Post-treatment Glioma Research Articles

CNSC-25. CONCURRENT IMMUNE CHECKPOINT BLOCKADE ENHANCES THE SURVIVAL BENEFIT OF CLINICALLY RELEVANT MAPK PATHWAY INHIBITORS IN A T CELL-DEPENDENT MANNER

Abstract BACKGROUND Despite the availability of targeted therapies, gliomas carrying the BRAFV600E mutation remain challenging to treat. Combined pharmacologic BRAFV600E and MEK inhibition is clinically used in patients with BRAFV600E mutant gliomas, but primary and acquired resistance is reported in ~70% of high-grade glioma patients. OBJECTIVES To gain mechanistic insights into therapy adaptation and escape for developing combination therapies that enhance clinical effects of combined BRAFV600E inhibition with Dabrafenib and MEK inhibition with Trametinib (BRAFi+MEKi) in high-grade gliomas. APPROACH Patients’ pre- and post-treatment glioma tissues, patient-derived and mouse cell lines, and two novel immunocompetent mouse models for BRAFV600E mutant high-grade gliomas were analyzed for the effect of BRAFi+MEKi using a range of techniques including bulk and single-cell RNA sequencing, immunofluorescence staining, flow cytometry, and mass cytometry. RESULTS We present new data showing that the BRAFi+MEKi combination significantly reduced glioma cell viability while inducing glial differentiation programs, potentially associated with programmed death receptor (PD-1) signaling. This suggests a profound shift in the glioma cell differentiation state that is linked to an inclination toward T cell inhibition. This prompted us to combine BRAFi+MEKi with immune checkpoint inhibitors targeting PD-L1 and CTLA-4, which significantly decreased T cell inhibition. Furthermore, from mouse studies, this combination therapy conferred a survival benefit over single BRAFi+MEKi combination therapy alone. Additionally, BRAFi+MEKi treatment triggered an interferon-gamma response, indicative of cytotoxicity, and enhanced the expression of MHC molecules associated with antigen presentation, only in drug-sensitive but not drug-resistant gliomas. The lack of improved therapeutic efficacy of immune checkpoint blockade in athymic mice, which lack T cells, emphasized the critical role of T cell activity in driving the success of the combination treatment. CLINICAL IMPACT Our preclinical findings highlight the potential of concurrent BRAFi+MEKi treatment and immune checkpoint blockade for overcoming therapy resistance in BRAF mutant high-grade glioma patients.

How to evaluate perfusion imaging in post-treatment glioma: a comparison of three different analysis methods

IntroductionDynamic susceptibility contrast (DSC) perfusion weighted (PW)-MRI can aid in differentiating treatment related abnormalities (TRA) from tumor progression (TP) in post-treatment glioma patients. Common methods, like the ‘hot spot’, or visual approach suffer from oversimplification and subjectivity. Using perfusion of the complete lesion potentially offers an objective and accurate alternative. This study aims to compare the diagnostic value and assess the subjectivity of these techniques.Methods50 Glioma patients with enhancing lesions post-surgery and chemo-radiotherapy were retrospectively included. Outcome was determined by clinical/radiological follow-up or biopsy. Imaging analysis used the ‘hot spot’, volume of interest (VOI) and visual approach. Diagnostic accuracy was compared using receiving operator characteristics (ROC) curves for the VOI and ‘hot spot’ approach, visual assessment was analysed with contingency tables. Inter-operator agreement was determined with Cohens kappa and intra-class coefficient (ICC).Results29 Patients suffered from TP, 21 had TRA. The visual assessment showed poor to substantial inter-operator agreement (κ = -0.72 – 0.68). Reliability of the ‘hot spot’ placement was excellent (ICC = 0.89), while reference placement was variable (ICC = 0.54). The area under the ROC (AUROC) of the mean- and maximum relative cerebral blood volume (rCBV) (VOI-analysis) were 0.82 and 0.72, while the rCBV-ratio (‘hot spot’ analysis) was 0.69. The VOI-analysis had a more balanced sensitivity and specificity compared to visual assessment.ConclusionsVOI analysis of DSC PW-MRI data holds greater diagnostic accuracy in single-moment differentiation of TP and TRA than ‘hot spot’ or visual analysis. This study underlines the subjectivity of visual placement and assessment.

External validation of the Brain Tumour Reporting and Data System (BT-RADS) in the multidisciplinary managementof post-treatment gliomas.

