Sebastian Echegaray

Glioblastoma Multiforme: Exploratory Radiogenomic Analysis by Using Quantitative Image Features

PURPOSE To derive quantitative image features from magnetic resonance (MR) images that characterize the radiographic phenotype of glioblastoma multiforme (GBM) lesions and to create radiogenomic maps associating these features with various molecular data. MATERIALS AND METHODS Clinical, molecular, and MR imaging data for GBMs in 55 patients were obtained from the Cancer Genome Atlas and the Cancer Imaging Archive after local ethics committee and institutional review board approval. Regions of interest (ROIs) corresponding to enhancing necrotic portions of tumor and peritumoral edema were drawn, and quantitative image features were derived from these ROIs. Robust quantitative image features were defined on the basis of an intraclass correlation coefficient of 0.6 for a digital algorithmic modification and a test-retest analysis. The robust features were visualized by using hierarchic clustering and were correlated with survival by using Cox proportional hazards modeling. Next, these robust image features were correlated with manual radiologist annotations from the Visually Accessible Rembrandt Images (VASARI) feature set and GBM molecular subgroups by using nonparametric statistical tests. A bioinformatic algorithm was used to create gene expression modules, defined as a set of coexpressed genes together with a multivariate model of cancer driver genes predictive of the modules expression pattern. Modules were correlated with robust image features by using the Spearman correlation test to create radiogenomic maps and to link robust image features with molecular pathways. RESULTS Eighteen image features passed the robustness analysis and were further analyzed for the three types of ROIs, for a total of 54 image features. Three enhancement features were significantly correlated with survival, 77 significant correlations were found between robust quantitative features and the VASARI feature set, and seven image features were correlated with molecular subgroups (P < .05 for all). A radiogenomics map was created to link image features with gene expression modules and allowed linkage of 56% (30 of 54) of the image features with biologic processes. CONCLUSION Radiogenomic approaches in GBM have the potential to predict clinical and molecular characteristics of tumors noninvasively. Online supplemental material is available for this article.

Magnetic resonance image features identify glioblastoma phenotypic subtypes with distinct molecular pathway activities

Quantitative imaging stratifies glioblastoma into three different phenotypes with distinct molecular activities independent of established molecular markers and clinical status. Brain images create cancer clusters When directing therapies toward tumors, a sample of the cancerous tissue is needed to identify molecular targets. For patients with glioblastoma, however, it is invasive to biopsy the brain. Itakura et al. sought to identify noninvasive determinants of tumor phenotype that would potentially correlate with molecular pathways, thus allowing for targeted therapy without such brain invasion. The authors used magnetic resonance imaging to look at solitary, unilateral tumors from 121 glioblastoma patients and then generated nearly 400 unique image features that could be used to describe each tumor. The tumors could be grouped into three different phenotypes or “clusters”: pre-multifocal cluster, with highly irregular tumor shapes; spherical cluster, with defined edges; and rim-enhancing cluster, with a hypointense center ringed by hyperintensity. The distinct clusters were further validated in a separate cohort of 144 patients. These clusters could be used to stratify patients not only according to molecular pathways for targeted therapy but also by survival, indicating the potential for such noninvasive image-based quantitative biomarkers to be used for patient prognosis. Glioblastoma (GBM) is the most common and highly lethal primary malignant brain tumor in adults. There is a dire need for easily accessible, noninvasive biomarkers that can delineate underlying molecular activities and predict response to therapy. To this end, we sought to identify subtypes of GBM, differentiated solely by quantitative magnetic resonance (MR) imaging features, that could be used for better management of GBM patients. Quantitative image features capturing the shape, texture, and edge sharpness of each lesion were extracted from MR images of 121 single-institution patients with de novo, solitary, unilateral GBM. Three distinct phenotypic “clusters” emerged in the development cohort using consensus clustering with 10,000 iterations on these image features. These three clusters—pre-multifocal, spherical, and rim-enhancing, names reflecting their image features—were validated in an independent cohort consisting of 144 multi-institution patients with similar tumor characteristics from The Cancer Genome Atlas (TCGA). Each cluster mapped to a unique set of molecular signaling pathways using pathway activity estimates derived from the analysis of TCGA tumor copy number and gene expression data with the PARADIGM (Pathway Recognition Algorithm Using Data Integration on Genomic Models) algorithm. Distinct pathways, such as c-Kit and FOXA, were enriched in each cluster, indicating differential molecular activities as determined by the image features. Each cluster also demonstrated differential probabilities of survival, indicating prognostic importance. Our imaging method offers a noninvasive approach to stratify GBM patients and also provides unique sets of molecular signatures to inform targeted therapy and personalized treatment of GBM.

