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PDF file, 257K, Western blot: doxorubicin-induced normoxic HIF-1� expression was compared to a positive control of HIF-1� induced by hypoxia (S1); Hoechst 33342 labeling: comparison of perfused tumor fraction in 4T1ODD-luc tumors on days 0, 1, 4, 7, and 16 post-treatment (n = 5, mean � SE). P > 0.05. Student t test (S2); Western blot: increasing concentration of doxorubicin led to higher HIF-1� expression 48 hours post-treatment (S3); WST-1 cell viability assay at 24, 48, and 72 hours post-treatment (S4), Western blot: the expressions of JAK2 and phosphorylated JAK2 (Tyr1007/1008) 48 hours post-treatment (S5); Quantification of iNOS band density which is normalized to loading control in Fig. 5D (S6); Comparison of TAM-specific marker CD68 fraction in 4T1ODD-luc tumors on days 0, 1, 4, 7, and 16 post-treatment (n = 5, mean � SE). P > 0.05, Student t test (S7).

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OBJECTIVE. The objective of this article was to study the effect of decreasing the time allowed an American Journal of Roentgenology (AJR) reviewer to consider an invitation to review on time for t...

OBJECTIVE. This article provides comments from a small group of highly qualified reviewers of the American Journal of Roentgenology (AJR) regarding their approach to assessing manuscripts. The objective is to educate authors about the issues to which reviewers particularly attend and about errors that will decrease the likelihood of publication. CONCLUSION. By following the advice provided in this article, authors should be able to compose better manuscripts and reviewers should be able to generate better reviews.

OBJECTIVE. Comments from manuscript reviews are helpful for guiding a decision about publication and also afford a source of valuable information about how to improve a manuscript. This article is a compendium of comments from reviews of AJR Neuroradiology/Head and Neck Imaging manuscripts that, collectively, serve as a guide for writing a manuscript in any field of radiology. The comments provide examples of previously published AJR guidelines for a manuscript that will have a high likelihood of being published. CONCLUSION. Reviewers devote substantial time and effort to manuscript reviews and provide them to authors at no cost. Their comments provide an important and valuable supply of instruction for authors. Those comments often reflect criteria for judging the worth of a manuscript and reflect sound principles for composing a manuscript. Authors are encouraged to avail themselves of these resources.

Hypoxia-inducible factor 1 (HIF-1) is a master transcription factor that controls cellular homeostasis. Although its activation benefits normal tissue, HIF-1 activation in tumors is a major risk factor for angiogenesis, therapeutic resistance, and poor prognosis. HIF-1 activity is usually suppressed under normoxic conditions because of rapid oxygen-dependent degradation of HIF-1α. Here, we show that, under normoxic conditions, HIF-1α is upregulated in tumor cells in response to doxorubicin, a chemotherapeutic agent used to treat many cancers. In addition, doxorubicin enhanced VEGF secretion by normoxic tumor cells and stimulated tumor angiogenesis. Doxorubicin-induced accumulation of HIF-1α in normoxic cells was caused by increased expression and activation of STAT1, the activation of which stimulated expression of iNOS and its synthesis of nitric oxide (NO) in tumor cells. Mechanistic investigations established that blocking NO synthesis or STAT1 activation was sufficient to attenuate the HIF-1α accumulation induced by doxorubicin in normoxic cancer cells. To our knowledge, this is the first report that a chemotherapeutic drug can induce HIF-1α accumulation in normoxic cells, an efficacy-limiting activity. Our results argue that HIF-1α-targeting strategies may enhance doxorubicin efficacy. More generally, they suggest a broader perspective on the design of combination chemotherapy approaches with immediate clinical impact. Cancer Res; 73(20); 6230–42. ©2013 AACR.

ObjectiveTo characterize the extent of CNS involvement in children with Pompe disease using brain MRI and developmental assessments.MethodsThe study included 14 children (ages 6–18 years) with infantile Pompe disease (IPD) (n = 12) or late-onset Pompe disease (LOPD) (n = 2) receiving enzyme replacement therapy. White matter (WM) hyperintense foci seen in the brain MRIs were systematically quantified using the Fazekas scale (FS) grading system with a novel approach: the individual FS scores from 10 anatomical areas were summed to yield a total FS score (range absent [0] to severe [30]) for each child. The FS scores were compared to developmental assessments of cognition and language obtained during the same time period.ResultsMild to severe WM hyperintense foci were seen in 10/12 children with IPD (median age 10.6 years) with total FS scores ranging from 2 to 23. Periventricular, subcortical, and deep WM were involved. WM hyperintense foci were seen throughout the path of the corticospinal tracts in the brain in children with IPD. Two children with IPD had no WM hyperintense foci. Children with IPD had relative weaknesses in processing speed, fluid reasoning, visual perception, and receptive vocabulary. The 2 children with LOPD had no WM hyperintense foci, and high scores on most developmental assessments.ConclusionThis study systematically characterized WM hyperintense foci in children with IPD, which could serve as a benchmark for longitudinal follow-up of WM abnormalities in patients with Pompe disease and other known neurodegenerative disorders or leukodystrophies in children.

Multisite and longitudinal neuroimaging studies are important in uncovering trajectories of recovery and neurodegeneration following traumatic brain injury (TBI) and concussion through the use of diffusion tensor imaging (DTI) and other imaging modalities. This study assessed differences in anisotropic diffusion measurement across four scanners using a human and a novel phantom developed in conjunction with the Chronic Effects of Neurotrauma Consortium.Human scans provided measurement within biological tissue, and the novel physical phantom provided measures of anisotropic intra-tubular diffusion to serve as a model for intra-axonal water diffusion. Intra- and inter-scanner measurement variances were compared, and the impact on effect size was calculated.Intra-scanner test-retest reliability estimates for fractional anisotropy (FA) demonstrated relative stability over testing intervals. The human tissue and phantom showed similar FA ranges, high linearity and large within-device effect sizes. However, inter-scanner measures of FA indicated substantial differences, some of which exceeded typical DTI effect sizes in mild TBI.The diffusion phantom may be used to better elucidate inter-scanner variability in DTI-based measurement and provides an opportunity to better calibrate results obtained from scanners used in multisite and longitudinal studies. Novel solutions are being evaluated to understand and potentially overcome these differences.

