Correlation of Radiomics with Treatment Response in Liver Metastases.

RATIONALE AND OBJECTIVES: To assess differences in radiomics derived from semi-automatic segmentation of liver metastases for stable disease (SD), partial response (PR), and progressive disease (PD) based on RECIST1.1 and to assess if radiomics alone at baseline can predict response. MATERIALS AND METHODS: Our IRB-approved study included 203 women (mean age 54 ± 11 years) with metastatic liver disease from breast cancer. All patients underwent contrast abdomen-pelvis CT in the portal venous phase at two points: baseline (pre-treatment) and follow-up (between 3 and 12 months following treatment). Patients were subcategorized into three subgroups based on RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors version 1.1): 66 with SD, 69 with PR, and 68 with PD on follow-up CT. The deidentified baseline and follow-up CT images were exported to the radiomics prototype. The prototype enabled semi-automatic segmentation of the target liver lesions for the extraction of first and high order radiomics. Statistical analyses with logistic regression and random forest classifiers were performed to differentiate SD from PD and PR. RESULTS: There was no significant difference between the radiomics on the baseline and follow-up CT images of patients with SD (area under the curve (AUC): 0.3). Random forest classifier differentiated patients with PR with an AUC of 0.845. The most relevant feature was the large dependence emphasis's high and low pass wavelet filter (derived gray level dependence matrix features). Random forest classifier differentiated PD with an AUC of 0.731, with the most relevant feature being the surface-to-volume ratio. There was no difference in radiomics among the three groups at baseline; therefore, a response could not be predicted. CONCLUSION: Radiomics of liver metastases with semi-automatic segmentation demonstrate differences between SD from PR and PD. SUMMARY STATEMENT: Semiautomatic segmentation and radiomics of metastatic liver disease demonstrate differences in SD from the PR and progressive metastatic on the baseline and follow-up CT. Despite substantial variations in the scanners, acquisition, and reconstruction parameters, radiomics had an AUC of 0.84-0.89 for differentiating stable hepatic metastases from decreasing and increasing metastatic disease.

Ten-Year Follow-up of Internal Neurofibroma Growth Behavior in Adult Patients With Neurofibromatosis Type 1 Using Whole-Body MRI.

BACKGROUND AND OBJECTIVES: Internal neurofibromas, including plexiform neurofibromas (PNF), can cause significant morbidity in patients with neurofibromatosis type 1 (NF1). PNF growth is most pronounced in children and young adults, with more rapid growth thought to occur in a subset of PNF termed distinct nodular lesions (DNL). Growth behavior of internal neurofibromas and DNL in older adults is not well documented; yet knowledge thereof is important for patient risk stratification and clinical trial design. The primary objective of this study was to evaluate the long-term growth behavior of internal neurofibromas in adults with NF1. Secondary objectives were to correlate tumor growth behavior with patient-specific, tumor-specific, and patient-reported variables. METHODS: In this prospective cohort study, internal neurofibromas were identified on coronal short TI inversion recovery sequences on baseline and follow-up whole-body MRIs (WBMRIs). Tumor growth and shrinkage were defined as a volume change ≥20%. The association between tumor growth and patient-specific (baseline age, sex, and genotype), tumor-specific (morphology, location, DNL presence on baseline WBMRI, and maximum standardized uptake value on baseline PET imaging), and patient-reported variables (endogenous and exogenous hormone exposure, pain intensity, and quality of life) was assessed using the Spearman correlation coefficient and Kruskal-Wallis test. RESULTS: Of 106 patients with a baseline WBMRI obtained as part of a previous research study, 44 had a follow-up WBMRI. Three additional patients with WBMRIs acquired for clinical care were included, generating 47 adults for this study. The median age during baseline WBMRI was 42 years (range 18-70). The median time between WBMRIs was 10.4 years. Among 324 internal neurofibromas, 62.8% (56% of PNF and 62.1% of DNL) shrank spontaneously without treatment and 17.1% (17.9% of PNF and 13.8% of DNL) grew. Growth patterns were heterogeneous within participants. Patient-specific, tumor-specific, and patient-reported variables (including endogenous and exogenous hormone exposure) were not strong predictors of tumor growth. DISCUSSION: Internal neurofibroma growth behavior in older adults differs fundamentally from that in children and young adults, with most tumors, including DNL, demonstrating spontaneous shrinkage. Better growth models are needed to understand factors that influence tumor growth. These results will inform clinical trial design for internal neurofibromas.

