Whole-cerebrum guanidino and amide CEST mapping at 3 T by a 3D stack-of-spirals gradient echo acquisition.

PURPOSE: To develop a 3D, high-sensitivity CEST mapping technique based on the 3D stack-of-spirals (SOS) gradient echo readout, the proposed approach was compared with conventional acquisition techniques and evaluated for its efficacy in concurrently mapping of guanidino (Guan) and amide CEST in human brain at 3 T, leveraging the polynomial Lorentzian line-shape fitting (PLOF) method. METHODS: Saturation time and recovery delay were optimized to achieve maximum CEST time efficiency. The 3DSOS method was compared with segmented 3D EPI (3DEPI), turbo spin echo, and gradient- and spin-echo techniques. Image quality, temporal SNR (tSNR), and test-retest reliability were assessed. Maps of Guan and amide CEST derived from 3DSOS were demonstrated on a low-grade glioma patient. RESULTS: The optimized recovery delay/saturation time was determined to be 1.4/2 s for Guan and amide CEST. In addition to nearly doubling the slice number, the gradient echo techniques also outperformed spin echo sequences in tSNR: 3DEPI (193.8 ± 6.6), 3DSOS (173.9 ± 5.6), and GRASE (141.0 ± 2.7). 3DSOS, compared with 3DEPI, demonstrated comparable GuanCEST signal in gray matter (GM) (3DSOS: [2.14%-2.59%] vs. 3DEPI: [2.15%-2.61%]), and white matter (WM) (3DSOS: [1.49%-2.11%] vs. 3DEPI: [1.64%-2.09%]). 3DSOS also achieves significantly higher amideCEST in both GM (3DSOS: [2.29%-3.00%] vs. 3DEPI: [2.06%-2.92%]) and WM (3DSOS: [2.23%-2.66%] vs. 3DEPI: [1.95%-2.57%]). 3DSOS outperforms 3DEPI in terms of scan-rescan reliability (correlation coefficient: 3DSOS: 0.58-0.96 vs. 3DEPI: -0.02 to 0.75) and robustness to motion as well. CONCLUSION: The 3DSOS CEST technique shows promise for whole-cerebrum CEST imaging, offering uniform contrast and robustness against motion artifacts.

d-glucose weighted chemical exchange saturation transfer (glucoCEST)-based dynamic glucose enhanced (DGE) MRI at 3T: early experience in healthy volunteers and brain tumor patients.

PURPOSE: Dynamic glucose enhanced (DGE) MRI has shown potential for imaging glucose delivery and blood-brain barrier permeability at fields of 7T and higher. Here, we evaluated issues involved with translating d-glucose weighted chemical exchange saturation transfer (glucoCEST) experiments to the clinical field strength of 3T. METHODS: Exchange rates of the different hydroxyl proton pools and the field-dependent T2 relaxivity of water in d-glucose solution were used to simulate the water saturation spectra (Z-spectra) and DGE signal differences as a function of static field strength B0 , radiofrequency field strength B1 , and saturation time tsat . Multislice DGE experiments were performed at 3T on 5 healthy volunteers and 3 glioma patients. RESULTS: Simulations showed that DGE signal decreases with B0 , because of decreased contributions of glucoCEST and transverse relaxivity, as well as coalescence of the hydroxyl and water proton signals in the Z-spectrum. At 3T, because of this coalescence and increased interference of direct water saturation and magnetization transfer contrast, the DGE effect can be assessed over a broad range of saturation frequencies. Multislice DGE experiments were performed in vivo using a B1 of 1.6 µT and a tsat of 1 second, leading to a small glucoCEST DGE effect at an offset frequency of 2 ppm from the water resonance. Motion correction was essential to detect DGE effects reliably. CONCLUSION: Multislice glucoCEST-based DGE experiments can be performed at 3T with sufficient temporal resolution. However, the effects are small and prone to motion influence. Therefore, motion correction should be used when performing DGE experiments at clinical field strengths.

Applying amide proton transfer-weighted MRI to distinguish pseudoprogression from true progression in malignant gliomas.

