Publications by authors named "Gordon J Harris"

66 Publications

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

Eur J Radiol Open 2020 4;7:100259. Epub 2020 Sep 4.

City of Hope Comprehensive Cancer Center, Duarte, CA, USA.

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.
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http://dx.doi.org/10.1016/j.ejro.2020.100259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481131PMC
September 2020

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

PLoS One 2020 10;15(8):e0236641. Epub 2020 Aug 10.

VA Boston Healthcare System, Boston, MA, United States of America.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236641PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416961PMC
October 2020

Initial Experience Integrating a Hands-On Innovation Curriculum Into a Radiology Residency Program and Department.

J Am Coll Radiol 2020 Oct 16;17(10):1329-1333. Epub 2020 May 16.

Medically Engineered Solutions in Healthcare (MESH) Incubator, Massachusetts General Hospital, Boston, Massachusetts; Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.jacr.2020.04.020DOI Listing
October 2020

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

Neurology 2020 06 28;94(24):e2521-e2531. Epub 2020 Apr 28.

From the Department of Radiology (Y.L., M.A.B., M.V., G.J.H., W.C.), Department of Neurology and Cancer Center (J.T.J., S.R.P.), and Center for Genomic Medicine (S.E., J.A.W.), Massachusetts General Hospital and Harvard Medical School, Boston.

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 ( < 0.05, Cramer V > 0.5), whereas tumor size and locations showed no correlations with imaging features ( = 0.79 and = 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 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 genotype and imaging phenotype on WBMRI.
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http://dx.doi.org/10.1212/WNL.0000000000009490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455335PMC
June 2020

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

JCO Clin Cancer Inform 2020 04;4:336-345

Open Health Imaging Foundation, Boston, MA.

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.
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http://dx.doi.org/10.1200/CCI.19.00131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259879PMC
April 2020

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

Neurology 2019 09 27;93(13):e1288-e1298. Epub 2019 Aug 27.

From the J. Philip Kistler Stroke Research Center (S.L., N.S.R., L.M.B., A.C., R.E.G., T.K.T., B.T.), Department of Neurology, and Department of Radiology (H.L., G.J.H.), Massachusetts General Hospital and Harvard Medical School, Boston; Department of Neurology (M.K., K.L.F.), Rhode Island Hospital, Alpert Medical School of Brown University, Providence; Massachusetts General Hospital Biostatistics Center (A.M.), Boston; Neuroprotection Research Laboratory (K.A., A.T.S., L.-D.D.P., E.H.L.), Neuroscience Center, Departments of Neurology and Radiology, Massachusetts General Hospital and Harvard Medical School; Athinoula A. Martinos Center for Biomedical Imaging (O.W.), Massachusetts General Hospital and Harvard Medical School, Charlestown; Antioxidant Research Laboratory (J.B.B.), Jean Mayer USDA Human Nutrition Research Center on Aging, and Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy (P.E.M.), Tufts University; and Department of Neurology (S.K.F.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

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 (ORAC and ORAC), 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 ORAC ( = 0.020) and F2-isoPs ( = 0.145). Multivariate binary logistic regression demonstrated that lnF2-isoP (odds ratio [OR] 2.44, 95% confidence interval [CI] 1.19-4.98, = 0.014) and lnORAC (OR 4.18, 95% CI 1.41-12.41, = 0.010) were independent predictors of >20% PWI-DWI mismatch and the stricter mismatch definition, respectively. lnORAC significantly predicted mismatch salvage volume (>20% mismatch = 0.010, stricter mismatch definition = 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.
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http://dx.doi.org/10.1212/WNL.0000000000008158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011868PMC
September 2019

Alcoholism gender differences in brain responsivity to emotional stimuli.

Elife 2019 04 30;8. Epub 2019 Apr 30.

Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, United States.

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 (ALC) was significantly lower than in nonalcoholic men (NC) in regions including rostral middle and superior frontal cortex, precentral gyrus, and inferior parietal cortex, whereas activation was higher in alcoholic women (ALC) than in nonalcoholic women (NC) in superior frontal and supramarginal cortical regions. The reduced brain reactivity of ALC, and increases for ALC, highlighted divergent brain regions and gender effects, suggesting possible differences in the underlying basis for development of alcohol use disorders.
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http://dx.doi.org/10.7554/eLife.41723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491039PMC
April 2019

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

Arthroscopy 2018 12 2;34(12):3141-3147. Epub 2018 Nov 2.

Steadman Philippon Research Institute and The Steadman, Vail, Colorado, U.S.A.