Intrinsic brain functional connectivity patterns in alcohol use disorder.

Alcohol use disorder is associated with damaging effects to the brain. This study aimed to examine differences in static and dynamic intrinsic functional connectivity patterns in individuals with a history of alcohol use disorder in comparison to those with no history of alcohol abuse. A total of 55 participants consisting of 23 patients and 32 control individuals underwent neuropsychological assessments and resting-state functional magnetic resonance imaging on a 3 Tesla MRI scanner. Differences in functional connectivity between the two groups were determined using static and dynamic independent component analysis. Differences in static functional connectivity between the two groups were identified in the default mode network, attention network, frontoparietal network, frontal cortical network and cerebellar network. Furthermore, the analyses revealed specific differences in the dynamic temporal characteristics of functional connectivity between the two groups of participants, in a cluster involving key regions in reward, sensorimotor and frontal cortical functional networks, with some connections correlating with the length of sobriety and some others with the severity of drinking. The findings altogether suggest dysregulation in the intrinsic connectivity of cortico-basal ganglia-thalamo-cortical loops that may reflect persistent alcohol use disorder-related network abnormalities, compensatory recovery-related processes whereby additional neural resources are recruited to achieve normal levels of performance, or a predisposition toward developing alcohol use disorder.

Management of neurofibromatosis type 1-associated plexiform neurofibromas.

Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant morbidity, with treatment options limited historically to surgery. There have been tremendous advances over the past two decades in our understanding of PN, and the recent regulatory approvals of the MEK inhibitor selumetinib are reshaping the landscape for PN management. At present, there is no agreed upon PN definition, diagnostic evaluation, surveillance strategy, or clear indications for when to initiate treatment and selection of treatment modality. In this review, we address these questions via consensus recommendations from a panel of multidisciplinary NF1 experts.

Integrating the OHIF Viewer into XNAT: Achievements, Challenges and Prospects for Quantitative Imaging Studies.

Purpose: XNAT is an informatics software platform to support imaging research, particularly in the context of large, multicentre studies of the type that are essential to validate quantitative imaging biomarkers. XNAT provides import, archiving, processing and secure distribution facilities for image and related study data. Until recently, however, modern data visualisation and annotation tools were lacking on the XNAT platform. We describe the background to, and implementation of, an integration of the Open Health Imaging Foundation (OHIF) Viewer into the XNAT environment. We explain the challenges overcome and discuss future prospects for quantitative imaging studies. Materials and methods: The OHIF Viewer adopts an approach based on the DICOM web protocol. To allow operation in an XNAT environment, a data-routing methodology was developed to overcome the mismatch between the DICOM and XNAT information models and a custom viewer panel created to allow navigation within the viewer between different XNAT projects, subjects and imaging sessions. Modifications to the development environment were made to allow developers to test new code more easily against a live XNAT instance. Major new developments focused on the creation and storage of regions-of-interest (ROIs) and included: ROI creation and editing tools for both contour- and mask-based regions; a "smart CT" paintbrush tool; the integration of NVIDIA's Artificial Intelligence Assisted Annotation (AIAA); the ability to view surface meshes, fractional segmentation maps and image overlays; and a rapid image reader tool aimed at radiologists. We have incorporated the OHIF microscopy extension and, in parallel, introduced support for microscopy session types within XNAT for the first time. Results: Integration of the OHIF Viewer within XNAT has been highly successful and numerous additional and enhanced tools have been created in a programme started in 2017 that is still ongoing. The software has been downloaded more than 3700 times during the course of the development work reported here, demonstrating the impact of the work. Conclusions: The OHIF open-source, zero-footprint web viewer has been incorporated into the XNAT platform and is now used at many institutions worldwide. Further innovations are envisaged in the near future.

