MRI and Molecular Characterization of Pediatric High-Grade Midline Thalamic Gliomas: The HERBY Phase II Trial

Background: Diffuse midline gliomas (DMG) are characterized by a high incidence of H3 K27 mutations and poorer outcome. The HERBY trial has provided one of the largest cohorts of pediatric DMGs with available radiologic, histologic-genotypic, and survival data. / Purpose: To define MRI and molecular characteristics of DMG. / Materials and Methods: This study is a secondary analysis of a prospective trial (HERBY; ClinicalTrials.gov identifier, NCT01390948) undertaken between October 2011 and February 2016. Among 121 HERBY participants, 50 had midline nonpontine-based tumors. Midline high-grade gliomas were reclassified into DMG H3 K27 mutant, H3 wild type with enhancer of zest homologs inhibitory protein overexpression, epidermal growth factor receptormutant, or not otherwise stated. The epicenter of each tumor and other radiologic characteristics were ascertained from MRI and correlated with the new subtype classification, histopathologic characteristics, surgical extent, and outcome parameters. Kaplan-Meier curves and log-rank tests were applied to determine and describe survival differences between groups. / Results: There were 42 participants (mean age, 12 years ± 4 [SD]; 23 girls) with radiologically evaluable thalamic-based DMG. Eighteen had partial thalamic involvement (12 thalamopulvinar, six anteromedial), 10 involved a whole thalamus, nine had unithalamic tumors with diffuse contiguous extension, and five had bithalamic tumors (two symmetric, three partial). Twenty-eight participants had DMG H3 K27 mutant tumors; there were no differences in outcome compared with other DMGs (n = 4). Participants who underwent major debulking or total or near-total resection had longer overall survival (OS): 18.5 months vs 11.4 months (P = .02). Enrolled participants who developed leptomeningeal metastatic dissemination before starting treatment had worse outcomes (event-free survival, 2.9 months vs 8.0 months [P = .02]; OS, 11.4 months vs 18.5 months [P = .004]). / Conclusion: Thalamic involvement of diffuse midline gliomas ranged from localized partial thalamic to holo- or bithalamic with diffuse contiguous spread and had poor outcomes, irrespective of H3 K27 subtype alterations. Leptomeningeal dissemination and less than 50% surgical resection were adverse risk factors for survival. / Clinical trial registration no. NCT0139094

Clinical, radiologic, pathologic, and molecular characteristics of long-term survivors of diffuse intrinsic pontine glioma (DIPG): a collaborative report from the International and European Society for Pediatric Oncology DIPG registries

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials

Radiological evaluation of newly diagnosed non-brainstem pediatric high-grade glioma in the HERBY phase II trial

Purpose: The HERBY trial evaluated the benefit of the addition of the antiangiogenic agent Bevacizumab (BEV) to radiotherapy/temozolomide (RT/TMZ) in pediatric patients with newly diagnosed non-brainstem high-grade glioma (HGG). The work presented here aims to correlate imaging characteristics and outcome measures with pathologic and molecular data.Experimental Design: Radiological, pathologic, and molecular data were correlated with trial clinical information to retrospectively re-evaluate event-free survival (EFS) and overall survival (OS).Results: One-hundred thirteen patients were randomized to the RT/TMZ arm (n = 54) or the RT/TMZ+BEV (BEV arm; n = 59). The tumor arose in the cerebral hemispheres in 68 patients (Cerebral group) and a midline location in 45 cases (Midline group). Pathologic diagnosis was available in all cases and molecular data in 86 of 113. H3 K27M histone mutations were present in 23 of 32 Midline cases and H3 G34R/V mutations in 7 of 54 Cerebral cases. Total/near-total resection occurred in 44 of 68 (65%) Cerebral cases but in only 5 of 45 (11%) Midline cases (P < 0.05). Leptomeningeal metastases (27 cases, 13 with subependymal spread) at relapse were more frequent in Midline (17/45) than in Cerebral tumors (10/68, P < 0.05). Mean OS (14.1 months) and EFS (9.0 months) in Midline tumors were significantly lower than mean OS (20.7 months) and EFS (14.9 months) in Cerebral tumors (P < 0.05). Pseudoprogression occurred in 8 of 111 (6.2%) cases.Conclusions: This study has shown that the poor outcome of midline tumors (compared with cerebral) may be related to (1) lesser surgical resection, (2) H3 K27M histone mutations, and (3) higher leptomeningeal dissemination

IRM multimodale sériée dans les gliomes infiltrants du tronc cérébral chez l'enfant