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 mm, 6.6%) vs 3D MRI (40 mm, 6.5%, P = .852). The mean GBSA was not different among the manual- and autocalculated 3D CT (644 mm vs 640 mm, P = .482). In addition, the manual MRI scan glenoid area was similar to the autocalculated 3D MRI (622 mm vs 618 mm, respectively; P = .482). Overall regression analysis demonstrated excellent correlation between CT and MRI for both GBSA and GBL calculations (R = 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.
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http://dx.doi.org/10.1016/j.arthro.2018.06.050DOI Listing
December 2018

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

Neuroimage Clin 2018 22;19:98-105. Epub 2018 Mar 22.

Department of Psychiatry, Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, USA; Center for Morphometric Analysis, Massachusetts General Hospital, Boston, MA, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.nicl.2018.03.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051309PMC
January 2019

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

Neuropsychopharmacology 2018 08 9;43(9):1876-1883. Epub 2018 May 9.

Radiology Computer Aided Diagnostics Laboratory, Center for Morphometric Analysis, Massachusetts General Hospital, Boston, MA, 02114, USA.

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.
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http://dx.doi.org/10.1038/s41386-018-0089-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046037PMC
August 2018

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

Ann Neurol 2018 05 27;83(5):980-993. Epub 2018 Apr 27.

Dell Medical School, University of Texas at Austin, Austin, TX.

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.
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http://dx.doi.org/10.1002/ana.25235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095471PMC
May 2018

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

Am J Med Genet A 2018 05;176(5):1258-1269

Hereditary Cancer Group, The Institute for Health Science Research Germans Trias i Pujol (IGTP)-PMPPC, Barcelona, Spain.

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.
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http://dx.doi.org/10.1002/ajmg.a.38675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918269PMC
May 2018

Pain correlates with germline mutation in schwannomatosis.

Medicine (Baltimore) 2018 Feb;97(5):e9717

Department of Neurology Cancer Center, Massachusetts General Hospital, Boston, MA Centre for Genomic Medicine, St Mary's Hospital, Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK Molecular Neurogenetics Unit, Center for Genomic Medicine Department of Radiology, Massachusetts General Hospital and Harvard Medical School Department of Genetics, Harvard Medical School, Boston, MA.

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.
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http://dx.doi.org/10.1097/MD.0000000000009717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805424PMC
February 2018

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

Stroke 2018 03 25;49(3):630-637. Epub 2018 Jan 25.

From the J. Philip Kistler Stroke Research Center, Department of Neurology (S.L., N.S.R., F.O.L., M.B.M., R.E.G., T.K.T., A.J.D.), Department of Radiology (H.L., G.J.H.), and Neuroprotection Research Laboratory, Neuroscience Center, Departments of Neurology and Radiology (K.A., A.T.S., L.-D.D.P., E.H.L.), Massachusetts General Hospital, Harvard Medical School, Boston; Department of Neurology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (M.K., K.L.F.); Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown (O.W.); Antioxidant Research Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging (J.B.B.) and Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy (P.E.M.), Tufts University, Boston, MA; and Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.K.F.).

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; =0.005) and final infarct volume (Spearman ρ=0.19; =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; =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; =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.
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http://dx.doi.org/10.1161/STROKEAHA.117.018440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828992PMC
March 2018

Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group.

Lancet Oncol 2018 01;19(1):e20-e32

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Patients with active CNS disease are often excluded from clinical trials, and data regarding the CNS efficacy of systemic agents are usually obtained late in the drug development process or not at all. In this guideline from the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group, we provide detailed recommendations on when patients with brain metastases from solid tumours should be included or excluded in clinical trials of systemic agents. We also discuss the limitations of retrospective studies in determining the CNS efficacy of systemic drugs. Inclusion of patients with brain metastases early on in the clinical development of a drug or a regimen is needed to generate appropriate CNS efficacy or non-efficacy signals. We consider how to optimally incorporate or exclude such patients in systemic therapy trials depending on the likelihood of CNS activity of the agent by considering three scenarios: drugs that are considered very unlikely to have CNS antitumour activity or efficacy; drugs that are considered very likely to have CNS activity or efficacy; and drugs with minimal baseline information on CNS activity or efficacy. We also address trial design issues unique to patients with brain metastases, including the selection of appropriate CNS endpoints in systemic therapy trials.
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http://dx.doi.org/10.1016/S1470-2045(17)30693-9DOI Listing
January 2018

Immune-related tumour response assessment criteria: a comprehensive review.

Br J Radiol 2018 Apr 14;91(1084):20170457. Epub 2018 Feb 14.

