Purpose-To conduct a controlled trial of bevacizumab for the treatment of symptomatic radiation necrosis of the brain.Methods and Materials-Fourteen patients were entered into a placebo-controlled randomized double-blind study of bevacizumab for the treatment of central nervous system (CNS) radiation necrosis. All patients were required to have radiographic or biopsy proof of CNS radiation necrosis and progressive neurological symptoms or signs. Eligible patients received irradiation for head and neck carcinomas, meningioma, or low-to mid-grade gliomas. Patients were randomized to receive IV saline or bevacizumab at 3-week intervals. MRI 3-weeks after the second treatment and clinical signs and symptoms defined response or progression. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. and T 1 -weighted gadolinium-enhanced volumes and decrease K trans . All bevacizumab-treated patients -and none of the placebo-treated patients -showed improvement in neurological symptoms or signs. At a median of 10 months after the last dose of bevacizumab in patients receiving all 4 study doses, only 2 patients had experienced a recurrence of MRI changes consistent with progressive radiation necrosis, and this was the only patient to receive only 2 treatments with bevacizumab. Results-The Conflict of InterestConclusions-This class I evidence of bevacizumab efficacy in the treatment of CNS radiation necrosis justifies consideration of this treatment option for people who suffer radiation necrosis secondary to the treatment of head and neck and brain cancers.

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.

The frequent diagnostic dilemma of recurrent neoplasm versus radiation necrosis is addressed in this study through a description of the varying spatial and temporal patterns of radiation necrosis at MR imaging.

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Chemical exchange saturation transfer (CEST) MRI provides a sensitive detection mechanism that allows characterization of dilute labile protons usually undetectable by conventional MRI. Particularly, amide proton transfer (APT) imaging, a variant of CEST MRI, has been shown capable of detecting ischemic acidosis, and may serve as a surrogate metabolic imaging marker. For preclinical CEST imaging, continuous-wave (CW) radiofrequency (RF) irradiation is often applied so that the steady state CEST contrast can be reached. On clinical scanners, however, specific absorption rate (SAR) limit and hardware preclude the use of CW irradiation, and instead require an irradiation scheme of repetitive RF pulses (pulsed-CEST imaging). In this work, CW-and pulsed-CEST MRI were systematically compared using a tissue-like pH phantom on an imager capable of both CW and pulsed RF irradiation schemes. The results showed that the maximally obtainable pulsed-CEST contrast is approximately 95% of CW-CEST contrast, and their optimal RF irradiation powers are equal. Moreover, the pulsed-CEST sequence was translated to a 3 Tesla clinical scanner and detected pH contrast from the labile creatine amine groups (1.9 ppm). In chemical exchange saturation transfer (CEST) imaging, bulk water magnetization is attenuated through its magnetization exchange with saturated labile protons, therefore making MRI, which usually detects bulk water only, sensitive to properties of dilute labile groups (1-4). Because chemical exchange is pH-dependent, CEST imaging may be applied to monitor microenvironment pH (5-7). In fact, amide proton transfer (APT) imaging, a variant of CEST imaging, has been shown capable of detecting tissue acidosis during acute stroke (8 -10). Whereas perfusion and diffusion MRI is increasingly used to image acute ischemia and help guide stroke treatment, in particular for patients admitted to hospitals beyond the conventional thrombolytic window, it appears to have some limitations (11-13). Specifically, perfusion MRI overestimates tissue susceptible to stroke, while the tissue outcome of the diffusion MRI lesion is heterogeneous. Portions of acute diffusion lesion may be reversed if promptly reperfused, suggesting that it may contain reversibly damaged ischemic tissue (14,15). While on the other hand, the final infarction area is often larger than the acute diffusion MRI lesion, which suggests that diffusion MRI may miss some irreversibly damaged tissue. Because maintenance of tissue metabolic energy is crucial to cell viability, markers of abnormal energy metabolism such as depletion of adenosine triphosphate (ATP), abnormal oxygen extraction ratio (OER), and tissue acidosis have been postulated capable of specifically highlighting ischemic tissue at risk to infarction (ischemic penumbra) (16 -19). Thus, a noninvasive metabolic imaging technique, such as the proposed pH-weighted APT MRI, may complement the commonly used perfusion and diffusion MRI for more accurate characterization of ischemic penumbra (20,21).Conventionally, a c...