Faculty Bibliography

Mutant isocitrate dehydrogenase 1 (IDH1) is common in gliomas, and produces D-2-hydroxyglutarate (D-2-HG). The full effects of IDH1 mutations on glioma biology and tumor microenvironment are unknown. We analyzed a discovery cohort of 169 World Health Organization (WHO) grade II-IV gliomas, followed by a validation cohort of 148 cases, for IDH1 mutations, intratumoral microthrombi, and venous thromboemboli (VTE). 430 gliomas from The Cancer Genome Atlas were analyzed for mRNAs associated with coagulation, and 95 gliomas in a tissue microarray were assessed for tissue factor (TF) protein. In vitro and in vivo assays evaluated platelet aggregation and clotting time in the presence of mutant IDH1 or D-2-HG. VTE occurred in 26-30 % of patients with wild-type IDH1 gliomas, but not in patients with mutant IDH1 gliomas (0 %). IDH1 mutation status was the most powerful predictive marker for VTE, independent of variables such as GBM diagnosis and prolonged hospital stay. Microthrombi were far less common within mutant IDH1 gliomas regardless of WHO grade (85-90 % in wild-type versus 2-6 % in mutant), and were an independent predictor of IDH1 wild-type status. Among all 35 coagulation-associated genes, F3 mRNA, encoding TF, showed the strongest inverse relationship with IDH1 mutations. Mutant IDH1 gliomas had F3 gene promoter hypermethylation, with lower TF protein expression. D-2-HG rapidly inhibited platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism. Mutant IDH1 glioma engraftment in mice significantly prolonged bleeding time. Our data suggest that mutant IDH1 has potent antithrombotic activity within gliomas and throughout the peripheral circulation. These findings have implications for the pathologic evaluation of gliomas, the effect of altered isocitrate metabolism on tumor microenvironment, and risk assessment of glioma patients for VTE.

Schwannomatosis is characterized by multiple non-intradermal schwannomas with patients often presenting with a painful mass in their extremities. In this syndrome malignant transformation of schwannomas is rare in spite of their large size at presentation. Non-invasive measures of assessing the biological behavior of plexiform neurofibromas in neurofibromatosis type 1 such as positron emission tomography (PET), CT scanning and MRI are well characterized but little information has been published on the use of PET imaging in schwannomatosis. We report a unique clinical presentation portraying the use of PET imaging in schwannomatosis. A 27-year-old woman presented with multiple, rapidly growing, large and painful schwannomas confirmed to be related to a constitutional mutation in the SMARCB1 complex. Whole body PET/MRI revealed numerous PET-avid tumors suggestive of malignant peripheral nerve sheath tumors. Surgery was performed on multiple tumors and none of them had histologic evidence of malignant transformation. Overall, PET imaging may not be a reliable predictor of malignant transformation in schwannomatosis, tempering enthusiasm for surgical interventions for tumors not producing significant clinical signs or symptoms.

H3K27 downregulates gene transcription. When H3K27 is trimethylated, it is tightly associated with inactive gene promoters. In malignant gliomas, the loss of histone H3K27 trimethylation is strongly associated with underlying K27M mutation; however the role of H3K27 in meningiomas has not been completely elucidated. Atypical and anaplastic meningiomas (WHO Grade II and III) are associated with higher risk of recurrence following gross total resection; however the molecular biology of anaplastic progression is not completely understood. We performed histological and molecular analysis of 14 WHO Grade II and III meningiomas and compared them with 6 locally invasive WHO Grade I meningiomas. Grade and atypical features were correlated with expression of histone H3K27 trimethylation by immunohistochemistry. Staining intensity (none, weak, moderate, strong) and extent of staining (0-100% of the tumor) were evaluated semi-quantitatively. We also tested the tumors for K27M mutation by mutation specific antibody. Out of 14 high grade meningiomas, 10 showed a complete loss of K27 trimethyl staining and 4 tumors showed small foci of preserved trimethyl staining, mostly in areas close to the dura; however staining intensity was weak. In contrary, all 6 (100%) WHO Grade I tumors showed preserved multifocal trimethyl mark expression in 25-50% of the tumor cells, with moderate (5) or strong (1) staining intensity. All tumors were negative for histone H3K27M mutation by immunohistochemistry. Atypical and anaplastic meningiomas show almost uniform loss of histone H3K27 trimethylation staining. However this loss of trimethylation is not caused by histone H3K27M mutation. Loss of histone H3K27 trimethylation leads to dysregulation of the PRC2 complex, which is involved in repression of non-cell-type specific promoters and may contribute to aggressive behavior. Clinically, loss of histone H3K27 trimethylation can be used as a diagnostic marker for a high grade meningiomaswhen histological features are inconclusive

Two new 3T MR imaging contrast methods, track density imaging and echo modulation curve T2 mapping, were combined with simultaneous multisection acquisition to reveal exquisite anatomic detail at 7 canonical levels of the brain stem. Compared with conventional MR imaging contrasts, many individual brain stem tracts and nuclear groups were directly visualized for the first time at 3T. This new approach is clinically practical and feasible (total scan time = 20 minutes), allowing better brain stem anatomic localization and characterization.

Tinnitus is an auditory perception of internal origin. Tinnitus is not a diagnosis but a symptom with many possible causes and correspondingly divergent pathophysiologic, anatomic, diagnostic, and therapeutic considerations. This article provides a summary of the imaging findings of structural causes of tinnitus.

The purpose of the present review is to discuss and display orbital lesions that demonstrate hypo-intense signal on T2-weighted images (T2WI). The physical basis for hypo-intense signal on T2WI produced by various substances is discussed. Orbital lesions that are hypo-intense on T2WI are subsequently reviewed, including a discussion on their composition as well as relevant clinical and imaging clues that may aid in their diagnosis.

Objectives: Classic radiological presentation of Wilson's disease (WD) with face of the "giant panda" is typically used to distinguish WD from other extrapyramidal disorders. Central pontine myelinolysis like (CPMlike) changes in WD are rarely reported and are distinct from the classic commonly known osmotic demyelination. Although CPM-like changes on MRI in young WD patients are common, there are no published reports of such radiological picture in the exceptional cases of late onset WD. We report on a late onset WD with sequential MRI changes with response to de-coppering therapy. Methods: A 64 year-old male with pulmonary sarcoidosis presented with a two-year history of worsening axial ataxia, postural, kinetic and rest tremors and cognitive decline. His examination was also significant for generalized hyperreflexia, Babinski sign and the presence of Kayser-Fleischer rings. WD diagnosis was confirmed with low ceruloplasmin and with the presence of homozygous mutation in the ATP7B gene. Results: MRI at symptom onset showed diffuse T2/FLAIR hyperintensity in the pons which was contiguous with hyperintensity of the midbrain, as well as focal hyperintensity in left thalamus and generalized cortical atrophy. Following nine months of chelation with trientine, partial resolution of the T2 hyperintensity in the pons was observed, while thalamus hyperintensity became less conspicuous. Conclusions: WD must be considered in all patients that present with hepatic or neurological symptoms without definitive diagnosis, regardless of age. WD and CPM-like radiological changes in older adult WD patients may be under-recognized, but genetic confirmation and clinical exam findings should guide treatment