2 Department of Radiology, Massachusetts General Hospital , Boston, MA , USA.

Growing emphasis on precision medicine in oncology has led to increasing use of targeted therapies that encompass a spectrum of drug classes including angiogenesis inhibitors, immune modulators, signal transduction inhibitors, DNA damage modulators, hormonal agents etc. Immune therapeutic drugs constitute a unique group among the novel therapeutic agents that are transforming cancer treatment, and their use is rising. The imaging manifestations in patients on immune therapies appear to be distinct from those typically seen with conventional cytotoxic therapies. Patients on immune therapies may demonstrate a delayed response, transient tumour enlargement followed by shrinkage, stable size, or initial appearance of new lesions followed by stability or response. These newer patterns of response to treatment have rendered conventional criteria such as World Health Organization and response evaluation criteria in solid tumours suboptimal in monitoring changes in tumour burden. As a consequence, newer imaging response criteria such as immune-related response evaluation criteria in solid tumours and immune-related response criteria are being implemented in many trials to effectively monitor patients on immune therapies. In this review, we discuss the traditional and new imaging response criteria for evaluation of solid tumours, review the outcomes of various articles which compared traditional criteria with the new immune-related criteria and discuss pseudo-progression and immune-related adverse events.
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http://dx.doi.org/10.1259/bjr.20170457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966001PMC
April 2018

Volumetric MRI Analysis of Plexiform Neurofibromas in Neurofibromatosis Type 1: Comparison of Two Methods.

Acad Radiol 2018 02 31;25(2):144-152. Epub 2017 Oct 31.

Center for Cancer Research, Pediatric Oncology Branch, National Cancer Institute, 10 Center Drive, CRC Room 1-5750, Bethesda, MD 20892. Electronic address:

Objectives: Plexiform neurofibromas (PNs) are complex, histologically benign peripheral nerve sheath tumors that are challenging to measure by simple line measurements. Computer-aided volumetric segmentation of PN has become the recommended method to assess response in clinical trials directed at PN. Different methods for volumetric analysis of PN have been developed. The goal of this study is to test the level of agreement in volume measurements and in interval changes using two separate methods of volumetric magnetic resonance imaging analysis.

Methods: Three independent volume measurements were performed on 15 PN imaged at three time-points using 3DQI software at Massachusetts General Hospital (MGH) and National Cancer Institute (NCI) and MEDx software at NCI.

Results: Median volume differences at each time-point comparing MGH-3DQI and NCI-3DQI were -0.5, -4.2, and -19.9 mL; comparing NCI-3DQI and NCI-MEDx were -21.0, -47.0, and -21.0 mL; comparing MGH-3DQI and NCI-MEDx were -10.0, -70.3, and -29.9 mL. Median differences in percentage change over time comparing MGH-3DQI and NCI-3DQI were -1.7, 1.1, and -1.0%; comparing NCI-3DQI and NCI-MEDx were -2.3, 3.3, and -1.1%; comparing MGH-3DQI and NCI-MEDx were -0.4, 2.0, and -1.5%. Volume differences were <20% of the mean of the two measurements in 117 of 135 comparisons (86.7%). Difference in interval change was <20% in 120 of the 135 comparisons (88.9%), while disease status classification was concordant in 115 of 135 comparisons (85.2%).

Conclusions: The volumes, interval changes, and progression status classifications were in good agreement. The comparison of two volumetric analysis methods suggests no systematic differences in tumor assessment. A prospective comparison of the two methods is planned.
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http://dx.doi.org/10.1016/j.acra.2017.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794522PMC
February 2018

LesionTracker: Extensible Open-Source Zero-Footprint Web Viewer for Cancer Imaging Research and Clinical Trials.

Cancer Res 2017 11;77(21):e119-e122

Open Health Imaging Foundation, Chicago, Illinois.

Oncology clinical trials have become increasingly dependent upon image-based surrogate endpoints for determining patient eligibility and treatment efficacy. As therapeutics have evolved and multiplied in number, the tumor metrics criteria used to characterize therapeutic response have become progressively more varied and complex. The growing intricacies of image-based response evaluation, together with rising expectations for rapid and consistent results reporting, make it difficult for site radiologists to adequately address local and multicenter imaging demands. These challenges demonstrate the need for advanced cancer imaging informatics tools that can help ensure protocol-compliant image evaluation while simultaneously promoting reviewer efficiency. LesionTracker is a quantitative imaging package optimized for oncology clinical trial workflows. The goal of the project is to create an open source zero-footprint viewer for image analysis that is designed to be extensible as well as capable of being integrated into third-party systems for advanced imaging tools and clinical trials informatics platforms. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-0334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679226PMC
November 2017

Gender dimorphism of brain reward system volumes in alcoholism.

Psychiatry Res Neuroimaging 2017 May 6;263:15-25. Epub 2017 Mar 6.

Center for Morphometric Analysis, and Athinoula A. Martinos Center, Departments of Neurology, Psychiatry, and Radiology, Massachusetts General Hospital, Boston, MA 02114, USA.