Diffuse Intrinsic Pontine Glioma is a pediatric tumor with very poor prognosis. Median survival is 9-12 months. Its typical MRI appearance allows for diagnosis without histological confirmation, but has limited understanding its pathophysiology for years. DIPGs molecular identity identified as histone H3K27M mutations in 2012 defined them as a separate entity. Two subgroups with different phenotypes and prognoses are associated with mutations in one of the two variants H3.1/H3.3 of histone H3. The aim of this thesis was to use multimodal imaging techniques to better understand the pathophysiology of DIPG, by observing the evolution of the effects of different treatments over time. 1st, we showed an increase in perfusion indices associated with decreased edema after radiotherapy. Secondly, we have described the phenomenon of pseudo-progression in MRI, an increase in tumor volume and enhancement associated with a significant increase in perfusion index. This shouldn’t be confused with true tumor progression. The ratio of increase in lesion’s blood flow after radiotherapy has high sensitivity and specificity to identify pseudo-progression. 3rd, we compared the imaging parameters with the histological data to better understand the differences between the histone mutations. The mutated tumors H3.1 have more edema, more necrosis and a lower perfusion. While mutated H3.3 tumors have a higher tumor burden. Tumor burden is positive correlated to lesion blood volume. Multimodal imaging is essential in monitoring and understanding the physiopathological mechanisms of DIPG. It should be included in the research protocols in order to advance and then one day to cure these small patients.Le gliome infiltrant du tronc cérébral est une tumeur gliale pédiatrique de très mauvais pronostic. La survie médiane des patients varie entre 9 et 12 mois. Son aspect typique en imagerie permet le diagnostic sans confirmation histologique mais a limité la compréhension de la physiopathologie de ces tumeurs pendant plusieurs années. L'identification des mutations des histones H3 K27M comme identité moléculaire des gliomes infiltrants du tronc cérébral définit cette tumeur comme une entité unique en 2012 et la sépare des autres tumeurs cérébrales. Il y a deux variantes des histones H3 à l’origine des tumeurs, la variante H.3.1 et la variante H3.3 qui forment deux sous-groupes présentant des phénotypes et des pronostics différents. L'objectif de cette thèse était d'utiliser les techniques d'imagerie multimodale pour mieux comprendre la physiopathologie des gliomes infiltrants du tronc cérébral, en observant l'évolution des effets des différents traitements à différents temps. Nous avons tout d'abord montré une augmentation des index de perfusion associée à une diminution de l'oedème lésionnel en post- radiothérapie. Puis nous avons décrit en imagerie le phénomène de pseudo-progression. Ce phénomène, qu’il ne faut pas prendre pour une vraie progression tumorale, est caractérisé par une augmentation du volume et du rehaussement tumoral associé à une augmentation importante des index de perfusion. Le ratio d’augmentation du flux sanguin lésionnel dans les suites de la radiothérapie permet identifier une pseudo-progression avec une sensibilité et une spécificité élevées. Ces 2 groupes de patients (sans et avec pseudo-progression) ont un comportement en imagerie très différents en fin de vie. Nous avons ensuite comparé les paramètres d'imagerie aux données histologiques pour mieux appréhender les deux types de mutation d'histones. Les tumeurs H3.1 présentent plus d'oedème, plus de nécrose et une perfusion moins élevée. Les tumeurs H3.3 ont une perfusion plus élevée et moins d'oedème. La valeur du volume sanguin lésionnel est positivement corrélée à la charge tumorale. L’imagerie multimodale est essentielle dans le suivi et la compréhension des mécanismes physiopathologiques des DIPG. Elle devra être incluse dans les protocoles de recherches (efficacité des nouvelles chimiothérapies ciblées et nouvelles techniques d’application, modèles murins, radiomics, corrélation avec les nouvelles quantifications histologiques) dans le but d’avancer puis un jour de guérir ces petits patients