Purpose We compared fractional anisotropy and radial diffusivity measurements between pediatric canines affected with mucopolysaccharidosis I and pediatric control canines. We hypothesized that lower fractional anisotropy and higher radial diffusivity values, consistent with dysmyelination, would be present in the mucopolysaccharidosis I cohort. Methods Six canine brains, three affected with mucopolysaccharidosis I and three unaffected, were euthanized at 7 weeks and imaged using a 7T small-animal magnetic resonance imaging system. Average fractional anisotropy and radial diffusivity values were calculated for four white-matter regions based on 100 regions of interest per region per specimen. A 95% confidence interval was calculated for each mean value. Results No difference was seen in fractional anisotropy or radial diffusivity values between mucopolysaccharidosis affected and unaffected brains in any region. In particular, the 95% confidence intervals for mucopolysaccharidosis affected and unaffected canines frequently overlapped for both fractional anisotropy and radial diffusivity measurements. In addition, in some brain regions a large range of fractional anisotropy and radial diffusivity values were seen within the same cohort. Conclusion The fractional anisotropy and radial diffusivity values of white matter did not differ between pediatric mucopolysaccharidosis affected canines and pediatric control canines. Possible explanations include: (a) a lack of white matter tissue differences between mucopolysaccharidosis affected and unaffected brains at early disease stages; (b) diffusion tensor imaging does not detect any existing differences; (c) inflammatory processes such as astrogliosis produce changes that offset the decreased fractional anisotropy values and increased radial diffusivity values that are expected in dysmyelination; and (d) our sample size was insufficient to detect differences. Further studies correlating diffusion tensor imaging findings to histology are warranted.

Purpose We investigated fractional anisotropy (FA) and radial diffusivity (RD) in a canine model of mucopolysaccharidosis (MPS). We hypothesized that canines affected with MPS would exhibit decreased FA and increased RD values when compared to unaffected canines, a trend that has been previously described in humans with white matter diseases. Methods Four unaffected canines and two canines with MPS were euthanized at 18 weeks of age. Their brains were imaged using high-resolution diffusion tensor imaging (DTI) on a 7T small-animal magnetic resonance imaging system. One hundred regions of interest (ROIs) were placed in each of four white matter regions: anterior and posterior regions of the internal capsule (AIC and PIC, respectively) and anterior and posterior regions of the centrum semiovale (ACS and PCS, respectively). For each specimen, average FA and RD values and associated 95% confidence intervals were calculated from 100 ROIs for each brain region. Results For each brain region, the FA values in MPS brains were consistently lower than in unaffected dogs, and the RD values in MPS dogs were consistently higher, supporting our hypothesis. The confidence intervals for affected and unaffected canines did not overlap in any brain region. Conclusion FA and RD values followed the predicted trend in canines affected with MPS, a trend that has been described in humans with lysosomal storage and dysmyelinating diseases. These findings suggest that the canine model parallels MPS in humans, and further indicates that quantitative DTI analysis of such animals may be suitable for future study of disease progression and therapeutic response in MPS.

Purpose The purpose of this study was to investigate a novel tensor shape plot analysis technique of diffusion tensor imaging data as a means to assess microstructural differences in brain tissue. We hypothesized that this technique could distinguish white matter regions with different microstructural compositions. Methods Three normal canines were euthanized at seven weeks old. Their brains were imaged using identical diffusion tensor imaging protocols on a 7T small-animal magnetic resonance imaging system. We examined two white matter regions, the internal capsule and the centrum semiovale, each subdivided into an anterior and posterior region. We placed 100 regions of interest in each of the four brain regions. Eigenvalues for each region of interest triangulated onto tensor shape plots as the weighted average of three shape metrics at the plot's vertices: CS, CL, and CP. Results The distribution of data on the plots for the internal capsule differed markedly from the centrum semiovale data, thus confirming our hypothesis. Furthermore, data for the internal capsule were distributed in a relatively tight cluster, possibly reflecting the compact and parallel nature of its fibers, while data for the centrum semiovale were more widely distributed, consistent with the less compact and often crossing pattern of its fibers. This indicates that the tensor shape plot technique can depict data in similar regions as being alike. Conclusion Tensor shape plots successfully depicted differences in tissue microstructure and reflected the microstructure of individual brain regions. This proof of principle study suggests that if our findings are reproduced in larger samples, including abnormal white matter states, the technique may be useful in assessment of white matter diseases.

Detecting circulating tumor cells (CTCs) with high sensitivity and specificity is critical to management of metastatic cancers. Although immuno-magnetic technology for in vitro detection of CTCs has shown promising potential for clinical applications, the biofouling effect, i.e., non-specific adhesion of biomolecules and non-cancerous cells in complex biological samples to the surface of a device/probe, can reduce the sensitivity and specificity of cell detection. Reported herein is the application of anti-biofouling polyethylene glycol-block-allyl glycidyl ether copolymer (PEG-b-AGE) coated iron oxide nanoparticles (IONPs) to improve the separation of targeted tumor cells from aqueous phase in an external magnetic field. PEG-b-AGE coated IONPs conjugated with transferrin (Tf) exhibited significant anti-biofouling properties against non-specific protein adsorption and off-target cell uptake, thus substantially enhancing the ability to target and separate transferrin receptor (TfR) over-expressed D556 medulloblastoma cells. Tf conjugated PEG-b-AGE coated IONPs exhibited a high capture rate of targeted tumor cells (D556 medulloblastoma cell) in cell media (58.7 ± 6.4%) when separating 100 targeted tumor cells from 1×105 non-targeted cells and 41 targeted tumor cells from 100 D556 medulloblastoma cells spiked into 1 mL blood. It is demonstrated that developed nanoparticle has higher efficiency in capturing targeted cells than widely used micron-sized particles (i.e., Dynabeads®).

