Machine learning for multi-parametric breast MRI: radiomics-based approaches for lesion classification.

In the artificial intelligence era, machine learning (ML) techniques have gained more and more importance in the advanced analysis of medical images in several fields of modern medicine. Radiomics extracts a huge number of medical imaging features revealing key components of tumor phenotype that can be linked to genomic pathways. The multi-dimensional nature of radiomics requires highly accurate and reliable machine-learning methods to create predictive models for classification or therapy response assessment.Multi-parametric breast magnetic resonance imaging (MRI) is routinely used for dense breast imaging as well for screening in high-risk patients and has shown its potential to improve clinical diagnosis of breast cancer. For this reason, the application of ML techniques to breast MRI, in particular to multi-parametric imaging, is rapidly expanding and enhancing both diagnostic and prognostic power. In this review we will focus on the recent literature related to the use of ML in multi-parametric breast MRI for tumor classification and differentiation of molecular subtypes. Indeed, at present, different models and approaches have been employed for this task, requiring a detailed description of the advantages and drawbacks of each technique and a general overview of their performances.

Computed tomography-based radiomic to predict resectability in locally advanced pancreatic cancer treated with chemotherapy and radiotherapy.

BACKGROUND: Surgical resection after neoadjuvant treatment is the main driver for improved survival in locally advanced pancreatic cancer (LAPC). However, the diagnostic performance of computed tomography (CT) imaging to evaluate the residual tumour burden at restaging after neoadjuvant therapy is low due to the difficulty in distinguishing neoplastic tissue from fibrous scar or inflammation. In this context, radiomics has gained popularity over conventional imaging as a complementary clinical tool capable of providing additional, unprecedented information regarding the intratumor heterogeneity and the residual neoplastic tissue, potentially serving in the therapeutic decision-making process. AIM: To assess the capability of radiomic features to predict surgical resection in LAPC treated with neoadjuvant chemotherapy and radiotherapy. METHODS: Patients with LAPC treated with intensive chemotherapy followed by ablative radiation therapy were retrospectively reviewed. One thousand six hundred and fifty-five radiomic features were extracted from planning CT inside the gross tumour volume. Both extracted features and clinical data contribute to create and validate the predictive model of resectability status. Patients were repeatedly divided into training and validation sets. The discriminating performance of each model, obtained applying a LASSO regression analysis, was assessed with the area under the receiver operating characteristic curve (AUC). The validated model was applied to the entire dataset to obtain the most significant features. RESULTS: Seventy-one patients were included in the analysis. Median age was 65 years and 57.8% of patients were male. All patients underwent induction chemotherapy followed by ablative radiotherapy, and 19 (26.8%) ultimately received surgical resection. After the first step of variable selections, a predictive model of resectability was developed with a median AUC for training and validation sets of 0.862 (95%CI: 0.792-0.921) and 0.853 (95%CI: 0.706-0.960), respectively. The validated model was applied to the entire dataset and 4 features were selected to build the model with predictive performance as measured using AUC of 0.944 (95%CI: 0.892-0.996). CONCLUSION: The present radiomic model could help predict resectability in LAPC after neoadjuvant chemotherapy and radiotherapy, potentially integrating clinical and morphological parameters in predicting surgical resection.

On the dependence of quantitative diffusion-weighted imaging on scanner system characteristics and acquisition parameters: A large multicenter and multiparametric phantom study with unsupervised clustering analysis.

