Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial.

Nonalcoholic steatohepatitis (NASH), a chronic liver disease without an approved therapy, is associated with lipotoxicity and insulin resistance and is a major cause of cirrhosis and hepatocellular carcinoma. Aramchol, a partial inhibitor of hepatic stearoyl-CoA desaturase (SCD1) improved steatohepatitis and fibrosis in rodents and reduced steatosis in an early clinical trial. ARREST, a 52-week, double-blind, placebo-controlled, phase 2b trial randomized 247 patients with NASH (n = 101, n = 98 and n = 48 in the Aramchol 400 mg, 600 mg and placebo arms, respectively; NCT02279524 ). The primary end point was a decrease in hepatic triglycerides by magnetic resonance spectroscopy at 52 weeks with a dose of 600 mg of Aramchol. Key secondary end points included liver histology and alanine aminotransferase (ALT). Aramchol 600 mg produced a placebo-corrected decrease in liver triglycerides without meeting the prespecified significance (-3.1, 95% confidence interval (CI) -6.4 to 0.2, P = 0.066), precluding further formal statistical analysis. NASH resolution without worsening fibrosis was achieved in 16.7% (13 out of 78) of Aramchol 600 mg versus 5% (2 out of 40) of the placebo arm (odds ratio (OR) = 4.74, 95% CI = 0.99 to 22.7) and fibrosis improvement by ≥1 stage without worsening NASH in 29.5% versus 17.5% (OR = 1.88, 95% CI = 0.7 to 5.0), respectively. The placebo-corrected decrease in ALT for 600 mg was -29.1 IU l-1 (95% CI = -41.6 to -16.5). Early termination due to adverse events (AEs) was <5%, and Aramchol 600 and 400 mg were safe, well tolerated and without imbalance in serious or severe AEs between arms. Although the primary end point of a reduction in liver fat did not meet the prespecified significance level with Aramchol 600 mg, the observed safety and changes in liver histology and enzymes provide a rationale for SCD1 modulation as a promising therapy for NASH and fibrosis and are being evaluated in an ongoing phase 3 program.

Cervical Cordotomy for Intractable Pain: Do Postoperative Imaging Features Correlate with Pain Outcomes and Mirror Pain?

BACKGROUND AND PURPOSE: Percutaneous cervical cordotomy offers relief of unilateral intractable oncologic pain. We aimed to find anatomic and postoperative imaging features that may correlate with clinical outcomes, including pain relief and postoperative contralateral pain. MATERIALS AND METHODS: We prospectively followed 15 patients with cancer who underwent cervical cordotomy for intractable pain during 2018 and 2019 and underwent preoperative and up to 1-month postoperative cervical MR imaging. Lesion volume and diameter were measured on T2-weighted imaging and diffusion tensor imaging (DTI). Lesion mean diffusivity and fractional anisotropy values were extracted. Pain improvement up to 1 month after surgery was assessed by the Numeric Rating Scale and Brief Pain Inventory. RESULTS: All patients reported pain relief from 8 (7-10) to 0 (0-4) immediately after surgery (P = .001), and 5 patients (33%) developed contralateral pain. The minimal percentages of the cord lesion volume required for pain relief were 10.0% on T2-weighted imaging and 6.2% on DTI. Smaller lesions on DWI correlated with pain improvement on the Brief Pain Inventory scale (r = 0.705, P = .023). Mean diffusivity and fractional anisotropy were significantly lower in the ablated tissue than contralateral nonlesioned tissue (P = .003 and P = .001, respectively), compatible with acute-phase tissue changes after injury. Minimal postoperative mean diffusivity values correlated with an improvement of Brief Pain Inventory severity scores (r = -0.821, P = .004). The average lesion mean diffusivity was lower among patients with postoperative contralateral pain (P = .037). CONCLUSIONS: Although a minimal ablation size is required during cordotomy, larger lesions do not indicate better outcomes. DWI metrics changes represent tissue damage after ablation and may correlate with pain outcomes.

