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.

Disentangling the Role of Cortico-Basal Ganglia Loops in Top-Down and Bottom-Up Visual Attention: An Investigation of Attention Deficits in Parkinson Disease.

It is solidly established that top-down (goal-driven) and bottom-up (stimulus-driven) attention mechanisms depend on distributed cortical networks, including prefrontal and frontoparietal regions. On the other hand, it is less clear whether the BG also contribute to one or the other of these mechanisms, or to both. The current study was principally undertaken to clarify this issue. Parkinson disease (PD), a neurodegenerative disorder primarily affecting the BG, has proven to be an effective model for investigating the contribution of the BG to different brain functions; therefore, we set out to investigate deficits of top-down and bottom-up attention in a selected cohort of PD patients. With this objective in mind, we compared the performance on three computerized tasks of two groups of 12 parkinsonian patients (assessed without any treatment), one otherwise pharmacologically treated and the other also surgically treated, with that of a group of controls. The main behavioral tool for our study was an attentional capture task, which enabled us to tap the competition between top-down and bottom-up mechanisms of visual attention. This task was suitably combined with a choice RT and a simple RT task to isolate any specific deficit of attention from deficits in motor response selection and initiation. In the two groups of patients, we found an equivalent increase of attentional capture but also comparable delays in target selection in the absence of any salient distractor (reflecting impaired top-down mechanisms) and movement initiation compared with controls. In contrast, motor response selection processes appeared to be prolonged only in the operated patients. Our results confirm that the BG are involved in both motor and cognitive domains. Specifically, damage to the BG, as it occurs in PD, leads to a distinct deficit of top-down control of visual attention, and this can account, albeit indirectly, for the enhancement of attentional capture, reflecting weakened ability of top-down mechanisms to antagonize bottom-up control.

Surgical implantation of STN-DBS leads using intraoperative MRI guidance: technique, accuracy, and clinical benefit at 1-year follow-up.

BACKGROUND: Improvement of surgical accuracy during DBS-lead implantation has been described recently, leading to "frameless" or "MRI-verified" techniques. However, combining a high-quality definition of the STN using intraoperative 1.5 MRI with the possibility to reduce errors due to co-registration and to monitor lead progression during surgical insertion while checking the absence of surgical complication is an appealing method. We report here surgical methodology, safety, application accuracy, and clinical benefit of STN-lead implantation under MRI guidance. METHODS: Two patients with a severe PD state were treated by bilateral STN-DBS. Leads were implanted under general anesthesia using intraoperative MRI guidance (ClearPoint system). Lead implantation accuracy was measured on T1 axial images at the level of the target. Clinical improvement was measured on the pre- and post-UPDRS 3 scale at 1-year follow-up. RESULTS: Surgery was safe and uneventful in both cases. Radial error was 0.36 (right) and 0.86 mm (left) in case 1, and 0.41 (right) and 0.14 mm (left) in case 2. No edema or hemorrhage were noticed. CONCLUSIONS: Intraoperative MRI guidance allows DBS lead implantation with high accuracy and with great clinical efficacy. A larger cohort of patients is needed to confirm these initial results.

Retinotopic and lateralized processing of spatial frequencies in human visual cortex during scene categorization.

Using large natural scenes filtered in spatial frequencies, we aimed to demonstrate that spatial frequency processing could not only be retinotopically mapped but could also be lateralized in both hemispheres. For this purpose, participants performed a categorization task using large black and white photographs of natural scenes (indoors vs. outdoors, with a visual angle of 24° × 18°) filtered in low spatial frequencies (LSF), high spatial frequencies (HSF), and nonfiltered scenes, in block-designed fMRI recording sessions. At the group level, the comparison between the spatial frequency content of scenes revealed first that, compared with HSF, LSF scene categorization elicited activation in the anterior half of the calcarine fissures linked to the peripheral visual field, whereas, compared with LSF, HSF scene categorization elicited activation in the posterior part of the occipital lobes, which are linked to the fovea, according to the retinotopic property of visual areas. At the individual level, functional activations projected on retinotopic maps revealed that LSF processing was mapped in the anterior part of V1, whereas HSF processing was mapped in the posterior and ventral part of V2, V3, and V4. Moreover, at the group level, direct interhemispheric comparisons performed on the same fMRI data highlighted a right-sided occipito-temporal predominance for LSF processing and a left-sided temporal cortex predominance for HSF processing, in accordance with hemispheric specialization theories. By using suitable method of analysis on the same data, our results enabled us to demonstrate for the first time that spatial frequencies processing is mapped retinotopically and lateralized in human occipital cortex.

