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.

Prevalence and Significance of Impaired Microvascular Tissue Reperfusion Despite Macrovascular Angiographic Reperfusion (No-Reflow)

BackgroundThe relevance of impaired microvascular tissue-level reperfusion despite complete upstream macrovascular angiographic reperfusion (no-reflow) in human stroke remains controversial. We investigated the prevalence and clinical-radiological features of this phenomenon, and its associations with outcomes in three international randomized controlled thrombectomy trials with pre-specified follow-up perfusion imaging.MethodsIn a pooled analysis of the EXTEND-IA (ClinicalTrials.gov number NCT01492725), EXTEND-IA TNK (NCT02388061) and EXTEND-IA TNK Part-two (NCT03340493) trials, patients undergoing thrombectomy with final angiographic extended Thrombolysis In Cerebral Ischemia 2c-3 score for anterior circulation large vessel occlusion and 24-hour follow-up CT or MRI perfusion imaging were included. No-reflow was defined as regions of visually demonstrable persistent hypoperfusion on relative Cerebral Blood Volume or Flow maps within the infarct and verified quantitatively by >15% asymmetry compared to a mirror homologue in the absence of carotid stenosis or re-occlusion.ResultsRegions of no-reflow were identified in 33 of 130 patients (25.3%), encompassed a median of 60.2% (Interquartile range 47.8-70.7%) of the infarct volume, and involved both subcortical (n=26/33,78.8%) and cortical (n=10/33,30.3%) regions. Patients with no-reflow had a median 25.2% ([Interquartile range 16.4-32.2%],p<0.00001) relative Cerebral Blood Volume interside reduction and 19.1% (Interquartile range 3.9-28.3%,p=0.00011) relative Cerebral Blood Flow reduction but similar mean-transit-time (median -3.3%, Interquartile range -11.9-24.4%,p=0.24) within the infarcted region. Baseline characteristics were similar between patients with and without no-reflow. The presence of no-reflow was associated with hemorrhagic transformation (aOR=1.79,95%CI2.32-15.57,p=0.0002), greater infarct growth (ß=11.00,95%CI5.22-16.78,p=0.00027), reduced National Institutes of Health Stroke Score improvement at 24-hours (ß=-4.06,95%CI-6.78--1.34,p=0.004) and being dependent or dead at 90-day as assessed on the modified Rankin Scale (aOR=3.72,95%CI1.35-10.20,p=0.011) in multivariable analysis.ConclusionCerebral no-reflow in humans is common, can be detected by its characteristic perfusion imaging profile using readily available sequences in the clinical setting, and is associated with post-treatment complications and being dependent or dead. Further studies evaluating the role of no-reflow in secondary injury after angiographic reperfusion are warranted.Classification of evidenceThis study provides Class II evidence that cerebral no-reflow on CT/MRI perfusion imaging at 24-hours is associated with post-treatment complications and poor 3-month functional outcome.

Detection of local microvascular proliferation in IDH wild-type Glioblastoma using relative Cerebral Blood Volume

ABSTRACTBackgroundThe microvascular proliferation (MVP) and the microvessel area (MVA) are known as diagnostic and prognostic biomarkers for glioblastoma; nevertheless, its measurement is costly, labor-intense, and invasive. MRI perfusion biomarkers such as such as relative cerebral blood volume (rCBV) may be a feasible alternative to predict MVP and estimate MVA.PurposeThis study aims to evaluate the detection capacity of MRI markers such as rCBV to detect local microvascular proliferation in IDH wild-type glioblastoma. In addition, we aim to analyze the association between rCBV values and the microvessel area in different regions of the tumor.Study typeRetrospective study.Population and subjectsData from 71 tissue blocks belonging to 17 IDH wild-type glioblastoma patients were compiled from the Ivy GAP database.Field Strength/Sequence1.5T or 3.0T. Pregadolinium and postgadolinium-based contrast agent-enhanced T1-weighted MRI, T2- and FLAIR T2-weighted, and dynamic susceptibility contrast (DSC) T2* perfusion.AssessmentWe analyzed preoperative MRIs to establish the association between the maximum and mean relative cerebral blood volume (rCBVmax and rCBVmean) with the presence/absence of microvascular proliferation and with the microvessel area for each tumor block.Statistical testsSpearman’s correlation and Mann-Whitney test.ResultsSignificant positive correlations were found between rCBV and MVA in the analyzed tumor blocks (p<0.001). Additionally, significant differences in rCBV were found between blocks with MVP and blocks without MVP (p<0.0001).Data conclusionThe rCBV is shown as significantly different in those tissue blocks with microvascular proliferation from those blocks without it, and it is significantly correlated with microvessels area. This method allows a local detection and definition of MVP and MVA in different regions of the glioblastoma since the first diagnostic stage and in a non-invasive way.

