Evaluating automated longitudinal tumor measurements for glioblastoma response assessment.

Automated tumor segmentation tools for glioblastoma show promising performance. To apply these tools for automated response assessment, longitudinal segmentation, and tumor measurement, consistency is critical. This study aimed to determine whether BraTumIA and HD-GLIO are suited for this task. We evaluated two segmentation tools with respect to automated response assessment on the single-center retrospective LUMIERE dataset with 80 patients and a total of 502 post-operative time points. Volumetry and automated bi-dimensional measurements were compared with expert measurements following the Response Assessment in Neuro-Oncology (RANO) guidelines. The longitudinal trend agreement between the expert and methods was evaluated, and the RANO progression thresholds were tested against the expert-derived time-to-progression (TTP). The TTP and overall survival (OS) correlation was used to check the progression thresholds. We evaluated the automated detection and influence of non-measurable lesions. The tumor volume trend agreement calculated between segmentation volumes and the expert bi-dimensional measurements was high (HD-GLIO: 81.1%, BraTumIA: 79.7%). BraTumIA achieved the closest match to the expert TTP using the recommended RANO progression threshold. HD-GLIO-derived tumor volumes reached the highest correlation between TTP and OS (0.55). Both tools failed at an accurate lesion count across time. Manual false-positive removal and restricting to a maximum number of measurable lesions had no beneficial effect. Expert supervision and manual corrections are still necessary when applying the tested automated segmentation tools for automated response assessment. The longitudinal consistency of current segmentation tools needs further improvement. Validation of volumetric and bi-dimensional progression thresholds with multi-center studies is required to move toward volumetry-based response assessment.

The LUMIERE dataset: Longitudinal Glioblastoma MRI with expert RANO evaluation.

Publicly available Glioblastoma (GBM) datasets predominantly include pre-operative Magnetic Resonance Imaging (MRI) or contain few follow-up images for each patient. Access to fully longitudinal datasets is critical to advance the refinement of treatment response assessment. We release a single-center longitudinal GBM MRI dataset with expert ratings of selected follow-up studies according to the response assessment in neuro-oncology criteria (RANO). The expert rating includes details about the rationale of the ratings. For a subset of patients, we provide pathology information regarding methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter status and isocitrate dehydrogenase 1 (IDH1), as well as the overall survival time. The data includes T1-weighted pre- and post-contrast, T2-weighted, and fluid-attenuated inversion recovery (FLAIR) MRI. Segmentations from state-of-the-art automated segmentation tools, as well as radiomic features, complement the data. Possible applications of this dataset are radiomics research, the development and validation of automated segmentation methods, and studies on response assessment. This collection includes MRI data of 91 GBM patients with a total of 638 study dates and 2487 images.

Radiomics for glioblastoma survival analysis in pre-operative MRI: exploring feature robustness, class boundaries, and machine learning techniques.

BACKGROUND: This study aims to identify robust radiomic features for Magnetic Resonance Imaging (MRI), assess feature selection and machine learning methods for overall survival classification of Glioblastoma multiforme patients, and to robustify models trained on single-center data when applied to multi-center data. METHODS: Tumor regions were automatically segmented on MRI data, and 8327 radiomic features extracted from these regions. Single-center data was perturbed to assess radiomic feature robustness, with over 16 million tests of typical perturbations. Robust features were selected based on the Intraclass Correlation Coefficient to measure agreement across perturbations. Feature selectors and machine learning methods were compared to classify overall survival. Models trained on single-center data (63 patients) were tested on multi-center data (76 patients). Priors using feature robustness and clinical knowledge were evaluated. RESULTS: We observed a very large performance drop when applying models trained on single-center on unseen multi-center data, e.g. a decrease of the area under the receiver operating curve (AUC) of 0.56 for the overall survival classification boundary at 1 year. By using robust features alongside priors for two overall survival classes, the AUC drop could be reduced by 21.2%. In contrast, sensitivity was 12.19% lower when applying a prior. CONCLUSIONS: Our experiments show that it is possible to attain improved levels of robustness and accuracy when models need to be applied to unseen multi-center data. The performance on multi-center data of models trained on single-center data can be increased by using robust features and introducing prior knowledge. For successful model robustification, tailoring perturbations for robustness testing to the target dataset is key.

