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Background: In glioblastoma (GBM), tumor progression occurs mainly within the irradiated tumor volume. To address this challenge, a radiosensitization strategy with intravenous gadolinium-based theranostic nanoparticles (AGuIX) is being explored in the NANO-GBM phase1b/2R trial (NCT04881032). Here, we present the results of the phase 1b part, which is the first-in-human use of these nanoparticles with radiotherapy and chemotherapy for the treatment of newly diagnosed GBM. Material and Methods: Eligible patients were aged 18 to 75 years with newly diagnosed and histologically confirmed GBM, with incomplete resection (biopsy or partial surgery). The phase 1b part was a dose escalation approach (Time-to-event Continuous Reassessment Method) with three dose levels: 50, 75, and 100 mg/kg. Patients were treated with RT (60 Gy), and concomitant and adjuvant TMZ, and 4 injections of AGuIX (D-3/-7, D1, D8, and D15). Dose-limiting-toxicity (DLT) was defined as any grade 3-4 adverse event (CTCAE v5.0), excluding alopecia, nausea, and rapidly controlled vomiting. Pharmacokinetic (PK), and biodistribution based on MRI were evaluated. Results: Between March 2022 and March 2023, eight patients were enrolled: 1 at 50 mg/kg, 1 at 75 mg/kg, and 6 at 100 mg/kg. All patients received the four AGuIX injections. Only one patient experienced a DLT (at 100 mg/kg): a grade 3 lymphopenia (related to TMZ). The RP2D of AGuIX was determined as 100 mg/kg. AGuIX mean AUC increased with dose. Regions of GBM with moderate (36-123 µM), and high (123-291 µM) or very high (>291 µM) AGuIX concentrations accounted in average for 38.7 and 26.8 %, respectively. Conclusion: These results confirm the lack of AGuIX-related toxicity and the widespread dispersion of nanoparticles throughout GBM. This supports progression to the randomized phase 2 part, utilizing an RP2D of AGuIX of 100 mg/kg (4 injections).

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A new efficient type of gadolinium-based theranostic agent (AGuIX®) has recently been developed for MRI-guided radiotherapy (RT). These new particles consist of a polysiloxane network surrounded by a number of gadolinium chelates, usually 10. Owing to their small size (<5 nm), AGuIX typically exhibit biodistributions that are almost ideal for diagnostic and therapeutic purposes. For example, although a significant proportion of these particles accumulate in tumours, the remainder is rapidly eliminated by the renal route. In addition, in the absence of irradiation, the nanoparticles are well tolerated even at very high dose (10 times more than the dose used for mouse treatment). AGuIX particles have been proven to act as efficient radiosensitizers in a large variety of experimental in vitro scenarios, including different radioresistant cell lines, irradiation energies and radiation sources (sensitizing enhancement ratio ranging from 1.1 to 2.5). Pre-clinical studies have also demonstrated the impact of these particles on different heterotopic and orthotopic tumours, with both intratumoural or intravenous injection routes. A significant therapeutical effect has been observed in all contexts. Furthermore, MRI monitoring was proven to efficiently aid in determining a RT protocol and assessing tumour evolution following treatment. The usual theoretical models, based on energy attenuation and macroscopic dose enhancement, cannot account for all the results that have been obtained. Only theoretical models, which take into account the Auger electron cascades that occur between the different atoms constituting the particle and the related high radical concentrations in the vicinity of the particle, provide an explanation for the complex cell damage and death observed.

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Hyperpolarised gases have been most recently used in magnetic resonance imaging to demonstrate new image-derived pulmonary function parameters. One of these parameters is the apparent diffusion coefficient, which reflects the sizes of the structures that compartmentalise gas within the lung (i.e. alveolar space). In the present study, noninvasive parameters were compared to microscopic measurements (mean linear intercept and mean alveolar internal area). Nonselective helium-3 gas density coronal ex vivo images and apparent diffusion maps were acquired in control and elastase-induced panacinar emphysema rats. Total lung capacity was considered the reference for both imaging experiments and lung fixation. A mild degree of emphysema was found based on mean linear intercept (134 +/- 25 microm) versus control (85 +/- 14 microm). The apparent diffusion coefficients were significantly different between the two groups (0.18 +/- 0.02 and 0.15 +/- 0.01 cm2 x s(-1) for elastase and control, respectively). A significant correlation between the apparent diffusion coefficient and corresponding morphometric parameters in mild emphysema was demonstrated for the first time. This study opens the possibility of estimating absolute airspace size using noninvasive techniques.