Early infantile Krabbe disease is rapidly fatal, but hematopoietic stem cell transplantation (HSCT) may improve outcomes if performed soon after birth. New York State began screening all newborns for Krabbe disease in 2006. Infants with abnormal newborn screen results for Krabbe disease were referred to specialty-care centers. Newborns found to be at high risk for Krabbe disease underwent a neurodiagnostic battery to determine the need for emergent HSCT. Almost 2 million infants were screened. Five infants were diagnosed with early infantile Krabbe disease. Three died, two from HSCT-related complications and one from untreated disease. Two children who received HSCT have moderate to severe developmental delays. Forty-six currently asymptomatic children are considered to be at moderate or high risk for development of later-onset Krabbe disease. These results show significant HSCT-associated morbidity and mortality in early infantile Krabbe disease and raise questions about its efficacy when performed in newborns diagnosed through newborn screening. The unanticipated identification of “at risk” children introduces unique ethical and medicolegal issues. New York’s experience raises questions about the risks, benefits, and practicality of screening newborns for Krabbe disease. It is imperative that objective assessments be made on an ongoing basis as additional states begin screening for this disorder. Genet Med 18 12, 1235–1243.

The purpose of this study is to discuss the evidence supporting the use of neuroimaging in adult patients presenting with new-onset seizure.Unenhanced CT should be the initial imaging examination performed for adults presenting with first unprovoked seizure in the acute setting to exclude conditions requiring urgent or emergent intervention. MRI has added benefits and should be considered for adults presenting acutely for whom the initial CT is negative and for those presenting with new-onset seizure in the nonacute setting.

We employed a novel diffusion tensor imaging phantom to study intra- and interscanner reproducibility on two 3T magnetic resonance (MR) scanners. Using a phantom containing thousands of hollow micron-size tubes in complex arrays, we performed two experiments using a b value of 1000 s/ms2 on two Siemens 3T Trio scanners. First, we performed 12-direction scans. Second, on one scanner, we performed two 64-direction protocols with different repetition times (TRs). We used a one-way analysis of variance to calculate differences between scanners and the Mann-Whitney U test to assess differences between 12-direction and 64-direction data. We calculated the coefficient of variation (CoV) for intrascanner and interscanner data. For 12-direction protocols, mean fractional anisotropy (FA) was 0.3003 for Scanner 1 (four scans) and 0.3094 for Scanner 2 (three scans). Lowest FA value on Scanner 1 was 2.56 standard deviations below the mean of Scanner 2. For 64-direction scans, mean FA was 0.2640 for 4000 ms TR and 0.2582 for 13,200 ms TR scans. For 12-direction scans, within-scanner CoV was 0.0326 for Scanner 1 and 0.0240 for Scanner 2; between-scanner CoV was 0.032. For 64-direction scans, CoV was 0.056 for TR 4000 ms and 0.0533 for TR 13,200 ms. The difference between median FA values of 12-direction and 64-direction scans was statistically significant ( p

Introduction Over the past decade, the potential for drug-associated progressive multifocal leukoencephalopathy (PML) has become an increasingly important consideration in certain drug development programmes, particularly those of immunomodulatory biologics. Whether the risk of PML with an investigational agent is proven (e.g. extrapolated from relevant experience, such as a class effect) or merely theoretical, the serious consequences of acquiring PML require careful risk minimisation and assessment. No single standard for such risk minimisation exists. Vedolizumab is a recently developed monoclonal antibody to α4β7 integrin. Its clinical development necessitated a dedicated PML risk minimisation assessment as part of a global preapproval regulatory requirement. Objective The aim of this study was to describe the multiple risk minimisation elements that were incorporated in vedolizumab clinical trials in inflammatory bowel disease patients as part of the risk assessment and minimisation of PML programme for vedolizumab. Methods A case evaluation algorithm was developed for sequential screening and diagnostic evaluation of subjects who met criteria that indicated a clinical suspicion of PML. An Independent Adjudication Committee provided an independent, unbiased opinion regarding the likelihood of PML. Results Although no cases were detected, all suspected PML events were thoroughly reviewed and successfully adjudicated, making it unlikely that cases were missed. Conclusion We suggest that this programme could serve as a model for pragmatic screening for PML during the clinical development of new drugs. Electronic supplementary material The online version of this article (10.1007/s40264-018-0669-8) contains supplementary material, which is available to authorized users.

The goal of this study was to apply image registration-based automated segmentation methods to measure diffusion tensor imaging (DTI) metrics within the canine brain. Specifically, we hypothesized that this method could measure DTI metrics within the canine brain with greater reproducibility than with hand-drawn region of interest (ROI) methods. We performed high-resolution post-mortem DTI imaging on two canine brains on a 7 T MR scanner. We designated the two brains as brain 1 and brain 2. We measured DTI metrics within the corpus callosum of brain 1 using a hand-drawn ROI method and an automated segmentation method in which ROIs from brain 2 were transformed into the space of brain 1. We repeated both methods in order to measure their reliability. Mean differences between the two sets of hand-drawn ROIs ranged from 4% to 10%. Mean differences between the hand-drawn ROIs and the automated ROIs were less than 3%. The mean differences between the first and second automated ROIs were all less than 0.25%. Our findings indicate that the image registration-based automated segmentation method was clearly the more reproducible method. These results provide the groundwork for using image registration-based automated segmentation methods to measure DTI metrics within the canine brain. Such methods will facilitate the study of white matter pathology in canine models of neurologic disease.