PURPOSE: The purpose of this multicenter phantom study was to exploit an innovative approach, based on an extensive acquisition protocol and unsupervised clustering analysis, in order to assess any potential bias in apparent diffusion coefficient (ADC) estimation due to different scanner characteristics. Moreover, we aimed at assessing, for the first time, any effect of acquisition plan/phase encoding direction on ADC estimation. METHODS: Water phantom acquisitions were carried out on 39 scanners. DWI acquisitions (b-value = 0-200-400-600-800-1000 s/mm2) with different acquisition plans (axial, coronal, sagittal) and phase encoding directions (anterior/posterior and right/left, for the axial acquisition plan), for 3 orthogonal diffusion weighting gradient directions, were performed. For each acquisition setup, ADC values were measured in-center and off-center (6 different positions), resulting in an entire dataset of 84 × 39 = 3276 ADC values. Spatial uniformity of ADC maps was assessed by means of the percentage difference between off-center and in-center ADC values (Δ). RESULTS: No significant dependence of in-center ADC values on acquisition plan/phase encoding direction was found. Ward unsupervised clustering analysis showed 3 distinct clusters of scanners and an association between Δ-values and manufacturer/model, whereas no association between Δ-values and maximum gradient strength, slew rate or static magnetic field strength was revealed. Several acquisition setups showed significant differences among groups, indicating the introduction of different biases in ADC estimation. CONCLUSIONS: Unsupervised clustering analysis of DWI data, obtained from several scanners using an extensive acquisition protocol, allows to reveal an association between measured ADC values and manufacturer/model of scanner, as well as to identify suboptimal DWI acquisition setups for accurate ADC estimation.

Automatic feathering algorithm for VMAT craniospinal irradiation: A comprehensive comparison with other VMAT planning strategies.

In craniospinal irradiation, field matching is very sensitive to intrafraction positional uncertainties in cranio-caudal direction, which could lead to severe overdoses/underdoses inside the planning target volume. During the last decade, significant efforts were made to develop volumetric-modulated arc therapy strategies, which were less sensitive to setup uncertainties. In this study, a treatment planning system-integrated method, named automatic feathering (AF) algorithm, was compared against other volumetric-modulated arc therapy strategies. Three patients were retrospectively included. Five different planning techniques were compared, including overlap (O), staggered overlap (SO), gradient optimization (GO), overlap with AF algorithm turned on (O-AF), and staggered overlap with AF algorithm turned on (SO-AF). Three overlapping lengths were considered (5 cm, 7.5 cm, and 10 cm). The middle isocenter was shifted of ±1 mm, ±3 mm, and ±5 mm to simulate setup uncertainties. Plan robustness against simulated uncertainties was evaluated by calculating near maximum and near minimum dose differences between shifted and nonshifted plans (ΔD2%, ΔD98%). Dose differences among combinations of techniques and junction lengths were tested using Wilcoxon signed-rank test. Higher ΔD2% and ΔD98% were obtained using the overlap technique (ΔD2% = 15.4%, ΔD98% = 15.0%). O-AF and SO-AF provided comparable plan robustness to GO technique. Their performance improved significantly for grater overlapping length. For 10-cm overlap and 5-mm shift, GO, O-AF, and SO-AF yielded to the better plan robustness (5.7% < ΔD2% < 6.0%, 6.1% < ΔD98% < 7.6%). SO provided an intermediate plan robustness (9.8% < ΔD2% < 10.8%, 8.9% < ΔD98% < 10.3%). The addition of AF to the overlap technique significantly improves plan robustness especially if larger overlapping lengths are used. Using the AF algorithm, plans become as robust as plans optimized with more sophisticated and time-consuming approaches (like GO).

Publisher Correction: Mice repeatedly exposed to Group-A ß-Haemolytic Streptococcus show perseverative behaviors, impaired sensorimotor gating, and immune activation in rostral diencephalon.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Anatomical and behavioral impact of a lentiviral tool tapping onto hippocampal serotonin reuptake in rats.

We aimed at the further characterization of rats in which SERT gene silencing was achieved by hippocampal injection of a lentiviral vector, carrying three si-RNA to block SERT mRNA at 66% of normal levels. Improved self-control and reduced restlessness were already demonstrated in these rats. Present further studies consisted of male adult rats, bilaterally inoculated within the hippocampus; control rats received lentivirus particles inactivated with heat. Both groups were maintained in isolation for 5 months, starting from inoculation. Neurochemical changes were studied by proton magnetic resonance spectroscopy (1H-MRS): we found increased hippocampal viability and bioenergetic potential; however, rats showed a behaviorally depressive pattern, also characterized by enhanced affiliation. Based on the extent of such effects, the whole lenti-SERT group was divided into two subgroups, termed intermediate- and extreme- phenotype profiles. While all rats had a widespread modification within dorsal/ventral striatum, amygdala, and hypothalamus, only the former subgroup showed an involvement of Raphé medialis, while, for the latter subgroup, an increase of SERT within hippocampus was unexpectedly caused. Within the less-affected "intermediate" rats, hippocampal 5-HT7 receptors were down-modulated, and also similarly within substantia nigra, septum, and neocortex. This picture demonstrates that additional rather than fewer neurobiological changes accompany a lower phenotypic expression. Overall, tapping hippocampal SERT affected the balance between habits versus strategies of coping by promoting morphogenetic processes indicative of a serotonergic fiber plasticity. Supplementary studies about serotonergic dynamics and neurogenesis within fronto-striatal circuits are needed.