Functional MRI assessment of orofacial articulators: neural correlates of lip, jaw, larynx, and tongue movements.

Compared with complex coordinated orofacial actions, few neuroimaging studies have attempted to determine the shared and distinct neural substrates of supralaryngeal and laryngeal articulatory movements when performed independently. To determine cortical and subcortical regions associated with supralaryngeal motor control, participants produced lip, tongue and jaw movements while undergoing functional magnetic resonance imaging (fMRI). For laryngeal motor activity, participants produced the steady-state/i/vowel. A sparse temporal sampling acquisition method was used to minimize movement-related artifacts. Three main findings were observed. First, the four tasks activated a set of largely overlapping, common brain areas: the sensorimotor and premotor cortices, the right inferior frontal gyrus, the supplementary motor area, the left parietal operculum and the adjacent inferior parietal lobule, the basal ganglia and the cerebellum. Second, differences between tasks were restricted to the bilateral auditory cortices and to the left ventrolateral sensorimotor cortex, with greater signal intensity for vowel vocalization. Finally, a dorso-ventral somatotopic organization of lip, jaw, vocalic/laryngeal, and tongue movements was observed within the primary motor and somatosensory cortices using individual region-of-interest (ROI) analyses. These results provide evidence for a core neural network involved in laryngeal and supralaryngeal motor control and further refine the sensorimotor somatotopic organization of orofacial articulators.

Assessment of white matter injury and outcome in severe brain trauma: a prospective multicenter cohort.

BACKGROUND: Existing methods to predict recovery after severe traumatic brain injury lack accuracy. The aim of this study is to determine the prognostic value of quantitative diffusion tensor imaging (DTI). METHODS: In a multicenter study, the authors prospectively enrolled 105 patients who remained comatose at least 7 days after traumatic brain injury. Patients underwent brain magnetic resonance imaging, including DTI in 20 preselected white matter tracts. Patients were evaluated at 1 yr with a modified Glasgow Outcome Scale. A composite DTI score was constructed for outcome prognostication on this training database and then validated on an independent database (n=38). DTI score was compared with the International Mission for Prognosis and Analysis of Clinical Trials Score. RESULTS: Using the DTI score for prediction of unfavorable outcome on the training database, the area under the receiver operating characteristic curve was 0.84 (95% CI: 0.75-0.91). The DTI score had a sensitivity of 64% and a specificity of 95% for the prediction of unfavorable outcome. On the validation-independent database, the area under the receiver operating characteristic curve was 0.80 (95% CI: 0.54-0.94). On the training database, reclassification methods showed significant improvement of classification accuracy (P < 0.05) compared with the International Mission for Prognosis and Analysis of Clinical Trials score. Similar results were observed on the validation database. CONCLUSIONS: White matter assessment with quantitative DTI increases the accuracy of long-term outcome prediction compared with the available clinical/radiographic prognostic score.

Perfusion magnetic resonance imaging: comparison of semiologic characteristics in first-pass perfusion of brain tumors at 1.5 and 3 Tesla.