The combined role of MR spectroscopy and perfusion imaging in preoperative differentiation between high- and low-grade gliomas

Background Brain tumors are an important health problem. The preoperative classification of gliomas by non-invasive techniques is a significant problem. Relative cerebral blood volume and spectroscopy have the ability to sample the entire lesion non-invasively. The present study aims to evaluate the combined role of dynamic susceptibility perfusion and spectroscopy in the classification of primary brain tumors. The combination of both provides overall diagnostic accuracy (100%). Relative cerebral blood volume in peritumoral region plays an important additional role in this regard. Results On the basis of histopathology, among 50 patients with brain tumors, high-grade gliomas accounted for 58%, while low-grade gliomas accounted for 42%. The relative cerebral blood volume in the tumor had the best sensitivity, specificity, and accuracy of 96.8%, 95.3%, and 96, respectively. The use of relative cerebral blood volume and choline/N-acetyl Aspartate increased diagnostic accuracy by 100%. Conclusion The combination of magnetic resonance spectroscopy and perfusion can increase sensitivity and positive predictive value to define the degree of glioma.

Inter-observer reproducibility of quantitative dynamic susceptibility contrast and diffusion MRI parameters in histogram analysis of gliomas

Background Dynamic-susceptibility contrast and diffusion-weighted imaging are promising techniques in diagnosing glioma grade. Purpose To compare the inter-observer reproducibility of multiple dynamic-susceptibility contrast and diffusion-weighted imaging parameters and to assess their potential in differentiating low- and high-grade gliomas. Material and Methods Thirty patients (16 men; mean age = 40.6 years) with low-grade (n = 13) and high-grade (n = 17) gliomas and known pathology, scanned with dynamic-susceptibility contrast and diffusion-weighted imaging were included retrospectively between March 2006 and March 2014. Three observers used three different methods to define the regions of interest: (i) circles at maximum perfusion and minimum apparent diffusion coefficient; (ii) freeform 2D encompassing the tumor at largest cross-section only; (iii) freeform 3D on all cross-sections. The dynamic-susceptibility contrast curve was analyzed voxelwise: maximum contrast enhancement; time-to-peak; wash-in rate; wash-out rate; and relative cerebral blood volume. The mean was calculated for all regions of interest. For 2D and 3D methods, histogram analysis yielded additional statistics: the minimum and maximum 5% and 10% pixel values of the tumor (min5%, min10%, max5%, max10%). Intraclass correlations coefficients (ICC) were calculated between observers. Low- and high-grade tumors were compared with independent t-tests or Mann–Whitney tests. Results ICCs were highest for 3D freeform (ICC = 0.836–0.986) followed by 2D freeform (ICC = 0.854–0.974) and circular regions of interest (0.141–0.641). High ICC and significant discrimination between low- and high-grade gliomas was found for the following optimized parameters: apparent diffusion coefficient ( P < 0.001; ICC = 0.641; mean; circle); time-to-peak ( P = 0.015; ICC = 0.986; mean; 3D); wash-in rate ( P = 0.004; ICC = 0.826; min10%; 3D); wash-out rate ( P < 0.001; ICC = 0.860; min10%; 2D); and relative cerebral blood volume ( P ≤ 0.001; ICC = 0.961; mean; 3D). Conclusion Dynamic-susceptibility contrast perfusion parameters relative cerebral blood volume and time-to-peak yielded high inter-observer reproducibility and significant glioma grade differentiation for the means of 2D and 3D freeform regions of interest. Choosing a freeform 2D method optimizes observer agreement and differentiation in clinical practice, while a freeform 3D method provides no additional benefit.