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    Dynamic Contrast Enhanced MRI Detects Early Response to Adoptive NK Cellular Immunotherapy Targeting the NG2 Proteoglycan in a Rat Model of Glioblastoma

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        There are currently no established radiological parameters that predict response to immunotherapy. We hypothesised that multiparametric, longitudinal magnetic resonance imaging (MRI) of physiological parameters and pharmacokinetic models might detect early biological responses to immunotherapy for glioblastoma targeting NG2/ CSPG4 with mAb9.2.27 combined with natural killer (NK) cells. Contrast enhanced conventional T1-weighted MRI at 7±1 and 17±2 days post-treatment failed to detect differences in tumour size between the treatment groups, whereas, follow-up scans at 3 months demonstrated diminished signal intensity and tumour volume in the surviving NK+mAb9.2.27 treated animals. Notably, interstitial volume fraction (v e), was significantly increased in the NK+mAb9.2.27 combination therapy group compared mAb9.2.27 and NK cell monotherapy groups (p = 0.002 and p = 0.017 respectively) in cohort 1 animals treated with 1 million NK cells. v e was reproducibly increased in the combination NK+mAb9.2.27 compared to NK cell monotherapy in cohort 2 treated with increased dose of 2 million NK cells (p<0.0001), indicating greater cell death induced by NK+mAb9.2.27 treatment. The interstitial volume fraction in the NK monotherapy group was significantly reduced compared to mAb9.2.27 monotherapy (p<0.0001) and untreated controls (p = 0.014) in the cohort 2 animals. NK cells in monotherapy were unable to kill the U87MG cells that highly expressed class I human leucocyte antigens, and diminished stress ligands for activating receptors. A significant association between apparent diffusion coefficient (ADC) of water and v e in combination NK+mAb9.2.27 and NK monotherapy treated tumours was evident, where increased ADC corresponded to reduced v e in both cases. Collectively, these data support histological measures at end-stage demonstrating diminished tumour cell proliferation and pronounced apoptosis in the NK+mAb9.2.27 treated tumours compared to the other groups. In conclusion, v e was the most reliable radiological parameter for detecting response to intralesional NK cellular therapy.

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        Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity. Copyright 2005 Massachusetts Medical Society.
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          Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas.
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            Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols.

            We describe a standard set of quantity names and symbols related to the estimation of kinetic parameters from dynamic contrast-enhanced T(1)-weighted magnetic resonance imaging data, using diffusable agents such as gadopentetate dimeglumine (Gd-DTPA). These include a) the volume transfer constant K(trans) (min(-1)); b) the volume of extravascular extracellular space (EES) per unit volume of tissue v(e) (0 < v(e) < 1); and c) the flux rate constant between EES and plasma k(ep) (min(-1)). The rate constant is the ratio of the transfer constant to the EES (k(ep) = K(trans)/v(e)). Under flow-limited conditions K(trans) equals the blood plasma flow per unit volume of tissue; under permeability-limited conditions K(trans) equals the permeability surface area product per unit volume of tissue. We relate these quantities to previously published work from our groups; our future publications will refer to these standardized terms, and we propose that these be adopted as international standards.

              Author and article information

              [1 ]Department of Biomedicine, University of Bergen, Bergen, Norway
              [2 ]Cardiovascular Research Group, Haukeland University Hospital, Bergen, Norway
              [3 ]MI Lab, Department of Circulation and Medical Imaging, NTNU, Trondheim, Norway
              [4 ]Molecular Imaging Center, Department of Biomedicine, University of Bergen, Bergen, Norway
              [5 ]Laboratoire d'Immunogénétique-Allergologie, CRP-Santé, Luxembourg City, Luxembourg
              [6 ]Department of Medical Imaging, St. Olavs Hospital, Trondheim, Norway
              [7 ]Institute for Clinical Dentistry, University of Bergen, Bergen, Norway
              [8 ]Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway
              Cedars-Sinai Medical Center, United States of America
              Author notes

              Competing Interests: Dr. Jacques Zimmer, who is a co-author of this paper, is a member of the academic editorial board of PLoS One. This does not alter the authors' adherence to PLOS ONE Editorial policies and criteria.

              Conceived and designed the experiments: CBR JW MC PØE MT. Performed the experiments: CBR JW MC AP FT JZ PØE AGN. Analyzed the data: CBR MT EMH MC. Contributed reagents/materials/analysis tools: OH MC. Wrote the paper: CBR MC. CBR Contributed to MRI scanning: CBR. Performed animal surgery: JW. MRI scanning: JW. Designed MRI protocol: MT. Contributed with tumour characterisation data: AGN. Contributed to MRI scanning: FT. Contributed to NK cell isolation: AP. Contributed to immunotherapy treatment: JZ. Provided resources for MRI data analysis: OH. Contributed with statistical analyses: SAL. Contributed to animal surgery and MRI scanning: PØE. Contributed to immunohistochemistry: MC. Contributed to critically editing and approved the manuscript: CBR JW MT AGN EMH FT AP JZ OH SAL PØE MC.

              Role: Editor
              PLoS One
              PLoS ONE
              PLoS ONE
              Public Library of Science (San Francisco, USA )
              30 September 2014
              : 9
              : 9
              25268630 4182474 PONE-D-14-12388 10.1371/journal.pone.0108414

              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.

              Pages: 12
              This work was supported by grants from The Bergen Medical Research Foundation, The Meltzer Research Fund, The Norwegian Research Council and The Norwegian Cancer Society. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
              Research Article
              Biology and Life Sciences
              Clinical Immunology
              Cancer Immunotherapy
              Medicine and Health Sciences
              Diagnostic Medicine
              Diagnostic Radiology
              Neurological Tumors
              Glioblastoma Multiforme
              Cancers and Neoplasms
              Malignant Tumors
              Cancer Detection and Diagnosis
              Cancer Treatment
              Radiology and Imaging
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              The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.



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