PURPOSE: To assess amide proton transfer-weighted (APTW) imaging features in patients with malignant gliomas after chemoradiation and the diagnostic performance of APT imaging for distinguishing true progression from pseudoprogression. MATERIALS AND METHODS: After approval by the Institutional Review Board, 32 patients with clinically suspected tumor progression in the first 3 months after chemoradiation were enrolled and scanned at 3T. Longitudinal routine magnetic resonance imaging (MRI) changes and medical records were assessed to confirm true progression versus pseudoprogression. True progression was defined as lesions progressing on serial imaging over 6 months, and pseudoprogression was defined as lesions stabilizing or regressing without intervention. The APTWmean and APTWmax signals were obtained from three to five regions of interests for each patient and compared between the true progression and pseudoprogression groups. The diagnostic performance was assessed with receiver operating characteristic curve analysis. RESULTS: The true progression was associated with APTW hyperintensity (APTWmean = 2.75% ± 0.42%), while pseudoprogression was associated with APTW isointensity to mild hyperintensity (APTWmean = 1.56% ± 0.42%). The APTW signal intensities were significantly higher in the true progression group (n = 20) than in the pseudoprogression group (P < 0.001; n = 12). The cutoff APTWmean and APTWmax intensity values to distinguish between true progression and pseudoprogression were 2.42% (with a sensitivity of 85.0% and a specificity of 100%) and 2.54% (with a sensitivity of 95.0% and a specificity of 91.7%), respectively. CONCLUSION: The APTW-MRI signal is a valuable imaging biomarker for distinguishing pseudoprogression from true progression in glioma patients. J. Magn. Reson. Imaging 2016;44:456-462.

Three-dimensional amide proton transfer MR imaging of gliomas: Initial experience and comparison with gadolinium enhancement.

PURPOSE: To investigate the feasibility of a three-dimensional amide-proton-transfer (APT) imaging sequence with gradient- and spin-echo readouts at 3 Tesla in patients with high- or low-grade gliomas. MATERIALS AND METHODS: Fourteen patients with newly diagnosed gliomas were recruited. After B0 inhomogeneity correction on a voxel-by-voxel basis, APT-weighted images were reconstructed using a magnetization-transfer-ratio asymmetry at offsets of ±3.5 ppm with respect to the water resonance. Analysis of variance post hoc tests were used for statistical evaluations, and results were validated with pathology. RESULTS: In six patients with gadolinium-enhancing high-grade gliomas, enhancing tumors on the postcontrast T1 -weighted images were consistently hyperintense on the APT-weighted images. Increased APT-weighted signal intensity was also clearly visible in two pathologically proven, high-grade gliomas without gadolinium enhancement. The average APT-weighted signal was significantly higher in the lesions than in the contralateral normal-appearing brain tissue (P < 0.001). In six low-grade gliomas, including two with gadolinium enhancement, APT-weighted imaging showed iso-intensity or mild punctate hyperintensity within all the lesions, which was significantly lower than that seen in the high-grade gliomas (P < 0.001). CONCLUSION: The proposed three-dimensional APT imaging sequence can be incorporated into standard brain MRI protocols for patients with malignant gliomas.

Downfield Proton MRSI at 3 Tesla: A Pilot Study in Human Brain Tumors.