Fully automated brain resection cavity delineation for radiation target volume definition in glioblastoma patients using deep learning.

BACKGROUND: Automated brain tumor segmentation methods are computational algorithms that yield tumor delineation from, in this case, multimodal magnetic resonance imaging (MRI). We present an automated segmentation method and its results for resection cavity (RC) in glioblastoma multiforme (GBM) patients using deep learning (DL) technologies. METHODS: Post-operative, T1w with and without contrast, T2w and fluid attenuated inversion recovery MRI studies of 30 GBM patients were included. Three radiation oncologists manually delineated the RC to obtain a reference segmentation. We developed a DL cavity segmentation method, which utilizes all four MRI sequences and the reference segmentation to learn to perform RC delineations. We evaluated the segmentation method in terms of Dice coefficient (DC) and estimated volume measurements. RESULTS: Median DC of the three radiation oncologist were 0.85 (interquartile range [IQR]: 0.08), 0.84 (IQR: 0.07), and 0.86 (IQR: 0.07). The results of the automatic segmentation compared to the three different raters were 0.83 (IQR: 0.14), 0.81 (IQR: 0.12), and 0.81 (IQR: 0.13) which was significantly lower compared to the DC among raters (chi-square = 11.63, p = 0.04). We did not detect a statistically significant difference of the measured RC volumes for the different raters and the automated method (Kruskal-Wallis test: chi-square = 1.46, p = 0.69). The main sources of error were due to signal inhomogeneity and similar intensity patterns between cavity and brain tissues. CONCLUSIONS: The proposed DL approach yields promising results for automated RC segmentation in this proof of concept study. Compared to human experts, the DC are still subpar.

Exploratory Analysis of Qualitative MR Imaging Features for the Differentiation of Glioblastoma and Brain Metastases.

OBJECTIVES: To identify qualitative VASARI (Visually AcceSIble Rembrandt Images) Magnetic Resonance (MR) Imaging features for differentiation of glioblastoma (GBM) and brain metastasis (BM) of different primary tumors. MATERIALS AND METHODS: T1-weighted pre- and post-contrast, T2-weighted, and T2-weighted, fluid attenuated inversion recovery (FLAIR) MR images of a total of 239 lesions from 109 patients with either GBM or BM (breast cancer, non-small cell (NSCLC) adenocarcinoma, NSCLC squamous cell carcinoma, small-cell lung cancer (SCLC)) were included. A set of adapted, qualitative VASARI MR features describing tumor appearance and location was scored (binary; 1 = presence of feature, 0 = absence of feature). Exploratory data analysis was performed on binary scores using a combination of descriptive statistics (proportions with 95% binomial confidence intervals), unsupervised methods and supervised methods including multivariate feature ranking using either repeated fitting or recursive feature elimination with Support Vector Machines (SVMs). RESULTS: GBMs were found to involve all lobes of the cerebrum with a fronto-occipital gradient, often affected the corpus callosum (32.4%, 95% CI 19.1-49.2), and showed a strong preference for the right hemisphere (79.4%, 95% CI 63.2-89.7). BMs occurred most frequently in the frontal lobe (35.1%, 95% CI 28.9-41.9) and cerebellum (28.3%, 95% CI 22.6-34.8). The appearance of GBMs was characterized by preference for well-defined non-enhancing tumor margin (100%, 89.8-100), ependymal extension (52.9%, 36.7-68.5) and substantially less enhancing foci than BMs (44.1%, 28.9-60.6 vs. 75.1%, 68.8-80.5). Unsupervised and supervised analyses showed that GBMs are distinctively different from BMs and that this difference is driven by definition of non-enhancing tumor margin, ependymal extension and features describing laterality. Differentiation of histological subtypes of BMs was driven by the presence of well-defined enhancing and non-enhancing tumor margins and localization in the vision center. SVM models with optimal hyperparameters led to weighted F1-score of 0.865 for differentiation of GBMs from BMs and weighted F1-score of 0.326 for differentiation of BM subtypes. CONCLUSION: VASARI MR imaging features related to definition of non-enhancing margin, ependymal extension, and tumor localization may serve as potential imaging biomarkers to differentiate GBMs from BMs.