Predictive radiogenomics modeling of EGFR mutation status in lung cancer

Molecular analysis of the mutation status for EGFR and KRAS are now routine in the management of non-small cell lung cancer. Radiogenomics, the linking of medical images with the genomic properties of human tumors, provides exciting opportunities for non-invasive diagnostics and prognostics. We investigated whether EGFR and KRAS mutation status can be predicted using imaging data. To accomplish this, we studied 186 cases of NSCLC with preoperative thin-slice CT scans. A thoracic radiologist annotated 89 semantic image features of each patient’s tumor. Next, we built a decision tree to predict the presence of EGFR and KRAS mutations. We found a statistically significant model for predicting EGFR but not for KRAS mutations. The test set area under the ROC curve for predicting EGFR mutation status was 0.89. The final decision tree used four variables: emphysema, airway abnormality, the percentage of ground glass component and the type of tumor margin. The presence of either of the first two features predicts a wild type status for EGFR while the presence of any ground glass component indicates EGFR mutations. These results show the potential of quantitative imaging to predict molecular properties in a non-invasive manner, as CT imaging is more readily available than biopsies.

Core samples for radiomics features that are insensitive to tumor segmentation: method and pilot study using CT images of hepatocellular carcinoma

Abstract. The purpose of this study is to investigate the utility of obtaining “core samples” of regions in CT volume scans for extraction of radiomic features. We asked four readers to outline tumors in three representative slices from each phase of multiphasic liver CT images taken from 29 patients (1128 segmentations) with hepatocellular carcinoma. Core samples were obtained by automatically tracing the maximal circle inscribed in the outlines. Image features describing the intensity, texture, shape, and margin were used to describe the segmented lesion. We calculated the intraclass correlation between the features extracted from the readers’ segmentations and their core samples to characterize robustness to segmentation between readers, and between human-based segmentation and core sampling. We conclude that despite the high interreader variability in manually delineating the tumor (average overlap of 43% across all readers), certain features such as intensity and texture features are robust to segmentation. More importantly, this same subset of features can be obtained from the core samples, providing as much information as detailed segmentation while being simpler and faster to obtain.

Quantitative Image Feature Engine (QIFE): an Open-Source, Modular Engine for 3D Quantitative Feature Extraction from Volumetric Medical Images

The aim of this study was to develop an open-source, modular, locally run or server-based system for 3D radiomics feature computation that can be used on any computer system and included in existing workflows for understanding associations and building predictive models between image features and clinical data, such as survival. The QIFE exploits various levels of parallelization for use on multiprocessor systems. It consists of a managing framework and four stages: input, pre-processing, feature computation, and output. Each stage contains one or more swappable components, allowing run-time customization. We benchmarked the engine using various levels of parallelization on a cohort of CT scans presenting 108 lung tumors. Two versions of the QIFE have been released: (1) the open-source MATLAB code posted to Github, (2) a compiled version loaded in a Docker container, posted to DockerHub, which can be easily deployed on any computer. The QIFE processed 108 objects (tumors) in 2:12 (h/mm) using 1 core, and 1:04 (h/mm) hours using four cores with object-level parallelization. We developed the Quantitative Image Feature Engine (QIFE), an open-source feature-extraction framework that focuses on modularity, standards, parallelism, provenance, and integration. Researchers can easily integrate it with their existing segmentation and imaging workflows by creating input and output components that implement their existing interfaces. Computational efficiency can be improved by parallelizing execution at the cost of memory usage. Different parallelization levels provide different trade-offs, and the optimal setting will depend on the size and composition of the dataset to be processed.

Prediction of EGFR and KRAS mutation in non-small cell lung cancer using quantitative 18 F FDG-PET/CT metrics