The brain's reward network has been reported to be smaller in alcoholic men compared to nonalcoholic men, but little is known about the volumes of reward regions in alcoholic women. Morphometric analyses were performed on magnetic resonance brain scans of 60 long-term chronic alcoholics (ALC; 30 men) and 60 nonalcoholic controls (NC; 29 men). We derived volumes of total brain, and cortical and subcortical reward-related structures including the dorsolateral prefrontal (DLPFC), orbitofrontal, and cingulate cortices, and the temporal pole, insula, amygdala, hippocampus, nucleus accumbens septi (NAc), and ventral diencephalon (VDC). We examined the relationships of the volumetric findings to drinking history. Analyses revealed a significant gender interaction for the association between alcoholism and total reward network volumes, with ALC men having smaller reward volumes than NC men and ALC women having larger reward volumes than NC women. Analyses of a priori subregions revealed a similar pattern of reward volume differences with significant gender interactions for DLPFC and VDC. Overall, the volume of the cerebral ventricles in ALC participants was negatively associated with duration of abstinence, suggesting decline in atrophy with greater length of sobriety.
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http://dx.doi.org/10.1016/j.pscychresns.2017.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5415444PMC
May 2017

Current whole-body MRI applications in the neurofibromatoses: NF1, NF2, and schwannomatosis.

Neurology 2016 Aug;87(7 Suppl 1):S31-9

From The Russell H. Morgan Department of Radiology and Radiological Science (S.A., L.M.F., M.A.J.), Sidney Kimmel Comprehensive Cancer Center (M.A.J.), and Department of Neurology (J.O.B.), Johns Hopkins University, Baltimore, MD; Khyber Medical College (M.S.K.), Peshawar, Pakistan; Department of Radiology (M.A.B., G.J.H., W.C.), Massachusetts General Hospital and Harvard Medical School, Boston; Genomic Medicine (D.G.E.), Manchester Academic Health Science Centre, The University of Manchester, UK; Department of Neurology (S.F., V.F.M.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Radiology & Orthopedic Surgery (A.C.), UT Southwestern Medical Center, Dallas, TX; Department of Diagnostic and Interventional Radiology (J.M.S.), University Hospital Hamburg-Eppendorf; Radiological Practice Altona (R.W.), Hamburg, Germany; Pediatric Oncology Branch (E.D.), National Cancer Institute, Bethesda, MD; and Department of Neurology and Cancer Center (S.R.P.), Massachusetts General Hospital, Boston.

Objectives: The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration Whole-Body MRI (WB-MRI) Working Group reviewed the existing literature on WB-MRI, an emerging technology for assessing disease in patients with neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN), to recommend optimal image acquisition and analysis methods to enable WB-MRI as an endpoint in NF clinical trials.

Methods: A systematic process was used to review all published data about WB-MRI in NF syndromes to assess diagnostic accuracy, feasibility and reproducibility, and data about specific techniques for assessment of tumor burden, characterization of neoplasms, and response to therapy.

Results: WB-MRI at 1.5T or 3.0T is feasible for image acquisition. Short tau inversion recovery (STIR) sequence is used in all investigations to date, suggesting consensus about the utility of this sequence for detection of WB tumor burden in people with NF. There are insufficient data to support a consensus statement about the optimal imaging planes (axial vs coronal) or 2D vs 3D approaches. Functional imaging, although used in some NF studies, has not been systematically applied or evaluated. There are no comparative studies between regional vs WB-MRI or evaluations of WB-MRI reproducibility.

Conclusions: WB-MRI is feasible for identifying tumors using both 1.5T and 3.0T systems. The STIR sequence is a core sequence. Additional investigation is needed to define the optimal approach for volumetric analysis, the reproducibility of WB-MRI in NF, and the diagnostic performance of WB-MRI vs regional MRI.
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http://dx.doi.org/10.1212/WNL.0000000000002929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578359PMC
August 2016

Alcoholism and sexual dimorphism in the middle longitudinal fascicle: a pilot study.

Brain Imaging Behav 2017 08;11(4):1006-1017

Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Alcoholism can lead to a complex mixture of cognitive and emotional deficits associated with abnormalities in fronto-cortico-striatal-limbic brain circuitries. Given the broad variety of neurobehavioral symptoms, one would also expect alterations of postrolandic neocortical systems. Thus, we used diffusion tensor imaging (DTI) to study the integrity of the middle longitudinal fascicle (MdLF), a major postrolandic association white matter tract that extends from the superior temporal gyrus to the parietal and occipital lobes, in individuals with a history of chronic alcohol abuse. DTI data were acquired on a 3 Tesla scanner in 30 abstinent alcoholics (AL; 9 men) and 25 nonalcoholic controls (NC; 8 men). The MdLF was determined using DTI-based tractography. Volume of the tract, fractional anisotropy (FA), radial (RD), and axial (AD) diffusivity, were compared between AL and NC, with sex and hemispheric laterality as independent variables. The association of DTI measures with neuropsychological performance was evaluated. Men showed bilateral reduction of MdLF volume and abnormal diffusion measurements of the left MdLF. Analyses also indicated that the left MdLF diffusion measurements in AL men were negatively associated with Verbal IQ and verbal fluency test scores. Abstinent alcoholic men display macrostructural abnormalities in the MdLF bilaterally, indicating an overall white matter deficit. Additionally, microstructural deficits of the left MdLF suggest more specific alterations associated with verbal skills in men.
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http://dx.doi.org/10.1007/s11682-016-9579-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253343PMC
August 2017

Associations Between Cerebellar Subregional Morphometry and Alcoholism History in Men and Women.

