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      Parametric Response Maps of Perfusion MRI May Identify Recurrent Glioblastomas Responsive to Bevacizumab and Irinotecan

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          Abstract

          Background

          Perfusion weighted imaging (PWI) can be used to measure key aspects of tumor vascularity in vivo and recent studies suggest that perfusion imaging may be useful in the early assessment of response to angiogenesis inhibitors. Aim of this work is to compare Parametric Response Maps (PRMs) with the Region Of Interest (ROI) approach in the analysis of tumor changes induced by bevacizumab and irinotecan in recurrent glioblastomas (rGBM), and to evaluate if changes in tumor blood volume measured by perfusion MRI may predict clinical outcome.

          Methods

          42 rGBM patients with KPS ≥50 were treated until progression, as defined by MRI with RANO criteria. Relative cerebral blood volume (rCBV) variation after 8 weeks of treatment was calculated through semi-automatic ROI placement in the same anatomic region as in baseline. Alternatively, rCBV variations with respect to baseline were calculated into the evolving tumor region using a voxel-by-voxel difference. PRMs were created showing where rCBV significantly increased, decreased or remained unchanged.

          Results

          An increased blood volume in PRM (PRM CBV+) higher than 18% (first quartile) after 8 weeks of treatment was associated with increased progression free survival (PFS; 24 versus 13 weeks, p = 0.045) and overall survival (OS; 38 versus 25 weeks, p = 0.016). After 8 weeks of treatment ROI analysis showed that mean rCBV remained elevated in non responsive patients (4.8±0.9 versus 5.1±1.2, p = 0.38), whereas decreased in responsive patients (4.2±1.3 versus 3.8±1.6 p = 0.04), and re-increased progressively when patients approached tumor progression.

          Conclusions

          Our data suggest that PRMs can provide an early marker of response to antiangiogenic treatment and warrant further confirmation in a larger cohort of GBM patients.

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          Most cited references25

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          Functional diffusion map: a noninvasive MRI biomarker for early stratification of clinical brain tumor response.

          Assessment of radiation and chemotherapy efficacy for brain cancer patients is traditionally accomplished by measuring changes in tumor size several months after therapy has been administered. The ability to use noninvasive imaging during the early stages of fractionated therapy to determine whether a particular treatment will be effective would provide an opportunity to optimize individual patient management and avoid unnecessary systemic toxicity, expense, and treatment delays. We investigated whether changes in the Brownian motion of water within tumor tissue as quantified by using diffusion MRI could be used as a biomarker for early prediction of treatment response in brain cancer patients. Twenty brain tumor patients were examined by standard and diffusion MRI before initiation of treatment. Additional images were acquired 3 weeks after initiation of chemo- and/or radiotherapy. Images were coregistered to pretreatment scans, and changes in tumor water diffusion values were calculated and displayed as a functional diffusion map (fDM) for correlation with clinical response. Of the 20 patients imaged during the course of therapy, 6 were classified as having a partial response, 6 as stable disease, and 8 as progressive disease. The fDMs were found to predict patient response at 3 weeks from the start of treatment, revealing that early changes in tumor diffusion values could be used as a prognostic indicator of subsequent volumetric tumor response. Overall, fDM analysis provided an early biomarker for predicting treatment response in brain tumor patients.
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            Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion.

            The abnormal vasculature of the tumor microenvironment supports progression and resistance to treatment. Judicious application of antiangiogenic therapy may normalize the structure and function of the tumor vasculature, promoting improved blood perfusion. However, direct clinical evidence is lacking for improvements in blood perfusion after antiangiogenic therapy. In this study, we used MRI to assess tumor blood perfusion in 30 recurrent glioblastoma patients who were undergoing treatment with cediranib, a pan-VEGF receptor tyrosine kinase inhibitor. Tumor blood perfusion increased durably for more than 1 month in 7 of 30 patients, in whom it was associated with longer survival. Together, our findings offer direct clinical evidence in support of the hypothesis that vascular normalization can increase tumor perfusion and help improve patient survival.
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              Posttherapeutic intraaxial brain tumor: the value of perfusion-sensitive contrast-enhanced MR imaging for differentiating tumor recurrence from nonneoplastic contrast-enhancing tissue.

