Refined modelling of the short-T2 signal component and ensuing detection of glutamate and glutamine in short-TE, localised, (1) H MR spectra of human glioma measured at 3 T.

Short-TE (1) H MRS has great potential for brain cancer diagnostics. A major difficulty in the analysis of the spectra is the contribution from short-T2 signal components, mainly coming from mobile lipids. This complicates the accurate estimation of the spectral parameters of the resonance lines from metabolites, so that a qualitative to semi-quantitative interpretation of the spectra dominates in practice. One solution to overcome this difficulty is to measure and estimate the short-T2 signal component and to subtract it from the total signal, thus leaving only the metabolite signals. The technique works well when applied to spectra obtained from healthy individuals, but requires some optimisation during data acquisition. In the clinical setting, time constraints hardly allow this. Here, we propose an iterative estimation of the short-T2 signal component, acquired in a single acquisition after measurement of the full spectrum. The method is based on QUEST (quantitation based on quantum estimation) and allows the refinement of the estimate of the short-T2 signal component after measurement. Thus, acquisition protocols used on healthy volunteers can also be used on patients without further optimisation. The aim is to improve metabolite detection and, ultimately, to enable the estimation of the glutamine and glutamate signals distinctly. These two metabolites are of great interest in the characterisation of brain cancer, gliomas in particular. When applied to spectra from healthy volunteers, the new algorithm yields similar results to QUEST and direct subtraction of the short-T2 signal component. With patients, up to 12 metabolites and, at least, seven can be quantified in each individual brain tumour spectrum, depending on the metabolic state of the tumour. The refinement of the short-T2 signal component significantly improves the fitting procedure and produces a separate short-T2 signal component that can be used for the analysis of mobile lipid resonances. Thus, in brain tumour spectra, distinct estimates of signals from glutamate and glutamine are possible. Copyright © 2016 John Wiley & Sons, Ltd.

Synergistic effect of cisplatin and synchrotron irradiation on F98 gliomas growing in nude mice.

Among brain tumors, glioblastoma multiforme appears as one of the most aggressive forms of cancer with poor prognosis and no curative treatment available. Recently, a new kind of radio-chemotherapy has been developed using synchrotron irradiation for the photoactivation of molecules with high-Z elements such as cisplatin (PAT-Plat). This protocol showed a cure of 33% of rats bearing the F98 glioma but the efficiency of the treatment was only measured in terms of overall survival. Here, characterization of the effects of the PAT-Plat on tumor volume and tumor blood perfusion are proposed. Changes in these parameters may predict the overall survival. Firstly, changes in tumor growth of the F98 glioma implanted in the hindlimb of nude mice after the PAT-Plat treatment and its different modalities have been characterized. Secondly, the effects of the treatment on tumor blood perfusion have been observed by intravital two-photon microscopy. Cisplatin alone had no detectable effect on the tumor volume. A reduction of tumor growth was measured after a 15 Gy synchrotron irradiation, but the whole therapy (15 Gy irradiation + cisplatin) showed the largest decrease in tumor growth, indicating a synergistic effect of both synchrotron irradiation and cisplatin treatment. A high number of unperfused vessels (52%) were observed in the peritumoral area in comparison with untreated controls. In the PAT-Plat protocol the transient tumor growth reduction may be due to synergistic interactions of tumor-cell-killing effects and reduction of the tumor blood perfusion.

Magnetic resonance imaging and fluorescence labeling of clinical-grade mesenchymal stem cells without impacting their phenotype: study in a rat model of stroke.

Human mesenchymal stem cells (hMSCs) have strong potential for cell therapy after stroke. Tracking stem cells in vivo following a graft can provide insight into many issues regarding optimal route and/or dosing. hMSCs were labeled for magnetic resonance imaging (MRI) and histology with micrometer-sized superparamagnetic iron oxides (M-SPIOs) that contained a fluorophore. We assessed whether M-SPIO labeling obtained without the use of a transfection agent induced any cell damage in clinical-grade hMSCs and whether it may be useful for in vivo MRI studies after stroke. M-SPIOs provided efficient intracellular hMSC labeling and did not modify cell viability, phenotype, or in vitro differentiation capacity. Following grafting in a rat model of stroke, labeled hMSCs could be detected using both in vivo MRI and fluorescent microscopy until 4 weeks following transplantation. However, whereas good label stability and unaffected hMSC viability were observed in vitro, grafted hMSCs may die and release iron particles in vivo.

Abnormal cortical sensorimotor activity during "Target" sound detection in subjects with acute acoustic trauma sequelae: an fMRI study.