OBJECTIVES: To investigate whether using 3 Tesla (T) instead of 1.5T modifies the data obtained from first-pass perfusion in relation to the quantitative values of cerebral blood volume (CBV) and estimation of micro-vascular leakage (MVL). To describe the differences in data in the setting of neuro-oncology cases and propose explanations based on the discrepancies. MATERIAL AND METHODS: In total, 21 patients presenting an intracranial intra-axial space-occupying lesion underwent two MRI explorations, one at 1.5T and another at 3T, including a first-pass perfusion sequence using sequence parameters, defined by the manufacturer Philips. Using a gamma variate analysis, the ratio of cerebral blood volume (rCBV) in tumor, peritumoral, and normal appearing areas was first assessed. After a global analysis, a subgroup analysis was conducted according to the rCBV value measured at 1.5T. Lastly, MVL was assessed based on the signal intensity recorded above baseline after the passage of the contrast medium. RESULTS: At 3T, compared to 1.5T data that are currently the reference, rCBV was constantly and significantly over-evaluated (P=0.0041 for all tumors), while MVL was constantly and significantly under-evaluated (P<0.0001 for all tumors). DISCUSSION: The increase in magnetic field strength along with the associated modifications in sequence parameters led to variations in rCBV and MVL when measured using first-pass perfusion. In some cases, such as lymphomas, there was a loss of diagnostic information. It therefore appears necessary to optimize the acquisition parameters to allow for radiologic semiology to become relevant again.

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.

Predicting cognitive dysfunctioning in nondemented patients early after stroke.

BACKGROUND: Cognitive dysfunctioning (CDF) is an important issue in stroke, interfering with recovery and social dysfunctioning. We aimed to investigate the clinical and imaging correlates of CDF in patients with a first-ever subacute ischemic stroke and no dementia. METHODS: We evaluated CDF 15 days after stroke in a prospective cohort of consecutive patients with a Mini Mental State Examination score > or =23 using a comprehensive neuropsychological battery. CDF was ranked into 3 categories according to Z scores calculated for each test and adjusted for age and education. CDF was analyzed in relation to stroke features. Imaging was assessed using MRI. An ordinal regression procedure was used to determine the clinical correlates of CDF and to compute probabilities. RESULTS: Cognitive evaluation was achieved in 177 consecutive patients (age 50.0 +/- 16.0 years). In bivariate analysis, CDF was associated with age, low level of education, depression, neurological deficit at day 15, stroke subtype, arterial territory and leukoaraiosis but not with stroke volume or location. The predictors of CDF were NIHSS score at day 15 (OR = 1.35; 95% CI = 1.05-1.73), middle cerebral artery infarct (OR = 2.96; 95% CI = 1.30-6.73), depression interacting with left stroke side (OR = 1.09; 95% CI = 1.03-1.15), and female gender interacting with high level of education (OR = 0.209; 95% CI = 0.085-0.514). CONCLUSIONS: Stroke features correlate with CDF in nondemented patients. These simple criteria may help to predict CDF at bedside in the subacute phase after stroke and to recommend a neuropsychological evaluation for patients' management. Modeling CDF soon after stroke using simple neurological criteria may be a useful tool for designing clinical trials.

Perfusion CT to quantify the cerebral vasospasm following subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: After subarachnoid hemorrhage (SAH), vasospasm is frequent and increases the risk of stroke and poor clinical outcome. The purpose of this study was to identify the best perfusion parameters in perfusion-CT (PCT) able to predict vasospasm diagnosed by angiography after SAH. METHODS: Seventy-six patients with SAH were investigated by PCT and cerebral angiography. Using regions of interest (ROI) on parametric maps of mean transit time (MTT), time to peak (TTP), cerebral blood volume (CBV) and cerebral blood flow (CBF), PCT data were compared to an arteriographic score in two categories (severe vasospasm: ≥ 50% and non-severe vasospasm: <50%) for each artery. Best PCT predictors of the arteriographic score were tested using multiparametric logistic regression. RESULTS: Among the 76 patients, PCT data were reliable in 65 patients. Twenty-seven patients had a severe vasospasm. Logistic regression showed that MTT was the best predictor of the arteriographic score. Using MTT, odds ratios having a vasospasm were superior to 3.1 and the occurrence of a vasospasm was accurately predicted in 78.5 to 100%, depending on the artery considered. However, no absolute value of the MTT could be identified to predict the occurrence of vasospasm. In fact, abnormal values of MTT ranged from 123 to 221% (m=146%) of the control values. DISCUSSION AND CONCLUSIONS: PCT may accurately identify severe vasospasm and might be used as a convenient noninvasive imaging modality to monitor patients with SAH. When detected, severe vasospasm could be confirmed and managed using angiography and endovascular treatment, appropriately.