Classification of High-Grade Glioma into Tumor and Nontumor Components Using Support Vector Machine.

BACKGROUND AND PURPOSE: Current imaging assessment of high-grade brain tumors relies on the Response Assessment in Neuro-Oncology criteria, which measure gross volume of enhancing and nonenhancing lesions from conventional MRI sequences. These assessments may fail to reliably distinguish tumor and nontumor. This study aimed to classify enhancing and nonenhancing lesion areas into tumor-versus-nontumor components. MATERIALS AND METHODS: A total of 140 MRI scans obtained from 32 patients with high-grade gliomas and 6 patients with brain metastases were included. Classification of lesion areas was performed using a support vector machine classifier trained on 4 components: enhancing and nonenhancing, tumor and nontumor, based on T1-weighted, FLAIR, and dynamic-contrast-enhancing MRI parameters. Classification results were evaluated by 2-fold cross-validation analysis of the training set and MR spectroscopy. Longitudinal changes of the component volumes were compared with Response Assessment in Neuro-Oncology criteria. RESULTS: Normalized T1-weighted values, FLAIR, plasma volume, volume transfer constant, and bolus-arrival-time parameters differentiated components. High sensitivity and specificity (100%) were obtained within the enhancing and nonenhancing areas. Longitudinal changes in component volumes correlated with the Response Assessment in Neuro-Oncology criteria in 27 patients; 5 patients (16%) demonstrated an increase in tumor component volumes indicating tumor progression. These changes preceded Response Assessment in Neuro-Oncology assessments by several months. Seven patients treated with bevacizumab showed a shift to an infiltrative pattern of progression. CONCLUSIONS: This study proposes an automatic classification method: segmented Response Assessment in Neuro-Oncology criteria based on advanced imaging that reliably differentiates tumor and nontumor components in high-grade gliomas. The segmented Response Assessment in Neuro-Oncology criteria may improve therapy-response assessment and provide earlier indication of progression.

Tumor burden evaluation in NF1 patients with plexiform neurofibromas in daily clinical practice.

BACKGROUND: Existing volumetric measurements of plexiform neurofibromas (PNs) are time consuming and error prone, as they require delineation of PN boundaries, a procedure that is not practical in the typical clinical setting. The aim of this study is to assess the Plexiform Neurofibroma Instant Segmentation Tool (PNist), a novel semi-automated segmentation program that we developed for PN delineation in a clinical context. PNist was designed to greatly simplify volumetric assessment of PNs through use of an intuitive user interface while providing objectively consistent results with minimal interobserver and intraobserver variabilities in reasonable time. MATERIALS AND METHODS: PNs were measured in 30 magnetic resonance imaging (MRI) scans from 12 patients with neurofibromatosis 1. Volumetric measurements were performed using PNist and compared to a standard semi-automated volumetric method (Analyze 9.0). RESULTS: High correlation was detected between PNist and the semi-automated method (R(2) = 0.996), with a mean volume overlap error of 9.54 % and low intraobserver and interobserver variabilities. The segmentation time required for PNist was 60 % of the time required for Analyze 9.0 (360 versus 900 s, respectively). PNist was also reliable when assessing changes in tumor size over time, compared to the existing commercial method. CONCLUSIONS: Our study suggests that the new PNist method is accurate, intuitive, and less time consuming for PN segmentation compared to existing commercial volumetric methods. The workflow is simple and user-friendly, making it an important clinical tool to be used by radiologists, neurologists and neurosurgeons on a daily basis, helping them deal with the complex task of evaluating PN burden and progression.

Fast reference based MRI.

