Preoperative neurocognitive function as an independent survival prognostic marker in primary glioblastoma.

Background: Aim of the present study is to investigate whether preoperative neurocognitive status is prognostically associated with overall survival (OS) in newly diagnosed glioblastoma (GBM) patients. Methods: Ninety patients with dominant-hemisphere IDH-wild-type GBM were assessed by Mini Mental Status Exam (MMSE), Trail Making Test (TMT) A and B parts, and Control Word Association Test (COWAT) phonemic and semantic subtests. Demographics, Karnofsky Performance Scale, tumor parameters, type of surgery, and adjuvant therapy data were available for patients. Results: According to Cox proportional hazards model the neurocognitive variables of TMT B (P < .01), COWAT semantic subset (P < .05), and the MMSE (P < .01) were found significantly associated with survival prediction. From all other factors, only tumor volume and operation type (debulking vs biopsy) showed a statistical association (P < .05) with survival prediction. Kaplan Meier Long rank test showed statistical significance (P < .01) between unimpaired and impaired groups for TMT B, with median survival for the unimpaired group 26 months and 10 months for the impaired group, for COWAT semantic (P < .01) with median survival 23 months and 12 months, respectively and for MMSE (P < .01) with medial survival 19 and 12 months respectively. Conclusions: Our study demonstrates that neurocognitive status at baseline-prior to treatment-is an independent prognostic factor for OS in wild-type GBM patients, adding another prognostic tool to assist physicians in selecting the best treatment plan.

Association between preoperative neurocognitive status and IDH1 mutation status in high-grade gliomas.

Background: High-grade glioma (HGG) patients present with variable impairment in neurocognitive function (NCF). Based on that, isocitrate dehydrogenase 1 (IDH1) wild-type HGGs are more aggressive than IDH1 mutant-type ones, we hypothesized that patients with IDH1 wild-type HGG would exhibit more severe NCF deficits than their IDH1 mutant counterparts. Methods: NCF was assessed by Mini Mental Status Exam (MMSE), Trail Making Test (TMT), Digit Span (DS), and Controlled Word Association Test (COWAT) tests in 147 HGG patients preoperatively. Results: Analyses between IDH1 groups revealed a significant difference on MMSE concentration component (p ≤ .01), DS (p ≤ .01), TMTB (p ≤ .01), and COWAT (p ≤ .01) scores, with the IDH1 wild group performing worse than the IDH1 mutant one. Age and tumor volume were inversely correlated with MMSE concentration component (r = -4.78, p < .01), and with MMSE concentration (r = -.401, p < .01), TMTB (r = -.328, p < .01), and COWAT phonemic scores (r = -.599, p < .01), respectively, but only for the IDH1 wild-type group. Analyses between age-matched subsamples of IDH1 groups revealed no age effect on NCF. Tumor grade showed nonsignificance on NCF (p > .05) between the 2 IDH1 mutation subgroups of grade IV tumor patients. On the contrary, grade III group showed a significant difference in TMTB (p < .01) and DS backwards (p < .01) between IDH1 subgroups, with the mutant one outperforming the IDH1 wild one. Conclusions: Our findings indicate that IDH1 wild-type HGG patients present greater NCF impairment, in executive functions particularly, compared to IDH1 mutant ones, suggesting that tumor growth kinetics may play a more profound role than other tumor and demographic parameters in clinical NCF of HGG patients.

Local detection of microvessels in IDH-wildtype glioblastoma using relative cerebral blood volume: an imaging marker useful for astrocytoma grade 4 classification.

BACKGROUND: The microvessels area (MVA), derived from microvascular proliferation, is a biomarker useful for high-grade glioma classification. Nevertheless, its measurement is costly, labor-intense, and invasive. Finding radiologic correlations with MVA could provide a complementary non-invasive approach without an extra cost and labor intensity and from the first stage. This study aims to correlate imaging markers, such as relative cerebral blood volume (rCBV), and local MVA in IDH-wildtype glioblastoma, and to propose this imaging marker as useful for astrocytoma grade 4 classification. METHODS: Data from 73 tissue blocks belonging to 17 IDH-wildtype glioblastomas and 7 blocks from 2 IDH-mutant astrocytomas were compiled from the Ivy GAP database. MRI processing and rCBV quantification were carried out using ONCOhabitats methodology. Histologic and MRI co-registration was done manually with experts' supervision, achieving an accuracy of 88.8% of overlay. Spearman's correlation was used to analyze the association between rCBV and microvessel area. Mann-Whitney test was used to study differences of rCBV between blocks with presence or absence of microvessels in IDH-wildtype glioblastoma, as well as to find differences with IDH-mutant astrocytoma samples. RESULTS: Significant positive correlations were found between rCBV and microvessel area in the IDH-wildtype blocks (p < 0.001), as well as significant differences in rCBV were found between blocks with microvascular proliferation and blocks without it (p < 0.0001). In addition, significant differences in rCBV were found between IDH-wildtype glioblastoma and IDH-mutant astrocytoma samples, being 2-2.5 times higher rCBV values in IDH-wildtype glioblastoma samples. CONCLUSIONS: The proposed rCBV marker, calculated from diagnostic MRIs, can detect in IDH-wildtype glioblastoma those regions with microvessels from those without it, and it is significantly correlated with local microvessels area. In addition, the proposed rCBV marker can differentiate the IDH mutation status, providing a complementary non-invasive method for high-grade glioma classification.

