In vivo characterization of physiological and metabolic changes related to isocitrate dehydrogenase 1 mutation expcression by multiparametric MRI and MRS in a rat model with orthotopically grafted human-derived glioblastoma cell lines.

The physiological mechanism induced by the isocitrate dehydrogenase 1 (IDH1) mutation, associated with better treatment response in gliomas, remains unknown. The aim of this preclinical study was to characterize the IDH1 mutation through in vivo multiparametric MRI and MRS. Multiparametric MRI, including the measurement of blood flow, vascularity, oxygenation, permeability, and in vivo MRS, was performed on a 4.7 T animal MRI system in rat brains grafted with human-derived glioblastoma U87 cell lines expressing or not the IDH1 mutation by the CRISPR/Cas9 method, and secondarily characterized with additional ex vivo HR-MAS and histological analyses. In univariate analyses, compared with IDH1-, IDH1+ tumors exhibited higher vascular density (p < 0.01) and better perfusion (p = 0.02 for cerebral blood flow), but lower vessel permeability (p < 0.01 for time to peak (TTP), p = 0.04 for contrast enhancement) and decreased T1 map values (p = 0.02). Using linear discriminant analysis, vascular density and TTP values were found to be independent MRI parameters for characterizing the IDH1 mutation (p < 0.01). In vivo MRS and ex vivo HR-MAS analysis showed lower metabolites of tumor aggressiveness for IDH1+ tumors (p < 0.01). Overall, the IDH1 mutation exhibited a higher vascularity on MRI, a lower permeability, and a less aggressive metabolic profile. These MRI features may prove helpful to better pinpoint the physiological mechanisms induced by this mutation.

Hypertonic Sodium Lactate to Alleviate Functional Deficits Following Diffuse Traumatic Brain Injury: An Osmotic or a Lactate-Related Effect?

BACKGROUND: There has been growing interest in the use of hypertonic sodium lactate (HSL) solution following traumatic brain injury (TBI) in humans. However, little is known about the effects of HSL on functional deficits with respect to the hyperosmotic nature of HSL. METHODS: We have compared the effects of HSL solution and isotonic saline solution using sensorimotor and cognitive tests for 14 days post-trauma in animals. Thirty minutes after trauma (impact-acceleration model), anesthetized rats were randomly allocated to receive a 2-h infusion of isotonic saline solution (TBI-saline group) or HSL (TBI-HSL group) (n = 10 rats per group). In another series of experiments using a similar protocol, the effects of equiosmolar doses of HSL and hypertonic saline solution (HSS) were compared in TBI rats (n = 10 rats per group). Blood lactate and ion concentrations were measured during the 2-h infusions. RESULTS: Compared to the TBI-saline group, the TBI-HSL group had a reduced latency to complete the adhesive removal test: 6 s (5-9) (median [25-75th centiles]) versus 13 s (8-17) on day 7, and 5 s (5-9) versus 11 s (8-26) on day 14 (P < 0.05), respectively, and a shorter delay to complete the radial arm maze test on day 7: 99 s (73-134) versus 176 s (127-300), respectively (P < 0.05). However, no differences were found between the TBI-HSL and TBI-HSS groups in neurocognitive tests performance. Compared to the TBI-saline group, the HSL and HSS groups had higher serum osmolality: 318 mOsm/Kg (315-321) and 315 mOsm/Kg (313-316) versus 307 mOsm/Kg (305-309), respectively (P < 0.05), and the HSL group had a higher serum lactate concentration: 6.4 mmol/L (5.3-7.2) versus 1.5 mmol/L (1.1-1.9) and 1.6 mmol/L (1.5-1.7), respectively (P < 0.05). CONCLUSIONS: These results indicate that improvements in cognitive and sensorimotor tests with HSL infusion post-TBI could be related to elevation of serum osmolality, not to exogenous administration of lactate.

Cluster versus ROI analysis to assess combined antiangiogenic therapy and radiotherapy in the F98 rat-glioma model.

