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Integrated molecular and multiparametric MRI mapping of high-grade glioma identifies regional biologic signatures

Sampling restrictions have hindered the comprehensive study of invasive non-enhancing (NE) high-grade glioma (HGG) cell populations driving tumor progression. Here, we present an integrated multi-omic analysis of spatially matched molecular and multi-parametric magnetic resonance imaging (MRI) profiling across 313 multi-regional tumor biopsies, including 111 from the NE, across 68 HGG patients. Whole exome and RNA sequencing uncover unique genomic alterations to unresectable invasive NE tumor, including subclonal events, which inform genomic models predictive of geographic evolution. Infiltrative NE tumor is alternatively enriched with tumor cells exhibiting neuronal or glycolytic/plurimetabolic cellular states, two principal transcriptomic pathway-based glioma subtypes, which respectively demonstrate abundant private mutations or enrichment in immune cell signatures. These NE phenotypes are non-invasively identified through normalized K2 imaging signatures, which discern cell size heterogeneity on dynamic susceptibility contrast (DSC)-MRI. NE tumor populations predicted to display increased cellular proliferation by mean diffusivity (MD) MRI metrics are uniquely associated with EGFR amplification and CDKN2A homozygous deletion. The biophysical mapping of infiltrative HGG potentially enables the clinical recognition of tumor subpopulations with aggressive molecular signatures driving tumor progression, thereby informing precision medicine targeting.

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A cross-sectional study to test equivalence of low- versus intermediate-flip angle dynamic susceptibility contrast MRI measures of relative cerebral blood volume in patients with high-grade gliomas at 1.5 Tesla field strength.

1.5 Tesla (1.5T) remain a significant field strength for brain imaging worldwide. Recent computer simulations and clinical studies at 3T MRI have suggested that dynamic susceptibility contrast (DSC) MRI using a 30° flip angle ("low-FA") with model-based leakage correction and no gadolinium-based contrast agent (GBCA) preload provides equivalent relative cerebral blood volume (rCBV) measurements to the reference-standard acquisition using a single-dose GBCA preload with a 60° flip angle ("intermediate-FA") and model-based leakage correction. However, it remains unclear whether this holds true at 1.5T. The purpose of this study was to test this at 1.5T in human high-grade glioma (HGG) patients. This was a single-institution cross-sectional study of patients who had undergone 1.5T MRI for HGG. DSC-MRI consisted of gradient-echo echo-planar imaging (GRE-EPI) with a low-FA without preload (30°/P-); this then subsequently served as a preload for the standard intermediate-FA acquisition (60°/P+). Both normalized (nrCBV) and standardized relative cerebral blood volumes (srCBV) were calculated using model-based leakage correction (C+) with IBNeuro™ software. Whole-enhancing lesion mean and median nrCBV and srCBV from the low- and intermediate-FA methods were compared using the Pearson's, Spearman's and intraclass correlation coefficients (ICC). Twenty-three HGG patients composing a total of 31 scans were analyzed. The Pearson and Spearman correlations and ICCs between the 30°/P-/C+ and 60°/P+/C+ acquisitions demonstrated high correlations for both mean and median nrCBV and srCBV. Our study provides preliminary evidence that for HGG patients at 1.5T MRI, a low FA, no preload DSC-MRI acquisition can be an appealing alternative to the reference standard higher FA acquisition that utilizes a preload.

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Multiinstitutional Evaluation of the Liver Surface Nodularity Score on CT for Staging Liver Fibrosis and Predicting Liver-Related Events in Patients With Hepatitis C.