Serial multimodal MRI of diffuse intrinsic pontine in children

Le gliome infiltrant du tronc cérébral est une tumeur gliale pédiatrique de très mauvais pronostic. La survie médiane des patients varie entre 9 et 12 mois. Son aspect typique en imagerie permet le diagnostic sans confirmation histologique mais a limité la compréhension de la physiopathologie de ces tumeurs pendant plusieurs années. L'identification des mutations des histones H3 K27M comme identité moléculaire des gliomes infiltrants du tronc cérébral définit cette tumeur comme une entité unique en 2012 et la sépare des autres tumeurs cérébrales. Il y a deux variantes des histones H3 à l’origine des tumeurs, la variante H.3.1 et la variante H3.3 qui forment deux sous-groupes présentant des phénotypes et des pronostics différents. L'objectif de cette thèse était d'utiliser les techniques d'imagerie multimodale pour mieux comprendre la physiopathologie des gliomes infiltrants du tronc cérébral, en observant l'évolution des effets des différents traitements à différents temps. Nous avons tout d'abord montré une augmentation des index de perfusion associée à une diminution de l'oedème lésionnel en post- radiothérapie. Puis nous avons décrit en imagerie le phénomène de pseudo-progression. Ce phénomène, qu’il ne faut pas prendre pour une vraie progression tumorale, est caractérisé par une augmentation du volume et du rehaussement tumoral associé à une augmentation importante des index de perfusion. Le ratio d’augmentation du flux sanguin lésionnel dans les suites de la radiothérapie permet identifier une pseudo-progression avec une sensibilité et une spécificité élevées. Ces 2 groupes de patients (sans et avec pseudo-progression) ont un comportement en imagerie très différents en fin de vie. Nous avons ensuite comparé les paramètres d'imagerie aux données histologiques pour mieux appréhender les deux types de mutation d'histones. Les tumeurs H3.1 présentent plus d'oedème, plus de nécrose et une perfusion moins élevée. Les tumeurs H3.3 ont une perfusion plus élevée et moins d'oedème. La valeur du volume sanguin lésionnel est positivement corrélée à la charge tumorale. L’imagerie multimodale est essentielle dans le suivi et la compréhension des mécanismes physiopathologiques des DIPG. Elle devra être incluse dans les protocoles de recherches (efficacité des nouvelles chimiothérapies ciblées et nouvelles techniques d’application, modèles murins, radiomics, corrélation avec les nouvelles quantifications histologiques) dans le but d’avancer puis un jour de guérir ces petits patients.Diffuse Intrinsic Pontine Glioma is a pediatric tumor with very poor prognosis. Median survival is 9-12 months. Its typical MRI appearance allows for diagnosis without histological confirmation, but has limited understanding its pathophysiology for years. DIPGs molecular identity identified as histone H3K27M mutations in 2012 defined them as a separate entity. Two subgroups with different phenotypes and prognoses are associated with mutations in one of the two variants H3.1/H3.3 of histone H3. The aim of this thesis was to use multimodal imaging techniques to better understand the pathophysiology of DIPG, by observing the evolution of the effects of different treatments over time. 1st, we showed an increase in perfusion indices associated with decreased edema after radiotherapy. Secondly, we have described the phenomenon of pseudo-progression in MRI, an increase in tumor volume and enhancement associated with a significant increase in perfusion index. This shouldn’t be confused with true tumor progression. The ratio of increase in lesion’s blood flow after radiotherapy has high sensitivity and specificity to identify pseudo-progression. 3rd, we compared the imaging parameters with the histological data to better understand the differences between the histone mutations. The mutated tumors H3.1 have more edema, more necrosis and a lower perfusion. While mutated H3.3 tumors have a higher tumor burden. Tumor burden is positive correlated to lesion blood volume. Multimodal imaging is essential in monitoring and understanding the physiopathological mechanisms of DIPG. It should be included in the research protocols in order to advance and then one day to cure these small patients

Object Detection Improves Tumour Segmentation in MR Images of Rare Brain Tumours

Tumour lesion segmentation is a key step to study and characterise cancer from MR neuroradiological images. Presently, numerous deep learning segmentation architectures have been shown to perform well on the specific tumour type they are trained on (e.g., glioblastoma in brain hemispheres). However, a high performing network heavily trained on a given tumour type may perform poorly on a rare tumour type for which no labelled cases allows training or transfer learning. Yet, because some visual similarities exist nevertheless between common and rare tumours, in the lesion and around it, one may split the problem into two steps: object detection and segmentation. For each step, trained networks on common lesions could be used on rare ones following a domain adaptation scheme without extra fine-tuning. This work proposes a resilient tumour lesion delineation strategy, based on the combination of established elementary networks that achieve detection and segmentation. Our strategy allowed us to achieve robust segmentation inference on a rare tumour located in an unseen tumour context region during training. As an example of a rare tumour, Diffuse Intrinsic Pontine Glioma (DIPG), we achieve an average dice score of 0.62 without further training or network architecture adaptation

The Secreted Metabolome of Hela Cells under Effect of Crotamine, a Cell-Penetrating Peptide from a Rattlesnake Using NMR-Based Metabolomics Analyses