Alcohol Clin Exp Res 2016 06 30;40(6):1262-72. Epub 2016 Apr 30.

Athinoula A. Martinos Center, Massachusetts General Hospital, Boston, Massachusetts.

Background: Alcoholism has been linked to deficits in cognitive, behavioral, and emotional functions, and the cerebellum is important for optimal functioning of these abilities. However, little is known about how individual differences such as gender and drinking history might influence regional cerebellar abnormalities.

Methods: Volumetric analyses of the cerebellum and its subregions were performed in relation to the interaction of gender and measures of drinking history. Structural magnetic resonance imaging scans of 44 alcoholic individuals (23 men) and 39 nonalcoholic controls (18 men) were obtained. In addition to measuring total cerebellar gray and white matter volumes, we measured 64 individual cerebellar parcellation units, as well as functionally defined a priori regions of interest that have been shown to correspond to functions impaired in alcoholism.

Results: Total cerebellar white matter volume was smaller in alcoholic relative to nonalcoholic participants. Moreover, volumes of parcellation units varied with drinking history, showing negative associations between years of heavy drinking and the anterior lobe, the vestibulocerebellar lobe, and the spinocerebellar subdivision. The negative association between anterior volume and years of heavy drinking was driven primarily by alcoholic men. Additionally, we observed larger white and gray matter volumes for alcoholic women than for alcoholic men.

Conclusions: The identification of drinking-related abnormalities in cerebellar subregions lays a foundation that can be utilized to inform how cerebro-cerebellar networks are perturbed in this pathological condition. These results also provide estimates of how gender and individual differences in drinking history can predict cerebellar volumes.
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http://dx.doi.org/10.1111/acer.13074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889497PMC
June 2016

Cancer Imaging at the Crossroads of Precision Medicine: Perspective From an Academic Imaging Department in a Comprehensive Cancer Center.

J Am Coll Radiol 2016 Apr 14;13(4):365-71. Epub 2016 Jan 14.

Department of Imaging, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts.

The authors propose one possible vision for the transformative role that cancer imaging in an academic setting can play in the current era of personalized and precision medicine by sharing a conceptual model that is based on experience and lessons learned designing a multidisciplinary, integrated clinical and research practice at their institution. The authors' practice and focus are disease-centric rather than imaging-centric. A "wall-less" infrastructure has been developed, with bidirectional integration of preclinical and clinical cancer imaging research platforms, enabling rapid translation of novel cancer drugs from discovery to clinical trial evaluation. The talents and expertise of medical professionals, scientists, and staff members have been coordinated in a horizontal and vertical fashion through the creation of Cancer Imaging Consultation Services and the "Adopt-a-Radiologist" campaign. Subspecialized imaging consultation services at the hub of an outpatient cancer center facilitate patient decision support and management at the point of care. The Adopt-a-Radiologist campaign has led to the creation of a novel generation of imaging clinician-scientists, fostered new collaborations, increased clinical and academic productivity, and improved employee satisfaction. Translational cancer research is supported, with a focus on early in vivo testing of novel cancer drugs, co-clinical trials, and longitudinal tumor imaging metrics through the imaging research core laboratory. Finally, a dedicated cancer imaging fellowship has been developed, promoting the future generation of cancer imaging specialists as multidisciplinary, multitalented professionals who are trained to effectively communicate with clinical colleagues and positively influence patient care.
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http://dx.doi.org/10.1016/j.jacr.2015.11.002DOI Listing
April 2016

Response assessment criteria for brain metastases: proposal from the RANO group.

Lancet Oncol 2015 Jun 27;16(6):e270-8. Epub 2015 May 27.

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

CNS metastases are the most common cause of malignant brain tumours in adults. Historically, patients with brain metastases have been excluded from most clinical trials, but their inclusion is now becoming more common. The medical literature is difficult to interpret because of substantial variation in the response and progression criteria used across clinical trials. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group is an international, multidisciplinary effort to develop standard response and progression criteria for use in clinical trials of treatment for brain metastases. Previous efforts have focused on aspects of trial design, such as patient population, variations in existing response and progression criteria, and challenges when incorporating neurological, neuro-cognitive, and quality-of-life endpoints into trials of patients with brain metastases. Here, we present our recommendations for standard response and progression criteria for the assessment of brain metastases in clinical trials. The proposed criteria will hopefully facilitate the development of novel approaches to this difficult problem by providing more uniformity in the assessment of CNS metastases across trials.
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http://dx.doi.org/10.1016/S1470-2045(15)70057-4DOI Listing
June 2015

Primary culture of human Schwann and schwannoma cells: improved and simplified protocol.