Divide and Conquer: Stratifying Training Data by Tumor Grade Improves Deep Learning-Based Brain Tumor Segmentation.

It is a general assumption in deep learning that more training data leads to better performance, and that models will learn to generalize well across heterogeneous input data as long as that variety is represented in the training set. Segmentation of brain tumors is a well-investigated topic in medical image computing, owing primarily to the availability of a large publicly-available dataset arising from the long-running yearly Multimodal Brain Tumor Segmentation (BraTS) challenge. Research efforts and publications addressing this dataset focus predominantly on technical improvements of model architectures and less on properties of the underlying data. Using the dataset and the method ranked third in the BraTS 2018 challenge, we performed experiments to examine the impact of tumor type on segmentation performance. We propose to stratify the training dataset into high-grade glioma (HGG) and low-grade glioma (LGG) subjects and train two separate models. Although we observed only minor gains in overall mean dice scores by this stratification, examining case-wise rankings of individual subjects revealed statistically significant improvements. Compared to a baseline model trained on both HGG and LGG cases, two separately trained models led to better performance in 64.9% of cases (p < 0.0001) for the tumor core. An analysis of subjects which did not profit from stratified training revealed that cases were missegmented which had poor image quality, or which presented clinically particularly challenging cases (e.g., underrepresented subtypes such as IDH1-mutant tumors), underlining the importance of such latent variables in the context of tumor segmentation. In summary, we found that segmentation models trained on the BraTS 2018 dataset, stratified according to tumor type, lead to a significant increase in segmentation performance. Furthermore, we demonstrated that this gain in segmentation performance is evident in the case-wise ranking of individual subjects but not in summary statistics. We conclude that it may be useful to consider the segmentation of brain tumors of different types or grades as separate tasks, rather than developing one tool to segment them all. Consequently, making this information available for the test data should be considered, potentially leading to a more clinically relevant BraTS competition.

Analysis of metabolic abnormalities in high-grade glioma using MRSI and convex NMF.

Clinical use of MRSI is limited by the level of experience required to properly translate MRSI examinations into relevant clinical information. To solve this, several methods have been proposed to automatically recognize a predefined set of reference metabolic patterns. Given the variety of metabolic patterns seen in glioma patients, the decision on the optimal number of patterns that need to be used to describe the data is not trivial. In this paper, we propose a novel framework to (1) separate healthy from abnormal metabolic patterns and (2) retrieve an optimal number of reference patterns describing the most important types of abnormality. Using 41 MRSI examinations (1.5 T, PRESS, TE 135 ms) from 22 glioma patients, four different patterns describing different types of abnormality were detected: edema, healthy without Glx, active tumor and necrosis. The identified patterns were then evaluated on 17 MRSI examinations from nine different glioma patients. The results were compared against BraTumIA, an automatic segmentation method trained to identify different tumor compartments on structural MRI data. Finally, the ability to predict future contrast enhancement using the proposed approach was also evaluated.

On the relation between MR spectroscopy features and the distance to MRI-visible solid tumor in GBM patients.