Bilateral pallidal deep brain stimulation for the treatment of patients with dystonia-choreoathetosis cerebral palsy: a prospective pilot study.

BACKGROUND: Cerebral palsy (CP) with dystonia-choreoathetosis is a common cause of disability in children and in adults, and responds poorly to medical treatment. Bilateral pallidal deep brain stimulation (BP-DBS) of the globus pallidus internus (GPi) is an effective treatment for primary dystonia, but the effect of this reversible surgical procedure on dystonia-choreoathetosis CP, which is a subtype of secondary dystonia, is unknown. Our aim was to test the effectiveness of BP-DBS in adults with dystonia-choreoathetosis CP. METHODS: We did a multicentre prospective pilot study of BP-DBS in 13 adults with dystonia-choreoathetosis CP who had no cognitive impairment, little spasticity, and only slight abnormalities of the basal ganglia on MRI. The primary endpoint was change in the severity of dystonia-choreoathetosis after 1 year of neurostimulation, as assessed with the Burke-Fahn-Marsden dystonia rating scale. The accuracy of surgical targeting to the GPi was assessed masked to the results of neurostimulation. Analysis was by intention to treat. FINDINGS: The mean Burke-Fahn-Marsden dystonia rating scale movement score improved from 44.2 (SD 21.1) before surgery to 34.7 (21.9) at 1 year post-operatively (p=0.009; mean improvement 24.4 [21.1]%, 95% CI 11.6-37.1). Functional disability, pain, and mental health-related quality of life were significantly improved. There was no worsening of cognition or mood. Adverse events were related to stimulation (arrest of the stimulator in one patient, and an adjustment to the current intensity in four patients). The optimum therapeutic target was the posterolateroventral region of the GPi. Little improvement was seen when the neurostimulation diffused to adjacent structures (mainly to the globus pallidus externus [GPe]). INTERPRETATION: Bilateral pallidal neurostimulation could be an effective treatment option for patients with dystonia-choreoathetosis CP. However, given the heterogeneity of motor outcomes and the small sample size, results should be interpreted with caution. The optimum placement of the leads seemed to be a crucial, but not exclusive, factor that could affect a good outcome. FUNDING: National PHRC; Cerebral Palsy Foundation: Fondation Motrice/APETREIMC; French INSERM Dystonia National Network; Medtronic.

Cerebral blood volume quantification in a C6 tumor model using gadolinium per (3,6-anhydro) alpha-cyclodextrin as a new magnetic resonance imaging preclinical contrast agent.

In magnetic resonance imaging (MRI), cerebral blood volume (CBV) quantification is dependent on the MRI sequence and on the properties of the contrast agents (CAs). By using the rapid steady-state T(1) method, we show the potential of gadolinium per (3,6-anhydro) alpha-cyclodextrin (Gd-ACX), a new MRI paramagnetic CA (inclusion complex of Gd(3+) with per (3,6-anhydro)-alpha-cyclodextrin), for the CBV quantification in the presence of blood-brain barrier lesions. After biocompatibility and relaxivity experiments, in vivo experiments on rats were performed on a C6 tumor model with 0.05 mmol Gd-ACX/kg (<1/10 of the median lethal dose) injected at a 25 mmol/L concentration, inducing neither nephrotoxicity nor hemolysis. On T(1)-weighted images, a signal enhancement of 170% appeared in vessels after injection, but not in the tumor (during the 1 h of observation), in contrast to the 90% signal enhancement obtained with Gd-DOTA (a clinical MRI CA) injected at a T(1) isoefficient dose. This result shows the absence of Gd-ACX extravasation into the tumor tissue and its confinement to the vascular space. Fractional CBV values were found similar to Gd-ACX and Gd-DOTA in healthy brain tissue and in the contralateral hemisphere of tumor-bearing rats, whereas only Gd-ACX was appropriate for CBV quantification in tumor regions.