In many clinical MRI scenarios, existing imaging information can be used to significantly shorten acquisition time or improve Signal to Noise Ratio (SNR). In those cases, a previously acquired image can serve as a reference image, that may exhibit similarity in some sense to the image being acquired. Examples include similarity between adjacent slices in high resolution MRI, similarity between various contrasts in the same scans and similarity between different scans of the same patients. In this paper we present a general framework for utilizing reference images for fast MRI. We take into account that the reference image may exhibit low similarity with the acquired image and develop a hybrid adaptive-weighted approach for sampling and reconstruction. Experiments demonstrate the performance of the method in three different clinical MRI scenarios: SNR improvement in high resolution brain MRI, utilizing similarity between T2-weighted and fluid-attenuated inversion recovery (FLAIR) for fast FLAIR scanning and utilizing similarity between baseline and follow-up scans for fast follow-up scanning.

MRI-based radiologic scoring system for extent of brain injury in children with hemiplegia.

BACKGROUND AND PURPOSE: Brain MR imaging is recommended in children with cerebral palsy. Descriptions of MR imaging findings lack uniformity, due to the absence of a validated quantitative approach. We developed a quantitative scoring method for brain injury based on anatomic MR imaging and examined the reliability and validity in correlation to motor function in children with hemiplegia. MATERIALS AND METHODS: Twenty-seven children with hemiplegia underwent MR imaging (T1, T2-weighted sequences, DTI) and motor assessment (Manual Ability Classification System, Gross Motor Functional Classification System, Assisting Hand Assessment, Jebsen Taylor Test of Hand Function, and Children's Hand Experience Questionnaire). A scoring system devised in our center was applied to all scans. Radiologic score covered 4 domains: number of affected lobes, volume and type of white matter injury, extent of gray matter damage, and major white matter tract injury. Inter- and intrarater reliability was evaluated and the relationship between radiologic score and motor assessments determined. RESULTS: Mean total radiologic score was 11.3 ± 4.5 (range 4-18). Good inter- (ρ = 0.909, P < .001) and intrarater (ρ = 0.926, P = < .001) reliability was demonstrated. Radiologic score correlated significantly with manual ability classification systems (ρ = 0.708, P < .001), and with motor assessments (assisting hand assessment [ρ = -0.753, P < .001]; Jebsen Taylor test of hand function [ρ = 0. 766, P < .001]; children's hand experience questionnaire [ρ = -0. 716, P < .001]), as well as with DTI parameters. CONCLUSIONS: We present a novel MR imaging-based scoring system that demonstrated high inter- and intrarater reliability and significant associations with manual ability classification systems and motor evaluations. This score provides a standardized radiologic assessment of brain injury extent in hemiplegic patients with predominantly unilateral injury, allowing comparison between groups, and providing an additional tool for counseling families.

Isolated mild white matter signal changes in preterm infants: a regional approach for comparison of cranial ultrasound and MRI findings.

OBJECTIVE: To compare echogenicity detected using cranial ultrasound (cUS) and diffuse excessive high signal intensity (DEHSI) detected using magnetic resonance imaging (MRI) by identical region-based scoring criteria in preterm infants. To explore the association between these white matter (WM) signal changes with early neurobehavior. STUDY DESIGN: Forty-nine pre-selected premature infants with only echogenicity on a first routine cUS1 underwent MRI and a repeated cUS2 at term equivalent age. Echogenicity and DEHSI were graded in various brain areas and diffusivity values were calculated. Neurobehavior was assessed using the Rapid Neonatal Neurobehavioral Assessment Procedure. RESULT: WM signal changes were significantly higher on cUS1 than cUS2; and higher in MRI than cUS2 in posterior regions. Infants with DEHSI demonstrated reduced tissue integrity. Imaging findings were not correlated with early neurobehavior. CONCLUSION: Echogenicity and DEHSI likely represent the same phenomenon. Reduction of over-interpretation of WM signal changes may help define criteria for the judicious use of imaging in routine follow-up of premature infants.

Automatic segmentation, internal classification, and follow-up of optic pathway gliomas in MRI.