To independently and externally validate the Brain Tumour Reporting and Data System (BT-RADS) for post-treatment gliomas and assess interobserver variability. In this retrospective observational study, consecutive MRIs of 100 post-treatment glioma patients were reviewed by two independent radiologists (RD1 and RD2) and assigned a BT-RADS score. Inter-observer agreement statistics were determined by kappa statistics. The BT-RADS-linked management recommendations per score were compared with the multidisciplinary meeting (MDM) decisions. The overall agreement rate between RD1 and RD2 was 62.7% (κ = 0.67). The agreement rate between RD1 and consensus was 83.3% (κ = 0.85), while the agreement between RD2 and consensus was 69.3% (κ = 0.79). Among the radiologists, agreement was highest for score 2 and lowest for score 3b. There was a 97.9% agreement between BT-RADS-linked management recommendations and MDM decisions. BT-RADS scoring led to improved consistency, and standardised language in the structured MRI reporting of post-treatment brain tumours. It demonstrated good overall agreement among the reporting radiologists at both extremes; however, variation rates increased in the middle part of the spectrum. The interpretation categories linked to management decisions showed a near-perfect match with MDM decisions.

Revealing tumor microstructure with oscillating diffusion encoding MRI in pre-surgical and post-treatment glioma patients.

We hypothesized that the time-dependent diffusivity at short diffusion times, as measured by oscillating gradient spin echo (OGSE) diffusion MRI, can characterize tissue microstructures in glioma patients. Five adult patients with known diffuse glioma, including two pre-surgical and three with new enhancing lesions after treatment for high-grade glioma, were scanned in an ultra-high-performance gradient 3.0T MRI system. OGSE diffusion MRI at 30-100 Hz and pulsed gradient spin echo diffusion imaging (approximated as 0 Hz) were obtained. The ADC and trace-diffusion-weighted image at each acquired frequency were calculated, that is, ADC (f) and TraceDWI (f). In pre-surgical patients, biopsy-confirmed solid enhancing tumor in a high-grade glioblastoma showed higher and lower , compared to that at same OGSE frequency in a low-grade astrocytoma. In post-treatment patients, the enhancing lesions of two patients who were diagnosed with tumor progression contained more voxels with high and low , compared to the enhancing lesions of a patient who was diagnosed with treatment effect. Non-enhancing T2 signal abnormality lesions in both the pre-surgical high-grade glioblastoma and post-treatment tumor progressions showed regions with high and low , consistent with infiltrative tumor. The solid tumor of the glioblastoma, the enhancing lesions of post-treatment tumor progressions, and the suspected infiltrative tumors showed high diffusion time-dependency from 30 to 100 Hz, consistent with high intra-tumoral volume fraction (cellular density). Different characteristics of OGSE-based time-dependent diffusivity can reveal heterogenous tissue microstructures that indicate cellular density in glioma patients.

Head-To-Head Comparison of PET and Perfusion Weighted MRI Techniques to Distinguish Treatment Related Abnormalities from Tumor Progression in Glioma.

The post-treatment imaging surveillance of gliomas is challenged by distinguishing tumor progression (TP) from treatment-related abnormalities (TRA). Sophisticated imaging techniques, such as perfusion-weighted magnetic resonance imaging (MRI PWI) and positron-emission tomography (PET) with a variety of radiotracers, have been suggested as being more reliable than standard imaging for distinguishing TP from TRA. However, it remains unclear if any technique holds diagnostic superiority. This meta-analysis provides a head-to-head comparison of the diagnostic accuracy of the aforementioned imaging techniques. Systematic literature searches on the use of PWI and PET imaging techniques were carried out in PubMed, Embase, the Cochrane Library, ClinicalTrials.gov and the reference lists of relevant papers. After the extraction of data on imaging technique specifications and diagnostic accuracy, a meta-analysis was carried out. The quality of the included papers was assessed using the QUADAS-2 checklist. Nineteen articles, totaling 697 treated patients with glioma (431 males; mean age ± standard deviation 50.5 ± 5.1 years) were included. The investigated PWI techniques included dynamic susceptibility contrast (DSC), dynamic contrast enhancement (DCE) and arterial spin labeling (ASL). The PET-tracers studied concerned [S-methyl-11C]methionine, 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG), O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) and 6-[18F]-fluoro-3,4-dihydroxy-L-phenylalanine ([18F]FDOPA). The meta-analysis of all data showed no diagnostic superior imaging technique. The included literature showed a low risk of bias. As no technique was found to be diagnostically superior, the local level of expertise is hypothesized to be the most important factor for diagnostically accurate results in post-treatment glioma patients regarding the distinction of TRA from TP.