Sequestering and reprogramming of cellular metabolism represents one of the principal hallmarks of several cells. Antimicrobial peptides have been shown to exhibit selective anticancer activities. In this study, the secreted metabolome of HeLa cells under action of the antimicrobial peptide Crotamine from the venom of the South American rattlesnake Crotalus durissus terrificus was evaluated. Crotamine has been shown to be selective for highly proliferating cells and is able to extend the in vivo lifespan. The present study using a cell line of cervical cancer, HeLa cells, provide insights into how Crotamine acts in cell metabolism. NMR spectroscopy was used to identify and quantify relative metabolite levels, which are associated with Crotamine uptake. Statistical analysis reveals that Crotamine dramatically affects metabolites related to glycolysis, metabolism and biosynthesis of amino acids and pyruvate metabolism. The developed machine learning model is found to be robust by ROC curve analysis, suggesting that the metabolic state of HeLa cells treated with Crotamine is different from the control samples. To account for metabolite levels, it is suggested that Crotamine would have to act on glycolysis, which, in turn, affects several other metabolic pathways, such as, glutathione metabolism, TCA cycle and pyruvate metabolism. The observed metabolic changes shed light into the mode of Crotamine function

Can Structural MRI Radiomics Predict DIPG Histone H3 Mutation and Patient Overall Survival at Diagnosis Time?

International audienceIdentifying tumor phenotypes non-invasively from quantitative imaging features is a challenge faced by radiomics. This study aimed at investigating if radiomic features measured at diagnosis time from conventional structural MRI can predict histone H3 mutations and overall survival of patients with diffuse intrinsic pontine glioma. To this end, 316 features from multimodal diagnostic MRI of 38 patients were extracted. Two approaches were proposed: a conventional estimation of features inside the whole region of interest and a mean estimation inside this region of local features that are computed from fixed size patches. A feature selection pipeline was then developed. Three machine learning models for H3 mutation classification and three regression models for overall survival prediction were evaluated. Leave-one-out F1-weighted scores for SVM model combining imaging and clinical features reached 0.84, showing a good prediction of H3 mutation using structural MRI. Some encouraging results were obtained to predict overall survival but they need to be reinforced on a larger number of patients

Neural basis of interindividual variability in social perception in typically developing children and adolescents using diffusion tensor imaging

International audienceHumans show great interindividual variability in the degree they engage in social relationship. The neural basis of this variability is still poorly understood, particularly in children. In this study, we aimed to investigate the neural basis of interindividual variability in the first step of social behavior, that is social perception, in typically developing children. For that purpose, we first used eye-tracking to objectively measure eye-gaze processing during passive visualization of social movie clips in 24 children and adolescents (10.5 ± 2.9 y). Secondly, we correlated eye-tracking data with measures of fractional anisotropy, an index of white matter microstructure, obtained using diffusion tensor imaging MRI. The results showed a large interindividual variability in the number of fixations to the eyes of characters during visualization of social scenes. In addition, whole-brain analysis showed a significant positive correlation between FA and number of fixations to the eyes,mainly in the temporal part of the superior longitudinal fasciculi bilaterally, adjacent to the posterior superior temporal cortex. Our results indicate the existence of a neural signature associated with the interindividual variability in social perception in children, contributing for better understanding the neural basis of typical and atypical development of a broader social expertise

Computation of reliable textural indices from multimodal brain MRI: suggestions based on a study of patients with diffuse intrinsic pontine glioma

International audienceFew methodological studies regarding widely used textural indices robustness in MRI have been reported. In this context, this study aims to propose some rules to compute reliable textural indices from multimodal 3D brain MRI. Diagnosis and post-biopsy MR scans including T1, post-contrast T1, T2 and FLAIR images from thirty children with diffuse intrinsic pontine glioma (DIPG) were considered. The hybrid white stripe method was adapted to standardize MR intensities. Sixty textural indices were then computed for each modality in different regions of interest (ROI), including tumor and white matter (WM). Three types of intensity binning were compared : constant bin width and relative bounds; constant number of bins and relative bounds; constant number of bins and absolute bounds. The impact of the volume of the region was also tested within the WM. First, the mean Hellinger distance between patient-based intensity distributions decreased by a factor greater than 10 in WM and greater than 2.5 in gray matter after standardization. Regarding the binning strategy, the ranking of patients was highly correlated for 188/240 features when comparing with , but for only 20 when comparing with , and nine when comparing with . Furthermore, when using or texture indices reflected tumor heterogeneity as assessed visually by experts. Last, 41 features presented statistically significant differences between contralateral WM regions when ROI size slightly varies across patients, and none when using ROI of the same size. For regions with similar size, 224 features were significantly different between WM and tumor. Valuable information from texture indices can be biased by methodological choices. Recommendations are to standardize intensities in MR brain volumes, to use intensity binning with constant bin width, and to define regions with the same volumes to get reliable textural indices