Hear Res 2014 Sep 6;315:25-33. Epub 2014 Jun 6.

Speech and Hearing Bioscience and Technology Program, Harvard - Massachusetts Institute of Technology, Division of Health Sciences and Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Department of Otology and Laryngology, Harvard Medical School, 651 Huntington Avenue, Boston, MA 02115, USA; Eaton Peabody Laboratories and Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA, 02114, USA. Electronic address:

Primary culture of human Schwann cells (SCs) and vestibular schwannoma (VS) cells are invaluable tools to investigate SC physiology and VS pathobiology, and to devise effective pharmacotherapies against VS, which are sorely needed. However, existing culture protocols, in aiming to create robust, pure cultures, employ methods that can lead to loss of biological characteristics of the original cells, potentially resulting in misleading biological findings. We have developed a minimally manipulative method to culture primary human SC and VS cells, without the use of selective mitogens, toxins, or time-consuming and potentially transformative laboratory techniques. Schwann cell purity was quantified longitudinally using S100 staining in SC cultures derived from the great auricular nerve and VS cultures followed for 7 and 12 weeks, respectively. SC cultures retained approximately ≥85% purity for 2 weeks. VS cultures retained approximately ≥80% purity for the majority of the span of 12 weeks, with maximal purity of 87% at 2 weeks. The VS cultures showed high level of biological similarity (68% on average) to their respective parent tumors, as assessed using a protein array featuring 41 growth factors and receptors. Apoptosis rate in vitro negatively correlated with tumor volume. Our results, obtained using a faster, simplified culturing method than previously utilized, indicate that highly pure, primary human SC and VS cultures can be established with minimal manipulation, reaching maximal purity at 2 weeks of culture. The VS cultures recapitulate the parent tumors' biology to a great degree, making them relevant models to investigate VS pathobiology.
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http://dx.doi.org/10.1016/j.heares.2014.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164296PMC
September 2014

Relationship between whole-body tumor burden, clinical phenotype, and quality of life in patients with neurofibromatosis.

Am J Med Genet A 2014 Jun 24;164A(6):1431-7. Epub 2014 Mar 24.

Department of Neurology and Cancer Center, Massachusetts General Hospital, Boston, Massachusetts.

Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis share a predisposition to develop multiple nerve sheath tumors. Previous studies have demonstrated that patients with NF1 and NF2 have reduced quality of life (QOL), but no studies have examined the relationship between whole-body tumor burden and QOL in these patients. We administered a QOL questionnaire (the SF-36) and a visual analog pain scale (VAS) to a previously described cohort of adult neurofibromatosis patients undergoing whole-body MRI. One-sample t-tests were used to compare norm-based SF-36 scores to weighted population means. Spearman correlation coefficients and multiple linear regression analyses controlling for demographic and disease-specific clinical variable were used to relate whole-body tumor volume to QOL scales. Two hundred forty-five patients (142 NF1, 53 NF2, 50 schwannomatosis) completed the study. Subjects showed deficits in selected subscales of the SF-36 compared to adjusted general population means. In bivariate analysis, increased tumor volume was significantly associated with pain in schwannomatosis patients, as measured by the SF-36 bodily pain subscale (rho = -0.287, P = 0.04) and VAS (rho = 0.34, P = 0.02). Regression models for NF2 patients showed a positive relationship between tumor burden and increased pain, as measured by the SF-36 (P = 0.008). Patients with NF1, NF2, and schwannomatosis suffer from reduced QOL, although only pain shows a clear relationship to patient's overall tumor burden. These findings suggest that internal tumor volume is not a primary contributor to QOL and emphasize the need for comprehensive treatment approaches that go beyond tumor-focused therapies such as surgery by including psychosocial interventions.
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http://dx.doi.org/10.1002/ajmg.a.36466DOI Listing
June 2014

Prognosis of untreated strokes due to anterior circulation proximal intracranial arterial occlusions detected by use of computed tomography angiography.

JAMA Neurol 2014 Feb;71(2):151-7

Neuroendovascular and Neurocritical Care Services, Marcus Stroke and Neuroscience Center, Grady Memorial Hospital, Emory University School of Medicine, Atlanta, Georgia.

Importance: Limited data exist regarding the natural history of proximal intracranial arterial occlusions. OBJECTIVE To investigate the outcomes of patients who had an acute ischemic stroke attributed to an anterior circulation proximal intracranial arterial occlusion.

Design, Setting, And Participants: A prospective cohort study at 2 university-based hospitals from 2003 to 2005 in which nonenhanced computed tomography scans and computed tomography angiograms were obtained at admission of all adult patients suspected of having an ischemic stroke in the first 24 hours of symptom onset.