Magnetic resonance imaging studies of maltreated children with posttraumatic stress disorder (PTSD) suggest that maltreatment-related PTSD is associated with adverse brain development. Maltreated youth resilient to chronic PTSD were not previously investigated and may elucidate neuromechanisms of the stress diathesis that leads to resilience to chronic PTSD. In this cross-sectional study, anatomical volumetric and corpus callosum diffusion tensor imaging measures were examined using magnetic resonance imaging in maltreated youth with chronic PTSD (N = 38), without PTSD (N = 35), and nonmaltreated participants (n = 59). Groups were sociodemographically similar. Participants underwent assessments for strict inclusion/exclusion criteria and psychopathology. Maltreated youth with PTSD were psychobiologically different from maltreated youth without PTSD and nonmaltreated controls. Maltreated youth with PTSD had smaller posterior cerebral and cerebellar gray matter volumes than did maltreated youth without PTSD and nonmaltreated participants. Cerebral and cerebellar gray matter volumes inversely correlated with PTSD symptoms. Posterior corpus callosum microstructure in pediatric maltreatment-related PTSD differed compared to maltreated youth without PTSD and controls. The group differences remained significant when controlling for psychopathology, numbers of Axis I disorders, and trauma load. Alterations of these posterior brain structures may result from a shared trauma-related mechanism or an inherent vulnerability that mediates the pathway from chronic PTSD to comorbidity.

Tumor recurrence following surgery is a common and unresolved medical problem of great importance since surgery is the most widely used treatment for solid-mass tumors worldwide. A contributing factor to tumor recurrence is the presence of residual tumor remaining at or near the surgical site following surgery. Goal: The primary objective of this study was to develop and evaluate an image-guided surgery system based on a near-infrared, handheld excitation source and spectrograph in combination with a widefield video imaging system. Methods: This system was designed to detect the fluorescence of near-infrared contrast agents and, in particular, indocyanine green (ICG). The imaging system was evaluated for its optical performance and ability to detect the presence of ICG in tumors in an ectopic murine tumor model as well as in spontaneous tumors arising in canines. Results: In both settings, an intravenous ICG infusion provided tumor contrast. In both the murine models and surgical specimens from canines, ICG preferentially accumulated in tumor tissue compared to surrounding normal tissue. The resulting contrast was sufficient to distinguish neoplasia from normal tissue; in the canine surgical specimens, the contrast was sufficient to permit identification of neoplasia on the marginal surface of the specimen. Conclusion: These results demonstrate a unique concept in image-guided surgery by combining local excitation and spectroscopy with widefield imaging. Significance: The ability to readily detect ICG in canines with spontaneous tumors in a clinical setting exemplifies the potential for further clinical translation; the promising results of detecting neoplasia on the marginal specimen surface underscore the clinical utility.

SUMMARY: The past decade has seen impressive advances in the types of neuroimaging information that can be acquired in patients with traumatic brain injury. However, despite this increase in information, understanding of the contribution of this information to prognostic accuracy and treatment pathways for patients is limited. Available techniques often allow us to infer the presence of microscopic changes indicative of alterations in physiology and function in brain tissue. However, because histologic confirmation is typically lacking, conclusions reached by using these techniques remain solely inferential in almost all cases. Hence, a need exists for validation of these techniques by using data from large population samples that are obtained in a uniform manner, analyzed according to well-accepted procedures, and correlated with closely monitored clinical outcomes. At present, many of these approaches remain confined to population-based research rather than diagnosis at an individual level, particularly with regard to traumatic brain injury that is mild or moderate in degree. A need and a priority exist for patient-centered tools that will allow advanced neuroimaging tools to be brought into clinical settings. One barrier to developing these tools is a lack of an age-, sex-, and comorbidities-stratified, sequence-specific, reference imaging data base that could provide a clear understanding of normal variations across populations. Such a data base would provide researchers and clinicians with the information necessary to develop computational tools for the patient-based interpretation of advanced neuroimaging studies in the clinical setting. The recent “Joint ASNR-ACR HII-ASFNR TBI Workshop: Bringing Advanced Neuroimaging for Traumatic Brain Injury into the Clinic” on May 23, 2014, in Montreal, Quebec, Canada, brought together neuroradiologists, neurologists, psychiatrists, neuropsychologists, neuroimaging scientists, members of the National Institute of Neurologic Disorders and Stroke, industry representatives, and other traumatic brain injury stakeholders to attempt to reach consensus on issues related to and develop consensus recommendations in terms of creating both a well-characterized normative data base of comprehensive imaging and ancillary data to serve as a reference for tools that will allow interpretation of advanced neuroimaging tests at an individual level of a patient with traumatic brain injury. The workshop involved discussions concerning the following: 1) designation of the policies and infrastructure needed for a normative data base, 2) principles for characterizing normal control subjects, and 3) standardizing research neuroimaging protocols for traumatic brain injury. The present article summarizes these recommendations and examines practical steps to achieve them.

The goal of this study was to determine the degree to which ex vivo diffusion tensor imaging (DTI) parameters correlate to one another in white matter regions on very high resolution MR scans. Specifically, we hypothesized that radial diffusivity (RD) and apparent diffusion coefficient (ADC) would correlate more closely than either would correlate with fractional anisotropy (FA). We performed post mortem DTI imaging on three canine brains on a 7T MR scanner (TR = 100 ms, NEX = 1, gradient amplitude = 600 mT/m, b = 1492–1,565 s/mm2) and generated maps of FA, RD, and ADC. We measured RD, FA and ADC within 14 regions of interest representative of various portions of white matter. We compared the three combinations of values, i.e., FA vs ADC, FA vs RD and ADC vs RD, using linear regression models. Linear regression demonstrated that RD was significantly correlated with FA (p ≪ 0.01; R2 = 0.3053) and also with ADC (p ≪ 0.01; R2 = 0.6755), but to a much greater degree. However, ADC was not significantly correlated with FA (p = 0.526; R2 = 0.101). Our findings suggest that both RD and ADC reflect similar cytoarchitectural features, most likely that of myelination, whereas FA values likely reflect both myelination and additional microstructural features that constrain the diffusion of water in white matter.

