How tissue T1-variability influences DCE-MRI perfusion parameters estimation of recurrent high-grade glioma after surgery followed by radiochemotherapy.

BACKGROUND: Quantification of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) kinetic parameters (KPs) requires a determination of native tissue T1. Two approaches are adopted: (i) tissue T1-maps are acquired; and (ii) an a priori T1 value (fT1) is fixed for all patients (fT1-approach). Although it is more attractive, the fT1-approach might bias the results of KP calculations due to tissue T1 variability. PURPOSE: To quantify the tissue T1 variability of recurrent high-grade glioma (HGG) and the error in KP estimation when the fT1-approach is adopted. MATERIAL AND METHODS: We reviewed the postoperative MRI scans of 28 patients with recurrent HGG after radiochemotherapy. MRI study included T1-maps from multiple-dynamic multiple-echo imaging, DCE-MRI, and contrast enhanced T1-weighted images. KPs were calculated using T1-map and fT1-approach. RESULTS: The tissue T1 variability of recurrent HGG was relevant. The absolute error in KP estimation, as a function of the deviation of fT1 from the true value, was 8% every 100 ms. The difference between the KPs obtained with fT1-approach from fT1 values of 1300, 1390, and 1500 ms and their reference values were mostly within the 95% confidence interval (± 1.96 standard deviation). Conversely, using fT1 values of 900, 1200, 1600, and 1900 ms causes a significant error in KP estimation (P<0.05). CONCLUSION: Recurrent HGG is characterized by a substantial T1 variability. Although the fT1-approach does not account for this variability, it results in a minor effect on the KP estimations provided the fT1 value is in the range of 1300-1500 ms.

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.

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.

The Influence of Contrast-to-Noise Ratio on the Discrimination Between Cortical and Juxtacortical Lesions in Multiple Sclerosis.

OBJECTIVE: The objective of this study was to investigate the contrast-to-noise ratio (CNR) between cortical gray matter (GM) and subcortical white matter (WM) across the cortex in relation to the ability of 3-dimensional fluid attenuated inversion recovery and 3-dimensional double inversion recovery to distinguish between cortical lesions (CLs) and juxtacortical lesions (JCs). METHODS: A total of 38 multiple sclerosis patients underwent magnetic resonance imaging. Two neuroradiologists scored CLs and JCs on magnetic resonance imaging in 9 cerebral areas. Lesions were marked as nonclassifiable (NCs) when blurred WM-GM boundary leads to inaccuracy of their discrimination. The CNR between WM and GM (CNRWM-GM) was evaluated across the cortical areas. RESULTS: The CNRWM-GM varies across the cortex; the lower values were found in motor and sensorimotor areas where almost all NCs were localized. A strong negative correlation was found between CNRWM-GM and NCs. CONCLUSIONS: Discrimination between CLs and JCs is affected from the sharp visualization of the WM-GM boundary, which is directly related to CNRWM-GM.

2-Hydroxyglutarate Detection by Short Echo Time Magnetic Resonance Spectroscopy in Routine Imaging Study of Brain Glioma at 3.0 T.

OBJECTIVE: The objective of this study was to assess the effective performance of short echo time magnetic resonance spectroscopy (short TE MRS) for 2HG detection as biomarker of isocitrate dehydrogenase (IDH) status in all grade glioma (GL). METHODS: A total of 82 GL patients were prospectively investigated by short TE MRS at 3.0 T as part of a multimodal magnetic resonance imaging study protocol. Spectral analysis was performed using linear combination model. Tumor specimens were diagnosed as IDH mutant or wild type according to the 2016 World Health Organization (WHO) classification of brain tumors. Spectra were analyzed for the presence of 2HG. The performance of short TE MRS was evaluated in terms of sensitivity, specificity, and positive and negative likelihood ratio on the overall sample and on GL WHO grades II and III and glioblastoma separately. RESULTS: The specificity and sensitivity estimated on the overall sample were 88% and 77%, respectively. In GL WHO grades II and III, 100% specificity and 75% sensitivity were estimated. CONCLUSIONS: We reiterate the feasibility to identify IDH status of brain GL using short TE MRS at 3.0 T. The method can correctly detect 2HG as expression of IDH mutation in WHO grades II and III GL with a 100% specificity but a 75% sensitivity. In the evaluation of glioblastoma, short TE MRS performs poorly having a 17% false positive rate.

Intensity-modulated radiation therapy and volumetric modulated arc therapy versus conventional conformal techniques at high energy: Dose assessment and impact on second primary cancer in the out-of-field region.