Glioblastoma versus solitary brain metastasis: MRI differentiation using the edema perfusion gradient.

BACKGROUND AND PURPOSE: Differentiation between glioblastoma multiforme (GBM) and solitary brain metastasis (SBM) remains a challenge in neuroradiology with up to 40% of the cases to be incorrectly classified using only conventional MRI. The inclusion of perfusion MRI parameters provides characteristic features that could support the distinction of these pathological entities. On these grounds, we aim to use a perfusion gradient in the peritumoral edema. METHODS: Twenty-four patients with GBM or an SBM underwent conventional and perfusion MR imaging sequences before tumors' surgical resection. After postprocessing of the images, quantification of dynamic susceptibility contrast (DSC) perfusion parameters was made. Three concentric areas around the tumor were defined in each case. The monocompartimental and pharmacokinetics parameters of perfusion MRI were analyzed in both series. RESULTS: DSC perfusion MRI models can provide useful information for the differentiation between GBM and SBM. It can be observed that most of the perfusion MR parameters (relative cerebral blood volume, relative cerebral blood flow, relative Ktrans, and relative volume fraction of the interstitial space) clearly show higher gradient for GBM than SBM. GBM also demonstrates higher heterogeneity in the peritumoral edema and most of the perfusion parameters demonstrate higher gradients in the area closest to the enhancing tumor. CONCLUSION: Our results show that there is a difference in the perfusion parameters of the edema between GBM and SBM demonstrating a vascularization gradient. This could help not only for the diagnosis, but also for planning surgical or radiotherapy treatments delineating the real extension of the tumor.

Differential effect of vascularity between long- and short-term survivors with IDH1/2 wild-type glioblastoma.

INTRODUCTION: IDH1/2 wt glioblastoma (GB) represents the most lethal tumour of the central nervous system. Tumour vascularity is associated with overall survival (OS), and the clinical relevance of vascular markers, such as rCBV, has already been validated. Nevertheless, molecular and clinical factors may have different influences on the beneficial effect of a favourable vascular signature. PURPOSE: To evaluate the association between the rCBV and OS of IDH1/2 wt GB patients for long-term survivors (LTSs) and short-term survivors (STSs). Given that initial high rCBV may affect the patient's OS in follow-up stages, we will assess whether a moderate vascularity is beneficial for OS in both groups of patients. MATERIALS AND METHODS: Ninety-nine IDH1/2 wt GB patients were divided into LTSs (OS ≥ 400 days) and STSs (OS < 400 days). Mann-Whitney and Fisher, uni- and multiparametric Cox, Aalen's additive regression and Kaplan-Meier tests were carried out. Tumour vascularity was represented by the mean rCBV of the high angiogenic tumour (HAT) habitat computed through the haemodynamic tissue signature methodology (available on the ONCOhabitats platform). RESULTS: For LTSs, we found a significant association between a moderate value of rCBVmean and higher OS (uni- and multiparametric Cox and Aalen's regression) (p = 0.0140, HR = 1.19; p = 0.0085, HR = 1.22) and significant stratification capability (p = 0.0343). For the STS group, no association between rCBVmean and survival was observed. Moreover, no significant differences (p > 0.05) in gender, age, resection status, chemoradiation, or MGMT methylation were observed between LTSs and STSs. CONCLUSION: We have found different prognostic and stratification effects of the vascular marker for the LTS and STS groups. We propose the use of rCBVmean at HAT as a vascular marker clinically relevant for LTSs with IDH1/2 wt GB and maybe as a potential target for randomized clinical trials focused on this group of patients.

MGMT methylation may benefit overall survival in patients with moderately vascularized glioblastomas.

