Advanced MRI assessment to predict benefit of anti-programmed cell death 1 protein immunotherapy response in patients with recurrent glioblastoma.
ABSTRACT: We describe the imaging findings encountered in GBM patients receiving immune checkpoint blockade and assess the potential of quantitative MRI biomarkers to differentiate patients who derive therapeutic benefit from those who do not.A retrospective analysis was performed on longitudinal MRIs obtained on recurrent GBM patients enrolled on clinical trials. Among 10 patients with analyzable data, bidirectional diameters were measured on contrast enhanced T1 (pGd-T1WI) and volumes of interest (VOI) representing measurable abnormality suggestive of tumor were selected on pGdT1WI (pGdT1 VOI), FLAIR-T2WI (FLAIR VOI), and ADC maps. Intermediate ADC (IADC) VOI represented voxels within the FLAIR VOI having ADC in the range of highly cellular tumor (0.7-1.1 × 10-3 mm2/s) (IADC VOI). Therapeutic benefit was determined by tissue pathology and survival on trial. IADC VOI, pGdT1 VOI, FLAIR VOI, and RANO assessment results were correlated with patient benefit.Five patients were deemed to have received therapeutic benefit and the other five patients did not. The average time on trial for the benefit group was 194 days, as compared to 81 days for the no benefit group. IADC VOI correlated well with the presence or absence of clinical benefit in 10 patients. Furthermore, pGd VOI, FLAIR VOI, and RANO assessment correlated less well with response.MRI reveals an initial increase in volumes of abnormal tissue with contrast enhancement, edema, and intermediate ADC suggesting hypercellularity within the first 0-6 months of immunotherapy. Subsequent stabilization and improvement in IADC VOI appear to better predict ultimate therapeutic benefit from these agents than conventional imaging.
Project description:BACKGROUND:Longitudinal measurement of glioma burden with MRI is the basis for treatment response assessment. In this study, we developed a deep learning algorithm that automatically segments abnormal fluid attenuated inversion recovery (FLAIR) hyperintensity and contrast-enhancing tumor, quantitating tumor volumes as well as the product of maximum bidimensional diameters according to the Response Assessment in Neuro-Oncology (RANO) criteria (AutoRANO). METHODS:Two cohorts of patients were used for this study. One consisted of 843 preoperative MRIs from 843 patients with low- or high-grade gliomas from 4 institutions and the second consisted of 713 longitudinal postoperative MRI visits from 54 patients with newly diagnosed glioblastomas (each with 2 pretreatment "baseline" MRIs) from 1 institution. RESULTS:The automatically generated FLAIR hyperintensity volume, contrast-enhancing tumor volume, and AutoRANO were highly repeatable for the double-baseline visits, with an intraclass correlation coefficient (ICC) of 0.986, 0.991, and 0.977, respectively, on the cohort of postoperative GBM patients. Furthermore, there was high agreement between manually and automatically measured tumor volumes, with ICC values of 0.915, 0.924, and 0.965 for preoperative FLAIR hyperintensity, postoperative FLAIR hyperintensity, and postoperative contrast-enhancing tumor volumes, respectively. Lastly, the ICCs for comparing manually and automatically derived longitudinal changes in tumor burden were 0.917, 0.966, and 0.850 for FLAIR hyperintensity volume, contrast-enhancing tumor volume, and RANO measures, respectively. CONCLUSIONS:Our automated algorithm demonstrates potential utility for evaluating tumor burden in complex posttreatment settings, although further validation in multicenter clinical trials will be needed prior to widespread implementation.