Acute deep-brain stimulation of the internal and external globus pallidus in primary dystonia: functional mapping of the pallidum.

BACKGROUND: Dystonia is a syndrome characterized by prolonged muscle contractions that cause sustained twisting movements and abnormal posturing of body parts. Patients with the severe and generalized forms can benefit from bilateral high-frequency pallidal stimulation. OBJECTIVE: To investigate the functional map of the globus pallidus (GP) in patients with primary generalized dystonia. DESIGN: Prospective multicenter, double-blind, video-controlled study in patients treated at a university hospital. SETTING: University secondary care centers. PATIENTS: Twenty-two patients with primary generalized dystonia. INTERVENTIONS: Acute internal and external pallidal deep-brain stimulation or pallidal deep-brain stimulation. MAIN OUTCOME MEASURES: The clinical effects of acute bilateral high-frequency ventral vs acute dorsal pallidal stimulation were assessed with the Movement subscale of the Burke-Fahn-Marsden Dystonia Rating Scale. Intrapallidal localization of the contacts of the quadripolar electrodes was performed using a 3-dimensional atlas-magnetic resonance imaging coregistration method by investigators blinded to the clinical outcome. RESULTS: Bilateral acute ventral stimulation of the GP significantly improved the Burke-Fahn-Marsden Dystonia Rating Scale score by 42% and resulted in stimulation of contacts located in the internal GP or medullary lamina in 18 of 21 patients. Bilateral acute dorsal pallidal stimulation, primarily localized within the external GP, had variable effects across patients, with half demonstrating slight or no improvement or even aggravation of dystonia compared with baseline. CONCLUSIONS: Ventral pallidal stimulation, primarily of the internal GP or medullary lamina or both, is the optimal method for the treatment of dystonia. The varying effects across patients of bilateral acute dorsal pallidal stimulation, primarily of the external GP, suggest that unknown factors associated with dystonia could have a role in and contribute to the effects of the electrical stimulation.

Functional MRI approach for assessing hemispheric predominance of regions activated by a phonological and a semantic task.

This fMRI study performed in healthy subjects aimed at using a statistical approach in order to determine significant functional differences between hemispheres and to assess specialized regions activated during a phonological and during a semantic task. This approach ("flip" method and subsequent statistical analyses of the parameter estimates extracted from regions of interest) allows identifying: (a) hemispheric specialized regions for each language task [semantic (living categorization) and phonological (rhyme detection)] and (b) condition-specific regions with respect to paradigm conditions (task and control). Our results showed that the rhyme-specific task regions were the inferior frontal (sub-region of BA 44, 45) and left inferior parietal (BA 40, 39) lobules. Furthermore, within the inferior parietal lobule, the angular gyrus was specific to target (rhyming) items (related to successfully grapho-phonemic processing). The categorization-specific task regions were the left inferior frontal (sub-region of BA 44, 45) and superior temporal (BA 22) cortices. Furthermore, the superior temporal gyrus was related to non-target (non-living) items (correlated to task difficulty). The relatively new approach used in this study has the advantage of providing: (a) statistical significance of the hemispheric specialized regions for a given language task and (b) supplementary information in terms of paradigm condition-specificity of the activated regions. The results (standard hemispheric specialized regions for a semantic and for a phonological task) obtained in healthy subjects may constitute a basement for mapping language and assessing hemispheric predominance in epileptic patients before surgery and avoiding post-surgical impairments of language.

Prolonged survival of Fischer rats bearing F98 glioma after iodine-enhanced synchrotron stereotactic radiotherapy.