Enhanced SPARCL1 expression in cancer stem cells improves preclinical modeling of glioblastoma by promoting both tumor infiltration and angiogenesis.

Glioblastoma (GBM) is the most malignant brain tumor of adults and is characterized by extensive cell dissemination within the brain parenchyma and enhanced angiogenesis. Effective preclinical modeling of these key features suffers from several shortcomings. Aim of this study was to determine whether modulating the expression of extracellular matrix (ECM) modifiers in proneural (PN) and mesenchymal (MES) cancer stem cells (CSCs) and in conventional glioma cell lines (GCLs) might improve tumor invasion and vascularization. To this end, we selected secreted, acidic and rich in cysteine-like 1 (SPARCL1) as a potential mediator of ECM remodeling in GBM. SPARCL1 transcript and protein expression was assessed in PN and MES CSCs as well as GCLs, in their xenografts and in patient-derived specimens by qPCR, WB and IHC. SPARCL1 expression was then enforced in both CSCs and GCLs by lentiviral-based transduction. The effect of SPARCL1 gain-of-function on microvascular proliferation, microglia activation and advanced imaging features was tested in intracranial xenografts by IHC and MRI and validated by chorioallantoic membrane (CAM) assays. SPARCL1 expression significantly enhanced the infiltrative and neoangiogenic features of PN and MES CSC/GCL-induced tumors, with the concomitant activation of inflammatory responses associated with the tumor microenvironment, thus resulting in experimental GBMs that reproduced both the parenchymal infiltration and the increased microvascular density, typical of GBM. Overall, these results indicate that SPARCL1 overexpression might be instrumental for the generation of CSC-derived preclinical models of GBM in which the main pathognomonic hallmarks of GBMs are retrievable, making them suitable for effective preclinical testing of therapeutics.

The proneural gene ASCL1 governs the transcriptional subgroup affiliation in glioblastoma stem cells by directly repressing the mesenchymal gene NDRG1.

Achaete-scute homolog 1 gene (ASCL1) is a gene classifier for the proneural (PN) transcriptional subgroup of glioblastoma (GBM) that has a relevant role in the neuronal-like differentiation of GBM cancer stem cells (CSCs) through the activation of a PN gene signature. Besides prototypical ASCL1 PN target genes, the molecular effectors mediating ASCL1 function in regulating GBM differentiation and, most relevantly, subgroup specification are currently unknown. Here we report that ASCL1 not only promotes the acquisition of a PN phenotype in CSCs by inducing a glial-to-neuronal lineage switch but also concomitantly represses mesenchymal (MES) features by directly downregulating the expression of N-Myc downstream-regulated gene 1 (NDRG1), which we propose as a novel gene classifier of MES GBMs. Increasing the expression of ASCL1 in PN CSCs results in suppression of self-renewal, promotion of differentiation and, most significantly, decrease in tumorigenesis, which is also reproduced by NDRG1 silencing. Conversely, both abrogation of ASCL1 expression in PN CSCs and enforcement of NDRG1 expression in either PN or MES CSCs induce proneural-to-mesenchymal transition (PMT) and enhanced mesenchymal features. Surprisingly, ASCL1 overexpression in MES CSCs increases malignant features and gives rise to a neuroendocrine-like secretory phenotype. Altogether, our results propose that the fine interplay between ASCL1 and its target NDRG1 might serve as potential subgroup-specific targetable vulnerability in GBM; enhancing ASCL1 expression in PN GBMs might reduce tumorigenesis, whereas repressing NDRG1 expression might be actionable to hamper the malignancy of GBM belonging to the MES subgroup.