Project description:Abstract BACKGROUND Evaluating changes induced by immunotherapies on conventional brain MRI can be difficult because those treatments may produce an inflammatory response. To explore the contribution of quantitative MRI biomarkers, we examined advanced MRI findings in first diagnosis glioblastoma (GBM) patients treated with dendritic cell (DC) immunotherapy added to standard treatment. METHODS A retrospective analysis was performed on longitudinal MRIs obtained by 22 patients enrolled in the EUDRACT N° 2008-005035-15 trial. The following parameters were collected: tumor volume (TV), mean normalized tumoral CBV (rCBV), Mean normalized tumoral ADC (rADC), semi-automatic ADC mean (ADCmean), ADC mode (ADCmode), ADC kurtosis (ADCkurt), ADC skewness (ADCskew). RESULTS Ten patients were defined, based on PFS >12 months, to have received benefit from the treatment (responder patients). After the first four vaccinations rADC significantly decreased in responders only (1.34 ± 0.17 vs 1.23 ±0.23 p=0.028). A decrease in rADC mean value ? 0.13 and a change in ADCskew ? -0.14 were significant predictors of longer PFS (17.2 vs 10.2 p=0.04; 15.4 vs 9.3 m p=0.02) and OS (33 vs 19.9 p=0.003; 29 vs 12.4 p=0.002). During the follow-up 18 patients experienced progression and 7 pseudoprogression according to RANO criteria. A significant increase of rCBV (4.25 to 5.38, p=0.04), and a significant decrease in rADCmean (1.17 vs 1.01) (p=0.004) were only observed in patients with true tumor progression. A ?rCBV value ? 2.07 was able to distinguish the two conditions with a sensitivity of 100% and specificity of 60% (p=0.004). CONCLUSION An early decrease in rADC and limited reduction of ADCskew are related to longer survival in GBM patients treated with DC immunotherapy, added to standard care, suggesting the relevance of hypercellularity in the first phase of the treatment. Modification of rCBV can be useful in distinguishing progression and pseudoprogression
Project description:Isocitrate dehydrogenase 1 (IDH1)-wildtype glioblastoma (GBM) has found to be accompanied with increased expression of branched-chain amino acid trasaminase1 (BCAT1), which is associated with tumor growth and disease progression. In this retrospective study, quantitative RT-PCR, immunohistochemistry, and western blot were performed with GBM patient tissues to evaluate the BCAT1 level. Quantitative MR imaging parameters were evaluated from DSC perfusion imaging, DWI, contrast-enhanced T1WI and FLAIR imaging using a 3T MR scanner. The level of BCAT1 was significantly higher in IDH1-wildtype patients than in IDH1-mutant patients obtained in immunohistochemistry and western blot. The BCAT1 level was significantly correlated with the mean and 95th percentile-normalized CBV as well as the mean ADC based on FLAIR images. In addition, the 95th percentile-normalized CBV from CE T1WI also had a significant correlation with the BCAT1 level. Moreover, the median PFS in patients with BCAT1 expression <100 was longer than in those with BCAT1 expression ?100. Taken together, we found that a high BCAT1 level is correlated with high CBV and a low ADC value as well as the poor prognosis of BCAT1 expression is related to the aggressive nature of GBM.
Project description:BACKGROUND: RANO criteria, which evaluate both contrast enhancement and T2/FLAIR alterations, have been recently defined, but no prospective validation exists. We examined the radiological data of patients with recurrent glioblastoma treated with bevacizumab (BEV) or fotemustine (FTM) in the randomized phase II AVAREG-ML25739 (EUDRACT 2011-001363-46) trial. METHODS: All MRIs of the pts have been evaluated (BEV/FTM: 59/32) accordingly with RANO and Macdonald's criteria, both locally and centrally. RESULTS: 223 MRIs were analyzed. Concordance between RANO and Macdonald criteria was found in 96.3% of cases at local evaluation and in 95.5% at central revision. Concordances between local and central assessments were 72.5% with RANO criteria and 71.1% with Macdonald's criteria. At local evaluation, pts treated with BEV had a disease control rate (DCR = CR/PR/SD) of 0.75 (95%CI: 0.62-0.85) with RANO criteria, and 0.76 (95%CI: 0.63-0.86) with Macdonald criteria, vs 0.59 (95%CI: 0.41-0.76) and 0.63 (95%CI: 0.44-0.79) with FTM. Central evaluation showed a DCR of 0.80 (95%CI: 0.68-0.90) both with RANO and Macdonald criteria for pts treated with BEV vs 0.50 (95%CI: 0.32-0.68)with FTM. In the BEV arm, only 6.8% of patients showed an increase of T2/FLAIR without T1 contrast enhancement. CONCLUSIONS: After 4 years from RANO proposal, we showed that there is a good concordance of disease evaluation in recurrent glioblastoma pts treated either with BEV or FTM in academic centers.