BACKGROUND. In single-institution multireader studies, the liver surface nodularity (LSN) score accurately detects advanced liver fibrosis and cirrhosis and predicts liver decompensation in patients with chronic liver disease (CLD) from hepatitis C virus (HCV). OBJECTIVE. The purpose of this study was to assess the diagnostic performance of the LSN score alone and in combination with the (FIB-4; fibrosis index based on four factors) to detect advanced fibrosis and cirrhosis and to predict future liver-related events in a multiinstitutional cohort of patients with CLD from HCV. METHODS. This retrospective study included 40 consecutive patients, from each of five academic medical centers, with CLD from HCV who underwent nontargeted liver biopsy within 6 months before or after abdominal CT. Clinical data were recorded in a secure web-based database. A single central reader measured LSN scores using software. Diagnostic performance for detecting liver fibrosis stage was determined. Multivariable models were constructed to predict baseline liver decompensation and future liver-related events. RESULTS. After exclusions, the study included 191 patients (67 women, 124 men; mean age, 54 years) with fibrosis stages of F0-F1 (n = 37), F2 (n = 44), F3 (n = 46), and F4 (n = 64). Mean LSN score increased with higher stages (F0-F1, 2.26 ± 0.44; F2, 2.35 ± 0.37; F3, 2.42 ± 0.38; F4, 3.19 ± 0.89; p < .001). The AUC of LSN score alone was 0.87 for detecting advanced fibrosis (≥ F3) and 0.89 for detecting cirrhosis (F4), increasing to 0.92 and 0.94, respectively, when combined with FIB-4 scores (both p = .005). Combined scores at optimal cutoff points yielded sensitivity of 75% and specificity of 82% for advanced fibrosis, and sensitivity of 84% and specificity of 85% for cirrhosis. In multivariable models, LSN score was the strongest predictor of baseline liver decompensation (odds ratio, 14.28 per 1-unit increase; p < .001) and future liver-related events (hazard ratio, 2.87 per 1-unit increase; p = .03). CONCLUSION. In a multiinstitutional cohort of patients with CLD from HCV, LSN score alone and in combination with FIB-4 score exhibited strong diagnostic performance in detecting advanced fibrosis and cirrhosis. LSN score also predicted future liver-related events. CLINICAL IMPACT. The LSN score warrants a role in clinical practice as a quantitative marker for detecting advanced liver fibrosis, compensated cirrhosis, and decompensated cirrhosis and for predicting future liver-related events in patients with CLD from HCV.

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Computed tomographic examination of the articular process joints of the cervical spine in warmblood horses: 86 cases (2015-2017).

To describe articular process joints (APJs) of the cervical spine in horses on the basis of CT and to determine whether abnormalities were associated with clinical signs. 86 client-owned warmblood horses. Horses that underwent CT of the cervical spine between January 2015 and January 2017 were eligible for study inclusion. Medical records were reviewed for age, body weight, breed, sex, history, clinical signs, and CT findings. Horses were divided into 3 case groups and 1 control group on the basis of clinical signs. 70 warmblood horses were cases, and 16 were controls. Abnormalities were more frequent from C5 through T1 and were severe in only horses from the case group. Narrowing of the intervertebral foramen was common in horses in the case group (85.7%), often owing to enlarged, misshaped articular processes, followed by degenerative changes, periarticular osteolysis, cyst-like lesions, and fragmentation. High articular process-to-vertebral body (C6) ratio (APBR) and high-grade narrowing of the intervertebral foramen and periarticular osteolysis were noted for horses with forelimb lameness or signs of cervical pain or stiffness. No association was identified between APBR and age or sex. An APBR > 1.5 was found in only horses in the case group, and 32.3% of APJs with APBRs > 1.5 did not have any degenerative changes and periarticular osteolysis. CT was useful to identify abnormalities of the APJs of the cervical spine. An association existed between CT findings and clinical signs. The APJs can be enlarged without concurrent degenerative changes.

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Can quantitative analysis of multi-parametric MRI independently predict failure of focal salvage HIFU therapy in men with radio-recurrent prostate cancer?

ObjectivesFocal salvage HIFU is a feasible therapeutic option in some men who have recurrence after primary radiotherapy for prostate cancer. We aimed to determine if multi-parametric quantitative parameters, in addition to clinical factors, might have a role in independently predicting focal salvage HIFU outcomes. MethodsA retrospective registry analysis included 150 consecutive men who underwent focal salvage HIFU (Sonablate500) (2006-2015); 89 had mpMRI available. Metastatic disease was excluded by nodal assessment on pelvic MRI, a radioisotope bone-scan and/or choline or FDG PET/CT scan. All men had mpMRI and either transperineal template prostate mapping biopsy or targeted and systematic TRUS-biopsy. mpMRI included T2‐weighted, diffusion‐weighted and dynamic contrast‐enhancement. Pre-HIFU quantitative mpMRI data was obtained using Horos DICOM Viewer v3.3.5 for general MRI parameters and IB DCE v2.0 plug-in. Progression-free survival (PFS) was defined by biochemical failure and/or positive localized or distant imaging results and/or positive biopsy and/or systemic therapy and/or metastases/prostate cancer‐specific death. Potential predictors of PFS were analyzed by univariable and multivariable Cox-regression. ResultsMedian age at focal salvage HIFU was 71 years (interquartile range [IQR] 65–74.5) and median PSA pre-focal salvage treatment was 5.8ng/ml (3.8-8). Median follow-up was 35 months (23-47) and median time to failure was 15 months (7.8–24.3). D-Amico low, intermediate and high-risk disease was present in 1% (1/89), 40% (36/89) and 43% (38/89) prior to focal salvage HIFU (16% missing data). 56% (50/89) failed by the composite outcome. A total of 22 factors were evaluated on univariable and 8 factors on multivariable analysis. The following quantitative parameters were included: Ktrans, Kep, Ve, Vp, IS, rTTP and TTP. On univariable analysis, PSA, prostate volume at time of radiotherapy failure and Ve (median) value were predictors for failure. Ve represents extracellular fraction of the whole tissue volume. On multivariable analysis, only Ve (median) value remained as an independent predictor. ConclusionsOne pharmacokinetic quantitative parameter based on DCE sequences seems to independently predict failure following focal salvage HIFU for radio-recurrent prostate cancer. This likely relates to the tumor microenvironment producing heat-sinks which counter the heating effect of HIFU. Further validation in larger datasets and evaluating mechanisms to reduce heat-sinks are required.