Inside the Developing Brain to Understand Teen Behavior From Rat Models: Metabolic, Structural, and Functional-Connectivity Alterations Among Limbic Structures Across Three Pre-adolescent Stages.

Adolescence is an age of transition when most brain structures undergo drastic modifications, becoming progressively more interconnected and undergoing several changes from a metabolic and structural viewpoint. In the present study, three MR techniques are used in rats to investigate how metabolites, structures and patterns of connectivity do change. We focused in particular on areas belonging to the limbic system, across three post-weaning developmental stages: from "early" (PND 21-25) to "mid" (i.e., a juvenile transition, PND 28-32) and then to "late" (i.e., the adolescent transition, PND 35-39). The rs-fMRI data, with comparison between early and mid (juvenile transition) age-stage rats, highlights patterns of enhanced connectivity from both Striata to both Hippocampi and from there to (left-sided) Nucleus accumbens (NAcc) and Orbitofrontal Cortex (OFC). Also, during this week there is a maturation of pathways from right Striatum to ipsilateral NAcc, from right OFC to ipsilateral NAcc and vice versa, from left Prefrontal Cortex to ipsilateral OFC and eventually from left Striatum, NAcc and Prefrontal Cortex to contralateral OFC. After only 1 week, in late age-stage rats entering into adolescence, the first pathway mentioned above keeps on growing while other patterns appear: both NAcc are reached from contralateral Striatum, right Hippocampus from both Amygdalae, and left NAcc -further- from right Hippocampus. It's interesting to notice the fact that, independently from the age when these connections develop, Striata of both hemispheres send axons to both Hippocampi and both NAcc sides, both Hippocampi reach left NAcc and OFC and finally both NAcc sides reach right OFC. Intriguingly, the Striatum only indirectly reaches the OFC by passing through Hippocampus and NAcc. Data obtained with DTI highlight how adolescents' neurite density may be affected within sub-cortical gray matter, especially for NAcc and OFC at "late" age-stage (adolescence). Finally, levels of metabolites were investigated by 1H-MRS in the anterior part of the hippocampus: we put into evidence an increase in myo-inositol during juvenile transition and a taurine reduction plus a total choline increase during adolescent transition. In this paper, the aforementioned pattern guides the formulation of hypotheses concerning the correlation between the establishment of novel brain connections and the emergence of behavioral traits that are typical of adolescence.

Integration of Diffusion Magnetic Resonance Tractography into tomotherapy radiation treatment planning for high-grade gliomas.

INTRODUCTION: Fractionated radiotherapy in brain tumors is commonly associated with several detrimental effects, largely related to the higher radiosensitivity of the white matter (WM) with respect to gray matter. However, no dose constraints are applied to preserve WM structures at present. Magnetic Resonance (MR) Tractography is the only technique that allows to visualize in vivo the course of WM eloquent tracts in the brain. In this study, the feasibility of integrating MR Tractography in tomotherapy treatment planning has been investigated, with the aim to spare eloquent WM regions from the dose delivered during treatment. METHODS: Nineteen high grade glioma patients treated with fractionated radiotherapy were enrolled. All the patients underwent pre-treatment MR imaging protocol including Diffusion Tensor Imaging (DTI) acquisitions for MR Tractography analysis. Bilateral tracts involved in several motor, language, cognitive functions were reconstructed and these fiber bundles were integrated into the Tomotherapy Treatment planning system. The original plans without tracts were compared with the optimized plans incorporating the fibers, to evaluate doses to WM structures in the two differently optimized plans. RESULTS: No significant differences were found between plans in terms of planning target volume (PTV) coverage between the original plans and the optimized plans incorporating fiber tracts. Comparing the mean as well as the maximal dose (Dmean and Dmax), a significant dose reduction was found for most of the tracts. The dose sparing was more relevant for contralateral tracts (P < 0.0001). CONCLUSION: The integration of MR Tractography into radiotherapy planning is feasible and beneficial to preserve important WM structures without reducing the clinical goal of radiation treatment.