The value of adding DWI and FLAIR signal changes in the resection cavity on the diagnostic performance of BT-RADS category 3 for tumor progression prediction in post-treated glioma patients: a prospective pilot study

BackgroundBT-RADS is a structured reporting system of post-treatment glioma. BT-RADS category 3 carries a probability of recurrent malignancy versus treatment-related changes. The aim of this study is to evaluate the additive value of DWI and resection cavity FLAIR signal changes to BT-RADS category 3 in the prediction of tumor progression. We prospectively evaluated follow-up contrast-enhanced MR imaging where 27 post-treated glioma patients were assigned BT-RADS category 3. In all images, FLAIR signal, enhancement component, mass effect, and ADCmean were assessed. We used imaging follow-up from the second stage of the study as the gold standard for comparing the diagnostic performance of BT-RADS category 3 for predicting tumor recurrence before and after the addition of DWI and resection cavity FLAIR signal changes. ROC curves analyses were assessed and compared using the Delong test.Results48.1% of patients had tumor recurrence and 51.9% of patients had treatment-related changes. There was significant difference between ADCmean in recurrent and non-recurrent groups measuring 0.9 and 1.15 × 10−3mm2/s, respectively (p value < 0.001). BT-RADS, BT-RADS added DWI, and BT-RADS added DWI and resection cavity FLAIR signal had a specificity of 64.3, 71.4, and 71.4%, sensitivity of 76.9, 84.6, and 92.3%, and accuracy of 70.5, 77.8, and 81.5%, with improved AUC from 0.706 (95% CI of 0.50–0.86) to 0.78 (95% CI of 0.58–0.92) to 0.819 (95% CI of 0.64–0.94), respectively.ConclusionsAdding DWI and resection cavity FLAIR signal alteration improves the diagnostic performance of BT-RADS category 3.

Conventional and Advanced Imaging Techniques in Post-treatment Glioma Imaging.

Despite decades of advancement in the diagnosis and therapy of gliomas, the most malignant primary brain tumors, the overall survival rate is still dismal, and their post-treatment imaging appearance remains very challenging to interpret. Since the limitations of conventional magnetic resonance imaging (MRI) in the distinction between recurrence and treatment effect have been recognized, a variety of advanced MR and functional imaging techniques including diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), perfusion-weighted imaging (PWI), MR spectroscopy (MRS), as well as a variety of radiotracers for single photon emission computed tomography (SPECT) and positron emission tomography (PET) have been investigated for this indication along with voxel-based and more quantitative analytical methods in recent years. Machine learning and radiomics approaches in recent years have shown promise in distinguishing between recurrence and treatment effect as well as improving prognostication in a malignancy with a very short life expectancy. This review provides a comprehensive overview of the conventional and advanced imaging techniques with the potential to differentiate recurrence from treatment effect and includes updates in the state-of-the-art in advanced imaging with a brief overview of emerging experimental techniques. A series of representative cases are provided to illustrate the synthesis of conventional and advanced imaging with the clinical context which informs the radiologic evaluation of gliomas in the post-treatment setting.

Reliability of dynamic susceptibility contrast perfusion metrics in pre- and post-treatment glioma

BackgroundIn neuro-oncology, dynamic susceptibility contrast magnetic resonance (DSC-MR) perfusion imaging emerged as a tool to aid in the diagnostic work-up and to surveil effectiveness of treatment. However, it is believed that a significant variability exists with regard to the measured in DSC-MR perfusion parameters. The aim of this study was to assess the observer variability in measured DSC-MR perfusion parameters in patients before and after treatment. In addition, we investigated whether region-of-interest (ROI) shape impacted the observer variability.Materials and methodsTwenty non-treated patients and a matched group of twenty patients post-treatment (neurosurgical resection and post-chemoradiotherapy) were included. Six ROIs were independently placed by three readers: circular ROIs and polygonal ROIs covering 1) the tumor hotspot; 2) the peritumoral region (T2/FLAIR-hyperintense region) and 3) the whole tumor region. A two-way random Intra-class coefficient (ICC) model was used to assess variability in measured DSC-MRI perfusion parameters. The perfusion metrics as assessed by the circular and the polygonal ROI were compared by use of the dependent T-test.ResultsIn the non-treated group, circular ROIs showed good–excellent overlap (ICC-values ranging from 0.741–0.963) with the exception of those representing the tumor hotspot. Polygonal ROIs showed lower ICC-values, ranging from 0.113 till 0.856. ROI-placement in the posttreatment group showed to be highly variable with a significant deterioration of ICC-values. Furthermore, perfusion metric assessment in similar tumor regions was not impacted by ROI shape.DiscussionThis study shows that posttreatment quantitative interpretation of DSC-MR perfusion imaging is highly variable and should be carried out with precaution. Pretreatment assessment of DSC-MR images, however, could be carried out be a single reader in order to provide valid data for further analyses.