The most common consequences of acute acoustic trauma (AAT) are hearing loss at frequencies above 3 kHz and tinnitus. In this study, we have used functional Magnetic Resonance Imaging (fMRI) to visualize neuronal activation patterns in military adults with AAT and various tinnitus sequelae during an auditory "oddball" attention task. AAT subjects displayed overactivities principally during reflex of target sound detection, in sensorimotor areas and in emotion-related areas such as the insula, anterior cingulate and prefrontal cortex, in premotor area, in cross-modal sensory associative areas, and, interestingly, in a region of the Rolandic operculum that has recently been shown to be involved in tympanic movements due to air pressure. We propose further investigations of this brain area and fine middle ear investigations, because our results might suggest a model in which AAT tinnitus may arise as a proprioceptive illusion caused by abnormal excitability of middle-ear muscle spindles possibly link with the acoustic reflex and associated with emotional and sensorimotor disturbances.

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.

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.

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).

fMRI retinotopic mapping at 3 T: benefits gained from correcting the spatial distortions due to static field inhomogeneity.

fMRI retinotopic mapping usually relies upon Fourier analysis of functional responses to periodic visual stimuli that encode eccentricity or polar angle in the visual field. Generally, phase estimations are assigned to a surface model of the cerebral cortex and borders between retinotopic areas are eventually determined following ad hoc phase analysis on the surface model. Assigning functional responses to a surface model of the cortex is particularly sensitive to geometric distortions of the 3D functional data due to static field inhomogeneity. Here, we assess and document the benefits gained from correcting the fMRI data for these effects, under standard experimental conditions (echo-planar imaging, 3.0-T field strength) and with well-chosen acquisition parameters (regarding slice orientation and phase-encoding direction). While it appears that, in the absence of correction, errors in the estimates of the borders between low-order visual areas do not then significantly exceed the variance of statistical origin, about half of the functional responses in a retinotopic experiment are misassigned to neighboring functional areas. Therefore, correction of the effects due to geometric distortions is important in any retinotopic mapping experiment and by extension in any fMRI experiment on the visual system.

Impaired fMRI activation in patients with primary brain tumors.

To characterize peritumoral BOLD contrast disorders, 25 patients referred for resection of primary frontal or parietal neoplasms (low-grade glioma (LGG) (n=8); high-grade glioma (HGG) (n=7); meningioma (n=10)) without macroscopic tumoral infiltration of the primary sensorimotor cortex (SM1) were examined preoperatively using BOLD fMRI during simple motor tasks. Overall cerebral BOLD signal was estimated using vasoreactivity to carbogen inhalation. Using bolus of gadolinium, cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) were estimated. In a 1cm(3) region-of-interest centered on maximal T-value in SM1 contralateral to movements, interhemispheric asymmetry was evaluated using interhemispheric ratios for BOLD and perfusion parameters. During motor tasks contralateral to the tumor, ipsitumoral sensorimotor activations were decreased in HGG and meningiomas, correlated to the distance between the tumor and SM1. Whereas CBV was decreased in ipsitumoral SM1 for HGG, it remained normal in meningiomas. Changes in basal perfusion could not explain motor activation impairment in SM1. Decreased interhemispheric ratio of the BOLD response to carbogen was the best predictor to model the asymmetry of motor activation (R=0.51). Moreover, 94.9+/-4.9% of all motor activations overlapped significant BOLD response to carbogen inhalation.

Characterization of the hemodynamic modes associated with interictal epileptic activity using a deformable model-based analysis of combined EEG and functional MRI recordings.

Simultaneous electroencephalography and functional magnetic resonance imaging (EEG/fMRI) have been proposed to contribute to the definition of the epileptic seizure onset zone. Following interictal epileptiform discharges, one usually assumes a canonical hemodynamic response function (HRF), which has been derived from fMRI studies in healthy subjects. However, recent findings suggest that the hemodynamic properties of the epileptic brain are likely to differ significantly from physiological responses. Here, we propose a simple and robust approach that provides HRFs, defined as a limited set of gamma functions, optimized so as to elicit strong activations after standard model-driven statistical analysis at the single subject level. The method is first validated on healthy subjects using experimental data acquired during motor, visual and memory encoding tasks. Second, interictal EEG/fMRI data measured in 10 patients suffering from epilepsy are analyzed. Results show dramatic changes of activation patterns, depending on whether physiological or pathological assumptions are made on the hemodynamics of the epileptic brain. Our study suggests that one cannot assume a priori that HRFs in epilepsy are similar to the canonical model. This may explain why a significant fraction of EEG/fMRI exams in epileptic patients are inconclusive after standard data processing. The heterogeneous perfusion in epileptic regions indicates that the properties of brain vasculature in epilepsy deserve careful attention.