Brain responsivity to emotional faces differs in men and women with and without a history of alcohol use disorder.

Inclusion of women in research on Alcohol Use Disorder (AUD) has shown that gender differences contribute to unique profiles of cognitive, emotional, and neuropsychological dysfunction. We employed functional magnetic resonance imaging (fMRI) of abstinent individuals with a history of AUD (21 women [AUDw], 21 men [AUDm]) and demographically similar non-AUD control (NC) participants without AUD (21 women [NCw], 21 men [NCm]) to explore how gender and AUD interact to influence brain responses during emotional processing and memory. Participants completed a delayed match-to-sample emotional face memory fMRI task, and brain activation contrasts between a fixation stimulus and pictures of emotional face elicited a similar overall pattern of activation for all four groups. Significant Group by Gender interactions revealed two activation clusters. A cluster in an anterior portion of the middle and superior temporal gyrus, elicited lower activation to the fixation stimulus than to faces for the AUDw as compared to the NCw; that abnormality was more pronounced than the one observed for men. Another cluster in the medial portion of the superior frontal cortex elicited higher activation to the faces by AUDm than NCm, a difference that was more evident than the one observed for women. Together, these findings have added new evidence of AUD-related gender differences in neural responses to facial expressions of emotion.

Comparative analysis of three-dimensional volume rendering and maximum intensity projection for preoperative planning in liver cancer.

Three-dimensional imaging is a useful tool to evaluate liver structure and surrounding vessels for preoperative planning. In this study, we compared two methods of visualizing vascular maps on computed tomography including maximum intensity projection (MIP) and 3D volume rendered (VR) imaging. We compiled important imaging components of pre-surgical planning, and developed criteria for comparison. The imaging techniques were compared based on colorization, volume quantification, rotation, vessel delineation, small vessel clarity, and segmental liver isolation. MIP had more overall limitations due to reduced differentiation of superimposed structures, motion artifact, and interference from calcifications. We determined that because 3D quantitative volume rendered imaging can provide more detail and perspective than MIP imaging, it may be more useful in preoperative planning for patients with liver malignancy. Advanced 3D imaging is a useful tool that can have profound clinical implications on cancer detection and surgical planning.

Hippocampal subfield volumes in abstinent men and women with a history of alcohol use disorder.

Alcohol Use Disorder (AUD) has been associated with abnormalities in hippocampal volumes, but these relationships have not been fully explored with respect to sub-regional volumes, nor in association with individual characteristics such as age, gender differences, drinking history, and memory. The present study examined the impact of those variables in relation to hippocampal subfield volumes in abstinent men and women with a history of AUD. Using Magnetic Resonance Imaging at 3 Tesla, we obtained brain images from 67 participants with AUD (31 women) and 64 nonalcoholic control (NC) participants (31 women). The average duration of the most recent period of sobriety for AUD participants was 7.1 years. We used Freesurfer 6.0 to segment the hippocampus into 12 regions. These were imputed into statistical models to examine the relationships of brain volume with AUD group, age, gender, memory, and drinking history. Interactions with gender and age were of particular interest. Compared to the NC group, the AUD group had approximately 5% smaller subiculum, CA1, molecular layer, and hippocampal tail regions. Age was negatively associated with volumes for the AUD group in the subiculum and the hippocampal tail, but no significant interactions with gender were identified. The relationships for delayed and immediate memory with hippocampal tail volume differed for AUD and NC groups: Higher scores on tests of immediate and delayed memory were associated with smaller volumes in the AUD group, but larger volumes in the NC group. Length of sobriety was associated with decreasing CA1 volume in women (0.19% per year) and increasing volume size in men (0.38% per year). The course of abstinence on CA1 volume differed for men and women, and the differential relationships of subfield volumes to age and memory could indicate a distinction in the impact of AUD on functions of the hippocampal tail. These findings confirm and extend evidence that AUD, age, gender, memory, and abstinence differentially impact volumes of component parts of the hippocampus.