Dependence of apparent diffusion coefficient measurement on diffusion gradient direction and spatial position - A quality assurance intercomparison study of forty-four scanners for quantitative diffusion-weighted imaging.

PURPOSE: To propose an MRI quality assurance procedure that can be used for routine controls and multi-centre comparison of different MR-scanners for quantitative diffusion-weighted imaging (DWI). MATERIALS AND METHODS: 44 MR-scanners with different field strengths (1 T, 1.5 T and 3 T) were included in the study. DWI acquisitions (b-value range 0-1000 s/mm2), with three different orthogonal diffusion gradient directions, were performed for each MR-scanner. All DWI acquisitions were performed by using a standard spherical plastic doped water phantom. Phantom solution ADC value and its dependence with temperature was measured using a DOSY sequence on a 600 MHz NMR spectrometer. Apparent diffusion coefficient (ADC) along each diffusion gradient direction and mean ADC were estimated, both at magnet isocentre and in six different position 50 mm away from isocentre, along positive and negative AP, RL and HF directions. RESULTS: A good agreement was found between the nominal and measured mean ADC at isocentre: more than 90% of mean ADC measurements were within 5% from the nominal value, and the highest deviation was 11.3%. Away from isocentre, the effect of the diffusion gradient direction on ADC estimation was larger than 5% in 47% of included scanners and a spatial non uniformity larger than 5% was reported in 13% of centres. CONCLUSION: ADC accuracy and spatial uniformity can vary appreciably depending on MR scanner model, sequence implementation (i.e. gradient diffusion direction) and hardware characteristics. The DWI quality assurance protocol proposed in this study can be employed in order to assess the accuracy and spatial uniformity of estimated ADC values, in single- as well as multi-centre studies.

A straightforward multiparametric quality control protocol for proton magnetic resonance spectroscopy: Validation and comparison of various 1.5 T and 3 T clinical scanner systems.

PURPOSE: The aim of this study was to propose and validate across various clinical scanner systems a straightforward multiparametric quality assurance procedure for proton magnetic resonance spectroscopy (MRS). METHODS: Eighteen clinical 1.5 T and 3 T scanner systems for MRS, from 16 centres and 3 different manufacturers, were enrolled in the study. A standard spherical water phantom was employed by all centres. The acquisition protocol included 3 sets of single (isotropic) voxel (size 20 mm) PRESS acquisitions with unsuppressed water signal and acquisition voxel position at isocenter as well as off-center, repeated 4/5 times within approximately 2 months. Water peak linewidth (LW) and area under the water peak (AP) were estimated. RESULTS: LW values [mean (standard deviation)] were 1.4 (1.0) Hz and 0.8 (0.3) Hz for 3 T and 1.5 T scanners, respectively. The mean (standard deviation) (across all scanners) coefficient of variation of LW and AP for different spatial positions of acquisition voxel were 43% (20%) and 11% (11%), respectively. The mean (standard deviation) phantom T2values were 1145 (50) ms and 1010 (95) ms for 1.5 T and 3 T scanners, respectively. The mean (standard deviation) (across all scanners) coefficients of variation for repeated measurements of LW, AP and T2 were 25% (20%), 10% (14%) and 5% (2%), respectively. CONCLUSIONS: We proposed a straightforward multiparametric and not time consuming quality control protocol for MRS, which can be included in routine and periodic quality assurance procedures. The protocol has been validated and proven to be feasible in a multicentre comparison study of a fairly large number of clinical 1.5 T and 3 T scanner systems.

Myocardial blood flow estimates from dynamic contrast-enhanced magnetic resonance imaging: three quantitative methods.

