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The current era of advanced computing has allowed for the development and implementation of the field of radiomics. In pediatric neuro-oncology, radiomics has been applied in determination of tumor histology, identification of disseminated disease, prognostication, and molecular classification of tumors (ie, radiogenomics). The field also comes with many challenges, such as limitations in study sample sizes, class imbalance, generalizability of the methods, and data harmonization across imaging centers. The aim of this review paper is twofold: first, to summarize existing literature in radiomics of pediatric neuro-oncology; second, to distill the themes and challenges of the field and discuss future directions in both a clinical and technical context.

Understanding the immune microenvironment in pediatric low-grade glioma (pLGG) patients may help in identification of the patients who benefit from anti-tumor immunotherapies. However, surgical resection is not feasible for many pLGG tumors in certain anatomical locations. Therefore, developing non-invasive tools that characterize the tumor microenvironment prior to therapeutic interventions could contribute to stratification and enrollment of the patients into relevant clinical trials. In this work, we derived radiomic signatures of immune profiles (radioimmunomics) based on machine learning (ML) analysis of readily available conventional MRI scans. Transcriptomic data for a cohort of 197 subjects was retrospectively collected from Open Pediatric Brain Tumor Atlas (OpenPBTA). The patients were categorized into three groups (Group1-3) based on their immunological profiles using consensus clustering algorithm. This analysis revealed greater immune cell infiltration in non-BRAF mutated pLGGs. Group1 showed more enrichment in M1 macrophages, and microenvironment and immune scores compared to Group2 and Group3. Elevated tumor inflammation score (TIS), as a predictor of clinical response to anti-PD-1 blockade, was observed in Group1 compared to Group2 (p= 1.4e-7) and Group3 (p= 0.0054). Radiomic features, including volumetric, morphologic, histogram, and texture descriptors, were extracted from the segmented tumor regions on multiparametric MRI (mpMRI) scans of 71 (of 197) patients. Multivariate ML models were trained to predict the three immunological groups based on radiomic features using cross-validated random forest classifier along with recursive feature elimination, which yielded AUC of 0.72 for this multi-class classification problem. Our findings indicate the presence of distinct immunological groups in pLGG tumors, with possibly more favorable response to immunotherapies in Group1 tumors. Furthermore, we developed radioimmunomic signatures based on pre-operative conventional mpMRI that can potentially stratify the patients based on their immune tumor microenvironment. Based on these initial promising results, we are exploring additional features to increase the accuracy of radioimmunomics model.

Volumetric measurements of whole tumor and its components on MRI scans, facilitated by automatic segmentation tools, are essential to reduce inter-observer variability in monitoring tumor progression and response assessment for pediatric brain tumors. Here, we present a fully automatic segmentation model based on deep learning that reliably delineates the tumor components recommended by the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group for evaluation of treatment response. Multi-parametric MRI (mpMRI) scans (T1-pre, T1-post, T2, and T2-FLAIR), acquired on multiple MRI scanners with different field strengths and vendors, for a cohort of 218 pediatric patients with a variety of histologically confirmed brain tumor subtypes were collected. The mpMRI scans were co-registered and manually segmented by experienced neuroradiologists in consensus to identify the tumor subregions including the enhancing tumor (ET), non-enhancing tumor (NET), cystic components (CC), and peritumoral edema (ED) regions. A convolutional neural network model based on DeepMedic architecture was trained using mpMRI scans as the inputs for segmentation of the whole tumor and subregions. The trained model showed excellent performance in segmentation of the whole tumor, as suggested by median dice of 0.90/0.85 for validation (n = 44)/independent test (n = 22) sets. ET and non-enhancing components (union of NET, CC, and ED) were segmented with median dice scores of 0.78/0.84 and 0.76/0.74 for validation/test sets, respectively. The automated and manual segmentations demonstrated strong agreement in estimating VASARI (Visually AcceSAble Rembrandt Images) MRI features with Pearson’s correlation coefficient R > 0.75 (p < 0.0001) for ET, NET, CC, and ED components. Our proposed automated segmentation method developed based on MRI scans acquired with different protocols, equipment, and from a variety of brain tumor subtypes, shows potential application for reliable and generalizable volumetric measurements which can be used for treatment response assessment in clinical trials.