Open Health Imaging Foundation Viewer: An Extensible Open-Source Framework for Building Web-Based Imaging Applications to Support Cancer Research.

PURPOSE: Zero-footprint Web architecture enables imaging applications to be deployed on premise or in the cloud without requiring installation of custom software on the user's computer. Benefits include decreased costs and information technology support requirements, as well as improved accessibility across sites. The Open Health Imaging Foundation (OHIF) Viewer is an extensible platform developed to leverage these benefits and address the demand for open-source Web-based imaging applications. The platform can be modified to support site-specific workflows and accommodate evolving research requirements. MATERIALS AND METHODS: The OHIF Viewer provides basic image review functionality (eg, image manipulation and measurement) as well as advanced visualization (eg, multiplanar reformatting). It is written as a client-only, single-page Web application that can easily be embedded into third-party applications or hosted as a standalone Web site. The platform provides extension points for software developers to include custom tools and adapt the system for their workflows. It is standards compliant and relies on DICOMweb for data exchange and OpenID Connect for authentication, but it can be configured to use any data source or authentication flow. Additionally, the user interface components are provided in a standalone component library so that developers can create custom extensions. RESULTS: The OHIF Viewer and its underlying components have been widely adopted and integrated into multiple clinical research platforms (e,g Precision Imaging Metrics, XNAT, LabCAS, ISB-CGC) and commercial applications (eg, Osirix). It has also been used to build custom imaging applications (eg, ProstateCancer.ai, Crowds Cure Cancer [presented as a case study]). CONCLUSION: The OHIF Viewer provides a flexible framework for building applications to support imaging research. Its adoption could reduce redundancies in software development for National Cancer Institute-funded projects, including Informatics Technology for Cancer Research and the Quantitative Imaging Network.

Correlation between NF1 genotype and imaging phenotype on whole-body MRI: NF1 radiogenomics.

OBJECTIVE: To investigate the genotype-phenotype correlation between neurofibromatosis 1 (NF1) germline mutations and imaging features of neurofibromas on whole-body MRI (WBMRI) by using radiomics image analysis techniques. MATERIALS AND METHODS: Twenty-nine patients with NF1 who had known germline mutations determined by targeted next-generation sequencing were selected from a previous WBMRI study using coronal short tau inversion recovery sequence. Each tumor was segmented in WBMRI and a set of 59 imaging features was calculated using our in-house volumetric image analysis platform, 3DQI. A radiomics heatmap of 59 imaging features was analyzed to investigate the per-tumor and per-patient associations between the imaging features and mutation domains and mutation types. Linear mixed-effect models and one-way analysis of variance tests were performed to assess the similarity of tumor imaging features within mutation groups, between mutation groups, and between randomly selected groups. RESULTS: A total of 218 neurofibromas (97 discrete neurofibromas and 121 plexiform neurofibromas) were identified in 19 of the 29 patients. The unsupervised hierarchical clustering in heatmap analysis revealed 6 major image feature patterns that were significantly correlated with gene mutation domains and types with strong to very strong associations of genotype-phenotype correlations in both per-tumor and per-patient studies (p < 0.05, Cramer V > 0.5), whereas tumor size and locations showed no correlations with imaging features (p = 0.79 and p = 0.42, respectively). The statistical analyses revealed that the number of significantly different features (SDFs) within mutation groups were significantly lower than those between mutation groups (mutation domains: 10.9 ± 9.5% vs 31.9 ± 23.8% and mutation types: 31.8 ± 30.7% vs 52.6 ± 29.3%). The first and second quartile p values of within-patient groups were more than 2 times higher than those between-patient groups. However, the numbers of SDFs between randomly selected groups were much lower (approximately 5.2%). CONCLUSION: This preliminary study identified the NF1 radiogenomics linkage between NF1 causative mutations and MRI radiomic features, i.e., the correlation between NF1 genotype and imaging phenotype on WBMRI.