BACKGROUND: Gliomas are the most common primary brain tumour. They are graded using the WHO classification system, with Grade II‐IV astrocytomas, oligodendrogliomas and oligoastrocytomas. Low‐grade gliomas (LGGs) are WHO Grade II infiltrative brain tumours that typically appear solid and non‐enhancing on magnetic resonance imaging (MRI) scans. People with LGG often have little or no neurologic deficit, so may opt for a watch‐and‐wait‐approach over surgical resection, radiotherapy or both, as surgery can result in early neurologic disability. Occasionally, high‐grade gliomas (HGGs, WHO Grade III and IV) may have the same MRI appearance as LGGs. Taking a watch‐and‐wait approach could be detrimental for the patient if the tumour progresses quickly. Advanced imaging techniques are increasingly used in clinical practice to predict the grade of the tumour and to aid clinical decision of when to intervene surgically. One such advanced imaging technique is magnetic resonance (MR) perfusion, which detects abnormal haemodynamic changes related to increased angiogenesis and vascular permeability, or "leakiness" that occur with aggressive tumour histology. These are reflected by changes in cerebral blood volume (CBV) expressed as rCBV (ratio of tumoural CBV to normal appearing white matter CBV) and permeability, measured by K(trans). OBJECTIVES: To determine the diagnostic test accuracy of MR perfusion for identifying patients with primary solid and non‐enhancing LGGs (WHO Grade II) at first presentation in children and adults. In performing the quantitative analysis for this review, patients with LGGs were considered disease positive while patients with HGGs were considered disease negative. To determine what clinical features and methodological features affect the accuracy of MR perfusion. SEARCH METHODS: Our search strategy used two concepts: (1) glioma and the various histologies of interest, and (2) MR perfusion. We used structured search strategies appropriate for each database searched, which included: MEDLINE (Ovid SP), Embase (Ovid SP), and Web of Science Core Collection (Science Citation Index Expanded and Conference Proceedings Citation Index). The most recent search for this review was run on 9 November 2016. We also identified 'grey literature' from online records of conference proceedings from the American College of Radiology, European Society of Radiology, American Society of Neuroradiology and European Society of Neuroradiology in the last 20 years. SELECTION CRITERIA: The titles and abstracts from the search results were screened to obtain full‐text articles for inclusion or exclusion. We contacted authors to clarify or obtain missing/unpublished data. We included cross‐sectional studies that performed dynamic susceptibility (DSC) or dynamic contrast‐enhanced (DCE) MR perfusion or both of untreated LGGs and HGGs, and where rCBV and/or K(trans) values were reported. We selected participants with solid and non‐enhancing gliomas who underwent MR perfusion within two months prior to histological confirmation. We excluded studies on participants who received radiation or chemotherapy before MR perfusion, or those without histologic confirmation. DATA COLLECTION AND ANALYSIS: Two review authors extracted information on study characteristics and data, and assessed the methodological quality using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS‐2) tool. We present a summary of the study characteristics and QUADAS‐2 results, and rate studies as good quality when they have low risk of bias in the domains of reference standard of tissue diagnosis and flow and timing between MR perfusion and tissue diagnosis. In the quantitative analysis, LGGs were considered disease positive, while HGGs were disease negative. The sensitivity refers to the proportion of LGGs detected by MR perfusion, and specificity as the proportion of detected HGGs. We constructed two‐by‐two tables with true positives and false negatives as the number of correctly and incorrectly diagnosed LGG, respectively, while true negatives and false positives are the number of correctly and incorrectly diagnosed HGG, respectively. Meta‐analysis was performed on studies with two‐by‐two tables, with further sensitivity analysis using good quality studies. Limited data precluded regression analysis to explore heterogeneity but subgroup analysis was performed on tumour histology groups. MAIN RESULTS: Seven studies with small sample sizes (4 to 48) met our inclusion criteria. These were mostly conducted in university hospitals and mostly recruited adult patients. All studies performed DSC MR perfusion and described heterogeneous acquisition and post‐processing methods. Only one study performed DCE MR perfusion, precluding quantitative analysis. Using patient‐level data allowed selection of individual participants relevant to the review, with generally low risks of bias for the participant selection, reference standard and flow and timing domains. Most studies did not use a pre‐specified threshold, which was considered a significant source of bias, however this did not affect quantitative analysis as we adopted a common rCBV threshold of 1.75 for the review. Concerns regarding applicability were low. From published and unpublished data, 115 participants were selected and included in the meta‐analysis. Average rCBV (range) of 83 LGGs and 32 HGGs were 1.29 (0.01 to 5.10) and 1.89 (0.30 to 6.51), respectively. Using the widely accepted rCBV threshold of

Purpose The purpose of this study was to compare quantitative diffusion tensor imaging metrics in dogs affected with a model of Krabbe disease to age-matched normal controls. We hypothesized that fractional anisotropy would be decreased and radial diffusivity would be increased in the Krabbe dogs. Methods We used a highly reproducible region-of-interest interrogation technique to measure fractional anisotropy and radial diffusivity in three different white matter regions within the internal capsule and centrum semiovale in four Krabbe affected brains and three age-matched normal control brains. Results Despite all four Krabbe dogs manifesting pelvic limb paralysis at the time of death, age-dependent differences in DTI metrics were observed. In the 9, 12, and 14 week old Krabbe dogs, FA values unexpectedly increased and RD values decreased. FA values were generally higher and RD values generally lower in both regions of the internal capsule in the Krabbe brains during this period. FA values in the brain from the 16 week old Krabbe dog decreased and were lower than in control brains and RD values increased and were higher than in control brain. Conclusion Our findings suggest that FA and RD in the internal capsule and centrum semiovale are affected differently at different ages, despite disease having progressed to pelvic limb paralysis in all dogs evaluated. In 9, 12, and 14 week old Krabbe dogs, higher FA values and lower RD values are seen in the internal capsule. However, in the 16 week old Krabbe dog, lower FA and higher RD values are seen, consistent with previous observations in Krabbe dogs, as well as observations in human Krabbe patients.