PURPOSE: To investigate the use of 3D downfield proton magnetic resonance spectroscopic imaging (DF-MRSI) for evaluation of tumor recurrence in patients with glioblastoma (GBM). METHODS: Seven patients (4F, age range 44-65 and mean ± standard deviation 59.3 ± 7.5 years) with previously treated GBM were scanned using a recently developed 3D DF-MRSI sequence at 3T. Short TE 3D DF-MRSI and water reference 3D-MRSI scans were collected with a nominal spatial resolution of 0.7 cm3. DF volume data in eight slices covered 12 cm of brain in the cranio-caudal axis. Data were analyzed using the 'LCModel' program and a basis set containing nine peaks ranging in frequency between 6.83 to 8.49 ppm. The DF8.18 (assigned to amides) and DF7.90 peaks were selected for the creation of metabolic images and statistical analysis. Longitudinal MR images and clinical history were used to classify brain lesions as either recurrent tumor or treatment effect, which may include necrosis. DF-MRSI data were compared between lesion groups (recurrent tumor, treatment effect) and normal-appearing brain. RESULTS: Of the seven brain tumor patients, two were classified as having recurrent tumor and the rest were classified as treatment effect. Amide metabolite levels from recurrent tumor regions were significantly (p < 0.05) higher compared to both normal-appearing brain and treatment effect regions. Amide levels in lesion voxels classified as treatment effect were significantly lower than normal brain. CONCLUSIONS: 3D DF-MRSI in human brain tumors at 3T is feasible and was well tolerated by all patients enrolled in this preliminary study. Amide levels measured by 3D DF-MRSI were significantly different between treatment effect and tumor regrowth.

Impact of Frontline Ivosidenib on Volumetric Growth Patterns in Isocitrate Dehydrogenase-mutant Astrocytic and Oligodendroglial Tumors.

PURPOSE: Isocitrate dehydrogenase (IDH)-mutant gliomas are usually treated with radiotherapy and chemotherapy, which increases the risk for neurocognitive sequelae during patients' most productive years. We report our experience using off-label first-in-class mutant IDH1 inhibitor ivosidenib and its impact on tumor volume in IDH-mutant gliomas. EXPERIMENTAL DESIGN: We retrospectively analyzed patients ages ≥18 years with radiation/chemotherapy-naïve, mutant IDH1, nonenhancing, radiographically active, grade 2/3 gliomas, and ≥2 pretreatment and ≥2 on-treatment ivosidenib MRIs. T2/FLAIR-based tumor volumes, growth rates, and progression-free survival (PFS) were analyzed. log-linear mixed-effect modeling of growth curves adjusted for grade, histology, and age was performed. RESULTS: We analyzed 116 MRIs of 12 patients [10 males, median age 46 years (range: 26-60)]: 8 astrocytomas (50% grade 3) and 4 grade 2 oligodendrogliomas. Median on-drug follow-up was 13.2 months [interquartile range (IQR): 9.7-22.2]. Tolerability was 100%. A total of 50% of patients experienced ≥20% tumor volume reduction on-treatment and absolute growth rate was lower during treatment (-1.2 ± 10.6 cc/year) than before treatment (8.0 ± 7.7 cc/year; P ≤ 0.05). log-linear models in the Stable group (n = 9) showed significant growth before treatment (53%/year; P = 0.013), and volume reduction (-34%/year; P = 0.037) after 5 months on treatment. After treatment, volume curves were significantly lower than before treatment (after/before treatment ratio 0.5; P < 0.01). Median time-to-best response was 11.2 (IQR: 1.7-33.4) months, and 16.8 (IQR: 2.6-33.5) months in patients on drug for ≥1 year. PFS at 9 months was 75%. CONCLUSIONS: Ivosidenib was well tolerated and induced a high volumetric response rate. Responders had significant reduction in tumor growth rates and volume reductions observed after a 5-month delay. Thus, ivosidenib appears useful to control tumor growth and delay more toxic therapies in IDH-mutant nonenhancing indolently growing gliomas. See related commentary by Lukas and Horbinski, p. 4709.

CEST2022: Amide proton transfer-weighted MRI improves the diagnostic performance of multiparametric non-contrast-enhanced MRI techniques in patients with post-treatment high-grade gliomas.