Early molecular oxidative stress biomarkers of ischemic penumbra in acute stroke.

OBJECTIVES: To assess whether plasma biomarkers of oxidative stress predict diffusion-perfusion mismatch in patients with acute ischemic stroke (AIS). METHODS: We measured plasma levels of oxidative stress biomarkers such as F2-isoprostanes (F2-isoPs), total and perchloric acid Oxygen Radical Absorbance Capacity (ORACTOT and ORACPCA), urinary levels of 8-oxo-7,8-dihydro-2'-deoxyguoanosine, and inflammatory and tissue-damage biomarkers (high-sensitivity C-reactive protein, matrix metalloproteinase-2 and -9) in a prospective study of patients with AIS presenting within 9 hours of symptom onset. Diffusion-weighted (DWI) and perfusion-weighted (PWI) MRI sequences were analyzed with a semiautomated volumetric method. Mismatch was defined as baseline mean transit time volume minus DWI volume. A percent mismatch cutoff of >20% was considered clinically significant. A stricter definition of mismatch was also used. Mismatch salvage was the region free of overlap by final infarction. RESULTS: Mismatch >20% was present in 153 of 216 (70.8%) patients (mean [±SD] age 69.2 ± 14.3 years, 41.2% women). Patients with mismatch >20% were more likely to have higher baseline plasma levels of ORACPCA (p = 0.020) and F2-isoPs (p = 0.145). Multivariate binary logistic regression demonstrated that lnF2-isoP (odds ratio [OR] 2.44, 95% confidence interval [CI] 1.19-4.98, p = 0.014) and lnORACPCA (OR 4.18, 95% CI 1.41-12.41, p = 0.010) were independent predictors of >20% PWI-DWI mismatch and the stricter mismatch definition, respectively. lnORACTOT significantly predicted mismatch salvage volume (>20% mismatch p = 0.010, stricter mismatch definition p = 0.003). CONCLUSIONS: Elevated hyperacute plasma levels of F2-isoP and ORAC are associated with radiographic evidence of mismatch and mismatch salvage in patients with AIS. If validated, these findings may add to our understanding of the role of oxidative stress in cerebral tissue fate during acute ischemia.

Alcoholism gender differences in brain responsivity to emotional stimuli.

Men and women may use alcohol to regulate emotions differently, with corresponding differences in neural responses. We explored how the viewing of different types of emotionally salient stimuli impacted brain activity observed through functional magnetic resonance imaging (fMRI) from 42 long-term abstinent alcoholic (25 women) and 46 nonalcoholic (24 women) participants. Analyses revealed blunted brain responsivity in alcoholic compared to nonalcoholic groups, as well as gender differences in those activation patterns. Brain activation in alcoholic men (ALCM) was significantly lower than in nonalcoholic men (NCM) in regions including rostral middle and superior frontal cortex, precentral gyrus, and inferior parietal cortex, whereas activation was higher in alcoholic women (ALCW) than in nonalcoholic women (NCW) in superior frontal and supramarginal cortical regions. The reduced brain reactivity of ALCM, and increases for ALCW, highlighted divergent brain regions and gender effects, suggesting possible differences in the underlying basis for development of alcohol use disorders.

Measurement of Glenoid Bone Loss With 3-Dimensional Magnetic Resonance Imaging: A Matched Computed Tomography Analysis.