              Differentiation of tumor recurrence from treatment-related changes may be difficult with conventional MR imaging when newly enhancing lesions appear. Our aim was to determine the value of perfusion-sensitive contrast-enhanced MR imaging for differentiating recurrent neoplasm from nonneoplastic contrast-enhancing tissue. Twenty patients in whom new enhancing lesions developed within irradiated regions were examined prospectively with perfusion-sensitive contrast-enhanced MR imaging. Twelve of them also underwent thallous chloride Tl 201 single-photon emission tomography (201Tl-SPECT). Normalized relative cerebral blood volume (rCBV) ratios and thallium indexes were evaluated to determine whether the new enhancing lesions were recurrent or not. Five instances of tumor recurrence and one of radiation necrosis were verified histologically; in the others, tumor recurrence was distinguished by lesions that progressively increased in size on serial MR examinations over at least 5 months, and nonneoplastic contrast-enhancing tissue was distinguished by lesions that disappeared or decreased in size on serial MR studies over at least 9 months. When normalized rCBV ratios were higher than 2.6 or lower than 0.6, enhancing lesions were either recurrent (n = 5) or nonneoplastic contrast-enhancing tissue (n = 3), respectively. All nonneoplastic contrast-enhancing tissue had a low thallium index, whereas three of four recurrent lesions had a high index. An enhancing lesion with a normalized rCBV ratio higher than 2.6 or lower than 0.6 may suggest tumor recurrence or nonneoplastic contrast-enhancing tissue, respectively. In these cases, further examination with 201Tl-SPECT may not be necessary. However, when the normalized rCBV ratio is between 0.6 and 2.6, 201Tl-SPECT may be useful in making the differentiation.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                27 March 2014
                : 9
                : 3
                : e90535
                Affiliations
                [1 ]Neuro-Radiology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
                [2 ]General Neurology Unit, Fondazione IRCCS Istituto Neurologico Nazionale C. Mondino, Pavia, Italy
                [3 ]Molecular Neuro-Oncology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
                University of California-San Francisco, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: DA ALDS AS ME MGB. Performed the experiments: DA ALDS AS ME. Analyzed the data: DA ALDS AS LC GF MGB ME. Contributed reagents/materials/analysis tools: DA ALDS AS EA. Wrote the paper: DA ALDS LC GF ME. Performed clinical follow up of patients: EA ME.

                Article
                PONE-D-13-39756
                10.1371/journal.pone.0090535
                3968002
                24675671
                5b31e7a8-89f1-4282-a08a-bdcf1a41bcb5
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 27 September 2013
                : 2 February 2014
                Page count
                Pages: 8
                Funding
                This work was partially supported by a grant from the Italian Ministry of Health [RF-INN-2008-1142520 to GF]. Drugs were supplied by Roche S.p.A. (Monza, Italy) and Hospira (Napoli, Italy). This work was partially funded by MIUR, FIRB project “Materiali fluorurati nanostrutturati come mezzi di contrasto intelligenti in 19F-RMN (FLUORIMAGING)” project no. RBAP1183B5. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.
                Categories
                Research Article
                Biology and Life Sciences
                Neuroscience
                Neuroimaging
                Medicine and Health Sciences
                Clinical Medicine
                Diagnostic Medicine
                Diagnostic Radiology
                Magnetic Resonance Imaging
                Neurology
                Neurological Tumors
                Glioblastoma Multiforme
                Oncology
                Cancer Treatment
                Antiangiogenesis Therapy
                Clinical Trials (Cancer Treatment)
                Cancers and Neoplasms
                Radiology and Imaging

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