OTEH-6. Algorithmic approach to characterize post-treatment recurrent glioma using RNA sequencing and quantitative histopathology

IntroductionDistinguishing between tumor and treatment effect in post-treatment glioma, although crucial for clinical management, is difficult because contrast-enhancing regions are mixtures of recurrent tumor and reactive tissue, and definitive histopathological criteria do not exist. This study disentangles the marked intra-tumoral heterogeneity in the treatment-recurrent setting by developing an unsupervised framework to algorithmically categorize intraoperative MRI-localized biopsies into three clinically-relevant tissue clusters based on joint analysis of RNA sequencing and histopathological data.MethodsA retrospective cohort of 84 MRI-localized biopsies from 37 patients with post-treatment recurrent glioblastoma underwent mRNA extraction and quantification via PLATEseq protocol. For 48 of 84 biopsies, a neighboring piece of tissue underwent quantitative histopathology based on labeling index (LI) for SOX2, CD68, NeuN, Ki67, and H&E. Correlation between LIs and gene expression for these 48 samples was performed. Genes significantly correlated (p<0.05) with ≥1 marker were used for hierarchical clustering of correlation matrix, identifying three mutually-exclusive tissue-specific gene sets. These sets were then used to perform ssGSEA to categorize each of 84 biopsies into one of three tissue types.ResultsCorrelation analysis identified 7779 genes significantly correlated with ≥1 histopathological marker. Clustering revealed three gene sets associated with specific markers: SetA-3688 genes associated with SOX2/Ki67/H&E; SetB-2418 genes associated with CD68; SetC-1673 genes associated with NeuN. ssGSEA using these sets categorized each biopsy into one of three tissue types: 27 biopsies enriched in SetA, 28 in SetB, and 29 in SetC.ConclusionsUsing MRI-localized biopsies with both RNAseq and histopathological data, this algorithmic approach allows development of three orthogonal tissue-specific gene sets that can be applied to characterize the heterogeneity in post-treatment recurrent glioma: SetA: genes correlated with SOX2/Ki67/H&E, representing recurrent tumor; SetB: genes correlated with CD68 (microglia) representing reactive tissue consistent with treatment effect; SetC: genes correlated with NeuN (neurons), representing infiltrated brain.

IMG-18. ASSESSMENT OF SUSPECTED DISEASE PROGRESSION USING MULTIPARAMETRIC 18F-CHOLINE PET/MRI IN CHILDHOOD AND TEENAGE-YOUNG ADULT GLIOMAS

OBJECTIVESEvaluation of post-treatment glioma burden remains a significant challenge in children, teenagers and young adults (TYA). The aim of this study was to evaluate the utility of ChoPET/MRI for evaluation of suspected disease progression in childhood and TYA gliomas.METHODS27 patients (mean age 14 years, range 6–21 years) with suspected glioma disease progression were evaluated with ChoPET/MRI (n=59). Relative cerebral blood volume (rCBV), apparent diffusion coefficient (ADC) and maximum standardised uptake values (SUVmax) in enhancing (enh) and non-enhancing (ne) tumour and normal-appearing white matter (wm) were calculated (rCBVenh, rCBVne, rCBVwm, ADCenh, ADCne, ADCwm, SUVenh, SUVne, SUVwm). 2 blinded radiologists scored tumour probability (1 = unlikely; 5 = definitely). Sensitivity and specificity calculated with gold standard histopathology or clinical follow-up.RESULTSAccuracy for the detection of residual/recurrent tumour on conventional MRI was 96.3% (91.7% ≤14 years, 100% ≥15 years) and ChoPET was 73.1% (66.7% ≤14 years, 80.0% ≥15 years). Lack of agreement was observed in 9/27 patients, with ChoPET superior to MRI in 1 case of a posterior fossa tumour. Tumour component analysis demonstrated significantly higher SUVenh and SUVne than SUVwm (SUVenh: p<0.001; SUVne: p=0.004, equivalent to results were observed for ADV and rCBV (ADCenh, ADCne: p<0.001 vs ADCwm; rCBVenh, rCBVne: p<0.001 vs rCBVwm).CONCLUSIONSMRI is more sensitive than ChoPET in the evaluation of suspected disease progression in TYA gliomas. However, quanititative ChoPET is able to detect enhancing and non-enhancing tumour and may be helpful in evaluating posterior fossa disease where MRI is equivocal.

NIMG-18. THE CLINICAL SIGNIFICANCE OF 13N-NH3, 18F-DOPA, AND 18F-FDG PET/CT IN THE DIFFERENTIAL DIAGNOSIS BETWEEN GLIOMA RECURRENCE AND TREATMENT EFFECTS