OBJECTIVES: To assess the combined role of tumor vascularity, estimated from perfusion MRI, and MGMT methylation status on overall survival (OS) in patients with glioblastoma. METHODS: A multicentric international dataset including 96 patients from NCT03439332 clinical study were used to study the prognostic relationships between MGMT and perfusion markers. Relative cerebral blood volume (rCBV) in the most vascularized tumor regions was automatically obtained from preoperative MRIs using ONCOhabitats online analysis service. Cox survival regression models and stratification strategies were conducted to define a subpopulation that is particularly favored by MGMT methylation in terms of OS. RESULTS: rCBV distributions did not differ significantly (p > 0.05) in the methylated and the non-methylated subpopulations. In patients with moderately vascularized tumors (rCBV < 10.73), MGMT methylation was a positive predictive factor for OS (HR = 2.73, p = 0.003, AUC = 0.70). In patients with highly vascularized tumors (rCBV > 10.73), however, there was no significant effect of MGMT methylation (HR = 1.72, p = 0.10, AUC = 0.56). CONCLUSIONS: Our results indicate the existence of complementary prognostic information provided by MGMT methylation and rCBV. Perfusion markers could identify a subpopulation of patients who will benefit the most from MGMT methylation. Not considering this information may lead to bias in the interpretation of clinical studies. KEY POINTS: • MRI perfusion provides complementary prognostic information to MGMT methylation. • MGMT methylation improves prognosis in glioblastoma patients with moderate vascular profile. • Failure to consider these relations may lead to bias in the interpretation of clinical studies.

Higher vascularity at infiltrated peripheral edema differentiates proneural glioblastoma subtype.

BACKGROUND AND PURPOSE: Genetic classifications are crucial for understanding the heterogeneity of glioblastoma. Recently, perfusion MRI techniques have demonstrated associations molecular alterations. In this work, we investigated whether perfusion markers within infiltrated peripheral edema were associated with proneural, mesenchymal, classical and neural subtypes. MATERIALS AND METHODS: ONCOhabitats open web services were used to obtain the cerebral blood volume at the infiltrated peripheral edema for MRI studies of 50 glioblastoma patients from The Cancer Imaging Archive: TCGA-GBM. ANOVA and Kruskal-Wallis tests were carried out in order to assess the association between vascular features and the Verhaak subtypes. For assessing specific differences, Mann-Whitney U-test was conducted. Finally, the association of overall survival with molecular and vascular features was assessed using univariate and multivariate Cox models. RESULTS: ANOVA and Kruskal-Wallis tests for the maximum cerebral blood volume at the infiltrated peripheral edema between the four subclasses yielded false discovery rate corrected p-values of <0.001 and 0.02, respectively. This vascular feature was significantly higher (p = 0.0043) in proneural patients compared to the rest of the subtypes while conducting Mann-Whitney U-test. The multivariate Cox model pointed to redundant information provided by vascular features at the peripheral edema and proneural subtype when analyzing overall survival. CONCLUSIONS: Higher relative cerebral blood volume at infiltrated peripheral edema is associated with proneural glioblastoma subtype suggesting underlying vascular behavior related to molecular composition in that area.

Robust association between vascular habitats and patient prognosis in glioblastoma: An international multicenter study.

BACKGROUND: Glioblastoma (GBM) is the most aggressive primary brain tumor, characterized by a heterogeneous and abnormal vascularity. Subtypes of vascular habitats within the tumor and edema can be distinguished: high angiogenic tumor (HAT), low angiogenic tumor (LAT), infiltrated peripheral edema (IPE), and vasogenic peripheral edema (VPE). PURPOSE: To validate the association between hemodynamic markers from vascular habitats and overall survival (OS) in glioblastoma patients, considering the intercenter variability of acquisition protocols. STUDY TYPE: Multicenter retrospective study. POPULATION: In all, 184 glioblastoma patients from seven European centers participating in the NCT03439332 clinical study. FIELD STRENGTH/SEQUENCE: 1.5T (for 54 patients) or 3.0T (for 130 patients). Pregadolinium and postgadolinium-based contrast agent-enhanced T1 -weighted MRI, T2 - and FLAIR T2 -weighted, and dynamic susceptibility contrast (DSC) T2 * perfusion. ASSESSMENT: We analyzed preoperative MRIs to establish the association between the maximum relative cerebral blood volume (rCBVmax ) at each habitat with OS. Moreover, the stratification capabilities of the markers to divide patients into "vascular" groups were tested. The variability in the markers between individual centers was also assessed. STATISTICAL TESTS: Uniparametric Cox regression; Kaplan-Meier test; Mann-Whitney test. RESULTS: The rCBVmax derived from the HAT, LAT, and IPE habitats were significantly associated with patient OS (P < 0.05; hazard ratio [HR]: 1.05, 1.11, 1.28, respectively). Moreover, these markers can stratify patients into "moderate-" and "high-vascular" groups (P < 0.05). The Mann-Whitney test did not find significant differences among most of the centers in markers (HAT: P = 0.02-0.685; LAT: P = 0.010-0.769; IPE: P = 0.093-0.939; VPE: P = 0.016-1.000). DATA CONCLUSION: The rCBVmax calculated in HAT, LAT, and IPE habitats have been validated as clinically relevant prognostic biomarkers for glioblastoma patients in the pretreatment stage. This study demonstrates the robustness of the hemodynamic tissue signature (HTS) habitats to assess the GBM vascular heterogeneity and their association with patient prognosis independently of intercenter variability. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1478-1486.