This paper presents an automatic method for the segmentation, internal classification and follow-up of optic pathway gliomas (OPGs) from multi-sequence MRI datasets. Our method starts with the automatic localization of the OPG and its core with an anatomical atlas followed by a binary voxel classification with a probabilistic tissue model whose parameters are estimated from the MR images. The method effectively incorporates prior location, tissue characteristics, and intensity information for the delineation of the OPG boundaries in a consistent and repeatable manner. Internal classification of the segmented OPG volume is then obtained with a robust method that overcomes grey-level differences between learning and testing datasets. Experimental results on 25 datasets yield a mean surface distance error of 0.73 mm as compared to manual segmentation by experienced radiologists. Our method exhibits reliable performance in OPG growth follow-up MR studies, which are crucial for monitoring disease progression. To the best of our knowledge, this is the first method that addresses automatic segmentation, internal classification, and follow-up of OPG.

Unsupervised multiparametric classification of dynamic susceptibility contrast imaging: study of the healthy brain.

Characterization and quantification of magnetic resonance perfusion images is important for clinical interpretation, though this calls for a reproducible and accurate method of analysis and a robust healthy reference. The few studies which have examined the perfusion of the healthy brain using dynamic susceptibility contrast (DSC) imaging were largely limited to manual definition of the regions of interest (ROI) and results were dependent on the location of the ROI. The current study aimed to develop a methodology for DSC data analysis and to obtain reference values of healthy subjects. Twenty three healthy volunteers underwent DSC. An unsupervised multiparametric clustering method was applied to four perfusion parameters. Three clusters were defined and identified as: dura-blood-vessels, gray matter and white matter and their vascular characteristics were obtained. Additionally, regional perfusion differences were studied and revealed a prolonged mean transient time and a trend for higher vascularity in the posterior compared with the anterior and middle cerebral vascular territories. While additional studies are required to confirm our findings, this result may have important clinical implications. The proposed unsupervised multiparametric method enabled accurate tissue differentiation, is easy replicable and has a wide range of applications in both pathological and healthy brains.

High b value q-space-analyzed diffusion MRI in vascular dementia: a preliminary study.

High b value diffusion weighted magnetic resonance imaging (high-b DWI) was used to characterize white matter changes in the brain of patients with vascular dementia (VaD). Hyperintense white matter areas detected by T2-weighted magnetic resonance imaging (MRI) represent lesions, also termed leukoaraiosis that are very common in VaD as well as in other types of dementia. Therefore, the role of white matter changes in the cognitive and memory decline that occurs in VaD patients is still under debate. High-b DWI, analyzed using the q-space approach, is a more sensitive MRI method for detection of white matter changes. High-b DWI revealed massive white matter loss in VaD patients that surpassed the boundaries of T2 hyperintensities. This technique, therefore, might serve as a better indication for the extensive nerve fiber loss in the white matter that is caused by vascular disease.

High b-value q-space analyzed diffusion-weighted MRI: application to multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) which affects nearly one million people worldwide, leading to a progressive decline of motor and sensory functions, and permanent disability. High b-value diffusion-weighted MR images (b of up to 14000 s/mm(2)) were acquired from the brains of controls and MS patients. These diffusion MR images, in which signal decay is not monoexponential, were analyzed using the q-space approach that emphasizes the diffusion characteristics of the slow-diffusing component. From this analysis, displacement and probability maps were constructed. The computed q-space analyzed MR images that were compared with conventional T(1), T(2) (fluid attenuated inversion recovery (FLAIR)), and diffusion tensor imaging (DTI) images were found to be sensitive to the pathophysiological state of white matter. The indices used to construct this q-space analyzed MR maps, provided a pronounced differentiation between normal tissue and tissues classified as MS plaques by the FLAIR images. More importantly, a pronounced differentiation was also observed between tissues classified by the FLAIR MR images as normal-appearing white matter (NAWM) in the MS brains, which are known to be abnormal, and the respective control tissues. The potential diagnostic capacity of high b-value diffusion q-space analyzed MR images is discussed, and experimental data that explains the consequences of using the q-space approach once the short pulse gradient approximation is violated are presented.