Abstract BACKGROUND Glioma often recurs and the imaging evaluation whether the tumor has returned after glioma treatment is still challenging. PET/CT is one of the most important techniques to assess the post-treatment of glioma. However, differentiating tumor recurrence (TuR) from treatment effects (TrE) remains difficult. In this study, we aim to retrospectively compare the diagnostic performance of three PET tracers 13N-NH3, 18F-DOPA, and 18F-FDG on PET/CT in differentiating between TuR and TrE in post-treatment glioma patients. METHODS Forty-three patients with MRI-suspected recurrent glioma were included. The maximum and mean standardized uptake value (SUVmax and SUVmean) of the lesion and the lesion-to-normal Gray-matter cortex uptake (L/G) ratio were recorded and the reference standard was verified by surgical histopathology or more than 6 months of follow-up with clinical/radiological. The diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis. RESULTS 34 patients were confirmed as glioma TuR and 9 patients met the standard of TrE. The median time interval from primary diagnosis surgery to PET/CT was 14.83 months (range, 4.10-62.77 months). The SUVmax of 13N-NH3 and 18F-DOPA PET/CT at the lesions was significantly higher than normal brain tissue (13N-NH3 0.696±0.095 vs 0.486±0.071, 18F-DOPA 0.455±0.079 vs 0.194±0.031, both P&amp;lt; 0.001), while 18F-FDG was not (6.918±0.525 vs 6.356±0.510, P=0.290). TuR showed significantly higher L/G ratios than TrE both in 13N-NH3 and 18F-DOPA PET/CT (13N-NH3, 1.573±0.099 vs 1.025±0.128, P=0.008; 18F-DOPA, 2.729±0.131 vs 1.514±0.141, P&amp;lt; 0.001). The sensitivity, specificity and the area under the curve (AUC) by ROC analysis were 57.7, 100% and 0.803 for 13N-NH3, and 84.6, 100% and 0.938 for 18F-DOPA respectively. CONCLUSIONS PET/CT is a powerful tool to distinguish glioma TuR from TrE, and 18F-DOPA PET/CT has remarkably better differential diagnosis efficacy than 13N-NH3 and 18F-FDG.

PATH-57. MRI-LOCALIZED BIOPSIES REVEAL HISTOPATHOLOGIC HETEROGENEITY IN POST-TREATMENT RECURRENT HIGH-GRADE GLIOMA

Abstract Evaluation of recurrence in post-treatment glioma is challenging because contrast-enhancing (CE) lesions are a mixture of tumor and treatment effect. This study characterizes intratumoral heterogeneity using quantitative digital pathology to correlate intraoperative MRI-localized biopsies with histopathology in the post-treatment setting. Findings will inform multiparametric radiographic models of intratumoral heterogeneity. A retrospective review was performed on adult patients with MRI-localized biopsies obtained during resection for post-treatment recurrent high-grade glioma. 68 patients and 170 MRI-localized samples were analyzed (median 2 samples/patient). Immunohistochemistry (IHC) for markers of glioma cells (SOX2), macrophages (CD68), and proliferating cells (KI67) was used to characterize biopsies. Slides were digitized and quantified using an automated cell-counting algorithm. Histopathological criteria based on IHC data was developed to classify biopsies. IHC quantification was compared across histological groups using ANOVA and paired t-tests. Most patients (52/68) yielded multiple biopsies. 75% (39/52) demonstrated heterogeneity in histological classification of all specimens obtained from their lesion. 47/170 (28%) biopsies were predominantly treatment effect, and most were CE (31/47 or 66%). Only 75/170 (44%) biopsies contained recurrent glioma, and 21/75 (28%) were NE. SOX2 labeling index was higher in biopsies containing recurrent tumor (p=5.13E-25). CD68 labeling index was higher in biopsies with predominant treatment effect (p=1.35E-12). IHC data from MRI-localized biopsies informed a multiple linear regression model which demonstrated significant predictive value for determining the distribution of recurrent tumor in the post-treatment setting. Contrast enhancement is not a reliable predictor of tumor in recurrent high-grade glioma. Most patients demonstrated marked intratumoral heterogeneity, highlighting the difficulty of accurate tumor sampling post-treatment glioma. Our histopathological classification significantly distinguished recurrent tumor from treatment effect and informed a multiparametric radiomic model which can guide surgical sampling and assess response to therapy.

Multiparametric 18F-Choline PET/MR in childhood and teenage-young adult gliomas: assessment of suspected disease progression