New or enlarged lesions in malignant gliomas after surgery and chemoradiation can be associated with tumor recurrence or treatment effect. Due to similar radiographic characteristics, conventional-and even some advanced MRI techniques-are limited in distinguishing these two pathologies. Amide proton transfer-weighted (APTw) MRI, a protein-based molecular imaging technique that does not require the administration of any exogenous contrast agent, was recently introduced into the clinical setting. In this study, we evaluated and compared the diagnostic performances of APTw MRI with several non-contrast-enhanced MRI sequences, such as diffusion-weighted imaging, susceptibility-weighted imaging, and pseudo-continuous arterial spin labeling. Thirty-nine scans from 28 glioma patients were obtained on a 3 T MRI scanner. A histogram analysis approach was employed to extract parameters from each tumor area. Statistically significant parameters (P < 0.05) were selected to train multivariate logistic regression models to evaluate the performance of MRI sequences. Multiple histogram parameters, particularly from APTw and pseudo-continuous arterial spin labeling images, demonstrated significant differences between treatment effect and recurrent tumor. The regression model trained on the combination of all significant histogram parameters achieved the best result (area under the curve = 0.89). We found that APTw images added value to other advanced MR images for the differentiation of treatment effect and tumor recurrence.

Use of personalized molecular biomarkers in the clinical care of adults with glioblastomas.

This study was conducted to assess the current pattern of use and the impact of available molecular predictive and prognostic biomarkers on clinical care in patients with glioblastoma (GBM). An online questionnaire consisting of 15 questions about the frequency of use and clinical utility of tissue-based molecular tests was distributed to 1,053 members of the Neuro-Oncology Community in the United States. A total of 320 responses (30.4 %) were collected. 73 respondents who did not see GBM patients were excluded from analysis. MGMT promoter methylation testing (MGMT-meth) was the most commonly requested (37.2; 95 % CI, 31-44), followed by EGFR amplification (22.7; 95 % CI, 18-28), co-deletion of 1p/19q (22.3 %), EGFR expression (21.5 %), P53 mutation (19.8 %), PTEN mutation or deletion (17.4 %), EGFRvIII mutation (12.1 %), IDH1/2 mutation (12.1 %), PDGFR (4.5 %), and PIK3CA (0.8 %). The perceived utility of these studies was variable between participants. A small percentage of respondents felt that any of the studies were "always" or "almost always" helpful in clinical decision making (MGMT-meth 10.9 %; range, 0-13.8 %), but more frequently "never" or "almost never" helpful (MGMT-meth 25.9 %; range, 25-54.7 %). 26.7 % reported not to routinely order any of these studies. Although molecular markers are frequently ordered for patients with GBM, only a minority of clinicians ordering these tests report that the results influence clinical decision-making. Molecular markers that are likely to affect patient care should be ordered with the goal to maximize benefit for patients and to avoid non-actionable results and additional costs.

Feasibility and Biological Activity of a Ketogenic/Intermittent-Fasting Diet in Patients With Glioma.

OBJECTIVE: To examine the feasibility, safety, systemic biological activity, and cerebral activity of a ketogenic dietary intervention in patients with glioma. METHODS: Twenty-five patients with biopsy-confirmed World Health Organization grade 2 to 4 astrocytoma with stable disease after adjuvant chemotherapy were enrolled in an 8-week Glioma Atkins-Based Diet (GLAD). GLAD consisted of 2 fasting days (calories <20% calculated estimated needs) interleaved between 5 modified Atkins diet days (net carbohydrates ≤20 g/d) each week. The primary outcome was dietary adherence by food records. Markers of systemic and cerebral activity included weekly urine ketones, serum insulin, glucose, hemoglobin A1c, insulin-like growth factor-1, and magnetic resonance spectroscopy at baseline and week 8. RESULTS: Twenty-one patients (84%) completed the study. Eighty percent of patients reached ≥40 mg/dL urine acetoacetate during the study. Forty-eight percent of patients were adherent by food record. The diet was well tolerated, with two grade 3 adverse events (neutropenia, seizure). Measures of systemic activity, including hemoglobin A1c, insulin, and fat body mass, decreased significantly, while lean body mass increased. Magnetic resonance spectroscopy demonstrated increased ketone concentrations (ß-hydroxybutyrate [bHB] and acetone) in both lesional and contralateral brain compared to baseline. Average ketonuria correlated with cerebral ketones in lesional (tumor) and contralateral brain (bHB R s = 0.52, p = 0.05). Subgroup analysis of isocitrate dehydrogenase-mutant glioma showed no differences in cerebral metabolites after controlling for ketonuria. CONCLUSION: The GLAD dietary intervention, while demanding, produced meaningful ketonuria and significant systemic and cerebral metabolic changes in participants. Ketonuria in participants correlated with cerebral ketone concentration and appears to be a better indicator of systemic activity than patient-reported food records. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02286167.