The impact of erythropoietin on short-term changes in phosphorylation of brain protein kinases in a rat model of traumatic brain injury.

We found that recombinant human erythropoietin (rhEPO) reduced significantly the development of brain edema in a rat model of diffuse traumatic brain injury (TBI) (impact-acceleration model). In this study, we investigated the molecular and intracellular changes potentially involved in these immediate effects. Brain tissue nitric oxide (NO) synthesis, phosphorylation level of two protein kinases (extracellular-regulated kinase (ERK)-1/-2 and Akt), and brain water content were measured 1 (H1) and 2 h (H2) after insult. Posttraumatic administration of rhEPO (5,000 IU/kg body weight, intravenously, 30 mins after injury) reduced TBI-induced upregulation of ERK phosphorylation, although it increased Akt phosphorylation at H1. These early molecular changes were associated with a reduction in brain NO synthesis at H1 and with an attenuation of brain edema at H2. Intraventricular administration of the ERK-1/-2 inhibitor, U0126, or the Akt inhibitor, LY294002, before injury showed that ERK was required for brain edema formation, and that rhEPO-induced reduction of edema could involve the ERK pathway. These results were obtained in the absence of any evidence of blood-brain barrier damage on contrast-enhanced magnetic resonance images. The findings of our study indicate that the anti edematous effect of rhEPO could be mediated through an early inhibition of ERK phosphorylation after diffuse TBI.

Intravenous administration of 99mTc-HMPAO-labeled human mesenchymal stem cells after stroke: in vivo imaging and biodistribution.

Human mesenchymal stem cells (hMSC) are a promising source for cell therapy after stroke. To deliver these cells, an IV injection appears safer than a local graft. We aimed to assess the whole-body biodistribution of IV-injected (99m)Tc-HMPAO-labeled hMSC in normal rats (n = 9) and following a right middle cerebral artery occlusion (MCAo, n = 9). Whole-body nuclear imaging, isolated organ counting (at 2 and 20 h after injection) and histology were performed. A higher activity was observed in the right damaged hemisphere of the MCAo group [6.5 +/- 0.9 x 10(-3) % of injected dose (ID)/g] than in the control group (3.6 +/- 1.2 x 10(-3) %ID/g), 20 h after injection. In MCAo rats, right hemisphere activity was higher than that observed in the contralateral hemisphere at 2 h after injection (11.6 +/- 2.8 vs. 9.8 +/- 1.7 x 10(-3) %ID/g). Following an initial hMSC lung accumulation, there was a decrease in pulmonary activity from 2 to 20 h after injection in both groups. The spleen was the only organ in which activity increased between 2 and 20 h. The presence of hMSC was documented in the spleen, liver, lung, and brain following histology. IV-injected hMSC are transiently trapped in the lungs, can be sequestered in the spleen, and are predominantly eliminated by kidneys. After 20 h, more hMSC are found in the ischemic lesion than into the undamaged cerebral tissue. IV delivery of hMSC could be the initial route for a clinical trial of tolerance.

Characterization of tumor angiogenesis in rat brain using iron-based vessel size index MRI in combination with gadolinium-based dynamic contrast-enhanced MRI.

This study aimed at combining an iron-based, steady-state, vessel size index magnetic resonance imaging (VSI MRI) approach, and a gadolinium (Gd)-based, dynamic contrast-enhanced MRI approach (DCE MRI) to characterize tumoral microvasculature. Rats bearing an orthotopic glioma (C6, n=14 and RG2, n=6) underwent DCE MRI and combined VSI and DCE MRI 4 h later, at 2.35 T. Gd-DOTA (200 mumol of Gd per kg) and ultrasmall superparamagnetic iron oxide (USPIO) (200 micromol of iron per kg) were used for DCE and VSI MRI, respectively. C6 and RG2 gliomas were equally permeable to Gd-DOTA but presented different blood volume fractions and VSI, in good agreement with histologic data. The presence of USPIO yielded reduced K(trans) values. The K(trans) values obtained with Gd-DOTA in the absence and in the presence of USPIO were well correlated for the C6 glioma but not for the RG2 glioma. It was also observed that, within the time frame of DCE MRI, USPIO remained intravascular in the C6 glioma whereas it extravasated in the RG2 glioma. In conclusion, VSI and DCE MRI can be combined provided that USPIO does not extravasate with the time frame of the DCE MRI experiment. The mechanisms at the origin of USPIO extravasation remain to be elucidated.

Short-term effects of synchrotron irradiation on vasculature and tissue in healthy mouse brain.