The aim of this work was to estimate peripheral neutron and photon doses associated with the conventional 3D conformal radiotherapy techniques in comparison to modern ones such as Intensity modulated radiation therapy and volumetric modulated arc therapy. Assessment in terms of second cancer incidence ought to peripheral doses was also considered. For that, a dosimetric methodology proposed by the authors has been applied beyond the region where there is no CT information and, thus, treatment planning systems do not calculate and where, nonetheless, about one third of second primary cancers occurs.

Effectiveness of a high relaxivity contrast agent administered at half dose in dynamic susceptibility contrast MRI of brain gliomas.

PURPOSE: To determine whether half of the approved dose of gadobenate dimeglumine (MultiHance) is as effective as a full dose of gadoterate meglumine (Dotarem) for qualitative and quantitative cerebral blood volume (CBV) perfusion evaluation at 3T in patients with brain gliomas. MATERIALS AND METHODS: We enrolled 65 adult patients in an interindividual comparative study. Patients were randomized to one of two study arms: 33 patients received 0.1 mmol/kg body weight (bw) of gadoterate, 32 patients received 0.05 mmol/kg bw of gadobenate. The patients underwent identical examinations at 3T. Arterial input function (AIF), tissue function (TF), and the maximum tumor CBV (CBV_T) were obtained from each patient. The quality of the CBV maps were independently reviewed by two neuroradiologists blinded to the administered contrast agent. RESULTS: The administration of a half dose of gadobenate led to a roughly 40% reduction in signal drop compared to that achieved with a full dose of gadoterate (P values for AIF and TF maximum and integral were <0.01); quantitative and qualitative assessment of CBV maps revealed no difference between contrast agents (P values for CBV_T of high- and low-grade gliomas, image quality evaluation were 0.87, 0.48, >0.65, respectively) CONCLUSION: The CBV maps obtained with a half dose gadobenate (0.05 mmol/kg bw) are of comparable diagnostic quality as the corresponding images acquired with a full dose of gadoterate (0.1 mmol/kg bw). LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:500-506.

T2*-Correction in Dynamic Contrast-Enhanced Magnetic Resonance Imaging of Glioblastoma From a Half Dose of High-Relaxivity Contrast Agent.

OBJECTIVE: The aim of this study was to evaluate the arterial input function (AIF) and tissue enhancement time curve (tissue function [TF]) obtained after the administration of a half-dose gadobenate dimeglumine (0.05-mmol/kg body weight [bw]) compared with a full dose (0.1-mmol/kg bw) of a standard-relaxivity contrast agent. METHODS: We enrolled 40 adult patients with glioblastoma in an interindividual comparative study. Patients were randomized to 1 of the 2 study arms: 20 patients received 0.1-mmol/kg bw of gadoterate; the other 20 patients received 0.05-mmol/kg bw of gadobenate. The patients underwent dynamic contrast-enhanced magnetic resonance imaging examinations. Arterial input function, tissue enhancement time curve (TF), tumor transfer rate (K), and tumor extracellular-extravascular volume fraction (Ve) were calculated for each patients. Averaged AIF, TF, K, and Ve of both groups were compared. RESULTS: A significant difference (P = 0.001) between the peak AIF values obtained with the 2 different gadolinium-based contrast agents was observed. No difference was found between TFs (P = 0.35). Comparison on kinetic parameters revealed a significant difference for K (P = 0.047) but no difference for Ve (P = 0.74). CONCLUSIONS: The administration of half dose of the high-relaxivity contrast agent gadobenate is effective in improving AIF by reducing T2*-shortening effects on dynamic contrast-enhanced magnetic resonance imaging and ensuring at the same time an adequate signal enhancement in tumor tissue. The use of 0.05-mmol/kg bw of gadobenate not only is feasible but also can lead to a better estimation of K based on a more accurate AIF assessment.

Quality assurance multicenter comparison of different MR scanners for quantitative diffusion-weighted imaging.

PURPOSE: To propose a magnetic resonance imaging (MRI) quality assurance procedure that can be used for multicenter comparison of different MR scanners for quantitative diffusion-weighted imaging (DWI). MATERIALS AND METHODS: Twenty-six centers (35 MR scanners with field strengths: 1T, 1.5T, and 3T) were enrolled in the study. Two different DWI acquisition series (b-value ranges 0-1000 and 0-3000 s/mm(2) , respectively) were performed for each MR scanner. All DWI acquisitions were performed by using a cylindrical doped water phantom. Mean apparent diffusion coefficient (ADC) values as well as ADC values along each of the three main orthogonal directions of the diffusion gradients (x, y, and z) were calculated. Short-term repeatability of ADC measurement was evaluated for 26 MR scanners. RESULTS: A good agreement was found between the nominal and measured mean ADC over all the centers. More than 80% of mean ADC measurements were within 5% from the nominal value, and the highest deviation and overall standard deviation were 9.3% and 3.5%, respectively. Short-term repeatability of ADC measurement was found <2.5% for all MR scanners. CONCLUSION: A specific and widely accepted protocol for quality controls in DWI is still lacking. The DWI quality assurance protocol proposed in this study can be applied in order to assess the reliability of DWI-derived indices before tackling single- as well as multicenter studies.