For glioblastoma (GBM), current therapeutic approaches focus on the combination of several therapies, each of them individually approved for GBM or other tumor types. Many efforts are made to decipher the best sequence of treatments that would ultimately promote the most efficient tumor response. There is therefore a strong interest in developing new clinical in vivo imaging procedures that can rapidly detect treatment efficacy and allow individual modulation of the treatment. In this preclinical study, we propose to evaluate tumor tissue changes under combined therapies, tumor vascular normalization under antiangiogenic treatment followed by radiotherapy, using a voxel-based clustering approach. This approach was applied to a rat model of glioma (F98). Six MRI parameters were mapped: apparent diffusion coefficient, vessel wall permeability, cerebral blood volume fraction, cerebral blood flow, tissue oxygen saturation and vessel size index. We compared the classical region of interest (ROI)-based analysis with a cluster-based analysis. Five clusters, defined by their MRI features, were sufficient to characterize tumor progression and tumor changes during treatments. These results suggest that the cluster-based analysis was as efficient as the ROI-based analysis to assess tumor physiological changes during treatment, but also gave additional information regarding the voxels impacted by treatments and their localization within the tumor. Overall, cluster-based analysis appears to be a powerful tool for subtle monitoring of tumor changes during combined therapies.

Mannitol Improves Brain Tissue Oxygenation in a Model of Diffuse Traumatic Brain Injury.

OBJECTIVES: Based on evidence supporting a potential relation between posttraumatic brain hypoxia and microcirculatory derangements with cell edema, we investigated the effects of the antiedematous agent mannitol on brain tissue oxygenation in a model of diffuse traumatic brain injury. DESIGN: Experimental study. SETTING: Neurosciences and physiology laboratories. SUBJECTS: Adult male Wistar rats. INTERVENTIONS: Thirty minutes after diffuse traumatic brain injury (impact-acceleration model), rats were IV administered with either a saline solution (traumatic brain injury-saline group) or 20% mannitol (1 g/kg) (traumatic brain injury-mannitol group). Sham-saline and sham-mannitol groups received no insult. MEASUREMENTS AND MAIN RESULTS: Two series of experiments were conducted 2 hours after traumatic brain injury (or equivalent) to investigate 1) the effect of mannitol on brain edema and oxygenation, using a multiparametric magnetic resonance-based approach (n = 10 rats per group) to measure the apparent diffusion coefficient, tissue oxygen saturation, mean transit time, and blood volume fraction in the cortex and caudoputamen; 2) the effect of mannitol on brain tissue PO2 and on venous oxygen saturation of the superior sagittal sinus (n = 5 rats per group); and 3) the cortical ultrastructural changes after treatment (n = 1 per group, taken from the first experiment). Compared with the sham-saline group, the traumatic brain injury-saline group had significantly lower tissue oxygen saturation, brain tissue PO2, and venous oxygen saturation of the superior sagittal sinus values concomitant with diffuse brain edema. These effects were associated with microcirculatory collapse due to astrocyte swelling. Treatment with mannitol after traumatic brain injury reversed all these effects. In the absence of traumatic brain injury, mannitol had no effect on brain oxygenation. Mean transit time and blood volume fraction were comparable between the four groups of rats. CONCLUSION: The development of posttraumatic brain edema can limit the oxygen utilization by brain tissue without evidence of brain ischemia. Our findings indicate that an antiedematous agent such as mannitol can improve brain tissue oxygenation, possibly by limiting astrocyte swelling and restoring capillary perfusion.

Imaging the microvessel caliber and density: Principles and applications of microvascular MRI.

Twenty years ago, theoretical developments were initiated to model the behavior of the NMR transverse relaxation rates in presence of vessels. These developments enabled the MRI-based mapping of mean vessel diameter, microvascular density, and vessel size index with comparable results to those obtained by a pathologist. The transfer of these techniques to routine clinical use has been hindered by the unavailability of the required sequences, namely fast gradient-echo spin-echo sequences. Based on the increasing accessibility of such sequences on MRI scanners over recent years, we review the principles governing microvascular MRI, the validation studies, and the applications that have been tested worldwide by several teams. We also provide some recommendations on how to measure microvessel caliber and density with MRI.

Multiparametric MRI as an early biomarker of individual therapy effects during concomitant treatment of brain tumours.