This study investigated the relationship between epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in non-small-cell lung cancer (NSCLC) and quantitative FDG-PET/CT parameters including tumor heterogeneity. 131 patients with NSCLC underwent staging FDG-PET/CT followed by tumor resection and histopathological analysis that included testing for the EGFR and KRAS gene mutations. Patient and lesion characteristics, including smoking habits and FDG uptake parameters, were correlated to each gene mutation. Never-smoker (P < 0.001) or low pack-year smoking history (p = 0.002) and female gender (p = 0.047) were predictive factors for the presence of the EGFR mutations. Being a current or former smoker was a predictive factor for the KRAS mutations (p = 0.018). The maximum standardized uptake value (SUVmax) of FDG uptake in lung lesions was a predictive factor of the EGFR mutations (p = 0.029), while metabolic tumor volume and total lesion glycolysis were not predictive. Amongst several tumor heterogeneity metrics included in our analysis, inverse coefficient of variation (1/COV) was a predictive factor (p < 0.02) of EGFR mutations status, independent of metabolic tumor diameter. Multivariate analysis showed that being a never-smoker was the most significant factor (p < 0.001) for the EGFR mutations in lung cancer overall. The tumor heterogeneity metric 1/COV and SUVmax were both predictive for the EGFR mutations in NSCLC in a univariate analysis. Overall, smoking status was the most significant factor for the presence of the EGFR and KRAS mutations in lung cancer.This study investigated the relationship between epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in non-small-cell lung cancer (NSCLC) and quantitative FDG-PET/CT parameters including tumor heterogeneity. 131 patients with NSCLC underwent staging FDG-PET/CT followed by tumor resection and histopathological analysis that included testing for the EGFR and KRAS gene mutations. Patient and lesion characteristics, including smoking habits and FDG uptake parameters, were correlated to each gene mutation. Never-smoker (P < 0.001) or low pack-year smoking history (p = 0.002) and female gender (p = 0.047) were predictive factors for the presence of the EGFR mutations. Being a current or former smoker was a predictive factor for the KRAS mutations (p = 0.018). The maximum standardized uptake value (SUVmax) of FDG uptake in lung lesions was a predictive factor of the EGFR mutations (p = 0.029), while metabolic tumor volume and total lesion glycolysis were not predictive. Amongst several tumor heterogeneity metrics included in our analysis, inverse coefficient of variation (1/COV) was a predictive factor (p < 0.02) of EGFR mutations status, independent of metabolic tumor diameter. Multivariate analysis showed that being a never-smoker was the most significant factor (p < 0.001) for the EGFR mutations in lung cancer overall. The tumor heterogeneity metric 1/COV and SUVmax were both predictive for the EGFR mutations in NSCLC in a univariate analysis. Overall, smoking status was the most significant factor for the presence of the EGFR and KRAS mutations in lung cancer.

Non–Small Cell Lung Cancer Radiogenomics Map Identifies Relationships between Molecular and Imaging Phenotypes with Prognostic Implications

Our study presented a radiogenomics map of non–small cell lung cancer that linked image phenotypes with ribonucleic acid signatures captured by metagenes and showed their association with molecular pathways.

A radiogenomic dataset of non-small cell lung cancer

Medical image biomarkers of cancer promise improvements in patient care through advances in precision medicine. Compared to genomic biomarkers, image biomarkers provide the advantages of being non-invasive, and characterizing a heterogeneous tumor in its entirety, as opposed to limited tissue available via biopsy. We developed a unique radiogenomic dataset from a Non-Small Cell Lung Cancer (NSCLC) cohort of 211 subjects. The dataset comprises Computed Tomography (CT), Positron Emission Tomography (PET)/CT images, semantic annotations of the tumors as observed on the medical images using a controlled vocabulary, and segmentation maps of tumors in the CT scans. Imaging data are also paired with results of gene mutation analyses, gene expression microarrays and RNA sequencing data from samples of surgically excised tumor tissue, and clinical data, including survival outcomes. This dataset was created to facilitate the discovery of the underlying relationship between tumor molecular and medical image features, as well as the development and evaluation of prognostic medical image biomarkers.

Noninvasive radiomics signature based on quantitative analysis of computed tomography images as a surrogate for microvascular invasion in hepatocellular carcinoma: a pilot study

Abstract. We explore noninvasive biomarkers of microvascular invasion (mVI) in patients with hepatocellular carcinoma (HCC) using quantitative and semantic image features extracted from contrast-enhanced, triphasic computed tomography (CT). Under institutional review board approval, we selected 28 treatment-naive HCC patients who underwent surgical resection. Four radiologists independently selected and delineated tumor margins on three axial CT images and extracted computational features capturing tumor shape, image intensities, and texture. We also computed two types of “delta features,” defined as the absolute difference and the ratio computed from all pairs of imaging phases for each feature. 717 arterial, portal-venous, delayed single-phase, and delta-phase features were robust against interreader variability (concordance correlation≥0.8). An enhanced cross-validation analysis showed that combining robust single-phase and delta features in the arterial and venous phases identified mVI (AUC 0.76±0.18). Compared to a previously reported semantic feature signature (AUC 0.47 to 0.58), these features in our cohort showed only slight to moderate agreement (Cohen’s kappa range: 0.03 to 0.59). Though preliminary, quantitative analysis of image features in arterial and venous phases may be potential surrogate biomarkers for mVI in HCC. Further study in a larger cohort is warranted.