ONCOhabitats: A system for glioblastoma heterogeneity assessment through MRI.

BACKGROUND: Neuroimaging analysis is currently crucial for an early assessment of glioblastoma, to help improving treatment and tumor follow-up. To this end, multiple functional and morphological MRI sequences are usually employed, requiring the development of automated tools capable to extract the relevant information from these sources. In this work we present ONCOhabitats (https://www.oncohabitats.upv.es): an online open access system for glioblastoma analysis based on MRI data. METHODS: ONCOhabitats provides two main services for untreated glioblastomas: (1) malignant tissue segmentation, and (2) vascular heterogeneity assessment of the tumor. The segmentation service implements a deep patch-wise 3D Convolutional Neural Network with residual connections. The vascular heterogeneity assessment service implements the Hemodynamic Tissue Signature (HTS) method patented in P201431289, which aims to identify habitats within the tumor with early prognostic capabilities. RESULTS: The segmentation service was validated against the BRATS 2017 reference dataset, showing comparable results with current state-of-the-art methods (whole tumor Dice segmentation: 0.89). The vascular heterogeneity assessment service was validated in a retrospective cohort of 50 patients, in a study focused on predicting patient overall survival based on the HTS habitats. Cox proportional hazard regression analysis and Kaplan-Meier survival study showed significant positive correlations (p-value <.05) between the HTS habitats and patient overall survival. ONCOhabitats system also generates radiological reports for each service, including volumetries and perfusion measurements of the different regions of the lesion. CONCLUSION: ONCOhabitats system provides open-access services for glioblastoma heterogeneity assessment, implementing consolidated state-of-the-art techniques for medical image analysis. Additionally, we also give access to the scientific community to our computational resources, offering a computational capacity of about 300 cases per day.

Multi-parametric MR Imaging Biomarkers Associated to Clinical Outcomes in Gliomas: A Systematic Review.

PURPOSE: To systematically review evidence regarding the association of multiparametric biomarkers with clinical outcomes and their capacity to explain relevant subcompartments of gliomas. MATERIALS AND METHODS: Scopus database was searched for original journal papers from January 1st, 2007 to February 20th, 2017 according to PRISMA. Four hundred forty-nine abstracts of papers were reviewed and scored independently by two out of six authors. Based on those papers we analyzed associations between biomarkers, subcompartments within the tumor lesion, and clinical outcomes. From all the articles analyzed, the twenty-seven papers with the highest scores were highlighted to represent the evidence about MR imaging biomarkers associated with clinical outcomes. Similarly, eighteen studies defining subcompartments within the tumor region were also highlighted to represent the evidence of MR imaging biomarkers. Their reports were critically appraised according to the QUADAS-2 criteria. RESULTS: It has been demonstrated that multi-parametric biomarkers are prepared for surrogating diagnosis, grading, segmentation, overall survival, progression-free survival, recurrence, molecular profiling and response to treatment in gliomas. Quantifications and radiomics features obtained from morphological exams (T1, T2, FLAIR, T1c), PWI (including DSC and DCE), diffusion (DWI, DTI) and chemical shift imaging (CSI) are the preferred MR biomarkers associated to clinical outcomes. Subcompartments relative to the peritumoral region, invasion, infiltration, proliferation, mass effect and pseudo flush, relapse compartments, gross tumor volumes, and highrisk regions have been defined to characterize the heterogeneity. For the majority of pairwise cooccurrences, we found no evidence to assert that observed co-occurrences were significantly different from their expected co-occurrences (Binomial test with False Discovery Rate correction, α=0.05). The co-occurrence among terms in the studied papers was found to be driven by their individual prevalence and trends in the literature. CONCLUSION: Combinations of MR imaging biomarkers from morphological, PWI, DWI and CSI exams have demonstrated their capability to predict clinical outcomes in different management moments of gliomas. Whereas morphologic-derived compartments have been mostly studied during the last ten years, new multi-parametric MRI approaches have also been proposed to discover specific subcompartments of the tumors. MR biomarkers from those subcompartments show the local behavior within the heterogeneous tumor and may quantify the prognosis and response to treatment of gliomas.