Detecting positive tumor margins and local malignant masses during surgery is critical for long-term patient survival. The use of image-guided surgery for tumor removal, particularly with near-infrared fluorescent imaging, is a potential method to facilitate removing all neoplastic tissue at the surgical site. In this study we demonstrate a series of hyaluronic acid (HLA)-derived nanoparticles that entrap the near-infrared dye indocyanine green, termed NanoICG, for improved delivery of the dye to tumors. Self-assembly of the nanoparticles was driven by conjugation of one of three hydrophobic moieties: aminopropyl-1-pyrenebutanamide (PBA), aminopropyl-5β-cholanamide (5βCA), or octadecylamine (ODA). Nanoparticle self-assembly, dye loading, and optical properties were characterized. NanoICG exhibited quenched fluorescence that could be activated by disassembly in a mixed solvent. NanoICG was found to be nontoxic at physiologically relevant concentrations and exposure was not found to inhibit cell growth. Using an MDA-MB-231 tumor xenograft model in mice, strong fluorescence enhancement in tumors was observed with NanoICG using a fluorescence image-guided surgery system and a whole-animal imaging system. Tumor contrast with NanoICG was significantly higher than with ICG alone.

OBJECTIVE. Brain arteriovenous malformation (AVM) rupture results in substantial morbidity and mortality. The goal of AVM treatment is eradication of the AVM, but the risk of treatment must be weighed against the risk of future hemorrhage. CONCLUSION. Imaging plays a vital role by providing the information necessary for AVM management. Here, we discuss the background, natural history, clinical presentation, and imaging of AVMs. In addition, we explain advances in techniques for imaging AVMs.

Pelizaeus-Merzbacher Disease (PMD) is a rare X-linked recessive leukodystrophy caused by mutations in the proteolipid protein 1 gene on the Xq22 chromosome. PMD is a dysmyelinating disorder characterized by variable clinical presentation and course. Symptoms range from mild motor deficits to progressive spasticity and neurologic decline resulting in death at an early age. There is no definitive curative treatment. This report presents the clinical course of 2 young boys with PMD who are the first known patients to receive umbilical cord blood transplantation as a therapeutic intervention to stabilize disease progression. Pretransplantation evaluation revealed that both patients had significant motor deficits as well as delayed cognitive function as compared with age-matched peers. Brain imaging revealed varying degrees of hypomyelination. Both patients received myeloablative chemotherapy followed by an unrelated donor umbilical cord blood infusion, which they tolerated well with no major transplantation-related complications. At 7-years and 1-year posttransplantation, respectively, both boys are making slow neurocognitive improvements and show no evidence of functional decline. Imaging results show stable or improving myelination. Although the results of unrelated donor umbilical cord blood transplantation in these 2 boys with PMD are encouraging, longer-term follow-up will be necessary to assess the effect of this treatment on the variable natural disease course.

Rationale and Objectives To evaluate whether the presence of facial photographs obtained at the point-of-care of portable radiography leads to increased detection of wrong-patient errors. Materials and Methods In this institutional review board–approved study, 166 radiograph–photograph combinations were obtained from 30 patients. Consecutive radiographs from the same patients resulted in 83 unique pairs (ie, a new radiograph and prior, comparison radiograph) for interpretation. To simulate wrong-patient errors, mismatched pairs were generated by pairing radiographs from different patients chosen randomly from the sample. Ninety radiologists each interpreted a unique randomly chosen set of 10 radiographic pairs, containing up to 10% mismatches (ie, error pairs). Radiologists were randomly assigned to interpret radiographs with or without photographs. The number of mismatches was identified, and interpretation times were recorded. Results Ninety radiologists with 21 ± 10 (mean ± standard deviation) years of experience were recruited to participate in this observer study. With the introduction of photographs, the proportion of errors detected increased from 31% (9 of 29) to 77% (23 of 30; P = .006). The odds ratio for detection of error with photographs to detection without photographs was 7.3 (95% confidence interval: 2.29–23.18). Observer qualifications, training, or practice in cardiothoracic radiology did not influence sensitivity for error detection. There is no significant difference in interpretation time for studies without photographs and those with photographs (60 ± 22 vs. 61 ± 25 seconds; P = .77). Conclusions In this observer study, facial photographs obtained simultaneously with portable chest radiographs increased the identification of any wrong-patient errors, without substantial increase in interpretation time. This technique offers a potential means to increase patient safety through correct patient identification.

Spontaneous intracranial hemorrhage is a neurological emergency commonly encountered by the emergency radiologist. This article reviews the approach to spontaneous brain parenchymal hemorrhage, including common causes and the role of various neuroimaging modalities in the diagnostic workup. We emphasize the need for a primary survey directed at conveying information needed for emergent clinical management of the patient and a secondary survey directed at identifying the etiology of the hemorrhage.

Dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) is used to track the first pass of an exogenous, paramagnetic, nondiffusible contrast agent through brain tissue, and has emerged as a powerful tool in the characterization of brain tumor hemodynamics. DSC-MRI parameters can be helpful in many aspects, including tumor grading, prediction of treatment response, likelihood of malignant transformation, discrimination between tumor recurrence and radiation necrosis, and differentiation between true early progression and pseudoprogression. This review aims to provide a conceptual overview of the underlying principles of DSC-MRI of the brain for clinical neuroradiologists, scientists, or students wishing to improve their understanding of the technical aspects, pitfalls, and controversies of DSC perfusion MRI of the brain. Future consensus on image acquisition parameters and postprocessing of DSC-MRI will most likely allow this technique to be evaluated and used in high-quality multicenter studies and ultimately help guide clinical care. J. Magn. Reson. Imaging 2015;41:296–313.© 2013 Wiley Periodicals, Inc.