PURPOSE: To improve the detection of peritumoral changes in GBM patients by exploring the relation between MRSI information and the distance to the solid tumor volume (STV) defined using structural MRI (sMRI). METHODS: Twenty-three MRSI studies (PRESS, TE 135 ms) acquired from different patients with untreated GBM were used in this study. For each MRSI examination, the STV was identified by segmenting the corresponding sMRI images using BraTumIA, an automatic segmentation method. The relation between different metabolite ratios and the distance to STV was analyzed. A regression forest was trained to predict the distance from each voxel to STV based on 14 metabolite ratios. Then, the trained model was used to determine the expected distance to tumor (EDT) for each voxel of the MRSI test data. EDT maps were compared against sMRI segmentation. RESULTS: The features showing abnormal values at the longest distances to the tumor were: %NAA, Glx/NAA, Cho/NAA, and Cho/Cr. These four features were also the most important for the prediction of the distances to STV. Each EDT value was associated with a specific metabolic pattern, ranging from normal brain tissue to actively proliferating tumor and necrosis. Low EDT values were highly associated with malignant features such as elevated Cho/NAA and Cho/Cr. CONCLUSION: The proposed method enables the automatic detection of metabolic patterns associated with different distances to the STV border and may assist tumor delineation of infiltrative brain tumors such as GBM.

Automatic estimation of extent of resection and residual tumor volume of patients with glioblastoma.

OBJECTIVE In the treatment of glioblastoma, residual tumor burden is the only prognostic factor that can be actively influenced by therapy. Therefore, an accurate, reproducible, and objective measurement of residual tumor burden is necessary. This study aimed to evaluate the use of a fully automatic segmentation method-brain tumor image analysis (BraTumIA)-for estimating the extent of resection (EOR) and residual tumor volume (RTV) of contrast-enhancing tumor after surgery. METHODS The imaging data of 19 patients who underwent primary resection of histologically confirmed supratentorial glioblastoma were retrospectively reviewed. Contrast-enhancing tumors apparent on structural preoperative and immediate postoperative MR imaging in this patient cohort were segmented by 4 different raters and the automatic segmentation BraTumIA software. The manual and automatic results were quantitatively compared. RESULTS First, the interrater variabilities in the estimates of EOR and RTV were assessed for all human raters. Interrater agreement in terms of the coefficient of concordance (W) was higher for RTV (W = 0.812; p < 0.001) than for EOR (W = 0.775; p < 0.001). Second, the volumetric estimates of BraTumIA for all 19 patients were compared with the estimates of the human raters, which showed that for both EOR (W = 0.713; p < 0.001) and RTV (W = 0.693; p < 0.001) the estimates of BraTumIA were generally located close to or between the estimates of the human raters. No statistically significant differences were detected between the manual and automatic estimates. BraTumIA showed a tendency to overestimate contrast-enhancing tumors, leading to moderate agreement with expert raters with respect to the literature-based, survival-relevant threshold values for EOR. CONCLUSIONS BraTumIA can generate volumetric estimates of EOR and RTV, in a fully automatic fashion, which are comparable to the estimates of human experts. However, automated analysis showed a tendency to overestimate the volume of a contrast-enhancing tumor, whereas manual analysis is prone to subjectivity, thereby causing considerable interrater variability.

Fully Automated Enhanced Tumor Compartmentalization: Man vs. Machine Reloaded.