PURPOSE: Heavy-atom-enhanced synchrotron stereotactic radiotherapy (SSR) is a treatment that involves selective accumulation of high-Z elements in tumors followed by stereotactic irradiation with X-rays from a synchrotron source. The purpose of this study was to determine whether the efficacy of iodine-enhanced SSR could be further improved in the F98 rodent glioma model, by using a concomitant injection of an iodinated contrast agent and a transient blood-brain barrier opener (mannitol) during irradiation. METHODS AND MATERIALS: Fourteen days after intracerebral inoculations of F98 cells, the rats were irradiated with 50-keV X-rays while receiving an infusion of hyperosmotic mannitol with iodine, either intravenously or via the carotid (9 to 15 rats per group, 117 rats total). RESULTS: For doses

Synchrotron photoactivation of cisplatin elicits an extra number of DNA breaks that stimulate RAD51-mediated repair pathways.

Combination of cis-platinum with ionizing radiation is one of the most promising anticancer treatments that appears to be more efficient than radiotherapy alone. Unlike conventional X-ray emitters, accelerators of high energy particles like synchrotrons display powerful and monochromatizable radiation that makes the induction of an Auger electron cascade in cis-platinum molecules [also called photoactivation of cis-platinum (PAT-Plat)] theoretically possible. Here, we examined the molecular consequences of one of the first attempts of synchrotron PAT-Plat, performed at the European Synchrotron Research Facility (Grenoble-France). PAT-Plat was found to result in an extra number of slowly repairable DNA double-strand breaks, inhibition of DNA-protein kinase activity, dramatic nuclear relocalization of RAD51, hyperphosphorylation of the BRCA1 protein, and activation of proto-oncogenic c-Abl tyrosine kinase.

High-resolution blood-brain barrier permeability and blood volume imaging using quantitative synchrotron radiation computed tomography: study on an F98 rat brain glioma.

The authors previously provided evidence of synchrotron radiation computed tomography (SRCT) efficacy for quantitative in vivo brain perfusion measurements using monochromatic X-ray beams. However, this technique was limited for small-animal studies by partial volume effects. In this paper, high-resolution absolute cerebral blood volume and blood-brain barrier permeability coefficient measurements were obtained on a rat glioma model using SRCT and a CCD camera (47x47 microm2 pixel size). This is the first report of in vivo high-resolution brain vasculature parameter assessment. The work gives interesting perspectives to quantify brain hemodynamic changes accurately in healthy and pathological small animals.

Enhanced delivery of iodine for synchrotron stereotactic radiotherapy by means of intracarotid injection and blood-brain barrier disruption: quantitative iodine biodistribution studies and associated dosimetry.

PURPOSE: Synchrotron stereotactic radiotherapy (SSR) is a binary cancer treatment modality that involves the selective accumulation of a high Z element, such as iodine, in tumors, followed by stereotactic irradiation with kilovoltage X-rays from a synchrotron source. The success of SSR is directly related to the absolute amount of iodine achievable in the tumor. The purposes of this preclinical study were to determine whether the delivery of iodine to brain tumor models in rats could be enhanced by the means of its intracarotid injection with or without a hyperosmotic solution and to evaluate corresponding absorbed X-ray doses. METHODS AND MATERIALS: Experiments were performed on four groups of F98 glioma-bearing rats, which received either intracarotid (IC) or intravenous (IV) infusions of a mixture (6 mL in 12 min) of an iodinated contrast agent associated or not with a transient blood-brain barrier opener (mannitol). The mixture volumetric proportions were 8/13 of Iomeron (C = 350 mg/mL) for 5/13 of mannitol or saline, respectively. Absolute iodine concentration kinetic was measured in vivo in the tumor, blood, contralateral and ipsilateral brain, and muscle by monochromatic computed tomography. Associated dosimetry was performed by computing the iodine dose enhancement factor (DEF) in each region and building dose distribution maps by analytical simulations. RESULTS: Infusion of mannitol significantly enhanced iodine tumor uptake compared with the control values (p < 0.0001 and p = 0.0138, for IC and IV protocols, respectively). The mean iodine concentrations (C) reached 20.5 +/- 0.98 mg/mL (DEF = 4.1) after administration of iodine and mannitol vs. 4.1 +/- 1.2 mg/mL i.c. with serum (DEF = 1.6). The tumor iodine uptakes after jugular injection with mannitol (C = 4.4 +/- 2.1 mg/mL, DEF = 1.7) were not significantly different from IC injection of iodine without mannitol (p = 0.8142). The IV injection of iodine with saline led to an iodine concentration in the tumor of 1.2 +/- 0.98 mg/mL and a DEF of 1.2. CONCLUSIONS: This study established that optimizing the delivery of iodine by means of IC injection combined with a blood-brain barrier opener (mannitol) significantly increases the iodine uptake of F98 rat gliomas. This infusion protocol could potentially enhance the efficacy of SSR treatment, because the radiation dose is proportional to the iodine amount present in the irradiation bed.