We prospectively compared the ability of neuroradiologists to diagnose medulloblastoma with novice raters using only apparent diffusion coefficient (ADC) values measured on ADC maps. One hundred and three pediatric patients with pre-operative magnetic resonance imaging scans showing a posterior fossa tumor with histological verification were retrospectively identified from a ten-year period at a tertiary care medical center. A single observer measured the lowest ADC values in all tumors to determine the mean minimum ADC (ADCmin) value that provided greatest accuracy in distinguishing medulloblastomas from other tumors, which was determined to be 0.66×10−3 mm2/s. Imaging studies, including ADC maps, from 90 patients were provided to two neuroradiologists, who provided a diagnosis, which was later dichotomized as medulloblastoma or other. Two medical students measured ADCmin within tumors and those with ADCmin < 0.66×10−3 mm2/s were recorded as medulloblastoma; any other value was recorded as other. Diagnostic accuracy was measured. ADCmin values allowed a correct identification of lesions as either medulloblastoma or other in 91% of cases. After diagnoses by the two neuroradiologists were categorized as either medulloblastoma or other, their diagnoses were correct in 90% and 84% of cases, respectively. In 19 cases, at least one neuroradiologist was incorrect; the addition of ADC values to clinical interpretation would have allowed a correct diagnosis in 63% of such cases. Diagnostic accuracy based on ADC values by medical students was comparable to that of sub specialty-trained neuroradiologists. Our findings suggest that the addition of ADC values to standard film interpretation may improve the diagnostic rate for these tumors.

Objective Whether febrile status epilepticus (FSE) produces hippocampal sclerosis (HS) and temporal lobe epilepsy (TLE) has long been debated. Our objective is to determine if FSE produces acute hippocampal injury that evolves to HS.

Pompe disease is a lysosomal storage disorder caused by deficiency of acid-alpha glucosidase. There are limited data on central nervous system (CNS) involvement in survivors of infantile Pompe disease (IPD). The objective of this cross-sectional study is to implement the Fazekas scale, a visual MRI rating scale, to quantify white matter hyperintensities (WMH) on T2-weighted-Fluid Attenuated Inversion Recovery (T2-FLAIR) brain MRI images and to determine the extent of white matter (WM) involvement in the CNS of patients with IPD. Twelve patients (aged 6.1-18.1 years, 7 males, 5 females) with IPD and on long-term enzyme replacement therapy were included in the study. We assessed WM involvement in ten anatomical areas of the brain- juxtacortical U-fibers, subcortical WM, periventricular WM in the centrum semiovale and in the frontal and parietal lobes at the level of corona radiata, corpus callosum, anterior and posterior limb of the internal capsule, external capsule, corticospinal tracts at cerebral peduncles, midbrain, and pons and the medullary decussation of corticospinal tracts. Based on the severity of WMH, each area was graded on the Fazekas scale from zero (absent) to 3 (severe) and a total score (range 0-30) was obtained. Ten patients (ages 6.6-18.1 years) had WMH on brain MRI (range of scores: 2-23) using the Fazekas scale. Five of the 10 patients (ages 6.7-18.1 years) had scores greater than 15 (range 16-23) indicating severe WMH and 2/10 patients (aged 6.1 years and 7.3 years) had no WM involvement with a score of zero. Our results provide a means to quantify WM involvement in the CNS of patients with IPD. Fazekas scale could serve as a biomarker for longitudinal follow up of WM abnormalities in patients with IPD and to better understand the extent of CNS involvement in IPD. [A portion of this study was funded by Genzyme Sanofi]

We set out to determine functional white matter (WM) connections passing through the canine corpus callosum; these WM connections would be useful for subsequent studies of canine brains that serve as models for human WM pathway disease. Based on prior studies, we anticipated that the anterior corpus callosum would send projections to the anterior cerebral cortex whereas progressively posterior segments would send projections to more posterior cortex.A postmortem canine brain was imaged using a 7-T MRI system producing 100-μm-isotropic-resolution diffusion-tensor imaging analyzed by tractography. Using regions of interest (ROIs) within cortical locations, which were confirmed by a Nissl stain that identified distinct cortical architecture, we successfully identified six important WM pathways. We also compared fractional anisotropy (FA), apparent diffusion coefficient (ADC), radial diffusivity, and axial diffusivity in tracts passing through the genu and splenium.Callosal fibers were organized on the basis of cortical destination (e.g., fibers from the genu project to the frontal cortex). Histologic results identified the motor cortex on the basis of cytoarchitectonic criteria that allowed placement of ROIs to discriminate between frontal and parietal lobes. We also identified cytoarchitecture typical of the orbital frontal, anterior frontal, and occipital regions and placed ROIs accordingly. FA, ADC, radial diffusivity, and axial diffusivity values were all higher in posterior corpus callosum fiber tracts.Using six cortical ROIs, we identified six major WM tracts that reflect major functional divisions of the cerebral hemispheres, and we derived quantitative values that can be used for study of canine models of human WM pathologic states.

Positron Emission Tomography (PET) is a medical imaging technique that can be used to show brain function. Courts have admitted PET scan evidence in cases involving brain damage, injury, toxic exposure, or illness ("brain trauma") and to support claims of diminished cognitive abilities and impulse control. Despite the limited data on the relationships between PET, brain trauma and behavior, many courts admit PET scan evidence without much critical analysis. This article examines the use of PET as proof of functional impairment and justification of abnormal behavior by explaining its diagnostic use and limitations, the limited support for claims of its relationship to behavior, and evidentiary considerations that should govern its admission into court as evidence. The authors urge courts to consider PET evidence, claims of experts, and the scope of the proposed testimony with greater deference to the clinical scope of PET, as outlined by the American College of Radiology's appropriateness criteria and the Working Group Report of the American Psychiatric Association.