Improving the estimation of prognosis for glioblastoma patients by MR based hemodynamic tissue signatures.

Advanced MRI and molecular markers have been raised as crucial to improve prognostic models for patients having glioblastoma (GBM) lesions. In particular, different MR perfusion based markers describing vascular intrapatient heterogeneity have been correlated with tumor aggressiveness, and represent key information to understand tumor resistance against effective therapies of these neoplasms. Recently, hemodynamic tissue signature (HTS) markers based on MR perfusion images have been demonstrated to be useful for describing the heterogeneity of GBM at the voxel level, as well as demonstrating significant correlations with the patient's overall survival. In this work, we analyze the abilities of these markers to improve the conventional prognostic models based on clinical, morphological, and demographic features. Our results, in both the regression and classification tests, show that inclusion of the HTS markers improves the reliability of prognostic models. The HTS method is fully automatic and it is available for research use at http://www.oncohabitats.upv.es.

Glioblastoma: Vascular Habitats Detected at Preoperative Dynamic Susceptibility-weighted Contrast-enhanced Perfusion MR Imaging Predict Survival.

Purpose To determine if preoperative vascular heterogeneity of glioblastoma is predictive of overall survival of patients undergoing standard-of-care treatment by using an unsupervised multiparametric perfusion-based habitat-discovery algorithm. Materials and Methods Preoperative magnetic resonance (MR) imaging including dynamic susceptibility-weighted contrast material-enhanced perfusion studies in 50 consecutive patients with glioblastoma were retrieved. Perfusion parameters of glioblastoma were analyzed and used to automatically draw four reproducible habitats that describe the tumor vascular heterogeneity: high-angiogenic and low-angiogenic regions of the enhancing tumor, potentially tumor-infiltrated peripheral edema, and vasogenic edema. Kaplan-Meier and Cox proportional hazard analyses were conducted to assess the prognostic potential of the hemodynamic tissue signature to predict patient survival. Results Cox regression analysis yielded a significant correlation between patients' survival and maximum relative cerebral blood volume (rCBVmax) and maximum relative cerebral blood flow (rCBFmax) in high-angiogenic and low-angiogenic habitats (P < .01, false discovery rate-corrected P < .05). Moreover, rCBFmax in the potentially tumor-infiltrated peripheral edema habitat was also significantly correlated (P < .05, false discovery rate-corrected P < .05). Kaplan-Meier analysis demonstrated significant differences between the observed survival of populations divided according to the median of the rCBVmax or rCBFmax at the high-angiogenic and low-angiogenic habitats (log-rank test P < .05, false discovery rate-corrected P < .05), with an average survival increase of 230 days. Conclusion Preoperative perfusion heterogeneity contains relevant information about overall survival in patients who undergo standard-of-care treatment. The hemodynamic tissue signature method automatically describes this heterogeneity, providing a set of vascular habitats with high prognostic capabilities. © RSNA, 2018.

Automated glioblastoma segmentation based on a multiparametric structured unsupervised classification.

Automatic brain tumour segmentation has become a key component for the future of brain tumour treatment. Currently, most of brain tumour segmentation approaches arise from the supervised learning standpoint, which requires a labelled training dataset from which to infer the models of the classes. The performance of these models is directly determined by the size and quality of the training corpus, whose retrieval becomes a tedious and time-consuming task. On the other hand, unsupervised approaches avoid these limitations but often do not reach comparable results than the supervised methods. In this sense, we propose an automated unsupervised method for brain tumour segmentation based on anatomical Magnetic Resonance (MR) images. Four unsupervised classification algorithms, grouped by their structured or non-structured condition, were evaluated within our pipeline. Considering the non-structured algorithms, we evaluated K-means, Fuzzy K-means and Gaussian Mixture Model (GMM), whereas as structured classification algorithms we evaluated Gaussian Hidden Markov Random Field (GHMRF). An automated postprocess based on a statistical approach supported by tissue probability maps is proposed to automatically identify the tumour classes after the segmentations. We evaluated our brain tumour segmentation method with the public BRAin Tumor Segmentation (BRATS) 2013 Test and Leaderboard datasets. Our approach based on the GMM model improves the results obtained by most of the supervised methods evaluated with the Leaderboard set and reaches the second position in the ranking. Our variant based on the GHMRF achieves the first position in the Test ranking of the unsupervised approaches and the seventh position in the general Test ranking, which confirms the method as a viable alternative for brain tumour segmentation.