Dynamic contrast-enhanced cardiovascular magnetic resonance imaging can be used to quantitatively assess the myocardial blood flow (MBF), recovering the tissue impulse response function for the transit of a gadolinium bolus through the myocardium. Several deconvolution techniques are available, using various models for the impulse response. The method of choice may influence the results, producing differences that have not been deeply investigated yet. Three methods for quantifying myocardial perfusion have been compared: Fermi function modelling (FFM), the Tofts model (TM) and the gamma function model (GF), with the latter traditionally used in brain perfusion MRI. Thirty human subjects were studied at rest as well as under cold pressor test stress (submerging hands in ice-cold water), and a single bolus of gadolinium weighing 0.1 ± 0.05 mmol kg-1 was injected. Perfusion estimate differences between the methods were analysed by paired comparisons with Student's t-test, linear regression analysis, and Bland-Altman plots, as well as also using the two-way ANOVA, considering the MBF values of all patients grouped according to two categories: calculation method and rest/stress conditions. Perfusion estimates obtained by various methods in both rest and stress conditions were not significantly different, and were in good agreement with the literature. The results obtained during the first-pass transit time (20 s) yielded p-values in the range 0.20-0.28 for Student's t-test, linear regression analysis slopes between 0.98-1.03, and R values between 0.92-1.01. From the Bland-Altman plots, the paired comparisons yielded a bias (and a 95% CI)-expressed as ml/min/g-for FFM versus TM, -0.01 (-0.20, 0.17) or 0.02 (-0.49, 0.52) at rest or under stress respectively, for FFM versus GF, -0.05 (-0.29, 0.20) or -0.07 (-0.55, 0.41) at rest or under stress, and for TM versus GF, -0.03 (-0.30, 0.24) or -0.09 (-0.43, 0.26) at rest or under stress. With the two-way ANOVA, the results were p = 0.20 for the method effect (not significant), p < 0.0001 for the rest/stress condition effect (highly significant, as expected), whereas no interaction resulted between the rest/stress condition and method (p = 0.70, not significant). Considering a wider time-frame (60 s), the estimates for both rest and stress conditions were 25%-30% higher (p in the range 0.016-0.025) than those obtained in the 20 s time-frame. MBF estimates obtained by various methods under rest/stress conditions were not significantly different in the first-pass transit time, encouraging quantitative perfusion estimates in DCE-CMRI with the used methods.

Theranostic Role of 32P-ATP as Radiopharmaceutical for the Induction of Massive Cell Death within Avascular Tumor Core.

Drug inaccessibility to vast areas of the tumor parenchyma is amongst the major hurdles for conventional therapies. Treatment efficacy rapidly decreases with distance from vessels and most of the tumor cells survive therapy. Also, between subsequent cycles of treatment, spared cancer cells replace those killed near the vessels, improving their access to nutrients, boosting their proliferation rate, and thus enabling tumor repopulation. Because of their property of "acting at a distance," radioisotopes are believed to overcome the physical barrier of vascular inaccessibility. Methods A novel molecular imaging tool called Cerenkov Luminescence Imaging (CLI) was employed for the detection of Cerenkov radiation emitted by beta particles, allowing in vivo tracking of beta-emitters. More precisely we investigated using a xenograft model of colon carcinoma the potential use of 32P-ATP as a novel theranostic radiopharmaceutical for tracing tumor lesions while simultaneously hampering their growth. Results Our analyses demonstrated that 32P-ATP injected into tumor-bearing mice reaches tumor lesions and persists for days and weeks within the tumor parenchyma. Also, the high-penetrating beta particles of 32P-ATP exert a "cross-fire" effect that induces massive cell death throughout the entire tumor parenchyma including core regions. Conclusion Our findings suggest 32P-ATP treatment as a potential approach to complement conventional therapies that fail to reach the tumor core and to prevent tumor repopulation.

Phosphatidylcholine-specific phospholipase C inhibition reduces HER2-overexpression, cell proliferation and in vivo tumor growth in a highly tumorigenic ovarian cancer model.