Project description:ADC as a marker of tumor cellularity has been promising for evaluating the response to therapy in patients with glioblastoma but does not successfully stratify patients according to outcomes, especially in the upfront setting. Here we investigate whether restriction spectrum imaging, an advanced diffusion imaging model, performed after an operation but before radiation therapy, could improve risk stratification in patients with newly diagnosed glioblastoma relative to ADC.Pre-radiation therapy diffusion-weighted and structural imaging of 40 patients with glioblastoma were examined retrospectively. Restriction spectrum imaging and ADC-based hypercellularity volume fraction (restriction spectrum imaging-FLAIR volume fraction, restriction spectrum imaging-contrast-enhanced volume fraction, ADC-FLAIR volume fraction, ADC-contrast-enhanced volume fraction) and intensities (restriction spectrum imaging-FLAIR 90th percentile, restriction spectrum imaging-contrast-enhanced 90th percentile, ADC-FLAIR 10th percentile, ADC-contrast-enhanced 10th percentile) within the contrast-enhanced and FLAIR hyperintensity VOIs were calculated. The association of diffusion imaging metrics, contrast-enhanced volume, and FLAIR hyperintensity volume with progression-free survival and overall survival was evaluated by using Cox proportional hazards models.Among the diffusion metrics, restriction spectrum imaging-FLAIR volume fraction was the strongest prognostic metric of progression-free survival (P = .036) and overall survival (P = .007) in a multivariate Cox proportional hazards analysis, with higher values indicating earlier progression and shorter survival. Restriction spectrum imaging-FLAIR 90th percentile was also associated with overall survival (P = .043), with higher intensities, indicating shorter survival. None of the ADC metrics were associated with progression-free survival/overall survival. Contrast-enhanced volume exhibited a trend toward significance for overall survival (P = .063).Restriction spectrum imaging-derived cellularity in FLAIR hyperintensity regions may be a more robust prognostic marker than ADC and conventional imaging for early progression and poorer survival in patients with glioblastoma. However, future studies with larger samples are needed to explore its predictive ability.
Project description:The EphA3 receptor has recently emerged as a functional tumour-specific therapeutic target in glioblastoma (GBM). EphA3 is significantly elevated in recurrent disease, is most highly expressed on glioma stem cells (GSCs), and has a functional role in maintaining self-renewal and tumourigenesis. An unlabelled EphA3-targeting therapeutic antibody is currently under clinical assessment in recurrent GBM patients. In this study, we assessed the efficacy of EphA3 antibody drug conjugate (ADC) and radioimmunotherapy (RIT) approaches using orthotopic animal xenograft models. Brain uptake studies, using positron emission tomography/computed tomography (PET/CT) imaging, show EphA3 antibodies are effectively delivered across the blood-tumour barrier and accumulate at the tumour site with no observed normal brain reactivity. A robust anti-tumour response, with no toxicity, was observed using EphA3, ADC, and RIT approaches, leading to a significant increase in overall survival. Our current research provides evidence that GBM patients may benefit from pay-loaded EphA3 antibody therapies.
Project description:Although there have been a plethora of radiogenomics studies related to glioblastoma (GBM), most of them only used genomic information from tumor cells. In this study, we used radiogenomics profiling to identify MRI-associated immune cell markers in GBM, which was also correlated with prognosis. Expression levels of immune cell markers were correlated with quantitative MRI parameters in a total of 60 GBM patients. Fourteen immune cell markers (i.e., CD11b, CD68, CSF1R, CD163, CD33, CD123, CD83, CD63, CD49d and CD117 for myeloid cells, and CD4, CD3e, CD25 and CD8 for lymphoid cells) were selected for RNA-level analysis using quantitative RT-PCR. For MRI analysis, quantitative MRI parameters from FLAIR, contrast-enhanced (CE) T1WI, dynamic susceptibility contrast perfusion MRI and diffusion-weighted images were used. In addition, PFS associated with interesting mRNA data was performed by Kaplan-Meier survival analysis. CD163, which marks tumor associated microglia/macrophages (TAMs), showed the highest expression level in GBM patients. CD68 (TAMs), CSF1R (TAMs), CD33 (myeloid-derived suppressor cell) and CD4 (helper T cell, regulatory T cell) levels were highly positively correlated with nCBV values, while CD3e (helper T cell, cytotoxic T cell) and CD49d showed a significantly negative correlation with apparent diffusion coefficient (ADC) values. Moreover, regardless of any other molecular characteristics, CD49d was revealed as one independent factor for PFS of GBM patients by Cox proportional-hazards regression analysis (P?=?0.0002). CD49d expression level CD49d correlated with ADC can be considered as a candidate biomarker to predict progression of GBM patients.