The aim of this study was to determine the ability of multiparametric MRI to identify the early effects of individual treatment, during combined chemo-radiotherapy on brain tumours. Eighty male rats bearing 9L gliosarcomas were randomized into four groups: untreated, anti-angiogenic therapy (SORA group), microbeam radiation therapy (MRT group) and both treatments (MRT+SORA group). Multiparametric MRI (tumour volume, diffusion-weighted MR imaging (ADC), blood volume fraction (BVf), microvessel index (VSI), vessel wall integrity (AUC(P846)) and tissue oxygen saturation (StO2)) was performed 1 day before and 2, 5 and 8 days after treatment initiation. Unpaired t-tests and one-way ANOVA were used for statistical analyses. Each MR parameter measured in our protocol was revealed to be sensitive to tumour changes induced by any of the therapies used (individually or combined). When compared with untreated tumours, SORA induced a decrease in BVf, VSI, StO2 and AUC(P846), MRT generated an increase in ADC and AUC(P846) and combined therapies yielded mixed effects: an increase in ADC and AUC(P846) and a decrease in BVf, StO2 and AUC(P846). MRT and MRT+SORA significantly slowed tumour growth. Despite these two groups presenting with similar tumour sizes, the information yielded from MR multiparameter assessment indicated that, when used concomitantly, each therapy induced distinguishable and appreciable physiological changes in the tumour. Our results suggest that multiparametric MRI can monitor the effects of individual treatments, used concomitantly, on brain tumours. Such monitoring would be useful for the detection of tumour resistance to drug/radiotherapy in patients undergoing concomitant therapies.

Characterization of the 9L gliosarcoma implanted in the Fischer rat: an orthotopic model for a grade IV brain tumor.

Among rodent models for brain tumors, the 9L gliosarcoma is one of the most widely used. Our 9L-European Synchrotron Radiation Facility (ESRF) model was developed from cells acquired at the Brookhaven National Laboratory (NY, USA) in 1997 and implanted in the right caudate nucleus of syngeneic Fisher rats. It has been largely used by the user community of the ESRF during the last decade, for imaging, radiotherapy, and chemotherapy, including innovative treatments based on particular irradiation techniques and/or use of new drugs. This work presents a detailed study of its characteristics, assessed by magnetic resonance imaging (MRI), histology, immunohistochemistry, and cytogenetic analysis. The data used for this work were from rats sampled in six experiments carried out over a 3-year period in our lab (total number of rats = 142). The 9L-ESRF tumors were induced by a stereotactic inoculation of 10(4) 9L cells in the right caudate nucleus of the brain. The assessment of vascular parameters was performed by MRI (blood volume fraction and vascular size index) and by immunostaining of vessels (rat endothelial cell antigen-1 and type IV collagen). Immunohistochemistry and regular histology were used to describe features such as tumor cell infiltration, necrosis area, nuclear pleomorphism, cellularity, mitotic characteristics, leukocytic infiltration, proliferation, and inflammation. Moreover, for each of the six experiments, the survival of the animals was assessed and related to the tumor growth observed by MRI or histology. Additionally, the cytogenetic status of the 9L cells used at ESRF lab was investigated by comparative genomics hybridization analysis. Finally, the response of the 9L-ESRF tumor to radiotherapy was estimated by plotting the survival curves after irradiation. The median survival time of 9L-ESRF tumor-bearing rats was highly reproducible (19-20 days). The 9L-ESRF tumors presented a quasi-exponential growth, were highly vascularized with a high cellular density and a high proliferative index, accompanied by signs of inflammatory responses. We also report an infiltrative pattern which is poorly observed on conventional 9 L tumor. The 9L-ESRF cells presented some cytogenetic specificities such as altered regions including CDK4, CDKN2A, CDKN2B, and MDM2 genes. Finally, the lifespan of 9L-ESRF tumor-bearing rats was enhanced up to 28, 35, and 45 days for single doses of 10, 20, and 2 × 20 Gy, respectively. First, this report describes an animal model that is used worldwide. Second, we describe few features typical of our model if compared to other 9L models worldwide. Altogether, the 9L-ESRF tumor model presents characteristics close to the human high-grade gliomas such as high proliferative capability, high vascularization and a high infiltrative pattern. Its response to radiotherapy demonstrates its potential as a tool for innovative radiotherapy protocols.