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A method - PA-keyhole - for 2D/3D dynamic magnetic resonance imaging with radial scanning is proposed. PA-keyhole exploits the inherent strong oversampling in the center of k-space, which contains crucial temporal information regarding contrast evolution. The method is based on: (1). a rearrangement of the temporal order of 2D/3D isotropic distributions of trajectories during the scan into subdistributions according to the desired time resolution, (2). a new post-acquisition keyhole approach based on the replacement of the central disk/sphere in k-space using data solely from a subdistribution, and (3). reconstruction of 2D/3D dynamic (time-resolved) images using 2D/3D-gridding with Pipe's approach to the sampling density compensation and 2D/3D-IFFT. The scan time is not increased with respect to a conventional 2D/3D radial scan of the same spatial resolution; in addition, one benefits from the dynamic information. The abilities of PA-keyhole and the sliding window techniques to restore simulated dynamic contrast changes are compared. Results are shown both for 2D and 3D dynamic imaging using experimental data. An application to in-vivo ventilation of rat lungs using hyperpolarized helium is demonstrated.

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In this work, the use of a new carrier agent for intravascular laser-polarized 3He imaging is reported. Lipid-based helium microbubbles were investigated. Their average diameter of 3 microm, which is smaller than that of the capillaries, makes it possible to conduct in vivo studies. The NMR relaxation parameters T1, T2, and T2* of a microbubble suspension were measured as 90 s, 300 ms, and 4.5 ms, respectively, and in vivo images of encapsulated 3He with signal-to-noise ratios (SNRs) larger than 30 were acquired. Dynamic cardiac images and vascular images of encapsulated 3He were obtained in rats using intravenous injections of microbubble suspensions. Excellent preservation of 3He polarization through the lung capillaries and heart cavities was observed. The first images of 3He microbubble distributions in the lungs were obtained. Additionally, the potential of this technique for lung perfusion assessment was validated through an experimental embolism model with the visualization of perfusion defects.

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In this work, the use of hyperpolarized (HP) 3He for in vivo intravascular imaging on animal is reported. To overcome the problem of the low solubility of helium in blood, we propose an approach based on helium encapsulation in lipid-based carrier agents. The mean diameter of the 3He microbubbles, measured equal to 3.0+/-0.2 microm, makes it possible to conduct in vivo studies. In vitro spectroscopy yielded a longitudinal relaxation time T(1) equal to 90 s and an apparent transverse relaxation time T(2)(*) of 4.5 ms. Angiographic imaging (venous and cardiac cavity visualization), as well as lung perfusion imaging, were demonstrated in rats using intravenous injections of microbubble suspensions. Suitable signal and spatial resolution were achieved. The potential of this technique for lung perfusion assessment was assessed using an experimental animal embolism model. Lung perfusion defects and recovery towards a normal perfusion state were visualized. This study was completed with the demonstration of a new ventilation-perfusion lung exploration method based entirely on HP 3He.

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Magnetic resonance imaging (MRI) using laser-polarized noble gases, such as (129)Xe and (3)He, allows unparalleled noninvasive information on gas distribution in lung airways and distal spaces. In addition to pulmonary ventilation, lung perfusion assessment is crucial for proper diagnosis of pathological conditions, such as pulmonary embolism. Magnetic resonance perfusion imaging usually can be performed using techniques based on the detection of water protons in tissues. However, lung proton imaging is extremely difficult due to the low proton density and the magnetically inhomogeneous structure of the lung parenchyma. Here we show that laser-polarized (3)He can be used as a noninvasive probe to image, in a single MRI experiment, not only the ventilation but also the perfusion state of the lungs. Blood volume maps of the lungs were generated based on the (3)He signal depletion during the first pass of a superparamagnetic contrast agent bolus. The combined and simultaneous lung ventilation and perfusion assessments are demonstrated in normal rat lungs and are applied to an experimental animal model of pulmonary embolism. Magn Reson Med 44:1-4, 2000.