Identifying Recurrent Malignant Glioma after Treatment Using Amide Proton Transfer-Weighted MR Imaging: A Validation Study with Image-Guided Stereotactic Biopsy.

PURPOSE: To quantify the accuracy of amide proton transfer-weighted (APTw) MRI for identifying active glioma after treatment via radiographically guided stereotactic tissue validation.Experimental Design: Twenty-one patients who were referred for surgery for MRI features concerning for tumor progression versus treatment effect underwent preoperative APTw imaging. Stereotactic biopsy samples were taken from regions of interest with varying APTw signal intensities. The relationship between final clinical pathology and the histopathology of each of the 64 specimens was analyzed relative to APTw results. Analysis of confirmed recurrent tumor or treatment effect tissue was used to perform ROC analysis. RESULTS: Eighteen of 21 patients had recurrent tumor, and 3 had treatment effect on clinical pathology. In 12 patients, there were multiple histopathologic assignments confirmed within the same tumor. Of the 64 total specimens, 20 specimens were active glioma, 27 mixed active and quiescent glioma, and 17 quiescent/no identifiable tumor. APTw signal intensity and histopathologic assignment, cellularity, and proliferation index had significant positive correlations (R = 0.651, 0.580, and 0.458, respectively; all P < 0.001). ROC analysis with a 1.79% APTw intensity cutoff differentiated active from nonactive tumor (AUC of 0.881) with 85.1% sensitivity and 94.1% specificity. Analysis of clinical pathology showed the mean APTw intensity for each patient had 94.4% sensitivity and 100% positive predictive value for identifying recurrent glioma at this cutoff. CONCLUSIONS: APTw imaging hyperintensity may be a marker of active malignant glioma. It is able to distinguish between regions of heterogeneous abnormality on anatomic brain MRI with high sensitivity and specificity.

Amide proton transfer-weighted magnetic resonance image-guided stereotactic biopsy in patients with newly diagnosed gliomas.

PURPOSE: Pathological assessment using World Health Organization (WHO) criteria is the gold standard for diagnosis of gliomas. However, the accuracy of diagnosis is limited by tissue sampling, particularly for infiltrating, heterogeneous tumours. We assessed the accuracy of amide proton transfer-weighted (APTw) magnetic resonance imaging (MRI)-guided tissue sampling to identify regions of high-grade glioma via radiographic-histopathologic correlation in patients with newly suspected glioma. PATIENTS AND METHODS: Twenty-four patients with previously undiagnosed gliomas underwent a volumetric APTw MRI prior to their first neurosurgical procedure. A total of 70 specimens were collected via APTw image-directed stereotactic biopsy. Cellularity, necrosis, proliferation and glioma WHO grade were analysed for all specimens and correlated with corresponding APTw signal intensities. RESULTS: Thirty-three specimens displayed grade-II pathology, 14 grade-III, 15 grade-IV, and eight specimens revealed only peritumoural oedema. Multiple glioma grades were found within a single lesion in six patients. APTw signal intensities of the biopsied sites and the maximum APTw values across all biopsied sites in each patient were significantly higher for high-grade versus low-grade specimens. APTw signal intensities were significantly positively correlated with cellularity (R = 0.757) and proliferation (R = 0.538). Multiple linear regression analysis showed that tumour cellularity and proliferation index were the best predictors of APTw signal intensities. CONCLUSION: APTw imaging identified tumour areas of higher cellularity and proliferation, allowing identification of high-grade regions within heterogeneous gliomas. APTw imaging can be readily translated for more widespread use and can assist diagnostic neurosurgical procedures by increasing the accuracy of tumour sampling in patients with infiltrating gliomas.