Sebastian Regnery

⁶⁸Ga-fibroblast activation protein inhibitors (FAPIs) 2, 4, and 46 have already been proposed as promising PET tracers. However, the short half-life of ⁶⁸Ga (68 min) creates problems with manufacture and delivery. ¹⁸F (half-life, 110 min) labeling would result in a more practical large-scale production, and a cold-kit formulation would improve the spontaneous availability. The NOTA chelator ligand FAPI-74 can be labeled with both ¹⁸F-AlF and ⁶⁸Ga. Here, we describe the in vivo evaluation of ¹⁸F-FAPI-74 and a proof of mechanism for ⁶⁸Ga-FAPI-74 labeled at ambient temperature. <b>Methods:</b> In 10 patients with lung cancer, PET scans were acquired at 10 min, 1 h, and 3 h after administration of 259 ± 26 MBq of ¹⁸F-FAPI-74. Physiologic biodistribution and tumor uptake were semiquantitatively evaluated on the basis of SUV at each time point. Absorbed doses were evaluated using OLINDA/EXM, version 1.1, and QDOSE dosimetry software with the dose calculator IDAC-Dose, version 2.1. Identical methods were used to evaluate one examination after injection of 263 MBq of ⁶⁸Ga-FAPI-74. <b>Results:</b> The highest contrast was achieved in primary tumors, lymph nodes, and distant metastases at 1 h after injection, with an SUV_max of more than 10. The effective dose per a 100-MBq administered activity of ¹⁸F-FAPI-74 was 1.4 ± 0.2 mSv, and for ⁶⁸Ga-FAPI-74 it was 1.6 mSv. Thus, the radiation burden of a diagnostic ¹⁸F-FAPI-74 PET scan is even lower than that of PET scans with ¹⁸F-FDG and other ¹⁸F tracers; ⁶⁸Ga-FAPI-74 is comparable to other ⁶⁸Ga ligands. FAPI PET/CT supported target volume definition for guiding radiotherapy. <b>Conclusion:</b> The high contrast and low radiation burden of FAPI-74 PET/CT favor multiple clinical applications. Centralized large-scale production of ¹⁸F-FAPI-74 or decentralized cold-kit labeling of ⁶⁸Ga-FAPI-74 allows flexible routine use.

Background: Early identification of prognostic superior characteristics in glioma patients such as isocitrate dehydrogenase (IDH) mutation and O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status is of great clinical importance. The study purpose was to investigate the non-invasive predictability of IDH mutation status, MGMT promoter methylation, and differentiation of low-grade versus high-grade glioma (LGG vs HGG) in newly diagnosed patients employing relaxation-compensated multipool chemical exchange saturation transfer (CEST) MRI at 7.0 Tesla. Methods: Thirty-one patients with newly diagnosed glioma were included in this prospective study. CEST MRI was performed at a 7T whole-body scanner. Nuclear Overhauser effect (NOE) and isolated amide proton transfer (APT; downfield NOE-suppressed APT = dns-APT) CEST signals (mean value and 90th signal percentile) were quantitatively investigated in the whole tumor area with regard to predictability of IDH mutation, MGMT promoter methylation status, and differentiation of LGG versus HGG. Statistics were performed using receiver operating characteristic (ROC) and area under the curve (AUC) analysis. Results were compared with advanced MRI methods (apparent diffusion coefficient and relative cerebral blood volume ROC/AUC analysis) obtained at 3T. Results: dns-APT CEST yielded highest AUCs in IDH mutation status prediction (dns-APTmean = 91.84%, P < 0.01; dns-APT90 = 97.96%, P < 0.001). Furthermore, dns-APT metrics enabled significant differentiation of LGG versus HGG (AUC: dns-APTmean = 0.78, P < 0.05; dns-APT90 = 0.83, P < 0.05). There was no significant difference regarding MGMT promoter methylation status at any contrast (P > 0.05). Conclusions: Relaxation-compensated multipool CEST MRI, particularly dns-APT imaging, enabled prediction of IDH mutation status and differentiation of LGG versus HGG and should therefore be considered as a non-invasive MR biomarker in the diagnostic workup.