Abstract Aim Evaluation of post-treatment glioma burden remains a significant challenge in childhood, Teenage and Young Adults (TYA). Although amino acid PET impacts on glioma imaging, 18fluoro-Choline Positron Emission Tomography (ChoPET) is more widely available. The aim was to evaluate the utility of ChoPET/MRI for suspected disease progression in childhood and TYA gliomas. Methods 27 consecutive patients with suspected glioma disease progression were evaluated with ChoPET/MR and 59 scans included. Relative cerebral blood volume (rCBV), ADC and SUVmax in enhancing (enh), non-enhancing (ne) tumour volumes and normal appearing white matter (wm) were calculated (rCBVenh, rCBVne, rCBVwm, ADCenh, ADCne, ADCwm, SUVenh, SUVne, SUVwm). Blinded nuclear medicine and neuroradiologist scored the images on tumour probability (1:unlikely-5:definitely). Receiver Operating Characteristic (ROC) analysis considering as gold standard histopathology or clinical follow-up was performed. Results Combined ChoPET/MR accuracy was 100% for residual tumour, conventional MR accuracy was 96.3% (91.7% &lt;14years, 100% ≥15years) and ChoPET accuracy was 73.1% (66.7% &lt;14years, 80.0% ≥15 years). Lack ack of agreement in 9/27 with ChoPET superior to MR in 1 case. Tumour component analysis demonstrated significantly higher SUVenh and SUVne than SUVwm (SUVenh: p&lt;0.001,SUVne: p=0.003) equivalent to ADC (ADCenh, ADCnenh: p&lt;0.001) and rCBV (rCBVenh, rCBVnenh: p&lt;0,001). Conclusions Combined ChoPET/MR has 100% accuracy in TYA gliomas with suspected disease progression. ChoPET is able to detect enhancing and non-enhancing tumour but it is more reliable for evaluating enhancing disease &gt;15 years. In selected cases where MRI is equivocal, a quantitative multi-modality ChoPET/MR better defines both enhancing and non-enhancing tumour for improved assessment of childhood and TYA gliomas.

Quantitative Improvement in Brain Tumor MRI Through Structured Reporting (BT-RADS)

Determine the objective benefits of structured reporting of brain tumors through Brain tumor-RADS (BT-RADS) by analyzing discrete quantifiable metrics of the reports themselves. Following Institutional Review Board approval, post-treatment glioma reports were acquired from two matched 3-month time periods for pre- and postimplementation of BT-RADS. The reports were analyzed for presence of history words, such as "Avastin" and "methylguanine-DNA methyltransferase," as well as hedge words, such as "Possibly" and "Likely." The word counts of the total report and of the impression section were also assessed, as well as whether or not the report contained addenda. In total, 211 pre-BT-RADS and 172 post-BT-RADS reports were analyzed. Post-BT-RADS reports demonstrated greater reporting of history words, including "Avastin" (7.6% vs. 20.9%, p < 0.001) and "methylguanine-DNA methyltransferase" (10.9% vs. 31.4%, p < 0.0001). They also demonstrated reduced usage of hedge words, including "Possibly" (3.8% vs. 0.6%, p < 0.05) and "Likely" (49.8% vs. 28.5%, p < 0.01). Furthermore, post-BT-RADS reports possessed fewer words in total report length (389 vs. 245.2, p < 0.001), as well as in the impression section (53.7 vs. 42.6, p < 0.01). Finally, fewer post-BT-RADS reports contained addenda (10% vs. 1.2%, p < 0.01). Following implementation of BT-RADS, glioma reports demonstrated greater consistency and completeness of clinical history, less ambiguity, and more conciseness.

Diagnostic performance of multiparametric MRI in the evaluation of treatment response in glioma patients at 3T.

MRI is one of the most important techniques to assess the treatment response of gliomas. However, differentiating tumor recurrence (TuR) from treatment effects (TrE) remains challenging. To compare the diagnostic performance of MR diffusion-weighted imaging (DWI), arterial spin labeling (ASL), proton MR spectroscopy (MRS), and amide proton transfer (APT) imaging in differentiating between TuR and TrE in posttreatment glioma patients. Prospective. Thirty patients with suspected tumor progression. DWI, ASL, proton MRS, and APT imaging were performed at 3T MR. MR indices, including ADC, relative cerebral blood flow (rCBF), ratios of Cho/Cr, Cho/NAA, and NAA/Cr and APT-weighted (APTw) effect were obtained from DWI, ASL, proton MRS, and APT imaging, respectively. Indices were measured in the contralateral normal-appearing white matter and lesions defined on the Gd-enhanced T1 w image. TuR or TrE was either determined histologically or clinically from longitudinal MRI follow-up for at least 6 months. The diagnostic performance of the indices was evaluated using Student's t-test, receiver operating characteristic (ROC) curve, and multivariate logistic regression analyses. Among the 30 patients, 16 were diagnosed as having TuR and the rest having TrE. The recurrent tumors showed a significantly higher APTw effect (1.56 ± 1.14%) and rCBF (1.44 ± 0.61) compared with lesions representing treatment effects (-0.44 ± 1.34% and 0.72 ± 0.25, respectively, with P < 0.001). The areas under the curve (AUCs) were 0.87 and 0.90 for APTw and rCBF, respectively, in differentiating between TuR and TrE. Combining APTw and rCBF achieved a higher AUC of 0.93. MRS index ratios of Cho/Cr (P = 0.25), Cho/NAA (P = 0.16), and NAA/Cr (P = 0.86) and ADC (P = 0.37) showed no significant differences between TuR and TrE lesions, with AUCs lower than 0.70. Compared with DWI and MRS, ASL and APT imaging techniques showed better diagnostic capability in distinguishing TuR from TrE. 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2020;51:1154-1161.