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The use of spiral scan techniques is investigated for (3)He lung imaging on small animals. Dynamic series of up to 40 high temporal resolution (3)He ventilation images are obtained using a single bolus of gas. General properties of the spiral technique are discussed and compared to those of standard imaging techniques in relation to the specific case of rare gas imaging. To improve temporal resolution of the image series, the efficiency of a sliding window technique, combining data from two consecutive spiral images, is demonstrated. An example of the typical global (3)He signal variation during the (3)He breathing of the animal is shown. Pixel-by-pixel measurements of the (3)He signal derivative during the gas inspiration are performed. A corresponding lung map of the magnetization per time unit entering the lung during gas inflow is presented.

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The effect of coherent rotational motion on images acquired with the ultrafast single-shot spin-echo Burst sequence has been analyzed. Previous experience has demonstrated that sample rotation during Burst experiments has the potential to cause severe image artifacts. In this paper we show that no distortions are visible when the readout gradient is parallel to the rotation axis, but that there is a very distinctive behavior for the case of the rotation axis orthogonal to the imaging plane. The mathematical expression that describes the resulting signal is presented and is used as a basis for a method of correcting the k-space data. The conditions under which undistorted images may be recovered are discussed. It is shown that there is an asymmetry, dependent on the rotation direction, in both the manifestation of the artifact and the range of angular velocities over which one can correct the images. Data from an agar gel phantom rotating at a known rate are used to show how the theory is successful at reconstructing images, with no free parameters. The range of angular velocities over which correction is possible depends on the timing parameters of the pulse sequence, but for these data was -0.016 < omega less, similar 0.1 revolutions/s. Volunteer experiments have confirmed that the theory is applicable to patient motion and can correct motional distortion even when the exact rate is not known a priori. By optimizing the reconstruction to restore a known sample geometry/aspect ratio, an estimate of the rotation angular frequency is obtained with a precision of +/-10%.

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The assessment of both pulmonary perfusion and ventilation is of crucial importance for a proper diagnosis of some lung diseases such as pulmonary embolism. In this study, we demonstrate the feasibility of combined magnetic resonance imaging lung ventilation and perfusion performed serially in rat lungs. Lung ventilation function was assessed using hyperpolarized 3He, and lung perfusion proton imaging was demonstrated using contrast agent injection. Both imaging techniques have been implemented using projection-reconstruction sequences with free induction decay signal acquisitions. The study focused on fast three-dimensional (3D) data acquisition. The projection-reconstruction sequences used in this study allowed 3D data set acquisition in several minutes without high-performance gradients. 3D proton perfusion/helium ventilation imaging has been demonstrated on an experimental rat model of pulmonary embolism showing normal lung ventilation associated with lung perfusion defect. Assuming the possibility, still under investigation, of showing lung obstruction pathologies using 3He imaging, these combined perfusion/ventilation methods could play a significant clinical role in the future for diagnosis of several pulmonary diseases.

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A new strategy designed to provide functional magnetic resonance images of the lung in small animals at microscopic resolution using hyperpolarized 3He is described. The pulse sequence is based on a combination of radial acquisition (RA) and CINE techniques, referred to as RA-CINE, and is designed for use with hyperpolarized 3He to explore lung ventilation with high temporal and spatial resolution in small animal models. Ventilation of the live guinea pig is demonstrated with effective temporal resolution of 50 msec and in-plane spatial resolution of <100 microm using hyperpolarized 3He. The RA-CINE sequence allows one to follow gas inflow and outflow in the airways as well as in the distal part of the lungs. Regional analysis of signal intensity variations can be performed and can help assess functional lung parameters such as residual gas volume and lung compliance to gas inflow.