Microbeam Radiation Therapy Opens a Several Days' Vessel Permeability Window for Small Molecules in Brain Tumor Vessels.

PURPOSE: Synchrotron microbeam radiation therapy (MRT), based on an inhomogeneous geometric and microscopic irradiation pattern of the tissues with high-dose and high-dose-rate x-rays, enhances the permeability of brain tumor vessels. This study attempted to determine the time and size range of the permeability window induced by MRT in the blood-brain (tumor) barrier. METHODS AND MATERIALS: Rats-bearing 9L gliomas were exposed to MRT, either unidirectional (tumor dose, 406 Gy) or bidirectional (crossfired) (2 × 203 Gy). We measured vessel permeability to molecules of 3 sizes (Gd-DOTA, Dotarem, 0.56 kDa; gadolinium-labeled albumin, ∼74 kDa; and gadolinium-labeled IgG, 160 kDa) by daily in vivo magnetic resonance imaging, from 1 day before to 10 days after irradiation. RESULTS: An equivalent tumor dose of bidirectional MRT delivered from 2 orthogonal directions increased tumor vessel permeability for the smallest molecule tested more effectively than unidirectional MRT. Bidirectional MRT also affected the permeability of normal contralateral vessels to a different extent than unidirectional MRT. Conversely, bidirectional MRT did not modify the permeability of normal or tumor vessels for both larger molecules (74 and 160 kDa). CONCLUSIONS: High-dose bidirectional (cross-fired) MRT induced a significant increase in tumor vessel permeability for small molecules between the first and the seventh day after irradiation, whereas permeability of vessels in normal brain tissue remained stable. Such a permeability window could facilitate an efficient and safe delivery of intravenous small molecules (≤0.56 kDa) to tumoral tissues. A permeability window was not achieved by molecules larger than gado-grafted albumin (74 kDa). Vascular permeability for molecules between these 2 sizes has not been determined.

In vivo imaging of vessel diameter, size, and density: a comparative study between MRI and histology.

The aim of this study was to compare magnetic resonance imaging (MRI) and histological estimates of the mean vessel diameter (mVD), the vessel density (Density), and the vessel size index (VSI) obtained in the same tumor-bearing animals. Twenty-seven rats bearing intracranial glioma (C6 or RG2) were imaged by MRI. Changes in transverse relaxations (ΔR 2* and R(2)) were induced by the injection of an iron-based contrast agent and were mapped using a multi gradient-echo spin-echo sequence. Then, brain vascular network was studied ex vivo by histology. Three regions of interest were drawn in apparently normal tissue (neocortex and striatum) and in the tumor. In vivo mVD(MRI), Density(MRI), and VSI(MRI) were measured; ex vivo, mVD(histo), Density(histo), and VSI(histo) were quantified on the same animals. MRI and histology measurements differed by -15 to 26%. A positive correlation was found between MRI and histology for mVD, Density, and VSI counterparts (R(2) = 0.62, 0.50, 0.73, respectively; P < 0.001 in all cases). This study indicates that MRI and histology yields well correlated the estimates of mVD, Density, and VSI. VSI is the closest MRI estimate to histology. As Density and mVD or VSI provide complementary information, it is worth computing them to characterize angiogenesis beyond blood volume fraction.

Prediction of therapeutic intensity level from automatic multiclass segmentation of traumatic brain injury lesions on CT-scans.