Integrated PET-MRI for Glioma Surveillance: Perfusion-Metabolism Discordance Rate and Association With Molecular Profiling.

Both 18F-FDG PET and perfusion MRI are commonly used techniques for posttreatment glioma surveillance. Using integrated PET-MRI, we assessed the rate of discordance between simultaneously acquired FDG PET images and dynamic contrast-enhanced (DCE) perfusion MR images and determined whether tumor genetics predicts discordance. Forty-one consecutive patients with high-grade gliomas (20 with grade IV gliomas and 21 with grade III gliomas) underwent a standardized tumor protocol performed using an integrated 3-T PET-MRI scanner. Quantitative measures of standardized uptake value, plasma volume, and permeability were obtained from segmented whole-tumor volumes of interest and targeted ROIs. ROC curve analysis and the Youden index were used to identify optimal cutoffs for FDG PET and DCE-MRI. Two-by-two contingency tables and percent agreement were used to assess accuracy and concordance. Twenty-six patients (63%) from the cohort underwent next-generation sequencing for tumor genetics. The best-performing FDG PET and DCE-MRI cutoffs achieved sensitivities of 94% and 91%, respectively; specificities of 56% and 89%, respectively; and accuracies of 80% and 83%, respectively. FDG PET and DCE-MRI findings were discordant for 11 patients (27%), with DCE-MRI findings correct for six of these patients (55%). Tumor grade, tumor volume, bevacizumab exposure, and time since radiation predicted discordance between FDG PET and DCE-MRI findings, with an ROC AUC value of 0.78. Isocitrate dehydrogenase gene and receptor tyrosine kinase gene pathway mutations increased the ROC AUC value to 0.83. FDG PET and DCE-MRI show comparable accuracy and sensitivity in identifying tumor progression. These modalities were shown to have discordant findings for more than a quarter of the patients assessed. Tumor genetics may contribute to perfusion-metabolism discordance, warranting further investigation.

Glioblastoma Recurrence Correlates With Increased APE1 and Polarization Toward an Immuno-Suppressive Microenvironment.

While treatment with surgery, radiotherapy and/or chemotherapy may prolong life for patients with glioblastoma, recurrence is inevitable. What is still being discovered is how much these treatments and recurrence of disease affect the molecular profiles of these tumors and how these tumors adapt to withstand these treatment pressures. Understanding such changes will uncover pathways used by the tumor to evade destruction and will elucidate new targets for treatment development. Nineteen matched pre-treatment and post-treatment glioblastoma tumors were subjected to gene expression profiling (Fluidigm, TaqMan assays), MGMT promoter methylation analysis (pyrosequencing) and protein expression analysis of the DNA repair pathways, known to be involved in temozolomide resistance (immunohistochemistry). Gene expression profiling to molecularly subtype tumors revealed that 26% of recurrent post-treatment specimens did not match their primary diagnostic specimen subtype. Post-treatment specimens had molecular changes which correlated with known resistance mechanisms including increased expression of APEX1 (p < 0.05) and altered MGMT methylation status. In addition, genes associated with immune suppression, invasion and aggression (GPNMB, CCL5, and KLRC1) and polarization toward an M2 phenotype (CD163 and MSR1) were up-regulated in post-treatment tumors, demonstrating an overall change in the tumor microenvironment favoring aggressive tumor growth and disease recurrence. This was confirmed by in vitro studies that determined that glioma cell migration was enhanced in the presence of M2 polarized macrophage conditioned media. Further, M2 macrophage-modulated migration was markedly enhanced in post-treatment (temozolomide resistant) glioma cells. These findings highlight the ability of glioblastomas to evade not only the toxic onslaught of therapy but also to evade the immune system suggesting that immune-altering therapies may be of value in treating this terrible disease.

Crossed cerebellar diaschisis in post-treatment glioma patients: A comparative study of arterial spin labelling and dynamic susceptibility contrast