PURPOSE: To compare the measurement of glenoid bone surface area (GBSA) and glenoid bone loss (GBL) between 3-dimensional computed tomography (3D CT) and an autosegmentation approach for 3D magnetic resonance imaging (MRI) of patients with recurrent shoulder instability. METHODS: Eight subjects (2 women and 6 men; age range, 15-72 years [mean, 44 ± 19 years]) were consecutively enrolled who had both CT and MRI of the shoulder for clinical shoulder instability. Inclusion criteria were patients with shoulder instability or other shoulder injury who had both a CT scan and MRI performed of the same shoulder. All patients underwent a 3D CT scan and a 3-Tesla 3D MRI with additional volumetric and autosegmented sequences. En face views of the glenoid for both CT and MRI were auto- and manually measured for overall GBSA and GBL using best-fit circle technique; the amount of GBL was compared with loss of GBSA and was expressed as a percentage of bone loss. RESULTS: There were no differences in GBL measured by 3D CT (41 mm2, 6.6%) vs 3D MRI (40 mm2, 6.5%, P = .852). The mean GBSA was not different among the manual- and autocalculated 3D CT (644 mm2 vs 640 mm2, P = .482). In addition, the manual MRI scan glenoid area was similar to the autocalculated 3D MRI (622 mm2 vs 618 mm2, respectively; P = .482). Overall regression analysis demonstrated excellent correlation between CT and MRI for both GBSA and GBL calculations (R2 = 0.84-0.90). CONCLUSIONS: 3D MRI of the glenoid is nearly identical to 3D CT scans for measurement of GBSA and GBL, making 3D MRI a reliable alternative to a CT scan for a preoperative shoulder evaluation of the glenoid pathology. This study shows that a 3D MRI could be a radiation-free and reliable alternative to a preoperative CT shoulder scan. LEVEL OF EVIDENCE: Level III, case-control study.

Sexually dimorphic structural abnormalities in major connections of the medial forebrain bundle in alcoholism.

Background: The mesocorticolimbic system is particularly susceptible to the effects of chronic alcoholism. Disruption of this system has been linked to drug seeking and the development of Reward Deficiency Syndrome, a neurobiological framework for describing the development and relapsing patterns of addictions. In this study, we evaluated the association of alcoholism and sex with major connections of the medial forebrain bundle (MFB), a prominent mesocorticolimbic fiber pathway connecting the ventral tegmental area with the basal forebrain. Given sex differences in clinical consequences of alcohol consumption, we hypothesized that alcoholic men and women would differ in structural abnormalities of the MFB. Methods: Diffusion magnetic resonance imaging (dMRI) data were acquired from 30 abstinent long-term alcoholic individuals (ALC; 9 men) and 25 non-alcoholic controls (NC; 8 men). Major connections of the MFB were extracted using multi-tensor tractography. We compared groups on MFB volume, fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD), with hemisphere and sex as independent variables. We also evaluated associations between abnormal structural measures and drinking measures. Results: Analyses revealed significant group-by-sex interactions for FA and RD: while ALC men had lower FA and higher RD compared to NC men, ALC women had higher FA and lower RD compared to NC women. We also detected a significant negative association between FA and number of daily drinks in ALC women. Conclusion: Alcoholism is associated with sexually dimorphic structural abnormalities in the MFB. The results expand upon other findings of differences in brain reward circuitry of alcoholic men and women.

Cerebral white matter sex dimorphism in alcoholism: a diffusion tensor imaging study.