Pediatric low-grade glioma (pLGG) encompasses a variety of tumor subtypes with heterogeneous treatment response and relatively long progression-free survival (PFS). Radiomics may serve as a non-invasive and in-vivo tool for early prediction of PFS as a surrogate marker for treatment response and to objectively gauge the efficacy of novel treatment strategies. Here, we present a multivariate model based on radiomic features and clinical variables for risk stratification of pLGGs in terms of PFS and seek associations of the predicted risk groups and mutations in key molecular markers using data from PedCBioportal. Pre-operative multi-parametric MRI scans (T1-pre, T1-post, T2, T2-FLAIR) of 129 patients with newly diagnosed pLGG (median age, 7.76, range, 0.35-19.58 years; median PFS, 28.5, range, 1.1-124.8 months) were collected and quantitative radiomic features (n = 881) were extracted. A multivariate Cox proportional hazard’s (Cox-PH) regression model was fitted based on clinical (age, sex, and extent of tumor resection) and radiomic variables using 4-fold cross-validation. A subset of radiomic features (n = 27) that were most predictive of PFS was selected by applying Elastic Net regularization penalty during Cox-PH model fitting. High-, medium- and low-risk groups were determined based on model predictions. Cox-PH modeling showed excellent performance for prediction of PFS as suggested by the concordance index of 0.78. Radiogenomic assessment (data available in 94/129 patients) showed more enrichment of mutations in NF1 and RB1 genes in the high-risk group, as compared to the low- and medium-risk groups. We showed the potential value of radiomics in providing upfront prediction of PFS, which may further be used as an added treatment arm for early assessment of treatment response of the pLGG patients enrolled in the clinical trials. In the next step of this work, we will expand the cohort and cross-validate these results in an external cohort.

Recent studies have shown preliminary evidence for differentiation of the tumor microenvironment (TME) and immune landscape between molecularly-defined medulloblastoma (MB) subtypes. Identifying radiological correlates of these TME patterns could establish a non-invasive method of immune profile characterization for guiding patient-centered therapies. Here, we examine immune profiles between MB subtypes using data from Open Pediatric Brain Tumor Atlas (OpenPBTA), and their relationship to tumor measurements from pre-operative MRIs. We identified a retrospective cohort of 94 pediatric MB patients with available molecular subtyping and immune profiles (36 cell types) from bulk gene expression data. A random forest analysis was used to classify the four MB subtypes based on immune profiles. Four cell types had high impact on classification performance: plasmacytoid dendritic cells (PDC; 25.8% accuracy decrease when randomized), hematopoietic stem cells (HSC; 21.9%), plasma B cells (20.3%), and cancer associated fibroblasts (18.8%). Pairwise comparisons revealed SHH and WNT tumors had significantly higher numbers of fibroblasts and HSCs compared to Group3/Group4. We also found novel evidence for significantly lower amounts of plasma B cells in the SHH group, and high PDC levels in Group4, followed by Group3, and low PDC in SHH/WNT. Multi-parametric MRI scans for 39 patients were used to segment tumor volumes. Overall tumor volume was significantly correlated with composite stroma scores (R = 0.34, p = 0.036). Additionally, patients with higher volumes of gadolinium contrast-enhancing compared to non-enhancing components had higher immune (R = 0.42, p = 0.009) and microenvironment (summed immune and stromal cell types; R = 0.44, p = 0.006) scores, regardless of their molecular subtype. Together, our results demonstrate: (1) the use of rich immune profiles for differentiating molecular subtypes of MB and their unique TME characterization; and (2) initial evidence for radiological correlates of these profiles based on pre-operative imaging collected through standard practices.

PURPOSE: Treatment response is heterogeneous among patients with pediatric low-grade glioma (pLGG), the most frequent childhood brain tumor. Upfront prediction of progression-free survival (PFS) may facilitate more personalized treatment planning and improve outcomes for the pLGG patients. In this work, we explored the additive value of radiomics to clinical measures for prediction of PFS in pLGGs. We further sought associations between the derived risk groups and underlying alterations in key genomic and transcriptomic variables. METHODS: Quantitative radiomic features were extracted from pre-operative multi-parametric MRI scans (T1, T1-post, T2, T2-FLAIR) of 96 patients with newly diagnosed pLGG (median age, 8.59, range, 0.35-18.87 years; median PFS, 25.23, range, 3.03-124.83 months). Multivariate Cox proportional hazard’s (Cox-PH) regression models were fitted using 5-fold cross-validation on a training cohort of 68 subjects and tested on 28 patients. Three models were generated using (1) only clinical variables (age, sex, and extent of tumor resection), (2) radiomic features, and (3) clinical and radiomic variables. The dimensionality of radiomic features in Cox-PH models was reduced by applying Elastic Net regularization penalty to identify a subset of variables that are most predictive of PFS. The patients were then stratified into three groups of high, medium, and low-risk based on model predictions. RESULTS: Cox-PH modeling resulted in a concordance index (c-index) of 0.55 for clinical data, 0.65 for radiomics, and 0.73 for a combination of clinical and radiomic variables, highlighting the additive value of radiomics to the readily available clinical information in prediction of PFS. Radiogenomic assessments revealed significant differences in expression of BRAF, NF1, TSC1, ALK (p