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An optimization scheme was developed for gradient echo imaging using a half-birdcage RF coil at 7 T to obtain maximal contrast between gray and white matter in the spinal cord of rodents. This optimization was combined with microimaging techniques to obtain in vivo pixel sizes of 78 x 78 x 700 microm. These techniques can be implemented in an in vivo study to investigate the myelin structure within the white matter of the rodent spinal cord.

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A multi-echo imaging sequence suitable for high-resolution and accurate in vivo transverse relaxation time (T2) mapping has been implemented. The sequence was tested on phantoms and was used to measure T2 values in vivo in the rat brain, muscle, and fat at 7 T. Brain T2 maps are shown and regional variations in brain T2 are reported (41.8 ms in cortex, 47.9 ms in hippocampus). Results are compared to literature values obtained at lower field in vivo as well as high-field T2 measurements on excised rat tissues. The reported T2 values are generally smaller compared to lower-field-strength literature values. A discussion of the possible causes of these field effects on T2 is included (dipolar interaction, fast chemical exchange, and diffusion in susceptibility gradients).

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The stimulated-echo acquisition mode-Burst sequence is a single-shot, multi-slice imaging technique that does not involve rapid gradient switching. A Burst excitation pulse train is followed by a 90 degrees hard pulse and, after a mixing time, by a 90 degrees slice-selective pulse. A read gradient refocuses a set of stimulated echoes, which can be phase-encoded to form an image. By repeating the selective pulse N times, each time with the carrier frequency offset differently, it is possible to sample N slices in a single-shot. A comparison is made of the sequence with other three-dimensional single-shot methods. Experiments implementing the technique on a 3 T whole-body imaging system and a 2 T, 31-cm bore animal imager are described. Both phantom and brain images are presented. The principal advantages of the new sequence are its speed, the absence of rapid gradient switching and corresponding freedom from artifacts, its insensitivity to static magnetic field inhomogeneities, and its low acoustic noise. The main disadvantages are the low signal-to-noise ratio of the images produced and the concomitant limitation in resolution.

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A new 3D Fourier imaging method based on sparse radial scanning (SRS-FT) of k space is proposed. It allows acquisition of FIDs and is therefore well suited to imaging objects with very short T2. Use of a Bayesian procedure allows (1) an important reduction of scan time to below that of the projection-reconstruction (PR) method by reducing the number of "Cartesian radial" encoding directions, and (2) a good image quality by estimating missing and corrupted Cartesian samples. SRS-FT images reconstructed from FIDs are compared to conventional FT and PR images.

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New, rapid two- and three-dimensional imaging sequences based on steady-state gradient echoes and projection-reconstruction (PR) techniques are proposed. Quantitative studies show that fast PR sequences and classical, fast gradient-echo Fourier transform sequences lead to identical contrasts. In order to minimize inhomogeneity effects, a particular focus has been placed on echo-time reduction. The use of a weighting window permits one to acquire severely truncated echoes; partial k-space scanning may be considered.

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OBJECTIVES: The purpose of this study was to correlate the size and the orientation of image disturbances observed on specific samples of dental materials with their magnetic susceptibility. The measurement of the magnetic susceptibility was performed in the 10(-5) or 10(-6) range using MRI to establish a classification of dental materials. METHODS: Cylindrical dental alloy samples incorporating gold, silver, and palladium were placed in a Pyrex beaker filled with distilled water. Images were performed at 0.13 Tesla using two-dimensional Fourier transformation and projection reconstruction at 360 degrees imaging methods. The magnetic susceptibilities were obtained by measuring distances between spots having the highest intensity on the image. RESULTS: A very discriminating classification may be established on MRI criteria. This method permits one to determine the dia- or para-magnetic character of the dental materials tested. Only palladium-based alloys have been detected to be paramagnetic with kappa > 0. One of the silver-based alloys did not induce detectable distortion because its susceptibility was very close to that of distilled water. Based on this MRI data, the use of this material may be recommended for applications that may be subjected to MRI evaluation. SIGNIFICANCE: With the increasing use of MRI as a diagnostic tool, it is useful to establish a classification of prosthetic biomaterials compatible with MRI.

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