Antagonizing the oncogenic effects of human epidermal growth factor receptor 2 (HER2) with current anti-HER2 agents has not yet yielded major progress in the treatment of advanced HER2-positive epithelial ovarian cancer (EOC). Using preclinical models to explore alternative molecular mechanisms affecting HER2 overexpression and oncogenicity may lead to new strategies for EOC patient treatment. We previously reported that phosphatidylcholine-specific phospholipase C (PC-PLC) exerts a pivotal role in regulating HER2 overexpression in breast cancer cells. The present study, conducted on two human HER2-overexpressing EOC cell lines - SKOV3 and its in vivo-passaged SKOV3.ip cell variant characterized by enhanced in vivo tumorigenicity - and on SKOV3.ip xenografts implanted in SCID mice, showed: a) about 2-fold higher PC-PLC and HER2 protein expression levels in SKOV3.ip compared to SKOV3 cells; b) physical association of PC-PLC with HER2 in non-raft domains; c) HER2 internalization and ca. 50% reduction of HER2 mRNA and protein expression levels in SKOV3.ip cells exposed to the PC-PLC inhibitor tricyclodecan-9-yl-potassium xanthate (D609); d) differential effects of D609 and trastuzumab on HER2 protein expression and cell proliferation; e) decreased in vivo tumor growth in SKOV3.ip xenografts during in vivo treatment with D609; f) potential use of in vivo magnetic resonance spectroscopy (MRS) and imaging (MRI) parameters as biomarkers of EOC response to PC-PLC inhibition. Overall, these findings support the view that PC-PLC inhibition may represent an effective means to target the tumorigenic effects of HER2 overexpression in EOC and that in vivo MR approaches can efficiently monitor its effects.

Reproducibility of dynamic contrast-enhanced MRI and dynamic susceptibility contrast MRI in the study of brain gliomas: a comparison of data obtained using different commercial software.

PURPOSE: Dynamic susceptibility contrast MRI (DSC) and dynamic contrast-enhanced MRI (DCE) are useful tools in the diagnosis and follow-up of brain gliomas; nevertheless, both techniques leave the open issue of data reproducibility. We evaluated the reproducibility of data obtained using two different commercial software for perfusion maps calculation and analysis, as one of the potential sources of variability can be the software itself. METHODS: DSC and DCE analyses from 20 patients with gliomas were tested for both the intrasoftware (as intraobserver and interobserver reproducibility) and the intersoftware reproducibility, as well as the impact of different postprocessing choices [vascular input function (VIF) selection and deconvolution algorithms] on the quantification of perfusion biomarkers plasma volume (Vp), volume transfer constant (K trans) and rCBV. Data reproducibility was evaluated with the intraclass correlation coefficient (ICC) and Bland-Altman analysis. RESULTS: For all the biomarkers, the intra- and interobserver reproducibility resulted in almost perfect agreement in each software, whereas for the intersoftware reproducibility the value ranged from 0.311 to 0.577, suggesting fair to moderate agreement; Bland-Altman analysis showed high dispersion of data, thus confirming these findings. Comparisons of different VIF estimation methods for DCE biomarkers resulted in ICC of 0.636 for K trans and 0.662 for Vp; comparison of two deconvolution algorithms in DSC resulted in an ICC of 0.999. CONCLUSIONS: The use of single software ensures very good intraobserver and interobservers reproducibility. Caution should be taken when comparing data obtained using different software or different postprocessing within the same software, as reproducibility is not guaranteed anymore.

A feasible and automatic free tool for T1 and ECV mapping.

PURPOSE: Cardiac magnetic resonance (CMR) is a useful non-invasive tool for characterizing tissues and detecting myocardial fibrosis and edema. Estimation of extracellular volume fraction (ECV) using T1 sequences is emerging as an accurate biomarker in cardiac diseases associated with diffuse fibrosis. In this study, automatic software for T1 and ECV map generation consisting of an executable file was developed and validated using phantom and human data. METHODS: T1 mapping was performed in phantoms and 30 subjects (22 patients and 8 healthy subjects) on a 1.5T MR scanner using the modified Look-Locker inversion-recovery (MOLLI) sequence prototype before and 15 min after contrast agent administration. T1 maps were generated using a Fast Nonlinear Least Squares algorithm. Myocardial ECV maps were generated using both pre- and post-contrast T1 image registration and automatic extraction of blood relaxation rates. RESULTS: Using our software, pre- and post-contrast T1 maps were obtained in phantoms and healthy subjects resulting in a robust and reliable quantification as compared to reference software. Coregistration of pre- and post-contrast images improved the quality of ECV maps. Mean ECV value in healthy subjects was 24.5%±2.5%. CONCLUSIONS: This study demonstrated that it is possible to obtain accurate T1 maps and informative ECV maps using our software. Pixel-wise ECV maps obtained with this automatic software made it possible to visualize and evaluate the extent and severity of ECV alterations.