OBJECTIVE: Comparison of a fully-automated segmentation method that uses compartmental volume information to a semi-automatic user-guided and FDA-approved segmentation technique. METHODS: Nineteen patients with a recently diagnosed and histologically confirmed glioblastoma (GBM) were included and MR images were acquired with a 1.5 T MR scanner. Manual segmentation for volumetric analyses was performed using the open source software 3D Slicer version 4.2.2.3 (www.slicer.org). Semi-automatic segmentation was done by four independent neurosurgeons and neuroradiologists using the computer-assisted segmentation tool SmartBrush® (referred to as SB), a semi-automatic user-guided and FDA-approved tumor-outlining program that uses contour expansion. Fully automatic segmentations were performed with the Brain Tumor Image Analysis (BraTumIA, referred to as BT) software. We compared manual (ground truth, referred to as GT), computer-assisted (SB) and fully-automated (BT) segmentations with regard to: (1) products of two maximum diameters for 2D measurements, (2) the Dice coefficient, (3) the positive predictive value, (4) the sensitivity and (5) the volume error. RESULTS: Segmentations by the four expert raters resulted in a mean Dice coefficient between 0.72 and 0.77 using SB. BT achieved a mean Dice coefficient of 0.68. Significant differences were found for intermodal (BT vs. SB) and for intramodal (four SB expert raters) performances. The BT and SB segmentations of the contrast-enhancing volumes achieved a high correlation with the GT. Pearson correlation was 0.8 for BT; however, there were a few discrepancies between raters (BT and SB 1 only). Additional non-enhancing tumor tissue extending the SB volumes was found with BT in 16/19 cases. The clinically motivated sum of products of diameters measure (SPD) revealed neither significant intermodal nor intramodal variations. The analysis time for the four expert raters was faster (1 minute and 47 seconds to 3 minutes and 39 seconds) than with BT (5 minutes). CONCLUSION: BT and SB provide comparable segmentation results in a clinical setting. SB provided similar SPD measures to BT and GT, but differed in the volume analysis in one of the four clinical raters. A major strength of BT may its independence from human interactions, it can thus be employed to handle large datasets and to associate tumor volumes with clinical and/or molecular datasets ("-omics") as well as for clinical analyses of brain tumor compartment volumes as baseline outcome parameters. Due to its multi-compartment segmentation it may provide information about GBM subcompartment compositions that may be subjected to clinical studies to investigate the delineation of the target volumes for adjuvant therapies in the future.

Adult anaplastic pilocytic astrocytoma - a diagnostic challenge? A case series and literature review.

INTRODUCTION: Anaplastic pilocytic astrocytoma (APA) is an exceptionally rare type of high-grade glioma in adults. Establishing histopathological diagnosis is challenging and its clinical and radiological appearance insidious. By this case series and first literature review we investigated the various clinical, neuroradiological, and histopathological features of APA in adults. METHODS: An in hospital screening of the database from the Institute of Pathology was conducted to identify cases of APA. Further, we performed a literature review in PubMed using the keywords "anaplastic/malignant/atypical AND pilocytic astrocytoma" and "anaplastic astrocytoma/glioblastoma AND Rosenthal fibers" and summarized the current knowledge about APA in adults. RESULTS: Over the last decade we were able to identify 3 adult patients with APA in our hospital. According to the pertinent literature, the prognosis of APA in adults (documented survival of up to 10 years) appears to be better than in other high-grade gliomas. Few cases were associated with neurofibromatosis type 1, which seems to predispose for development of APA. Although molecular genetics is still of limited value for differentiation of APA from other high-grade glioma, advanced neuroimaging techniques such as magnetic resonance perfusion imaging and spectroscopy allow improved differential work-up. In particular, APA in adults has the ability to mimic various neurological diseases such as tumefactive demyelinating lesions, low-, or high-grade gliomas. CONCLUSIONS: Although currently not explicitly recognized as a distinct clinico-pathologic entity it seems that adult APA behaves differently from conventional high-grade glioma and should be included in differential diagnostics to enable adequate patient care. However, further studies are needed to better understand this extremely rare disease.

Automatic quality control in clinical (1)H MRSI of brain cancer.