Project description:Recent conflicting reports have found both brain tumor hypercellularity and necrosis in regions of restricted diffusion on MRI-derived apparent diffusion coefficient (ADC) images. This study precisely compares ADC and cell density voxel by voxel using postmortem human whole brain samples.Patients with meningioma were evaluated to determine a normative ADC distribution within benign fluid attenuated inversion recovery (FLAIR) T2/hyperintensity surrounding tumor. This distribution was used to calculate a minimum ADC threshold to define regions of ADC-FLAIR mismatch (AFMM), where restricted diffusion presented in conjunction with T2/FLAIR hyperintensity. Contrast-enhancing voxels were excluded from this analysis. AFMM maps were generated using imaging acquired prior to death in 7 patients with high-grade glioma who eventually donated their brains upon death. Histological samples were taken from numerous regions of abnormal FLAIR and AFMM. Each sample was computationally processed to determine cell density. Custom software was then used to downsample coregistered microscopic histology to the more coarse MRI resolution. A voxel-by-voxel evaluation comparing ADC and cellularity was then performed.An ADC threshold of 0.929 × 10(-3) mm(2)/s was calculated from meningioma-induced edema and was used to define AFMM. Regions of AFMM showed significantly greater cell density in 6 of 7 high-grade glioma cases compared with regions of hyperintense FLAIR alone (P < .0001). Two patients had small regions of diffusion-restricted necrosis that had significantly lower ADC than nearby hypercellularity.Regions of AFMM contain hypercellularity except for regions with extremely restricted diffusion, where necrosis is present.
Project description:AbstractBackgroundThis study aimed to assess the validity and pathophysiology of the T2/FLAIR-mismatch sign for noninvasive identification of isocitrate dehydrogenase (IDH)-mutant 1p/19q non-codeleted glioma.MethodsMagnetic resonance imaging scans from 408 consecutive patients with newly diagnosed glioma (113 lower-grade gliomas and 295 glioblastomas) were evaluated for the presence of T2/FLAIR-mismatch sign by 2 independent reviewers. Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were calculated to assess the performance of the T2/FLAIR-mismatch sign for identifying IDH-mutant 1p/19q non-codeleted tumors. An exploratory analysis of differences in contrast-enhancing tumor volumes, apparent diffusion coefficient (ADC) values, and relative cerebral blood volume (rCBV) values in IDH-mutant gliomas with versus without the presence of a T2/FLAIR-mismatch sign (as well as analysis of spatial differences within tumors with the presence of a T2/FLAIR-mismatch sign) was performed.ResultsThe T2/FLAIR-mismatch sign was present in 12 cases with lower-grade glioma (10.6%), all of them being IDH-mutant 1p/19q non-codeleted tumors (sensitivity = 10.9%, specificity = 100%, PPV = 100%, NPV = 3.0%, accuracy = 13.3%). There was a substantial interrater agreement to identify the T2/FLAIR-mismatch sign (Cohen’s kappa = 0.75 [95% CI, 0.57–0.93]). The T2/FLAIR-mismatch sign was not identified in any other molecular subgroup, including IDH-mutant glioblastoma cases (n = 5). IDH-mutant gliomas with a T2/FLAIR-mismatch sign showed significantly higher ADC (P < .0001) and lower rCBV values (P = .0123) as compared to IDH-mutant gliomas without a T2/FLAIR-mismatch sign. Moreover, in IDH-mutant gliomas with T2/FLAIR-mismatch sign the ADC values were significantly lower in the FLAIR-hyperintense rim as compared to the FLAIR-hypointense core of the tumor (P = .0005).ConclusionsThis study confirms the high specificity of the T2/FLAIR-mismatch sign for noninvasive identification of IDH-mutant 1p/19q non-codeleted gliomas; however, sensitivity is low and applicability is limited to lower-grade gliomas. Whether the higher ADC and lower rCBV values in IDH-mutant gliomas with a T2/FLAIR-mismatch sign (as compared to those without) translate into a measurable prognostic effect requires investigation in future studies. Moreover, spatial differences in ADC values between the core and rim of tumors with a T2/FLAIR-mismatch sign potentially reflect specific distinctions in tumor cellularity and microenvironment.
Project description:This dataset is based on multimodal MRI and FAP-specific PET/CT Imaging applied to 13 patients with histologically proven glioblastomas. Imaging Data was processed using Medical Imaging Interaction Toolkit (MITK) software. MRI images (contrast enhanced T1w, T2w/FLAIR, ADC, rCBV) were co-registrated with FAP-specific PET images. T2w/FLAIR hyperintensities and contrast enhancing lesions were segmented manually. Necrotic areas were segmented manually and subtracted from T2w/FLAIR hyperintensities and contrast enhancing lesions. Voxelwise ADC/rCBV and PET signal intensities in projection on T2w/FLAIR hyperintensities and contrast enhancing lesions were extracted using the pixel dumper function of the MITK software and stored as excel-files. The data presented in this article has been analysed and described in the article FAP-specific "PET signaling shows a moderately positive correlation with relative CBV and no correlation with ADC in 13 IDH wildtype Glioblastomas" published in the European Journal of Radiology.