Faculty Bibliography

The arginine 132 (R132) mutation of isocitrate dehydrogenase -1 (IDH1(R132)) results in production of 2-hydroxyglutarate (2-HG) and is associated with a better prognosis compared with wild-type (WT) in glioma patients. The majority of lower-grade gliomas express IDH1(R132), whereas this mutation is rare in grade IV gliomas. The aim of this study was to noninvasively investigate metabolic and physiologic changes associated with the IDH1 mutation in a mouse glioma model. Using a 7T magnet, we compared MRI and proton magnetic resonance spectroscopy (MRS) in U87 glioma cells overexpressing either the mutated IDH1(R132) or IDH1 wild-type (IDH1(WT)) gene in a mouse flank xenograft model. Flank tumors overexpressing IDH1(R132) showed a resonance at 2.25 ppm corresponding to the 2-HG peak described for human IDH1(R132) gliomas. WT tumors lacked this peak in all cases. IDH1 mutant tumors demonstrated significantly reduced glutamate by in vivo MRS. There were no significant differences in T(2), apparent diffusion coefficient (ADC), or perfusion values between the mutant and IDH1(WT) tumors. The IDH1(R132) mutation results in 2-HG resonance at 2.25 ppm and a reduction of glutamate levels as determined by MRS. Our results establish a model system where 2-HG can be monitored noninvasively, which should be helpful in validating 2-HG levels as a prognostic and/or predictive biomarker in glioma.

BACKGROUND AND PURPOSE/OBJECTIVE:A subset of patients with malignant glioma develops conspicuous lesions characterized by persistent restricted diffusion during treatment with bevacizumab. The purpose of the current study was to characterize the evolution of these lesions and to determine their relationship to patient outcome. MATERIALS AND METHODS/METHODS:Twenty patients with malignant glioma with persistent restricted-diffusion lesions undergoing treatment with bevacizumab were included in the current study. Mean ADC and the volume of restricted diffusion were computed for each patient during serial follow-up. Differences in TTP, TTS, and OS were compared between patients with restricted diffusion and matched controls by using Kaplan-Meier analysis with the logrank test and Cox hazard models. RESULTS:Mean ADC values were generally stable with time (mean, 5.2 ± 12.6% change from baseline). The volume of restricted diffusion increased a median of 23% from baseline by 6 months. Patients with restricted-diffusion lesions had significantly greater TTP (logrank, P = .013), TTS (logrank, P = .008), and OS (logrank, P = .010) than matched controls. When available, advanced physiologic imaging of restricted-diffusion lesions showed hypovascularity on perfusion MR imaging and decreased amino acid uptake on (18)F-FDOPA PET scans. Atypical gelatinous necrotic tissue was confirmed in the area of restricted diffusion in 1 patient. CONCLUSIONS:Restricted-diffusion lesions in malignant gliomas treated with bevacizumab are generally stable with time and are associated with improved outcomes. These results combined with physiologic imaging and histopathologic data suggest that these lesions are not consistent with aggressive tumor.

BACKGROUND AND PURPOSE/OBJECTIVE:ADC histogram analysis can stratify outcomes in patients with GBM treated with bevacizumab. Therefore, we compared gene expression between high-versus-low ADC tumors to identify gene expression modules that could underlie this difference and impact patient prognosis. MATERIALS AND METHODS/METHODS:Up-front bevacizumab-treated patients (N = 38) with newly diagnosed glioblastoma were analyzed by using an ADC histogram approach based on enhancing tumor. Using microarrays, we compared gene expression in high-versus-low ADC tumors in patients subsequently treated with bevacizumab. Tissue sections from a subset of tumors were stained for collagen and collagen-binding proteins. Progression-free and overall survival was determined by using Cox proportional hazard ratios and the Kaplan-Meier method with the log rank test. RESULTS:A total of 13 genes were expressed at 2-fold or greater levels in high- compared with low-ADC tumors at the P < .05 level. Of these, 6 encode for collagen or collagen-binding proteins. High gene expression for the collagen-binding protein decorin was associated with shorter survival (HR, 2.5; P = .03). The pattern and degree of collagen staining were highly variable in both high- and low-ADC tumors. CONCLUSIONS:High-ADC GBMs show greater levels of ECM protein gene expression compared with low-ADC GBMs. It is unclear whether this translates to the accumulation of higher levels of the encoded proteins. However, because ECM molecules could contribute to a proinvasive phenotype, this relationship merits further investigation.

OBJECTIVE:To discuss the role of bilateral adrenalectomy in Cushing syndrome, as illustrated in a case of severe hypercortisolism that was unresponsive to combination agent medical therapy. METHODS:We report the clinical, laboratory, imaging, and pathologic findings in a patient with ectopic Cushing syndrome attributable to an adrenocorticotropic hormone (ACTH)-secreting neuroblastoma. In addition, we provide a literature review regarding olfactory neuroblastoma and discuss current and emerging therapeutic options for Cushing syndrome. RESULTS:A 59-year-old man presented with nasal congestion and neck swelling and was noted to have hypokalemia, hypertension, and hyperglycemia. A nasal biopsy demonstrated a poorly differentiated carcinoma with neuroendocrine features. He was subsequently diagnosed as having ACTH-dependent Cushing syndrome, but despite high-dose combination medical therapy, his condition rapidly deteriorated. Urgent bilateral adrenalectomy provided rapid control of the hypercortisolism, and the patient was later able to undergo an uncomplicated total macroscopic resection of his locally metastatic primary tumor. CONCLUSION/CONCLUSIONS:This report describes the challenges in the diagnosis and management of ACTH-dependent Cushing syndrome and highlights the important role that bilateral adrenalectomy can still have in patients with severe hypercortisolism causing life-threatening complications.