In vivo and ex vivo magnetic resonance spectroscopy in the characterization of hemangioblastoma cyst fluid.

Peritumoral cyst formation is commonly associated with hemangioblastomas of the central nervous system. Results of a proteomic profiling of hemangioblastoma cyst fluid suggested that cyst formation, whether intratumoral or peritumoral, is a consequence of vascular leakage because protein profiles of cyst fluid and blood serum were similar. To the best of our knowledge, this is the first report of in vivo and ex vivo magnetic resonance spectroscopy analyses of hemangioblastoma cyst fluid that investigates on the mechanism leading to peritumoral cyst formation.

Lipid and macromolecules quantitation in differentiating glioblastoma from solitary metastasis: a short-echo time single-voxel magnetic resonance spectroscopy study at 3 T.

OBJECTIVE: The differentiation between solitary metastasis (MET) and glioblastoma (GBM) is difficult using only magnetic resonance imaging techniques. Magnetic resonance spectroscopy (MRS) lipid signal indicates cellular necrosis both in GBMs and METs. The purpose of this prospective study was to determine whether a class of lipids and/or macromolecules (MMs), able to efficiently discriminate between these two types of lesions, exists. METHODS: Forty-one patients with solitary brain tumor (23 GBMs and 18 METs) underwent magnetic resonance imaging and single-voxel MRS. Short-echo time point resolved spectroscopy sequence acquisition with water suppression technique was used. Spectra were analyzed using LCModel. Absolute quantification was performed with "water-scaling" procedure. The analysis was focused on sums of lipid and macromolecular (LM) components at 0.9 and 1.3 ppm. RESULTS: The LM13 absolute concentration was statistically different (P < 0.0001) between GBMs and METs. With a cutoff of 81 mM in LM13 absolute concentration, METs and GBMs can be distinguished with a 78% of specificity and an 81% of sensitivity. The presence of the MM12 peak, related to the fucose II complex, in tumors harboring a K-ras gene mutation has been investigated. CONCLUSIONS: We exploited the performance of a clinically easily implementable method, such as short-echo time single-voxel MRS, for the differentiation between brain metastasis and primary brain tumors. The study showed that MRS absolute lipid and macromolecular signals could be helpful in differentiating GBM from metastasis. LM13 class was found to be a discriminant parameter with an accuracy of 85%. Detection of the MM12-fucose peak may also have a role in understanding molecular biology of brain metastasis and should be further investigated to address specific metabolic phenotypes.

Real-time assessment of individual optimal CT perfusion acquisition time in patients with ischemic stroke.

BACKGROUND AND PURPOSE: This study aims to investigate the feasibility of a "real-time" estimate of the optimal CT perfusion (CTP) acquisition time (Top ) in ischemic stroke patients. METHODS: The arterial input function, the venous output function (VOF), and the time-attenuation curves of ischemic core and ischemic penumbra of 51 patients with acute ischemic stroke in anterior circulation were obtained. The curves were analyzed to determine for each patient the Top value; additionally, several time parameters were derived from each waveform. The relationship between each of these parameters and Top was investigated. RESULTS: We found a strong linear correlation between each time parameter derived from VOF curve and Top , suggesting that the VOF waveform is rescaled from patient to patient without significant change in shape. CONCLUSIONS: The linear correlation between Top and the VOF time to peak is well suited to implement a new technique to automatically customize the patient's CTP acquisition time. The method does not require an additional dose of contrast medium and does not increase the overall study time, so its use would be desirable to decrease the average radiation dose.

Predicting MGMT Promoter Methylation of Glioblastoma from Dynamic Susceptibility Contrast Perfusion: A Radiomic Approach.