Exposure: Anterior circulation proximal intracranial arterial occlusion.

Main Outcomes And Measures: Frequency of good outcome (defined as a modified Rankin Scale score of ≤ 2) and mortality at 6 months.

Results: A total of 126 patients with a unilateral complete occlusion of the intracranial internal carotid artery (ICA; 26 patients: median National Institutes of Health Stroke Scale [NIHSS] score, 11 [interquartile range, 5-17]), of the M1 segment of the middle cerebral artery (MCA; 52 patients: median NIHSS score, 13 [interquartile range, 6-16]), or of the M2 segment of the MCA (48 patients: median NIHSS score, 7 [interquartile range, 4-15]) were included. Of these 3 groups of patients, 10 (38.5%), 20 (38.5%), and 26 (54.2%) with ICA, MCA-M1, and MCA-M2 occlusions, respectively, achieved a modified Rankin Scale score of 2 or less, and 6 (23.1%), 12 (23.1%), and 10 (20.8%) were dead at 6 months. Worse outcomes were seen in patients with a baseline NIHSS score of 10 or higher, with a modified Rankin Scale score of 2 or less achieved in only 7.1% (1 of 14), 23.5% (8 of 34), and 22.7% (5 of 22) of patients and mortality rates of 35.7% (5 of 14), 32.4% (11 of 34), and 40.9% (9 of 22) among patients with ICA, MCA-M1, and MCA-M2 occlusions, respectively. Age (odds ratio, 0.94 [95% CI, 0.91-0.98]), NIHSS score (odds ratio, 0.73 [95% CI, 0.64-0.83]), and strength of leptomeningeal collaterals (odds ratio, 2.37 [95% CI, 1.08-5.20]) were independently associated with outcome, whereas the level of proximal intracranial arterial occlusion (ICA vs MCA-M1 vs MCA-M2) was not.

Conclusions And Relevance: The natural history of proximal intracranial arterial occlusion is variable, with poor outcomes overall. Stroke severity and collateral flow appear to be more important than the level of proximal intracranial arterial occlusion in determining outcomes. Our results provide useful data for proper patient selection and sample size calculations in the design of new clinical trials aimed at recanalization therapies.
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http://dx.doi.org/10.1001/jamaneurol.2013.5007DOI Listing
February 2014

Recommendations for imaging tumor response in neurofibromatosis clinical trials.

Neurology 2013 Nov;81(21 Suppl 1):S33-40

From the Pediatric Oncology Branch (E.D., B.C.W.), National Cancer Institute, Bethesda, MD; Department of Neurology (S.L.A.-H.), The Children's Hospital at Westmead, Sydney, Australia; Department of Medical Genetics (D. B.-V.), Mayo Clinic, Rochester, MN; Neurosurgical Service (F.G.B.), Department of Radiology (G.J.H.), and Department of Neurology and Cancer Center (S.R.P.), Massachusetts General Hospital, Boston, MA; Department of Neuroradiology (S.C.), King's College Hospital, London, UK; Department of Genetic Medicine (D.G.E.), MAHSC, St Mary's Hospital, Manchester, UK; Division of Oncology (M.J.F.) and Department of Radiology (D.J.), The Children's Hospital of Philadelphia; Department of Pediatrics (M.J.F.), The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Department of Neurosurgery (S.G.), Hôpital Beaujon, Clichy, France; Division of Pediatric Hematology/Oncology and NYU Cancer Institute (M.A.K.), NYU Langone Medical Center, New York, NY; Department of Genetics (B.R.K.), University of Alabama at Birmingham, Birmingham, AL; Department of Neurology (V.M.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Radiology (T.Y.P.), Boston Children's Hospital, Boston, MA; and Department of Pediatrics (K.R., C.-S.S.), Riley Hospital for Children, Indianapolis, IN.

Objective: Neurofibromatosis (NF)-related benign tumors such as plexiform neurofibromas (PN) and vestibular schwannomas (VS) can cause substantial morbidity. Clinical trials directed at these tumors have become available. Due to differences in disease manifestations and the natural history of NF-related tumors, response criteria used for solid cancers (1-dimensional/RECIST [Response Evaluation Criteria in Solid Tumors] and bidimensional/World Health Organization) have limited applicability. No standardized response criteria for benign NF tumors exist. The goal of the Tumor Measurement Working Group of the REiNS (Response Evaluation in Neurofibromatosis and Schwannomatosis) committee is to propose consensus guidelines for the evaluation of imaging response in clinical trials for NF tumors.

Methods: Currently used imaging endpoints, designs of NF clinical trials, and knowledge of the natural history of NF-related tumors, in particular PN and VS, were reviewed. Consensus recommendations for response evaluation for future studies were developed based on this review and the expertise of group members.

