Ashok J. Kumar

Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice.

Patients with recurrent malignant glioma treated with bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), alone or in combination with irinotecan have had impressive reductions in MRI contrast enhancement and vasogenic edema. Responses to this regimen, as defined by a decrease in contrast enhancement, have led to significant improvements in progression-free survival rates but not in overall survival duration. Some patients for whom this treatment regimen fails have an uncharacteristic pattern of tumor progression, which can be observed radiographically as an increase in hyperintensity on T2-weighted or fluid-attenuated inverse recovery (FLAIR) MRI. To date, there have been no reports of paired correlations between radiographic results and histopathologic findings describing the features of this aggressive tumor phenotype. In this study, we correlate such findings for 3 illustrative cases of gliomas that demonstrated an apparent phenotypic shift to a predominantly infiltrative pattern of tumor progression after treatment with bevacizumab. Pathologic examination of abnormal FLAIR areas on MRI revealed infiltrative tumor with areas of thin-walled blood vessels, suggesting vascular “normalization,” which was uncharacteristically adjacent to regions of necrosis. High levels of insulin-like growth factor binding protein-2 and matrix metalloprotease-2 expression were seen within the infiltrating tumor. In an attempt to better understand this infiltrative phenotype associated with anti-VEGF therapy, we forced a highly angiogenic, noninvasive orthotopic U87 xenograft tumor to become infiltrative by treating the mice with bevacizumab. This model mimicked many of the histopathologic findings from the human cases and will augment the discovery of alternative or additive therapies to prevent this type of tumor recurrence in clinical practice.

Clinical InvestigationRandomized Double-Blind Placebo-Controlled Trial of Bevacizumab Therapy for Radiation Necrosis of the Central Nervous System

PURPOSE To conduct a controlled trial of bevacizumab for the treatment of symptomatic radiation necrosis of the brain. METHODS AND MATERIALS A total of 14 patients were entered into a placebo-controlled randomized double-blind study of bevacizumab for the treatment of central nervous system radiation necrosis. All patients were required to have radiographic or biopsy proof of central nervous system radiation necrosis and progressive neurologic symptoms or signs. Eligible patients had undergone irradiation for head-and-neck carcinoma, meningioma, or low- to mid-grade glioma. Patients were randomized to receive intravenous saline or bevacizumab at 3-week intervals. The magnetic resonance imaging findings 3 weeks after the second treatment and clinical signs and symptoms defined the response or progression. RESULTS The volumes of necrosis estimated on T(2)-weighted fluid-attenuated inversion recovery and T(1)-weighted gadolinium-enhanced magnetic resonance imaging scans demonstrated that although no patient receiving placebo responded (0 of 7), all bevacizumab-treated patients did so (5 of 5 randomized and 7 of 7 crossover) with decreases in T(2)-weighted fluid-attenuated inversion recovery and T(1)-weighted gadolinium-enhanced volumes and a decrease in endothelial transfer constant. All bevacizumab-treated patients-and none of the placebo-treated patients-showed improvement in neurologic symptoms or signs. At a median of 10 months after the last dose of bevacizumab in patients receiving all four study doses, only 2 patients had experienced a recurrence of magnetic resonance imaging changes consistent with progressive radiation necrosis; one patient received a single additional dose of bevacizumab and the other patient received two doses. CONCLUSION The Class I evidence of bevacizumab efficacy from the present study in the treatment of central nervous system radiation necrosis justifies consideration of this treatment option for people with radiation necrosis secondary to the treatment of head-and-neck cancer and brain cancer.

Anti-Ro(SS-A) autoantibodies in central nervous system disease associated with Sjögren's syndrome (CNS-SS): Clinical, neuroimaging, and angiographic correlates

Objective: To examine in Sjögrens syndrome (SS) the interrelationship between the presence of the anti-Ro(SS-A) antibody response and (1) concomitant presence and type (ie, focal or nonfocal) of CNS disease (CNS-SS), (2) cross-sectional brain MRI or CT, and (3) abnormal cerebral angiography. Methods: Neurologic, neuroimaging, and angiographic features of CNS-SS patients were correlated with the presence of precipitating anti-Ro(SS-A) autoantibodies detected by gel double-immunodiffusion or quantitative ELISA, which detects antibodies directed against the 60-kd peptide. Statistical analyses were performed using Fishers exact test (two-tailed) with Haldanes adjustment and odds ratio with Cornfield 95% confidence intervals. Results: Precipitating antibodies against the Ro(SS-A) antigen, determined by gel double-immunodiffusion, were present in an increased frequency in CNS-SS patients with (1) documented clinical CNS disease, (2) focal clinical CNS manifestations and serious complications, (3) large regions of increased signal intensity, consistent with ischemia/infarcts on brain MRI scans or regions of decreased attenuation consistent with infarcts on CT, and (4) abnormal cerebral angiograms consistent with small-vessel angiitis. Finally, the anti-Ro(SS-A) antibody response in CNS was directed against the 60-kd peptide specificity, determined by ELISA. Conclusions: Clinical, neuroimaging (cerebral CT), and angiographic observation suggest that a subset of anti-Ro(SS-A) antibody-positive, in contrast with negative, CNS-SS patients have more serious and extensive CNS disease, some with frank cerebral angiopathy. Anti-Ro(SS-A) antibodies are postulated to play a role in mediating or potentiating vascular injury in CNS-SS.