Excessive alcohol consumption is associated with brain aberrations, including abnormalities in frontal and limbic brain regions. In a prior diffusion tensor magnetic resonance imaging (dMRI) study of neuronal circuitry connecting the frontal lobes and limbic system structures, we demonstrated decreases in white matter fractional anisotropy in abstinent alcoholic men. In the present study, we examined sex differences in alcoholism-related abnormalities of white matter connectivity and their association with alcoholism history. The dMRI scans were acquired from 49 abstinent alcoholic individuals (26 women) and 41 nonalcoholic controls (22 women). Tract-based spatial statistical tools were used to estimate regional FA of white matter tracts and to determine sex differences and their relation to measures of alcoholism history. Sex-related differences in white matter connectivity were observed in association with alcoholism: Compared to nonalcoholic men, alcoholic men had diminished FA in portions of the corpus callosum, the superior longitudinal fasciculi II and III, and the arcuate fasciculus and extreme capsule. In contrast, alcoholic women had higher FA in these regions. Sex differences also were observed for correlations between corpus callosum FA and length of sobriety. Our results suggest that sexual dimorphism in white matter microstructure in abstinent alcoholics may implicate underlying differences in the neurobehavioral liabilities for developing alcohol abuse disorders, or for sequelae following abuse.

Intravenous thrombolysis in unwitnessed stroke onset: MR WITNESS trial results.

OBJECTIVE: Most acute ischemic stroke (AIS) patients with unwitnessed symptom onset are ineligible for intravenous thrombolysis due to timing alone. Lesion evolution on fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) correlates with stroke duration, and quantitative mismatch of diffusion-weighted MRI with FLAIR (qDFM) might indicate stroke duration within guideline-recommended thrombolysis. We tested whether intravenous thrombolysis ≤4.5 hours from the time of symptom discovery is safe in patients with qDFM in an open-label, phase 2a, prospective study (NCT01282242). METHODS: Patients aged 18 to 85 years with AIS of unwitnessed onset at 4.5 to 24 hours since they were last known to be well, treatable within 4.5 hours of symptom discovery with intravenous alteplase (0.9mg/kg), and presenting with qDFM were screened across 14 hospitals. The primary outcome was the risk of symptomatic intracranial hemorrhage (sICH) with preplanned stopping rules. Secondary outcomes included symptomatic brain edema risk, and functional outcomes of 90-day modified Rankin Scale (mRS). RESULTS: Eighty subjects were enrolled between January 31, 2011 and October 4, 2015 and treated with alteplase at median 11.2 hours (IQR = 9.5-13.3) from when they were last known to be well. There was 1 sICH (1.3%) and 3 cases of symptomatic edema (3.8%). At 90 days, 39% of subjects achieved mRS = 0-1, as did 48% of subjects who had vessel imaging and were without large vessel occlusions. INTERPRETATION: Intravenous thrombolysis within 4.5 hours of symptom discovery in patients with unwitnessed stroke selected by qDFM, who are beyond the recommended time windows, is safe. A randomized trial testing efficacy using qDFM appears feasible and is warranted in patients without large vessel occlusions. Ann Neurol 2018;83:980-993.

2016 Children's Tumor Foundation conference on neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis.

Organized and hosted by the Children's Tumor Foundation (CTF), the Neurofibromatosis (NF) conference is the premier annual gathering for clinicians and researchers interested in neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). The 2016 edition constituted a blend of clinical and basic aspects of NF research that helped in clarifying different advances in the field. The incorporation of next generation sequencing is changing the way genetic diagnostics is performed for NF and related disorders, providing solutions to problems like genetic heterogeneity, overlapping clinical manifestations, or the presence of mosaicism. The transformation from plexiform neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) is being clarified, along with new management and treatments for benign and premalignant tumors. Promising new cellular and in vivo models for understanding the musculoskeletal abnormalities in NF1, the development of NF2 or SWN associated schwannomas, and clarifying the cells that give rise to NF1-associated optic pathway glioma were presented. The interaction of neurofibromin and SPRED1 was described comprehensively, providing functional insight that will help in the interpretation of pathogenicity of certain missense variants identified in NF1 and Legius syndrome patients. Novel promising imaging techniques are being developed, as well as new integrative and holistic management models for patients that take into account psychological, social, and biological factors. Importantly, new therapeutic approaches for schwannomas, meningiomas, ependymomas, PNF, and MPNST are being pursued. This report highlights the major advances that were presented at the 2016 CTF NF conference.