MRSI grids frequently show spectra with poor quality, mainly because of the high sensitivity of MRS to field inhomogeneities. These poor quality spectra are prone to quantification and/or interpretation errors that can have a significant impact on the clinical use of spectroscopic data. Therefore, quality control of the spectra should always precede their clinical use. When performed manually, quality assessment of MRSI spectra is not only a tedious and time-consuming task, but is also affected by human subjectivity. Consequently, automatic, fast and reliable methods for spectral quality assessment are of utmost interest. In this article, we present a new random forest-based method for automatic quality assessment of (1)H MRSI brain spectra, which uses a new set of MRS signal features. The random forest classifier was trained on spectra from 40 MRSI grids that were classified as acceptable or non-acceptable by two expert spectroscopists. To account for the effects of intra-rater reliability, each spectrum was rated for quality three times by each rater. The automatic method classified these spectra with an area under the curve (AUC) of 0.976. Furthermore, in the subset of spectra containing only the cases that were classified every time in the same way by the spectroscopists, an AUC of 0.998 was obtained. Feature importance for the classification was also evaluated. Frequency domain skewness and kurtosis, as well as time domain signal-to-noise ratios (SNRs) in the ranges 50-75 ms and 75-100 ms, were the most important features. Given that the method is able to assess a whole MRSI grid faster than a spectroscopist (approximately 3 s versus approximately 3 min), and without loss of accuracy (agreement between classifier trained with just one session and any of the other labelling sessions, 89.88%; agreement between any two labelling sessions, 89.03%), the authors suggest its implementation in the clinical routine. The method presented in this article was implemented in jMRUI's SpectrIm plugin.

Clinical Evaluation of a Fully-automatic Segmentation Method for Longitudinal Brain Tumor Volumetry.

Information about the size of a tumor and its temporal evolution is needed for diagnosis as well as treatment of brain tumor patients. The aim of the study was to investigate the potential of a fully-automatic segmentation method, called BraTumIA, for longitudinal brain tumor volumetry by comparing the automatically estimated volumes with ground truth data acquired via manual segmentation. Longitudinal Magnetic Resonance (MR) Imaging data of 14 patients with newly diagnosed glioblastoma encompassing 64 MR acquisitions, ranging from preoperative up to 12 month follow-up images, was analysed. Manual segmentation was performed by two human raters. Strong correlations (R = 0.83-0.96, p < 0.001) were observed between volumetric estimates of BraTumIA and of each of the human raters for the contrast-enhancing (CET) and non-enhancing T2-hyperintense tumor compartments (NCE-T2). A quantitative analysis of the inter-rater disagreement showed that the disagreement between BraTumIA and each of the human raters was comparable to the disagreement between the human raters. In summary, BraTumIA generated volumetric trend curves of contrast-enhancing and non-enhancing T2-hyperintense tumor compartments comparable to estimates of human raters. These findings suggest the potential of automated longitudinal tumor segmentation to substitute manual volumetric follow-up of contrast-enhancing and non-enhancing T2-hyperintense tumor compartments.

A model of cerebral aspergillosis in non-immunosuppressed nursing rats.

Central nervous system aspergillosis is an often fatal complication of invasive Aspergillus infection. Relevant disease models are needed to study the pathophysiology of cerebral aspergillosis and to develop novel therapeutic approaches. This study presents a model of central nervous system aspergillosis that mimics important aspects of human disease. Eleven-day-old non-immunosuppressed male Wistar rats were infected by an intracisternal injection of 10 mul of a conidial suspension of Aspergillus fumigatus. An inoculum of 7.18 log(10) colony-forming units (CFU) consistently produced cerebral infection and resulted in death of all animals (n = 25) within 3-10 days. Median survival time was 3 days. Histomorphologically, all animals developed intracerebral abscesses (2-26 per brain) containing abundant fungal hyphae and neutrophils. Fungal culture of cortical homogenates yielded maximal growth on day 3 after infection (5.4 log(10) CFU/g, n = 15) that declined over time. Galactomannan concentrations in cortical homogenates, assessed as an index for hyphal burden, peaked on days 3-5. Fungal infection spread to peripheral organs in 83% of animals. Fungal burden in lung, liver, spleen and kidney was two orders of magnitude lower than in the brain. The successful establishment of a model of cerebral aspergillosis in a non-immunosuppressed host provides the opportunity to investigate mechanisms of disease and to develop novel treatment regimens for this commonly fatal infection.