The prediction of the therapeutic intensity level (TIL) for severe traumatic brain injury (TBI) patients at the early phase of intensive care unit (ICU) remains challenging. Computed tomography images are still manually quantified and then underexploited. In this study, we develop an artificial intelligence-based tool to segment brain lesions on admission CT-scan and predict TIL within the first week in the ICU. A cohort of 29 head injured patients (87 CT-scans; Dataset1) was used to localize (using a structural atlas), segment (manually or automatically with or without transfer learning) 4 or 7 types of lesions and use these metrics to train classifiers, evaluated with AUC on a nested cross-validation, to predict requirements for TIL sum of 11 points or more during the 8 first days in ICU. The validation of the performances of both segmentation and classification tasks was done with Dice and accuracy scores on a sub-dataset of Dataset1 (internal validation) and an external dataset of 12 TBI patients (12 CT-scans; Dataset2). Automatic 4-class segmentation (without transfer learning) was not able to correctly predict the apparition of a day of extreme TIL (AUC = 60 ± 23%). In contrast, manual quantification of volumes of 7 lesions and their spatial location provided a significantly better prediction power (AUC = 89 ± 17%). Transfer learning significantly improved the automatic 4-class segmentation (DICE scores 0.63 vs 0.34) and trained more efficiently a 7-class convolutional neural network (DICE = 0.64). Both validations showed that segmentations based on transfer learning were able to predict extreme TIL with better or equivalent accuracy (83%) as those made with manual segmentations. Our automatic characterization (volume, type and spatial location) of initial brain lesions observed on CT-scan, publicly available on a dedicated computing platform, could predict requirements for high TIL during the first 8 days after severe TBI. Transfer learning strategies may improve the accuracy of CNN-based segmentation models.Trial registrations Radiomic-TBI cohort; NCT04058379, first posted: 15 august 2019; Radioxy-TC cohort; Health Data Hub index F20220207212747, first posted: 7 February 2022.

Is T2* enough to assess oxygenation? Quantitative blood oxygen level-dependent analysis in brain tumor.

PURPOSE: To analyze the contribution of the transverse relaxation parameter (T2), macroscopic field inhomogeneities (B0), and blood volume fraction (BVf) to blood oxygen level-dependent (BOLD)-based magnetic resonance (MR) measurements of blood oxygen saturation (SO2) obtained in a brain tumor model. MATERIALS AND METHODS: This study was approved by the local committee for animal care and use. Experiments were performed in accordance with permit 380 820 from the French Ministry of Agriculture. The 9L gliosarcoma cells were implanted in the brain of eight rats. Fifteen days later, 4.7-T MR examinations were performed to estimate T2*, T2, BVf, and T2*ΔB0corrected in the tumor and contralateral regions. MR estimates of SO2 were derived by combining T2, BVf, and T2*ΔB0corrected according to a recently described quantitative BOLD approach. Scatterplots and linear regression analysis were used to identify correlation between parameters. Paired Student t tests were used to compare the tumor region with the contralateral region. RESULTS: No significant correlations were found between T2* and any parameter in either tumor tissue or healthy tissue. T2* in the tumor and T2* in the uninvolved contralateral brain were the same (36 msec±4 [standard deviation] vs 36 msec±5, respectively), which might suggest similar oxygenation. Adding T2 information (98 msec±7 vs 68 msec±2, respectively) alone yields results that suggest apparent hypo-oxygenation of the tumor, while incorporating BVf (5.3%±0.6 vs 2.6%±0.3, respectively) alone yields results that suggest apparent hyperoxygenation. MR estimates of SO2 obtained with a complete quantitative BOLD analysis, although not correlated with T2* values, suggest normal oxygenation (68%±3 vs 65%±4, respectively). MR estimates of SO2 obtained in the contralateral tissue agree with previously reported values. CONCLUSION: Additional measurements, such as BVf, T2, and B0, are needed to obtain reliable information on oxygenation with BOLD MR imaging. The proposed quantitative BOLD approach, which includes these measurements, appears to be a promising tool with which to map tumor oxygenation.

Evaluation of the relationship between MR estimates of blood oxygen saturation and hypoxia: effect of an antiangiogenic treatment on a gliosarcoma model.