Novel cardiac magnetic resonance biomarkers: native T1 and extracellular volume myocardial mapping.

Cardiac magnetic resonance (CMR) is a non-invasive diagnostic tool playing a key role in the assessment of cardiac morphology and function as well as in tissue characterization. Late gadolinium enhancement is a fundamental CMR technique for detecting focal or regional abnormalities such as scar tissue, replacement fibrosis, or inflammation using qualitative, semi-quantitative, or quantitative methods, but not allowing for evaluating the whole myocardium in the presence of diffuse disease. The novel T1 mapping approach permits a quantitative assessment of the entire myocardium providing a voxel-by-voxel map of native T1 relaxation time, obtained before the intravenous administration of gadolinium-based contrast material. Combining T1 data obtained before and after contrast injection, it is also possible to calculate the voxel-by-voxel extracellular volume (ECV), resulting in another myocardial parametric map. This article describes technical challenges and clinical perspectives of these two novel CMR biomarkers: myocardial native T1 and ECV mapping.

Mice repeatedly exposed to Group-A ß-Haemolytic Streptococcus show perseverative behaviors, impaired sensorimotor gating, and immune activation in rostral diencephalon.

Repeated exposure to Group-A ß-Haemolytic Streptococcus (GAS) may constitute a vulnerability factor in the onset and course of pediatric motor disturbances. GAS infections/colonization can stimulate the production of antibodies, which may cross the blood brain barrier, target selected brain areas (e.g. basal ganglia), and exacerbate motor alterations. Here, we exposed developing SJL male mice to four injections with a GAS homogenate and evaluated the following domains: motor coordination; general locomotion; repetitive behaviors; perseverative responses; and sensorimotor gating (pre-pulse inhibition, PPI). To demonstrate that behavioral changes were associated with immune-mediated brain alterations, we analyzed, in selected brain areas, the presence of infiltrates and microglial activation (immunohistochemistry), monoamines (HPLC), and brain metabolites (in vivo Magnetic Resonance Spectroscopy). GAS-exposed mice showed increased repetitive and perseverative behaviors, impaired PPI, and reduced concentrations of serotonin in prefrontal cortex, a brain area linked to the behavioral domains investigated, wherein they also showed remarkable elevations in lactate. Active inflammatory processes were substantiated by the observation of infiltrates and microglial activation in the white matter of the anterior diencephalon. These data support the hypothesis that repeated GAS exposure may elicit inflammatory responses in brain areas involved in motor control and perseverative behavior, and result in phenotypic abnormalities.

Deficient Purposeful Use of Forepaws in Female Mice Modelling Rett Syndrome.

Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioural and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases. Motor abnormalities represent a significant part of the spectrum of RTT symptoms. In the present study we investigated motor coordination and fine motor skill domains in MeCP2-308 female mice, a validated RTT model. This was complemented by the in vivo magnetic resonance spectroscopy (MRS) analysis of metabolic profile in behaviourally relevant brain areas. MeCP2-308 heterozygous female mice (Het, 10-12 months of age) were impaired in tasks validated for the assessment of purposeful and coordinated forepaw use (Morag test and Capellini handling task). A fine-grain analysis of spontaneous behaviour in the home-cage also revealed an abnormal handling pattern when interacting with the nesting material, reduced motivation to explore the environment, and increased time devoted to feeding in Het mice. The brain MRS evaluation highlighted decreased levels of bioenergetic metabolites in the striatal area in Het mice compared to controls. Present results confirm behavioural and brain alterations previously reported in MeCP2-308 males and identify novel endpoints on which the efficacy of innovative therapeutic strategies for RTT may be tested.