The purpose of this study is to measure the effects of a tomographic synchrotron irradiation on healthy mouse brain. The cerebral cortexes of healthy nude mice were irradiated with a monochromatic synchrotron beam of 79 keV at a dose of 15 Gy in accordance with a protocol of photoactivation of cisplatin previously tested in our laboratory. Forty-eight hours, one week and one month after irradiation, the blood brain barrier (BBB) permeability was measured in the irradiated area with intravital multiphoton microscopy using fluorescent dyes with molecular weights of 4 and 70 kDa. Vascular parameters and gliosis were also assessed using quantitative immunohistochemistry. No extravasation of the fluorescent dyes was observed in the irradiated area at any measurement time (48 h, 1 week, 1 month). It appears that the BBB remains impermeable to molecules with a molecular weight of 4 kDa and above. The vascular density and vascular surface were unaffected by irradiation and no gliosis was induced. These findings suggest that a 15 Gy/79 keV synchrotron irradiation does not induce important damage on brain vasculature and tissue on the short term following irradiation.

The sensory-motor specificity of taxonomic and thematic conceptual relations: a behavioral and fMRI study.

Previous behavioral data suggest that the salience of taxonomic (e.g., hammer-saw) and thematic (e.g., hammer-nail) conceptual relations depends on object categories. Furthermore, taxonomic and thematic relations would be differentially grounded in the sensory-motor system. Using a picture matching task, we asked adult participants to identify taxonomic and thematic relations for non-manipulable and manipulable natural and artifact targets (e.g., animals, fruit, tools and vehicles, respectively) inside and outside a 3 T MR scanner. Behavioral data indicated that taxonomic relations are identified faster in natural objects while thematic relations are processed faster in artifacts, particularly manipulable ones (e.g., tools). Neuroimaging findings revealed that taxonomic processing specifically activates the bilateral visual areas (cuneus, BA 18), particularly for non-manipulable natural objects (e.g., animals). On the contrary, thematic processing specifically recruited a bilateral temporo-parietal network including the inferior parietal lobules (IPL, BA 40) and middle temporal gyri (MTG, BA 39/21/22). Left IPL and MTG activation was stronger for manipulable than for non-manipulable artifacts (e.g., tools vs. vehicles) during thematic processing. Right IPL and MTG activation was greater for both artifacts compared to natural objects during thematic processing (manipulable and non-manipulable ones, e.g., tools and vehicles). While taxonomic relations would selectively rely on perceptual similarity processing, thematic relations would specifically activate visuo-motor regions involved in action and space processing. In line with embodied views of concepts, our findings show that taxonomic and thematic conceptual relations are based on different sensory-motor processes. It suggests that they may have different roles in concept formation and processing depending on object categories.

Identifying neural drivers with functional MRI: an electrophysiological validation.

Whether functional magnetic resonance imaging (fMRI) allows the identification of neural drivers remains an open question of particular importance to refine physiological and neuropsychological models of the brain, and/or to understand neurophysiopathology. Here, in a rat model of absence epilepsy showing spontaneous spike-and-wave discharges originating from the first somatosensory cortex (S1BF), we performed simultaneous electroencephalographic (EEG) and fMRI measurements, and subsequent intracerebral EEG (iEEG) recordings in regions strongly activated in fMRI (S1BF, thalamus, and striatum). fMRI connectivity was determined from fMRI time series directly and from hidden state variables using a measure of Granger causality and Dynamic Causal Modelling that relates synaptic activity to fMRI. fMRI connectivity was compared to directed functional coupling estimated from iEEG using asymmetry in generalised synchronisation metrics. The neural driver of spike-and-wave discharges was estimated in S1BF from iEEG, and from fMRI only when hemodynamic effects were explicitly removed. Functional connectivity analysis applied directly on fMRI signals failed because hemodynamics varied between regions, rendering temporal precedence irrelevant. This paper provides the first experimental substantiation of the theoretical possibility to improve interregional coupling estimation from hidden neural states of fMRI. As such, it has important implications for future studies on brain connectivity using functional neuroimaging.

Hyperosmolar treatment of soman-induced brain lesions in mice: evaluation of the effects through diffusion-weighted magnetic resonance imaging and through histology.