PURPOSE: To assess the reproducibility of the magnetic resonance (MR) estimate of blood oxygen saturation (sO(2)) in the rat brain, to evaluate the relationship between low MR estimate of sO(2) values and tissue hypoxia in a hypoxic and necrotic glioscarcoma model (9L gliosarcoma cells), and to evaluate the capability of the MR estimate of sO(2) parameter to help identify modifications induced by an antiangiogenic treatment (sorafenib) in 9L gliosarcoma tumors. MATERIALS AND METHODS: Experiments were performed with permits from the French Ministry of Agriculture. Forty-eight male rats bearing a 9L gliosarcoma were randomized in untreated and treated (sorafenib) groups. MR blood volume fraction and MR estimate of sO(2) parameters were estimated 1 day before and 1, 3, 5, and 8 days after the start of the treatment. The in vivo MR estimate of sO(2) measurement was correlated with the ex vivo hypoxia assessment by using pimonidazole staining. Paired and unpaired t tests, as well as parametric Pearson tests, were used for the statistical analyses. RESULTS: In healthy tissues, MR estimate of sO(2) measurements were comparable to literature values and were reproducible (mean across all animals, 68.0% ± 6.5 [standard deviation]). In untreated tumors, MR estimate of sO(2) and immunohistochemical analysis yielded correlated fractional hypoxic-necrotic areas (R(2) = 0.81). In tumors treated with antiangiogenic therapy, tumor MR estimate of sO(2) was decreased with respect to the healthy tissue (P< .001). CONCLUSION: Results of this study suggest that the MR estimate of sO(2) is a reproducible estimate that could be used as an in vivo probe of hypoxia in brain tumors and as a sensitive reporter of the hypoxic effects of antiangiogenic therapies.

Vessel size index measurements in a rat model of glioma: comparison of the dynamic (Gd) and steady-state (iron-oxide) susceptibility contrast MRI approaches.

Vessel size index (VSI), a parameter related to the distribution of vessel diameters, may be estimated using two MRI approaches: (i) dynamic susceptibility contrast (DSC) MRI following the injection of a bolus of Gd-chelate. This technique is routinely applied in the clinic to assess intracranial tissue perfusion in patients; (ii) steady-state susceptibility contrast with USPIO contrast agents, which is considered here as the standard method. Such agents are not available for human yet and the steady-state approach is currently limited to animal studies. The aim is to compare VSI estimates obtained with these two approaches on rats bearing C6 glioma (n = 7). In a first session, VSI was estimated from two consecutive injections of Gd-Chelate (Gd(1) and Gd(2)). In a second session (4 hours later), VSI was estimated using USPIO. Our findings indicate that both approaches yield comparable VSI estimates both in contralateral (VSI{USPIO} = 7.5 ± 2.0 µm, VSI{Gd(1)} = 6.5 ± 0.7 µm) and in brain tumour tissues (VSI{USPIO} = 19.4 ± 7.1 µm, VSI{Gd(1)} = 16.6 ± 4.5 µm). We also observed that, in the presence of BBB leakage (as it occurs typically in brain tumours), applying a preload of Gd-chelate improves the VSI estimate with the DSC approach both in contralateral (VSI{Gd(2)} = 7.1 ± 0.4 µm) and in brain tumour tissues (VSI{Gd(2)} = 18.5 ± 4.3 µm) but is not mandatory. VSI estimates do not appear to be sensitive to T(1) changes related to Gd extravasation. These results suggest that robust VSI estimates may be obtained in patients at 3 T or higher magnetic fields with the DSC approach.

Radiomics-Based Detection of Radionecrosis Using Harmonized Multiparametric MRI.

In this study, a radiomics analysis was conducted to provide insights into the differentiation of radionecrosis and tumor progression in multiparametric MRI in the context of a multicentric clinical trial. First, the sensitivity of radiomic features to the unwanted variability caused by different protocol settings was assessed for each modality. Then, the ability of image normalization and ComBat-based harmonization to reduce the scanner-related variability was evaluated. Finally, the performances of several radiomic models dedicated to the classification of MRI examinations were measured. Our results showed that using radiomic models trained on harmonized data achieved better predictive performance for the investigated clinical outcome (balanced accuracy of 0.61 with the model based on raw data and 0.72 with ComBat harmonization). A comparison of several models based on information extracted from different MR modalities showed that the best classification accuracy was achieved with a model based on MR perfusion features in conjunction with clinical observation (balanced accuracy of 0.76 using LASSO feature selection and a Random Forest classifier). Although multimodality did not provide additional benefit in predictive power, the model based on T1-weighted MRI before injection provided an accuracy close to the performance achieved with perfusion.