Vase or face? A neural correlate of shape-selective grouping processes in the human brain.

Recent neuroimaging studies have described a differential activation pattern associated with specific object images (e.g., face-related and building-related activation) in human occipito-temporal cortex. However, it is as yet unclear to what extent this selectivity is due to differences in the statistics of local object features present in the different object categories, and to what extent it reflects holistic grouping processes operating across the entire object image. To resolve this question it is essential to use images in which identical sets of local features elicit the perception of different object categories. The classic Rubin vase-face illusion provides an excellent experimental set to test this question. In the illusion, the same local contours lead to the perception of different objects (vase or face). Here we employed a modified Rubin vase-face illusion to explore to what extent the activation in face-related regions is attributable to the presence of local face features, or is due to a more holistic grouping process that involves the entire face figure. Biasing cues (gratings and color) were used to control the perceptual state of the observer. We found enhanced activation in face-related regions during the "face profile" perceptual state compared to the "vase" perceptual state. Control images ruled out the involvement of the biasing cues in the effect. Thus, object-selective activation in human face-related regions entails global grouping processes that go beyond the local processing of stimulus features.

A hierarchical axis of object processing stages in the human visual cortex.

How are objects represented in the human visual cortex? Two conflicting theories suggest either a holistic representation, in which objects are represented by a collection of object templates, or a part-based representation, in which objects are represented as collections of features or object parts. We studied this question using a gradual object-scrambling paradigm in which pictures of objects (faces and cars) were broken in a stepwise manner into an increasing number of blocks. Our results reveal a hierarchical axis oriented anterior--posteriorly in the organization of ventral object-areas. Along this axis, representations are arranged in bands of increasing sensitivity to image scrambling. The axis starts in early visual areas through retinotopic areas V4/V8 and continues into the lateral-occipital sulcus dorsally and the posterior fusiform girus ventrally, corresponding together to the previously described object-related lateral occipital complex (LOC). Regions showing the highest sensitivity to scrambling tended to be located at the most anterior-lateral regions of the complex. In these more anterior regions, breaking the images into 16 parts produced a significant reduction in activation. Interestingly, activation was not affected when images were cut in two halves, either horizontally or vertically. Car images generally produced a weaker activation compared to faces in the lateral occipital complex but showed the same tendency of increased scrambling sensitivity along the anterior--posterior axis. These results suggest the existence of a hierarchical axis along ventral occipito-temporal object-areas, in which the neuronal properties shift from sensitivity to local object features to a more global and holistic representation.

Excretion of a phosphorus-containing carbohydrate by Streptomyces sp. A50.

A new phosphorus-containing compound (1) was detected by (31)P NMR spectroscopy in Streptomyces sp. A50. Compound 1, 1(alpha)-O-methyl-2-(N-acetyl)glucoseamine-6-O-phosphate-1(alpha)-2-(N-acetyl)glucosamine, exhibited a pK(a) value around zero. The compound was found both in the extracellular culture broth and in the cells. While very low concentrations of 1 were found in the culture broth of other species of Streptomyces, its presence in high concentrations was specific to Streptomyces sp. A50. The highly acidic compound was isolated from the broth, and its structure was elucidated by a combination of 1D-, 2D-homonuclear, and inverse heteronuclear NMR techniques and mass spectroscopy.

31P NMR methods for the direct determination of ADP in the presence of ATP.

A new method is presented for the direct measurement of the amount of ADP in the presence of ATP by selectively eliminating the alpha- and gamma-ATP signals. The method is compared with other methods, both experimentally and theoretically, using the product-operator formalism. An analysis of the effect of beta 1 inhomogeneity on the efficiency of the methods is also given. Experimental results obtained using adiabatic pulses to compensate for such effects are shown. The accuracy of this new method is demonstrated by measuring various ADP concentrations in a series of solutions containing ADP and ATP.