Pain correlates with germline mutation in schwannomatosis.

Schwannomatosis has been linked to germline mutations in the SMARCB1 and LZTR1 genes, and is frequently associated with pain.In a cohort study, we assessed the mutation status of 37 patients with clinically diagnosed schwannomatosis and compared to clinical data, whole body MRI (WBMRI), visual analog pain scale, and Short Form 36 (SF-36) bodily pain subscale.We identified a germline mutation in LZTR1 in 5 patients (13.5%) and SMARCB1 in 15 patients (40.5%), but found no germline mutation in 17 patients (45.9%). Peripheral schwannomas were detected in 3 LZTR1-mutant (60%) and 10 SMARCB1-mutant subjects (66.7%). Among those with peripheral tumors, the median tumor number was 4 in the LZTR1 group (median total body tumor volume 30 cc) and 10 in the SMARCB1 group (median volume 85cc), (P=.2915 for tumor number and P = .2289 for volume). mutation was associated with an increased prevalence of spinal schwannomas (100% vs 41%, P = .0197). The median pain score was 3.9/10 in the LZTR1 group and 0.5/10 in the SMARCB1 group (P = .0414), and SF-36 pain-associated quality of life was significantly worse in the LZTR1 group (P = .0106). Pain scores correlated with total body tumor volume (rho = 0.32471, P = .0499), but not with number of tumors (rho = 0.23065, P = .1696).We found no significant difference in quantitative tumor burden between mutational groups, but spinal schwannomas were more common in LZTR1-mutant patients. Pain was significantly higher in LZTR1-mutant than in SMARCB1-mutant patients, though spinal tumor location did not significantly correlate with pain. This suggests a possible genetic association with schwannomatosis-associated pain.

Oxidative Stress Biomarkers of Brain Damage: Hyperacute Plasma F2-Isoprostane Predicts Infarct Growth in Stroke.

BACKGROUND AND PURPOSE: Oxidative stress is an early response to cerebral ischemia and is likely to play an important role in the pathogenesis of cerebral ischemic injury. We sought to evaluate whether hyperacute plasma concentrations of biomarkers of oxidative stress, inflammation, and tissue damage predict infarct growth (IG). METHODS: We prospectively measured plasma F2-isoprostane (F2-isoP), urinary 8-oxo-7,8-dihydro-2'-deoxyguoanosine, plasma oxygen radical absorbance capacity assay, high sensitivity C reactive protein, and matrix metalloproteinase 2 and 9 in consecutive patients with acute ischemic stroke presenting within 9 hours of symptom onset. Patients with baseline diffusion-weighted magnetic resonance imaging and follow-up diffusion-weighted imaging or computed tomographic scan were included to evaluate the final infarct volume. Baseline diffusion-weighted imaging volume and final infarct volume were analyzed using semiautomated volumetric method. IG volume was defined as the difference between final infarct volume and baseline diffusion-weighted imaging volume. RESULTS: A total of 220 acute ischemic stroke subjects were included in the final analysis. One hundred seventy of these had IG. Baseline F2-isoP significantly correlated with IG volume (Spearman ρ=0.20; P=0.005) and final infarct volume (Spearman ρ=0.19; P=0.009). In a multivariate binary logistic regression model, baseline F2-isoP emerged as an independent predictor of the occurrence of IG (odds ratio, 2.57; 95% confidence interval, 1.37-4.83; P=0.007). In a multivariate linear regression model, baseline F2-isoP was independently associated with IG volume (B, 0.38; 95% confidence interval, 0.04-0.72; P=0.03). CONCLUSIONS: Elevated hyperacute plasma F2-isoP concentrations independently predict the occurrence of IG and IG volume in patients with acute ischemic stroke. If validated in future studies, measuring plasma F2-isoP might be helpful in the acute setting to stratify patients with acute ischemic stroke for relative severity of ischemic injury and expected progression.