Computed tomography of extracranial nerve sheath tumors with pathological correlation

Computed tomography was obtained in 15 patients with extracranial nerve sheath tumors, including eight with neurofibromatosis. The studies included two schwannomas, six neurofibromas, four plexiform neurofibromas, and three neurofibrosarcomas. Lesions with attenuation values exceeding 30 Hounsfield units had dense bands of collagen in resected specimens. Eleven of the lesions had attenuation values which were significantly lower than muscle. Histological examination of hypodense lesions revealed five factors contributing to reduced attenuation values: (a) a population of lipid-rich Schwann cells; (b) the presence of adipocytes (transformed fibroblasts) in neurofibromas; (c) entrapment of perineural adipose tissue by plexiform neurofibromas; (d) a coalescence of interstitial fluid to form cystic spaces in schwannoma with Antoni B tissue; and (e) cystic degeneration secondary to infarction or necrosis within neurofibromas and neurofibrosarcomas.

Bone marrow transplant in adrenoleukodystrophy

An allogeneic bone marrow transplant (BMT) from a normal HLA identical sibling donor was performed in a 13-year-old boy with rapidly progressive adrenoleukodystrophy (ALD). Engraftment and complete hematologic recovery occurred within 4 weeks, but neurologic deterioration continued. The patient died of an adenovirus infection 141 days after BMT. ALD is characterized by abnormally high plasma levels of very long chain fatty acids (VLCFA) as a result of impaired capacity to degrade them. Ten days after BMT, the white blood cell VLCFA levels and enzyme activity became normal; after 3 months, there was progressive reduction of plasma VLCFA to levels only slightly above normal.

Successful treatment of progressive multifocal leukoencephalopathy with low-dose interleukin-2

A patient with low-grade lymphoma presented 8 months after autologous marrow transplantation with dizziness, aphasia and hemiparesis. Magnetic resonance imaging (MRI) showed an abnormal T2 signal in the frontoparietal region unilaterally. Biopsy of the area demonstrated progressive multifocal leukoencephalopathy positive for JC virus and p53. Treatment with interleukin-2 at 0.5 MU/m2/day i.v. continuous infusion resulted in near complete resolution of symptoms and MRI abnormalities. The absolute number of CD3+CD4+ and CD3−CD56+ cells in the peripheral blood also increased, and the CD4/CD8 ratio normalized. She remains free of evidence of progressive multifocal leukoencephalopathy 1 year off therapy.

MR imaging of normal nasal cycle: comparison with sinus pathology.

Sequential MR examinations of the nasal cavity and paranasal sinuses were performed within a 6–8 h period in five normal volunteers. The nasal mucosal volume and signal intensities (T2 weighted) were shown to alternate from one side to the other during this period. When a topical vasoconstrictor was applied, this cycle was interrupted. These cyclical changes were limited to the mucosa of the turbinates, nasal cavity, and ethmoid sinus, representative of the nasal cycle. The maxillary, frontal, and sphenoid sinuses were not affected. The hyperintensity of the nasal cycle on T2-weighted images was similar to that shown by inflammatory mucosa. Squamous cell carcinoma within the nasal cavity and paranasal sinuses has characteristically demonstrated a lower signal intensity on T2-weighted images. Awareness of these cyclical nasal and paranasal appearances reduces the likelihood of inflammatory disease being confused with normal physiologic changes within the nasal area.

Method for efficient fast spin echo Dixon imaging

In order to satisfy the Carr‐Purcell‐Meiboom‐Gill (CPMG) condition, echo shift as dictated in fast‐spin‐echo (FSE)‐based Dixon imaging was previously achieved by applying a time shift to the readout gradient and the data acquisition window. Accordingly, interecho spacing is increased, which entails increased image blurring and, in multislice imaging, a significant reduction in the slice coverage for a given imaging time. In this work, a new method is developed by which the echo shift is induced by “sandwiching” in time the readout gradient with a pair of small gradients of equal area and of opposite polarity. While data with non‐zero phase shifts between water and fat signals are collected as fractional echoes, no increase in echo spacing is necessary with the modified acquisition strategy, and increased time efficiency is therefore achieved. In order to generate separate water‐only and fat‐only images in data processing, a set of low‐resolution images are first reconstructed from the central symmetric portion (either 128 × 128 or 64 × 64) of the acquired multipoint Dixon data. High‐resolution images using all the acquired data, including some partial Fourier‐reconstructed images, are then phase demodulated using the phase errors determined from the low‐resolution images. The feasibility of the technique is demonstrated using a water and fat phantom as well as in clinical patient imaging. Magn Reson Med 48:1021–1027, 2002.

Physiologic mucosal changes within the nose and ethmoid sinus: Imaging of the nasal cycle by MRI

Magnetic resonance studies frequently demonstrate increased T   2 ‐weighted signal in the nasal area. To further evaluate this phenomenon, several MRI examinations of the nasal cavity were performed within an 8‐ to 12‐hour period. The study demonstrated that changes alternated from side to side and were interrupted by the administration of topical vasoconstriction, confirming imaging of the normal nasal cycle. Changes were also observed within the ethmoid sinuses. Signal intensity on T   2 ‐weighted images during the congested phase was similar to inflammatory mucosa. Occasionally, these changes make interpretation of the extent of pathology difficult in patients with sinus disease, and raise the possibility of inflammatory pathology in asymptomatic patients. Awareness of MRI imaging of nasal cycle should reduce the likelihood of diagnostic errors and provides another method for study of this physiologic phenomenon.

T2-weighted spine imaging with a fast three-point dixon technique: comparison with chemical shift selective fat suppression

To develop a phased‐array coil‐compatible, fast three‐point Dixon (TPD) technique, and compare its performance in T2‐weighted spine imaging with that of the standard chemical shift selective (CHESS) fat suppression technique.