies. We have found that the subject-specific liver modeling appears more accurate than the population-based approach. The former is particularly interesting for clinical applications, such as improved target delineation and 4D dose reconstruction for patient-specific QA to allow for inter- and/or intra-fractional plan corrections.

Respiratory motion-management in stereotactic body radiation therapy for lung cancer - A dosimetric comparison in an anthropomorphic lung phantom (LuCa).

BACKGROUND AND PURPOSE: The objective of this study was to compare the latest respiratory motion-management strategies, namely the internal-target-volume (ITV) concept, the mid-ventilation (MidV) principle, respiratory gating and dynamic couch tracking. MATERIALS AND METHODS: An anthropomorphic, deformable and dynamic lung phantom was used for the dosimetric validation of these techniques. Stereotactic treatments were adapted to match the techniques and five distinct respiration patterns, and delivered to the phantom while radiographic film measurements were taken inside the tumor. To report on tumor coverage, these dose distributions were used to calculate mean doses (Dmean), changes in homogeneity indices (ΔH2-98), gamma agreement, and areas covered by the planned minimum dose (A>Dmin). RESULTS: All techniques achieved good tumor coverage (A>Dmin>99.0%) and minor changes in Dmean (±3.2%). Gating and tracking strategies showed superior results in gamma agreement and ΔH2-98 compared to ITV and MidV concepts, which seem to be more influenced by the interplay and the gradient effect. For lung, heart and spinal cord, significant dose differences between the four techniques were found (p<0.05), with lowest doses for gating and tracking strategies. CONCLUSION: Active motion-management techniques, such as gating or tracking, showed superior tumor dose coverage and better organ dose sparing than the passive techniques based on tumor margins.