ObjectivesTo assess crossed cerebellar diaschisis (CCD) in post-treatment glioma patients, and to compare the performance of arterial spin labelling (ASL) and dynamic susceptibility contrast (DSC) in detecting CCD. Methods and materialsThis retrospective study included 130 patients who had both DSC and ASL. Among them, 16 had underwent fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). We investigated the relationship between CCD and the location and size of supratentorial lesions, and compared PET diagnostic performance with that of ASL and DSC. We assessed the inter-methods agreement for ASL and DSC, and performed quantitative analysis by calculating the asymmetry index (AI) between bilateral cerebellum and exploring how the AI values for ASL-CBF, DSC-rCBF, and DSC-rCBV maps correlated with each other. ResultSupratentorial lesions affecting the corona radiata (P < 0.001), basal ganglia (P < 0.001), and insula (P = 0.046) were significantly associated with the occurrence of CCD. Lesion size was significantly larger (P = 0.005) in the CCD positive group. With PET as a reference, ASL-CBF and DSC-rCBF maps exhibited the best diagnostic performance compared with the other DSC-generated maps (diagnostic accuracy = 83.3% for both, area under curve (AUC) of ASL = 0.967, AUC of rCBF = 0.983), although differences were not statistically significant. The κ value for the inter-methods (ASL and DSC) agreement in detecting CCD was 0.893, while the degree of perfusion asymmetry was more significant in ASL- than DSC-generated maps. Bland-Altman plots showed that the AI for ASL-CBF was moderately correlated with those for DSC-rCBF and DSC-rCBV. ConclusionsCCD can present in post-treatment glioma patients and is detectable on MR-perfusion images including ASL-CBF, DSC-rCBF, and DSC-rCBV maps.

Management-Based Structured Reporting of Posttreatment Glioma Response With the Brain Tumor Reporting and Data System

Patients with newly diagnosed glioblastomas have a 15-month median survival, and fewer than 10% of patients survive beyond 5 years [ 1 Stupp R. Hegi M.E. Mason W.P. et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009; 10: 459-466 Abstract Full Text Full Text PDF PubMed Scopus (4767) Google Scholar ]. That poor prognosis highlights the importance of accurately monitoring disease progression and treatment response. MRI evaluation has played a crucial role in the management of patients with brain tumors [ 2 Quant E.C. Wen P.Y. Response assessment in neuro-oncology. Curr Oncol Rep. 2011; 13: 50-56 Crossref PubMed Scopus (81) Google Scholar ], but challenges in differentiating tumor progression from treatment effects can cause ambiguous and inconsistent interpretations, limiting the usefulness of imaging. A structured glioma surveillance reporting system with standardized management-based suggestions has the potential to improve the ability of radiologists and referring providers to assess posttreatment tumor imaging and facilitate more effective patient communication and valued care [ 3 Aiken A.H. Farley A. Baugnon K.L. et al. Implementation of a novel surveillance template for head and neck cancer: Neck Imaging Reporting and Data System (NI-RADS). J Am Coll Radiol. 2016; 13: 743-746.e1 Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar ]. Currently no such standardized and widely used radiology reporting system exists.

NIMG-36COMPREHENSIVE EVALUATION OF GLIOMA RECURRENCE WITH SIMULTANEOUS O-(2-18F-FLUOROETHYL)-L-TYROSINE (18F-FET) POSITRON EMISSION TOMOGRAPHY MAGNETIC RESONANCE IMAGING (PET MRI)

BACKGROUND: Simultaneous PET MRI offers opportunity to combine attributes of 18F-FET PET and MRI together during a single examination in the evaluation of post treatment glioma recurrence. The purpose of this study was to examine its potential in distinguishing glioma recurrence vs. radiation necrosis. METHODS: 27 patients with 36 suspicious brain lesions were evaluated with contrast enhanced 18F FET PET MRI using Biograph mMR acquired over 25 min immediately following tracer administration. Dynamic (20/27 patients: 5 data points), and static PET data ( 0 to 25 min) & MR images were analyzed using manually drawn ROI over the area of maximal contrast enhancement and/or FET uptake and migrating the same over corresponding other images to obtain various PET and MR parametric values for analysis. Statistical analysis was done for each parameter individually and in various combinations using Sigma Plot 13.0 and PASW 18. Positive histopathology and long term imaging/clinical follow up served as gold standard. RESULTS: 21 patients were classified as recurrence and 6 patients as radiation necrosis Individually, TBRmax, TBRmean, ADCmean, Cho: Cr ratios and normalized rCBVmean were significant in differentiating recurrence from radiation necrosis with an accuracy of 94.4% for TBRmax, 91% for TBRmean, 83.3% for ADCmean, 94.4% for Cho: Cr ratio and 86.1% for N rCBVmean respectively. TBRmax with Cho: Cr ratio yielded the highest accuracy of 97.2 % (AUC, 0.979± 0.03; sensitivity, 93.1%; specificity, 100%; P< 0.001). TTP & SUVmax of the lesion were found to be most significant parameters in distinguishing between recurrence & radiation necrosis with a p value of <0.05. SUVmax (p < 0.05) & slope to peak (p < 0.05) were most useful in differentiating low grade recurrence from radiation necrosis. CONCLUSION: Simultaneous FET PET MRI offers a quick and comprehensive method in differentiating glioma recurrence and treatment effect with high accuracy.