BACKGROUND AND PURPOSE: This study aims to investigate whether radiomic quantitative image features (IFs) from perfusion dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) retain sufficient strength to predict O6-methylguanine-DNA methyltransferase promoter methylation (MGMT_pm) in newly diagnosed glioblastoma (GB) patients. METHODS: We retrospectively reviewed the perfusion DSC-MRI of 59 patients with GB. Patients were classified into three groups: (1) unmethylated if MGMT_pm ≤ 9% (UM); (2) intermediate-methylated if MGMT_pm ranged between 10% and 29% (IM); (3) methylated if MGMT_pm ≥ 30% (M). A total of 92 quantitative IFs were obtained from relative cerebral blood volume and relative cerebral blood flow maps. The Mann-Whitney U-test was applied to assess whether there were statistical differences in IFs between patient groups. Those IFs showing significant difference between two patient groups were termed relevant IFs (rIFs). rIFs were uploaded to a machine learning model to predict the MGMT_pm. RESULTS: No rIFs were found between UM and IM groups. Fourteen rIFs were found among UM-M, IM-M, and (UM + IM)-M groups. We built a multilayer perceptron deep learning model that classified patients as belonging to UM + IM and M group. The model performed well with 75% sensitivity, 85% specificity, and an area under the receiver-operating curve of .84. CONCLUSION: rIFs from perfusion DSC-MRI are potential biomarkers in GBs with a ≥30% MGMT_pm. Otherwise, unmethylated and intermediate-methylated GBs lack of rIFs. Five of 14 rIFs show sufficient strength to build an accurate prediction model of MGMT_pm.

Arterial Spin Labeling MRI to Measure Cerebral Blood Flow in Untreated Ischemic Stroke.

BACKGROUND AND PURPOSE: This study aims to investigate the significance of regional hyperperfusion (RH) detected by arterial spin labeling (ASL) in a group of untreated stroke patients, within 24-36 hours after symptom onset. The relationship between RH volume and infarcted volume (DIV) as defined on diffusion weighted images (DWIs) was evaluated. METHODS: Of the 346 consecutive acute stroke patients who attended our center, we retrospectively reviewed MRI studies of 47 patients who were ineligible for standard treatment with intravenous tissue plasminogen activator. The MRI study included ASL and DWI. The ASL-derived cerebral blood flow (CBF) maps were coregistered on the DWI images. RH volume and DIV were calculated and compared. Patient NIHSS scores were also evaluated at admission, discharge, and after 1 and 6-month follow-up. RESULTS: Twenty-two patients showed RH with CBF twice than baseline. In all 22 patients, RH overlaps with DWI infarcted area. No significant difference (P = .94) between RH volume and DIV was found (7.2 ± 9.6 and 9.0 ± 11.9 cm3 ). The Pearson's correlation coefficient between RH and DIV was .93. On univariate analysis, a significant difference was found between patient's groups on NIHSS at any time points, after covariates adjustment NIHSS difference was significant only at admission. CONCLUSIONS: The study showed that ASL perfusion could be an integral part of the MRI examination in the assessment of 24-36 hours not-treated stroke patients as sustained RH group had improved outcomes. More importantly, ASL perfusion may provide evidence of beneficial effects of reperfusion induced by recanalization treatment.

ASSESSMENT OF MOVEMENT-INDUCED TIME-VARYING MAGNETIC FIELDS EXPOSURE IN MAGNETIC RESONANCE IMAGING BY A COMMERCIAL PORTABLE MAGNETOMETER.

The purpose of this study was to describe a simple procedure to assess head exposure of MRI workers to time-varying magnetic field, due to their movements in the static magnetic field of a 3T MRI scanner. A group of MRI workers were provided with a commercial portable meter that stored in its internal memory the instantaneous B values. The dB/dt was obtained by the post hoc processing of measured data. The movement-induced time-varying electric field (TVEF) was calculated from dB/dt. The weighted peak index was evaluated in the frequency domain, by first computing the spectrum of dB/dt waveform, to verify the compliance with the exposure limits. The portable magnetometer may be useful to locally explore the MRI workers exposure to time-varying magnetic field and perform the local risk assessments in order to carry out the obligations laid down by Directive 2013/35/EU.

Dynamic Contrast-Enhanced Perfusion MRI of High Grade Brain Gliomas Obtained with Arterial or Venous Waveform Input Function.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate the differences in dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) perfusion estimates of high-grade brain gliomas (HGG) due to the use of an input function (IF) obtained respectively from arterial (AIF) and venous (VIF) approaches by two different commercially available software applications. METHODS: This prospective study includes 20 patients with pathologically confirmed diagnosis of high-grade gliomas. The data source was processed by using two DCE dedicated commercial packages, both based on the extended Toft model, but the first customized to obtain input function from arterial measurement and the second from sagittal sinus sampling. The quantitative parametric perfusion maps estimated from the two software packages were compared by means of a region of interest (ROI) analysis. The resulting input functions from venous and arterial data were also compared. RESULTS: No significant difference has been found between the perfusion parameters obtained with the two different software packages (P-value < .05). The comparison of the VIFs and AIFs obtained by the two packages showed no statistical differences. CONCLUSIONS: Direct comparison of DCE-MRI measurements with IF generated by means of arterial or venous waveform led to no statistical difference in quantitative metrics for evaluating HGG. However, additional research involving DCE-MRI acquisition protocols and post-processing would be beneficial to further substantiate the effectiveness of venous approach as the IF method compared with arterial-based IF measurement.