This study examined the relationship between histological variables and diffusion tensor imaging (DTI) values in a normal canine brain. We hypothesized that radial diffusivity (RD) would correlate with myelin density and fractional anisotropy (FA) would correlate with white matter fiber coherence. We acquired DTI maps of a normal canine brain post mortem on a 7T MR scanner (TR = 100 ms, TE = 18.1 ms, NEX = 1, width [d] = 4 ms, separation [D] = 8.9 ms, gradient amplitude = 600 mT/m, b=1,565 s/mm2) and generated maps of FA, RD, and axial diffusivity. The brain was subsequently sectioned and stained for myelin with gold chloride, which also allowed for measurement of fiber coherence. DTI metrics were then directly compared with the optical density of the myelin stain and the coherence of stained fibers. Multivariate linear regression demonstrated that RD, but not FA, significantly correlated with both myelin stain intensity (p = 0.031) and fiber coherence (p = 0.035). The Pearson correlation coefficient between these two histological variables and FA was 0.122; and was 0.607 for the histological variables and RD. We found that RD significantly correlated with both optical density of myelinated fibers and fiber coherence, but FA correlated with neither histological finding. Factors other than degree of myelination and fiber coherence should be considered to fully account for regional variation in FA.

We compared results from various methods of analysis of diffusion tensor imaging (DTI) data from a single dataset consisting of 10 healthy adolescents.All subjects were imaged on a single 3-T MRI system (single-shot echo-planar imaging pulse sequence; b value, 1000 s/mm(2)). We measured fractional anisotropy (FA), apparent diffusion coefficient (ADC), and axial and radial diffusivity values using 64-pixel rectangular regions of interest (ROIs) in the right side, midline, and left side of the central portion of the splenium of the corpus callosum for fixed (i.e., at same sites in all subjects) and targeted (i.e., at sites of highest FA values) locations. We compared results with those obtained using 64-pixel oval ROIs and 100-pixel rectangular ROIs in the same locations. Finally, we compared results from ROI-based methods and from tractography. All comparisons used the Wilcoxon signed rank test and the intraclass correlation of individual values.Compared to tractography, the average of mean ROI-based values was significantly higher for fixed (approximately 14%) and targeted (approximately 39%) FA values and was significantly lower for ADC (approximately 16%) and radial diffusivity (approximately 38%) values. For solely ROI-based comparisons, statistically significant differences were found in the following comparisons: 64- versus 100-pixel ROI, oval versus rectangular ROI, targeted FA left of midline versus mean targeted FA value, and targeted ROI right of midline versus mean targeted FA value.Markedly different values were obtained when using either ROI- or tractography-based techniques or ROI analysis techniques that differ only relatively slightly.

Metachromatic leukodystrophy (MLD) is an inherited demyelinating disease that causes progressive neurologic deterioration, leading to severe motor disability, developmental regression, seizures, blindness, deafness, and death. The disease presents as a late-infantile, juvenile, or adult form. Hematopoietic stem cell transplantation has been shown to slow disease progression. The purpose of this longitudinal study was to evaluate long-term treatment outcomes after unrelated donor umbilical cord blood (UCB) transplantation in pediatric patients according to disease burden and age at onset (ie, late-infantile versus juvenile). Engraftment, survival, treatment-related toxicity, graft-versus-host disease, neurophysiologic measures, and neurodevelopmental function were assessed. To evaluate whether signal intensity abnormalities on magnetic resonance imaging (ie, modified Loes scores) predict post-transplant cognitive and gross motor development, a general linear mixed model was fit to the data. Twenty-seven patients underwent transplantation after myeloablative chemotherapy; 24 patients engrafted after the initial transplantation. Seven patients died of infection, regimen-related toxicity, or disease progression. Twenty patients (6 with late-infantile onset and 14 with juvenile onset) were followed for a median of 5.1 years (range, 2.4 to 14.7). We found that patients with motor function symptoms at the time of transplant did not improve after transplantation. Brainstem auditory evoked responses, visual evoked potentials, electroencephalogram, and/or peripheral nerve conduction velocities stabilized or improved in juvenile patients but continued to worsen in most patients with the late-infantile presentation. Pretransplant modified Loes scores were highly correlated with developmental outcomes and predictive of cognitive and motor function. Children who were asymptomatic at the time of transplantation benefited most from the procedure. Children with juvenile onset and minimal symptoms showed stabilization or deterioration of motor skills but maintained cognitive skills. Overall, children with juvenile onset had better outcomes than those with late-infantile onset. As in other leukodystrophies, early intervention correlated with optimal outcomes. We conclude that UCB transplantation benefits children with presymptomatic late-infantile MLD or minimally symptomatic juvenile MLD.

The objective of our study was to evaluate whether facial and chest photographs obtained simultaneously with radiographs increase radiologists' detection rate of labeling errors.We obtained simultaneous portable radiographs and photographs of 34 patients. We generated 88 pairs of chest radiographs (one recent radiograph, one prior radiograph) and compiled a set of 20 pairs for reader review. Two, three, or four mismatched pairs (i.e., pairs containing radiographs of different patients) were introduced into each list. Ten radiologist readers blinded to the presence of mismatches interpreted the 20 radiograph pairs. Readers then reviewed a second set of 20 pairs containing mismatches but photographs of the patients obtained at the time of imaging were attached to the radiographs. Readers were not instructed regarding the purpose of the photographs. The mismatch detection rate and time for interpretation was recorded for both sessions. The two-tailed Fisher exact test was used to evaluate differences in mismatch detection rates between sessions, with a p value of less than 0.05 being considered significant.The error detection rates without (3/24 = 12.5%) and with (16/25 = 64%) photographs significantly differed (p = 0.0003). The average interpretation times without and with photographs were 35.73 and 26.51 minutes, respectively (two-tailed Student t test, p = 0.1165).The use of photographs increased the detection of errors without a concomitant increase in film interpretation time, which may translate into improvements in patient safety without an increase in interpretation time.