Evaluation of a quantitative blood oxygenation level-dependent (qBOLD) approach to map local blood oxygen saturation.

Blood oxygen saturation (SO(2)) is a promising parameter for the assessment of brain tissue viability in numerous pathologies. Quantitative blood oxygenation level-dependent (qBOLD)-like approaches allow the estimation of SO(2) by modelling the contribution of deoxyhaemoglobin to the MR signal decay. These methods require a high signal-to-noise ratio to obtain accurate maps through fitting procedures. In this article, we present a version of the qBOLD method at long TE taking into account separate estimates of T(2), total blood volume fraction (BV(f)) and magnetic field inhomogeneities. Our approach was applied to the brains of 13 healthy rats under normoxia, hyperoxia and hypoxia. MR estimates of local SO(2) (MR_LSO(2)) were compared with measurements obtained from blood gas analysis. A very good correlation (R(2) = 0.89) was found between brain MR_LSO(2) and sagittal sinus SO(2).

Assessment of multiparametric MRI in a human glioma model to monitor cytotoxic and anti-angiogenic drug effects.

Early imaging or blood biomarkers of tumor response is needed to customize anti-tumor therapy on an individual basis. This study evaluates the sensitivity and relevance of five potential MRI biomarkers. Sixty nude rats were implanted with human glioma cells (U-87 MG) and randomized into three groups: one group received an anti-angiogenic treatment (Sorafenib), a second a cytotoxic drug [1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU (Carmustine)] and a third no treatment. The tumor volume, apparent diffusion coefficient (ADC) of water, blood volume fraction (BVf), microvessel diameter (vessel size index, VSI) and vessel wall integrity (contrast enhancement, CE) were monitored before and during treatment. Sorafenib reduced tumor CE as early as 1 day after treatment onset. By 4 days after treatment onset, tumor BVf was reduced and tumor VSI was increased. By 14 days after treatment onset, ADC was increased and the tumor growth rate was reduced. With BCNU, ADC was increased and the tumor growth rate was reduced 14 days after treatment onset. Thus, the estimated MRI parameters were sensitive to treatment at different times after treatment onset and in a treatment-dependent manner. This study suggests that multiparametric MR monitoring could allow the assessment of new anti-tumor drugs and the optimization of combined therapies.

Bayesian Inverse Regression for Vascular Magnetic Resonance Fingerprinting.

Standard parameter estimation from vascular magnetic resonance fingerprinting (MRF) data is based on matching the MRF signals to their best counterparts in a grid of coupled simulated signals and parameters, referred to as a dictionary. To reach a good accuracy, the matching requires an informative dictionary whose cost, in terms of design, storage and exploration, is rapidly prohibitive for even moderate numbers of parameters. In this work, we propose an alternative dictionary-based statistical learning (DB-SL) approach made of three steps: 1) a quasi-random sampling strategy to produce efficiently an informative dictionary, 2) an inverse statistical regression model to learn from the dictionary a correspondence between fingerprints and parameters, and 3) the use of this mapping to provide both parameter estimates and their confidence indices. The proposed DB-SL approach is compared to both the standard dictionary-based matching (DBM) method and to a dictionary-based deep learning (DB-DL) method. Performance is illustrated first on synthetic signals including scalable and standard MRF signals with spatial undersampling noise. Then, vascular MRF signals are considered both through simulations and real data acquired in tumor bearing rats. Overall, the two learning methods yield more accurate parameter estimates than matching and to a range not limited to the dictionary boundaries. DB-SL in particular resists to higher noise levels and provides in addition confidence indices on the estimates at no additional cost. DB-SL appears as a promising method to reduce simulation needs and computational requirements, while modeling sources of uncertainty and providing both accurate and interpretable results.

Calcified cartilage revealed in whole joint by X-ray phase contrast imaging.