PURPOSE: A convulsive dose of soman induces seizure-related brain damage (SRBD), including cerebral edema (CE) and neuronal loss. In the present study on soman-intoxicated mice, we applied diffusion-weighted magnetic resonance imaging (DW-MRI) and quantitative histology, and we measured brain water content to investigate the antiedematous and neuroprotective efficacies of two hyperosmolar treatments: mannitol (Mann) and hypertonic saline (HTS). METHODS: Mice intoxicated with soman (172 microg/kg after a protective pretreatment) were administered 1 min and 5-h post-challenge an i.v. bolus of saline, of Mann or of HTS. 1 day later, mice were examined with DW-MRI and then sacrificed for brain histology. Additional animals were intoxicated and treated similarly for the measurement of the brain water content (dry/wet weight method). RESULTS: In intoxicated controls, a significant decrease of the apparent diffusion coefficient (ADC), numerous damaged (eosinophilic) cells, high edema scores, and a significant increase in brain water content were detected 24-h post-challenge in sensitive brain structures. These soman-induced changes were not significantly modified by treatment with Mann or HTS. CONCLUSIONS: Treatment with hyperosmolar solutions did not reduce the effects of soman on ADC, on cell damage and on CE. Therefore, despite similar treatment protocols, the prominent protection by Mann that was previously demonstrated by others in poisoned rats, was not reproduced in our murine model.

Assessment of blood volume, vessel size, and the expression of angiogenic factors in two rat glioma models: a longitudinal in vivo and ex vivo study.

Assessment of angiogenesis may help to determine tumor grade and therapy follow-up. In vivo imaging methods for non-invasively monitoring microvasculature evolution are therefore of major interest for tumor management. MRI evaluation of blood volume fraction (BVf) and vessel size index (VSI) was applied to assess the evolution of tumor microvasculature in two rat models of glioma (C6 and RG2). The results show that repeated MRI of BVf and VSI - which involves repeated injection of an iron-based MR contrast agent - does not affect either the physiological status of the animals or the accuracy of the MR estimates of the microvascular parameters. The MR measurements were found to correlate well with those obtained from histology. They indicate that microvascular evolution differs significantly between the two glioma models, in good agreement with expression of angiogenic factors (vascular endothelial growth factor, angiopoietin-2) and with activities of matrix metalloproteinases, also assessed in this study. These MRI methods thus provide considerable potential for assessing the response of gliomas to anti-angiogenic and anti-vascular agents, in preclinical studies as well as in the clinic. Furthermore, as differences between the fate of tumor microvasculature may underlie differences in therapeutic response, there is a need for preclinical study of several tumor models.

Brain tumor vessel response to synchrotron microbeam radiation therapy: a short-term in vivo study.

The aim of this work focuses on the description of the short-term response of a 9L brain tumor model and its vasculature to microbeam radiation therapy (MRT) using magnetic resonance imaging (MRI). Rat 9L gliosarcomas implanted in nude mice brains were irradiated by MRT 13 days after tumor inoculation using two orthogonal arrays of equally spaced 28 planar microbeams (25 microm width, 211 microm spacing and dose 500 Gy). At 1, 7 and 14 days after MRT, apparent diffusion coefficient, blood volume and vessel size index were mapped by MRI. Mean survival time after tumor inoculation increased significantly between MRT-treated and untreated groups (23 and 28 days respectively, log-rank test, p < 0.0001). A significant increase of apparent diffusion coefficient was observed 24 h after MRT in irradiated tumors versus non-irradiated ones. In the untreated group, both tumor size and vessel size index increased significantly (from 7.6 +/- 2.2 to 19.2 +/- 4.0 mm(2) and +23%, respectively) between the 14th and the 21st day after tumor cell inoculation. During the same period, in the MRT-treated group, no difference in tumor size was observed. The vessel size index measured in the MRT-treated group increased significantly (+26%) between 14 and 28 days of tumor growth. We did not observe the significant difference in blood volume between the MRT-treated and untreated groups. MRT slows 9L tumor growth in a mouse brain but MRI results suggest that the increase in survival time after our MRT approach may be rather due to a cytoreduction than to early direct effects of ionizing radiation on tumor vessels. These results suggest that MRT parameters need to be optimized to further damage tumor vessels.

In vivo MRI tracking of exogenous monocytes/macrophages targeting brain tumors in a rat model of glioma.

This study has shown that murine monocytes/macrophages (Mo/Ma) can be labeled simply and efficiently with large, green-fluorescent, micrometer-sized particles of iron-oxide (MPIO). Neither size nor proliferation rate of the Mo/Ma is significantly affected by this labeling. The labeled Mo/Ma have been administered intravenously to rats that had developed a glioma following stereotactic injection of C6 cells. The labeled Mo/Ma were shown to target the brain tumors, a process that could be monitored non-invasively using T2*-weighted MRI. MRI observations were confirmed by Prussian blue staining, lectin staining and fluorescence histology. Overall, the results of this study suggest that the use of Mo/Ma may be envisaged in the clinic for vectorizing therapeutic agents toward gliomas.