// Sebastian Regnery 1, 2 , Sebastian Adeberg 3 , Constantin Dreher 2 , Johanna Oberhollenzer 2 , Jan-Eric Meissner 4 , Steffen Goerke 4 , Johannes Windschuh 4 , Katerina Deike-Hofmann 2 , Sebastian Bickelhaupt 2 , Moritz Zaiss 5 , Alexander Radbruch 2 , Martin Bendszus 6 , Wolfgang Wick 7 , Andreas Unterberg 8 , Stefan Rieken 1 , J&uuml;rgen Debus 1 , Peter Bachert 4 , Mark Ladd 4, 9, 10 , Heinz-Peter Schlemmer 2 and Daniel Paech 2 1 Department of Radiation Oncology, University Hospital Heidelberg, Heidelberg, Germany 2 German Cancer Research Center (DKFZ), Division of Radiology, Heidelberg, Germany 3 German Cancer Research Center (DKFZ), HIRO (Heidelberg Institute for Radiation Oncology), Heidelberg, Germany 4 German Cancer Research Center (DKFZ), Division of Medical Physics in Radiology, Heidelberg, Germany 5 Max-Planck-Institute, T&uuml;bingen, Germany 6 Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany 7 Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany 8 Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany 9 Faculty of Physics and Astronomy, University of Heidelberg, Heidelberg, Germany 10 Faculty of Medicine, University of Heidelberg, Heidelberg, Germany Correspondence to: Daniel Paech, email: d.paech@dkfz.de Keywords: magnetic resonance imaging; amide-proton-transfer-imaging; nuclear overhauser imaging; glioblastoma; predictive biomarker Received: March 29, 2018&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: May 24, 2018&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: June 19, 2018 ABSTRACT Purpose: To prospectively investigate chemical exchange saturation transfer (CEST) MRI in glioblastoma patients as predictor of early tumor progression after first-line treatment. Experimental Design: Twenty previously untreated glioblastoma patients underwent CEST MRI employing a 7T whole-body scanner. Nuclear Overhauser effect (NOE) as well as amide proton transfer (APT) CEST signals were isolated using Lorentzian difference (LD) analysis and relaxation compensated by the apparent exchange-dependent relaxation rate (AREX) evaluation. Additionally, NOE-weighted asymmetric magnetic transfer ratio (MTRasym) and downfield-NOE-suppressed APT (dns-APT) were calculated. Patient response to consecutive treatment was determined according to the RANO criteria. Mean signal intensities of each contrast in the whole tumor area were compared between early-progressive and stable disease. Results: Pre-treatment tumor signal intensity differed significantly regarding responsiveness to first-line therapy in NOE-LD ( p = 0.0001), NOE-weighted MTRasym ( p = 0.0186) and dns-APT ( p = 0.0328) contrasts. Hence, significant prediction of early progression was possible employing NOE-LD (AUC = 0.98, p = 0.0005), NOE-weighted MTRasym (AUC = 0.83, p = 0.0166) and dns-APT (AUC = 0.80, p = 0.0318). The NOE-LD provided the highest sensitivity (91%) and specificity (100%). Conclusions: CEST derived contrasts, particularly NOE-weighted imaging and dns-APT, yielded significant predictors of early progression after fist-line therapy in glioblastoma. Therefore, CEST MRI might be considered as non-invasive tool for customization of treatment in the future.

Background Patients with newly diagnosed inoperable glioma receive chemoradiotherapy (CRT). Standard Response Assessment in Neuro‐Oncology (RANO) takes a minimum of 4 weeks after the end of treatment. Purpose/Hypothesis To investigate whether chemical exchange saturation transfer (CEST) MRI enables earlier assessment of response to CRT in glioma patients. Study Type Longitudinal prospective study. Population Twelve brain tumor patients who underwent definitive CRT were included in this study. Three longitudinal CEST MRI measurements were performed for each patient at 7T: first before, second immediately after completion of CRT, and a third measurement as a 6‐week follow‐up. Field Strength/Sequence Conventional MRI (contrast‐enhanced, T 2 w and diffusion‐weighted imaging) at 3T and T 2 w and CEST MRI at 7T was performed for all patients. Assessment The mean relaxation‐compensated relayed nuclear‐Overhauser‐effect CEST signal (rNOE) and the mean downfield‐rNOE‐suppressed amide proton transfer (dns‐APT) CEST signal were investigated. Additionally, choline‐to‐N‐acetyl‐aspartate ratios (Cho/NAA) were evaluated using single‐voxel 1 H‐MRS in six of these patients. Performance of obtained contrasts was analyzed in assessing treatment response as classified according to the updated RANO criteria. Statistical Test Unpaired Student's t ‐test. Results The rNOE signal significantly separated stable and progressive disease directly after the end of therapy (post‐treatment normalized to pre‐treatment mean ± SD: rNOE responder = 1.090 ± 0.110, rNOE non‐responder = 0.808 ± 0.155, P = 0.015). In contrast, no significant difference was observed between either group when assessing the normalized dns‐APT (dns‐APT responder = 0.953 ± 0.384, dns‐APT non‐responder = 0.972 ± 0.477, P = 0.95). In the smaller MRS subcohort, normalized Cho/NAA decreased in therapy responders (Cho/NAA responder = 0.632 ± 0.007, Cho/NAA non‐responder = 0.946 ± 0.124, P = 0.070). Data Conclusion rNOE mediated CEST imaging at 7T allowed for discrimination of responders and non‐responders immediately after the end of CRT, additionally supported by 1 H‐MRS data. This is at least 4 weeks earlier than the standard clinical evaluation according to RANO. Therefore, CEST MRI may enable early response assessment in glioma patients. Level of Evidence : 1 Technical Efficacy Stage : 5 J. Magn. Reson. Imaging 2019;50:1268–1277.