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Multisite Concordance of DSC-MRI Analysis for Brain Tumors: Results of a National Cancer Institute Quantitative Imaging Network Collaborative Project.

Standard assessment criteria for brain tumors that only include anatomic imaging continue to be insufficient. While numerous studies have demonstrated the value of DSC-MR imaging perfusion metrics for this purpose, they have not been incorporated due to a lack of confidence in the consistency of DSC-MR imaging metrics across sites and platforms. This study addresses this limitation with a comparison of multisite/multiplatform analyses of shared DSC-MR imaging datasets of patients with brain tumors. DSC-MR imaging data were collected after a preload and during a bolus injection of gadolinium contrast agent using a gradient recalled-echo-EPI sequence (TE/TR = 30/1200 ms; flip angle = 72°). Forty-nine low-grade (n = 13) and high-grade (n = 36) glioma datasets were uploaded to The Cancer Imaging Archive. Datasets included a predetermined arterial input function, enhancing tumor ROIs, and ROIs necessary to create normalized relative CBV and CBF maps. Seven sites computed 20 different perfusion metrics. Pair-wise agreement among sites was assessed with the Lin concordance correlation coefficient. Distinction of low- from high-grade tumors was evaluated with the Wilcoxon rank sum test followed by receiver operating characteristic analysis to identify the optimal thresholds based on sensitivity and specificity. For normalized relative CBV and normalized CBF, 93% and 94% of entries showed good or excellent cross-site agreement (0.8 ≤ Lin concordance correlation coefficient ≤ 1.0). All metrics could distinguish low- from high-grade tumors. Optimum thresholds were determined for pooled data (normalized relative CBV = 1.4, sensitivity/specificity = 90%:77%; normalized CBF = 1.58, sensitivity/specificity = 86%:77%). By means of DSC-MR imaging data obtained after a preload of contrast agent, substantial consistency resulted across sites for brain tumor perfusion metrics with a common threshold discoverable for distinguishing low- from high-grade tumors.

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Computer-aided detection of brain tumor invasion using multiparametric MRI.

To determine the potential of using a computer-aided detection method to intelligently distinguish peritumoral edema alone from peritumor edema consisting of tumor using a combination of high-resolution morphological and physiological magnetic resonance imaging (MRI) techniques available on most clinical MRI scanners. This retrospective study consisted of patients with two types of primary brain tumors: meningiomas (n = 7) and glioblastomas (n = 11). Meningiomas are typically benign and have a clear delineation of tumor and edema. Glioblastomas are known to invade outside the contrast-enhancing area. Four classifiers of differing designs were trained using morphological, diffusion-weighted, and perfusion-weighted features derived from MRI to discriminate tumor and edema, tested on edematous regions surrounding tumors, and assessed for their ability to detect nonenhancing tumor invasion. The four classifiers provided similar measures of accuracy when applied to the training and testing data. Each classifier was able to identify areas of nonenhancing tumor invasion supported with adjunct images or follow-up studies. The combination of features derived from morphological and physiological imaging techniques contains the information necessary for computer-aided detection of tumor invasion and allows for the identification of tumor invasion not previously visualized on morphological, diffusion-weighted, and perfusion-weighted images and maps. Further validation of this approach requires obtaining spatially coregistered tissue samples in a study with a larger sample size.

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