Objective: X-ray Phase Contrast Imaging (PCI) is an emerging modality that will be in the next few years available in a wider range of preclinical set-ups. In this study, we compare this imaging technique with conventional preclinical modalities in an osteoarthritis mouse model. Method: Phase contrast technique was performed on 6 post-mortem, monoiodoacetate-induced osteoarthritis knees and 6 control knees. The mice knees were then imaged using magnetic resonance imaging and conventional micro computed tomography. Examples of imaging surrogate markers are reported: local distances within the articular space, cartilage surface roughness, calcified cartilage thickness, number, volume and locations of osteophytes. Results: Thanks to PCI, we can show in 3D calcified cartilage without contrast agent by a non-invasive technique. The phase contrast images reveal more details than conventional imaging techniques, especially at smaller scales, with for instance a higher number of micro-calcifications detected (57, 314 and 329 for MRI, conventional micro-CT and phase contrast imaging respectively). Calcified cartilage thickness was measured with a significant difference (p â€‹< â€‹0.01) between the control (23.4 â€‹± â€‹17.2 â€‹µm) and the osteoarthritis induced animal (46.9 â€‹± â€‹19.0 â€‹µm). Conclusions: X-ray phase contrast imaging outperforms the conventional imaging modalities for assessing the different tissue types (soft and hard). This new imaging modality seems to bring new relevant surrogate markers for following-up small animal models even for low-grade osteoarthritis.

Parametric Response Mapping of FLAIR MRI Provides an Early Indication of Progression Risk in Glioblastoma.

RATIONALE AND OBJECTIVES: Glioblastoma image evaluation utilizes Magnetic Resonance Imaging contrast-enhanced, T1-weighted, and noncontrast T2-weighted fluid-attenuated inversion recovery (FLAIR) acquisitions. Disease progression assessment relies on changes in tumor diameter, which correlate poorly with survival. To improve treatment monitoring in glioblastoma, we investigated serial voxel-wise comparison of anatomically-aligned FLAIR signal as an early predictor of GBM progression. MATERIALS AND METHODS: We analyzed longitudinal normalized FLAIR images (rFLAIR) from 52 subjects using voxel-wise Parametric Response Mapping (PRM) to monitor volume fractions of increased (PRMrFLAIR+), decreased (PRMrFLAIR-), or unchanged (PRMrFLAIR0) rFLAIR intensity. We determined response by rFLAIR between pretreatment and 10 weeks posttreatment. Risk of disease progression in a subset of subjects (N = 26) with stable disease or partial response as defined by Response Assessment in Neuro-Oncology (RANO) criteria was assessed by PRMrFLAIR between weeks 10 and 20 and continuously until the PRMrFLAIR+ exceeded a defined threshold. RANO defined criteria were compared with PRM-derived outcomes for tumor progression detection. RESULTS: Patient stratification for progression-free survival (PFS) and overall survival (OS) was achieved at week 10 using RANO criteria (PFS: p <0.0001; OS: p <0.0001), relative change in FLAIR-hyperintense volume (PFS: p = 0.0011; OS: p <0.0001), and PRMrFLAIR+ (PFS: p <0.01; OS: p <0.001). PRMrFLAIR+ also stratified responding patients' progression between weeks 10 and 20 (PFS: p <0.05; OS: p = 0.01) while changes in FLAIR-volume measurements were not predictive. As a continuous evaluation, PRMrFLAIR+ exceeding 10% stratified patients for PFA after 5.6 months (p<0.0001), while RANO criteria did not stratify patients until 15.4 months (p <0.0001). CONCLUSION: PRMrFLAIR may provide an early biomarker of disease progression in glioblastoma.

Contribution of CT-Scan Analysis by Artificial Intelligence to the Clinical Care of TBI Patients.

The gold standard to diagnose intracerebral lesions after traumatic brain injury (TBI) is computed tomography (CT) scan, and due to its accessibility and improved quality of images, the global burden of CT scan for TBI patients is increasing. The recent developments of automated determination of traumatic brain lesions and medical-decision process using artificial intelligence (AI) represent opportunities to help clinicians in screening more patients, identifying the nature and volume of lesions and estimating the patient outcome. This short review will summarize what is ongoing with the use of AI and CT scan for patients with TBI.