Multicenter prospective clinical study to evaluate children short-term neurodevelopmental outcome in congenital heart disease (children NEURO-HEART): study protocol.

BACKGROUND: Congenital heart disease (CHD) is the most prevalent congenital malformation affecting 1 in 100 newborns. While advances in early diagnosis and postnatal management have increased survival in CHD children, worrying long-term outcomes, particularly neurodevelopmental disability, have emerged as a key prognostic factor in the counseling of these pregnancies. METHODS: Eligible participants are women presenting at 20 to < 37 weeks of gestation carrying a fetus with CHD. Maternal/neonatal recordings are performed at regular intervals, from the fetal period to 24 months of age, and include: placental and fetal hemodynamics, fetal brain magnetic resonance imaging (MRI), functional echocardiography, cerebral oxymetry, electroencephalography and serum neurological and cardiac biomarkers. Neurodevelopmental assessment is planned at 12 months of age using the ages and stages questionnaire (ASQ) and at 24 months of age with the Bayley-III test. Target recruitment is at least 150 cases classified in three groups according to three main severe CHD groups: transposition of great arteries (TGA), Tetralogy of Fallot (TOF) and Left Ventricular Outflow Tract Obstruction (LVOTO). DISCUSSION: The results of NEURO-HEART study will provide the most comprehensive knowledge until date of children's neurologic prognosis in CHD and will have the potential for developing future clinical decisive tools and improving preventive strategies in CHD. TRIAL REGISTRATION: NCT02996630 , on 4th December 2016 (retrospectively registered).

Dimethyl sulfoxide (DMSO) as a potential contrast agent for brain tumors.

Dimethyl sulfoxide (DMSO) is commonly used in preclinical studies of animal models of high-grade glioma as a solvent for chemotherapeutic agents. A strong DMSO signal was detected by single-voxel MRS in the brain of three C57BL/6 control mice during a pilot study of DMSO tolerance after intragastric administration. This led us to investigate the accumulation and wash-out kinetics of DMSO in both normal brain parenchyma (n=3 control mice) by single-voxel MRS, and in 12 GL261 glioblastomas (GBMs) by single-voxel MRS (n=3) and MRSI (n=9). DMSO accumulated differently in each tissue type, reaching its highest concentration in tumors: 6.18 ± 0.85 µmol/g water, 1.5-fold higher than in control mouse brain (p<0.05). A faster wash-out was detected in normal brain parenchyma with respect to GBM tissue: half-lives of 2.06 ± 0.58 and 4.57 ± 1.15 h, respectively. MRSI maps of time-course DMSO changes revealed clear hotspots of differential spatial accumulation in GL261 tumors. Additional MRSI studies with four mice bearing oligodendrogliomas (ODs) revealed similar results as in GBM tumors. The lack of T(1) contrast enhancement post-gadolinium (gadopentetate dimeglumine, Gd-DTPA) in control mouse brain and mice with ODs suggested that DMSO was fully able to cross the intact blood-brain barrier in both normal brain parenchyma and in low-grade tumors. Our results indicate a potential role for DMSO as a contrast agent for brain tumor detection, even in those tumors 'invisible' to standard gadolinium-enhanced MRI, and possibly for monitoring heterogeneities associated with progression or with therapeutic response.

1H-MRSI pattern perturbation in a mouse glioma: the effects of acute hyperglycemia and moderate hypothermia.

MR spectroscopic Imaging (MRSI), with PRESS localization, is used here to monitor the effects of acute hyperglycemia in the spectral pattern of 11 mice bearing GL261 gliomas at normothermia (36.5-37.5 degrees C) and at hypothermia (28.5-29.5 degrees C). These in vivo studies were complemented by ex vivo high resolution magic angle spinning (HR-MAS) analysis of GL261 tumor samples from 6 animals sacrificed by focused microwave irradiation, and blood glucose measurements in 12 control mice. Apparent glucose levels, monitored by in vivo MRSI in brain tumors during acute hyperglycemia, rose to an average of 1.6-fold during hypothermia (p < 0.05), while no significant changes were detected at normothermia, or in control experiments performed at euglycemia, or in normal/peritumoral brain regions. Ex vivo analysis of glioma-bearing mouse brains at hypothermia revealed higher glucose increases in distinct regions during the acute hyperglycemic challenge (up to 6.6-fold at the tumor center), in agreement with maximal in vivo blood glucose changes (5-fold). Phantom studies on taurine plus glucose containing solutions explained the differences between in vivo and ex vivo measurements. Our results also indicate brain tumor heterogeneity in the four animal tumors investigated in response to a defined metabolic challenge.

Perturbation of mouse glioma MRS pattern by induced acute hyperglycemia.

(1)H MRS is evolving into an invaluable tool for brain tumor classification in humans based on pattern recognition analysis, but there is still room for improvement. Here we propose a new approach: to challenge tumor metabolism in vivo by a defined perturbation, and study the induced changes in MRS pattern. For this we recorded single voxel (1)H MR spectra from mice bearing a stereotactically induced GL261 grade IV brain glioma during a period of induced acute hyperglycemia. A total of 29 C57BL/6 mice were used. Single voxel spectra were acquired at 7 T with point resolved spectroscopy and TE of 12, 30 and 136 ms. Tumors were induced by stereotactic injection of 10(5) GL261cells in 17 mice. Hyperglycemia (up to 338 +/- 36 mg/dL glucose in the blood) was induced by intraperitoneal bolus injection. Maximal increases in glucose resonances of up to 2.4-fold were recorded from tumors in vivo. Our observations are in agreement with extracellular accumulation of glucose, which may suggest that glucose transport and/or metabolism are working close to their maximum capacity in GL261 tumors. The significant and specific MRS pattern changes observed when comparing euglycemia and hyperglycemia may be of use for future pattern-recognition studies of animal and human brain tumors by enhancing MRS-based discrimination between tumor types and grades.

Preliminary characterization of an experimental breast cancer cells brain metastasis mouse model by MRI/MRS.

PURPOSE: Chemotherapy increases survival in breast cancer patients. Consequently, cerebral metastases have recently become a significant clinical problem, with an incidence of 30-40% among breast carcinoma patients. As this phenomenon cannot be studied longitudinally in humans, models which mimic brain metastasis are needed to investigate its pathogenesis. Such models may later be used in experimental therapeutic approaches. MATERIAL AND METHODS/RESULTS: We report a model in which 69% of the animals (9/13 BALB/c nude mice) developed MR-detectable abnormal masses in the brain parenchyma within a 20 to 62-day time window post intra-carotid injection of 435-Br1 human cells. The masses detected in vivo were either single (7 animals) or multiple (2 animals). Longitudinal MR (MRI/MRS) studies and post-mortem histological data were correlated, revealing a total incidence of experimental brain metastases of 85% in the cases studied (11/13 animals). ADC maps perfectly differentiated edema and/or CSF areas from metastasis. Preliminary MRS data also revealed additional features: decrease in N-acetyl aspartate (NAA) was the first MRS-based marker of metastasis growth in the brain (micrometastasis); choline-containing compounds (Cho) rose and creatine (Cr) levels decreased as these lesions evolved, with mobile lipids and lactate also becoming visible. Furthermore, MRS pattern recognition-based analysis suggested that this approach may help to discriminate different growth stages. CONCLUSIONS: This study paves the way for further in vivo studies oriented towards detection of different tumor progression states and for improving treatment efficiency.