Results: MRI with volumetric analysis is recommended to sensitively and reproducibly evaluate changes in tumor size in clinical trials. Volumetric analysis requires adherence to specific imaging recommendations. A 20% volume change was chosen to indicate a decrease or increase in tumor size. Use of these criteria in future trials will enable meaningful comparison of results across studies.

Conclusions: The proposed imaging response evaluation guidelines, along with validated clinical outcome measures, will maximize the ability to identify potentially active agents for patients with NF and benign tumors.
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http://dx.doi.org/10.1212/01.wnl.0000435744.57038.afDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3908340PMC
November 2013

A phase I study of lapatinib with whole brain radiotherapy in patients with Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer brain metastases.

Breast Cancer Res Treat 2013 Nov 7;142(2):405-14. Epub 2013 Nov 7.

Harvard Medical School, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA,

Brain metastases are common in patients with advanced, Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer. We evaluated the maximum tolerated dose (MTD) and feasibility of lapatinib given concurrently with whole brain radiotherapy (WBRT). Eligible patients had (HER2)-positive breast cancer and ≥1 brain metastasis. Patients received lapatinib 750 mg twice on day one followed by 1000, 1250, or 1500 mg once daily. WBRT (37.5 Gy, 15 fractions) began 1-8 days after starting lapatinib. Lapatinib was continued through WBRT. Following WBRT, patients received trastuzumab 2 mg/kg weekly and lapatinib 1000 mg once daily. The regimen would be considered feasible if <3/27 pts treated at the MTD experienced a dose-limiting toxicity (DLT). Thirty-five patients were enrolled; 17 % had central nervous disease (CNS) only. During dose escalation, no patients receiving 1,000 or 1,250 mg and two of five patients receiving 1,500 mg experienced DLTs (grade 3 mucositis and rash). Overall, 7/27 patients at 1,250 mg (MTD) had DLTs: grade 3 rash (n = 2), diarrhea (n = 2), hypoxia (n = 1), and grade 4 pulmonary embolus (n = 2). Among 28 evaluable patients, the CNS objective response rate (ORR) was 79 % [95% confidence interval (CI) 59-92 %] by pre-specified volumetric criteria; 46 % remained progression-free (CNS or non-CNS) at 6 months. The study did not meet the pre-defined criteria for feasibility because of toxicity, although the relationship between study treatment and some DLTs was uncertain. Given the high ORR, concurrent lapatinib-WBRT could still be considered for future study with careful safety monitoring.
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http://dx.doi.org/10.1007/s10549-013-2754-0DOI Listing
November 2013

Benign whole body tumor volume is a risk factor for malignant peripheral nerve sheath tumors in neurofibromatosis type 1.

J Neurooncol 2014 Jan 29;116(2):307-13. Epub 2013 Oct 29.

Department of Pediatrics, University of Maryland, 22 South Greene St, N5W70, Baltimore, MD, 21201, USA,

The purpose of this study is to determine whether benign whole body tumor volume of plexiform neurofibromas (PNs) is a risk factor for malignant peripheral nerve sheath tumors (MPNST) in individuals with neurofibromatosis type 1 (NF1). Thirty-one NF1 patients with MPNSTs and 62 age- and sex-matched NF1 patients without MPNSTs, who had undergone whole body magnetic resonance imaging (MRI) were analyzed for benign whole body tumor volume. Mann-Whitney U test, Wilcoxon signed ranks test, Fisher's exact test (two-tailed), and logistic regression analysis were used for statistical analysis. Sixteen percent of all patients with MPNST did not have internal PN. The median whole body benign tumor volume in patients with PN was 352.0 mL among the MPNST group and 3.8 mL in the comparison group (p < 0.001). When the patients were stratified by age as younger or older than 30 years (median age of MPNST diagnosis), the median benign whole body tumor volume was 693.0 mL in MPNST patients and 0.0 mL in control patients younger than 30 years (p < 0.001). The mean number of PNs in MPNST patients was 2.8 (range 0-13, median 2.0) and 1.4 (range 0-13, median 1.0) in patients without MPNST (p = 0.001). The risk of MPNST development increased 0.2 % with each additional mL of benign PN volume (adjusted odds ratio [OR] = 1.002, 95 % confidence interval [CI] 1.001-1.003, p = 0.005) and was higher in patients younger than 30 years (adjusted OR = 1.007, 95 % CI 1.002-1.012, p = 0.003). Higher numbers of PNs, larger whole body benign tumor volume, and younger age are important risk factors for MPNST. We identified a subgroup of patients with MPNST without internal PN on MRI and the lack of correlation of MPNST development with tumor burden in older patients. These findings may alter our belief that all MPNSTs arise from pre-existing PNs and suggest that surveillance MRI based on clinical suspicion may be warranted in older patients, respectively.
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http://dx.doi.org/10.1007/s11060-013-1293-1DOI Listing
January 2014