Sensitivity variation of doped Fricke gel irradiated with monochromatic synchrotron X rays between 33.5 and 80 keV.

An experimental binary radiotherapy proposes the concomitant use of a high-Z compound and synchrotron X rays for enhancing radiation dose selectively in tumours by a photoelectric effect. This study aimed at measuring the resulting dose enhancement in irradiated material. A doped Fricke gel dosemeter model was manufactured with 10 mg ml(-1) of iodine (Telebrix) or barium (Micropaque). Samples were irradiated with a monochromatic synchrotron beam at 33.5, 50, 65 and 80 keV. The ensuing enhancement of the sensitivity of the dosemeter was derived from the nuclear magnetic resonance relaxation rates measured at different X-ray doses. Our results demonstrate (1) the preservation of a linear relationship between relaxation rates and X-ray doses for dosemeters doped with high-Z atoms and (2) a clear energy-dependent sensitivity enhancement for barium-doped Fricke gels. This enhancement was neither reproducible with iodinated compounds nor clearly related to the expected dose enhancement factor. However 1% barium sulphate in the gel could significantly improve the gel's response when it was irradiated by low-energy X rays.

Technical Note: Clinical translation of the Rapid-Steady-State-T1 MRI method for direct cerebral blood volume quantification.

PURPOSE: In preclinical studies, the Rapid-Steady-State-T1 (RSST1) MRI method has advantages over conventional MRI methods for blood volume fraction (BVf) mapping, since after contrast agent administration, the BVf is directly quantifiable from the signal amplitude corresponding to the vascular equilibrium magnetization. This study focuses on its clinical implementation and feasibility. METHODS: Following sequence implementation on clinical Philips Achieva scanners, the RSST1-method is assessed at 1.5 and 3 T in the follow-up examination of neurooncological patients receiving 0.1-0.2 mmol/kg Gd-DOTA to determine the threshold dose needed for cerebral BVf quantification. Confounding effects on BVf quantification such as transendothelial water exchange, transverse relaxation, and contrast agent extravasation are evaluated. RESULTS: For a dose≥0.13 mmol/kg at 1.5 T and ≥0.16 mmol/kg at 3 T, the RSST1-signal time course in macrovessels and brain tissue with Gd-DOTA impermeable vasculature reaches a steady state at maximum amplitude for about 8 s. In macrovessels, a BVf of 100% was obtained validating cerebral microvascular BVf quantification (3.5%-4.5% in gray matter and 1.5%-2.0% in white matter). In tumor tissue, a continuously increasing signal is detected, necessitating signal modeling for tumor BVf calculation. CONCLUSIONS: Using approved doses of Gd-DOTA, the steady state RSST1-signal in brain tissue is reached during the first pass and corresponds to the BVf. The first-pass duration is sufficient to allow accurate BVf quantification. The RSST1-method is appropriate for serial clinical studies since it allows fast and straightforward BVf quantification without arterial input function determination. This quantitative MRI method is particularly useful to assess the efficacy of antiangiogenic agents.