Washout Slope Research Articles

Automatic removal of large blood vasculature for objective assessment of brain tumors using quantitative dynamic contrast-enhanced magnetic resonance imaging.

The presence of a normal large blood vessel (LBV) in a tumor region can impact the evaluation of quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters and tumor classification. Hence, there is a need for automatic removal of LBVs from brain tissues including intratumoral regions for achieving an objective assessment of tumors. This retrospective study included 103 histopathologically confirmed brain tumor patients who underwent MRI, including DCE-MRI data acquisition. Quantitative DCE-MRI analysis was performed for computing various parameters such as wash-out slope (Slope-2), relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), blood plasma volume fraction (Vp), and volume transfer constant (Ktrans). An approach based on data-clustering algorithm, morphological operations, and quantitative DCE-MRI maps was proposed for the segmentation of normal LBVs in brain tissues, including the tumor region. Here, three widely used data-clustering algorithms were evaluated on two types of quantitative maps: (a) Slope-2, and (b) a new proposed combination of rCBV and Slope-2 maps. Fluid-attenuated inversion recovery-MRI hyperintense lesionswere also automatically segmented using deep learning-based architecture. The accuracy of LBV segmentation was qualitatively assessed blindly by two experienced observers, and Likert scoring was also obtained from each individual and compared using Cohen's Kappa test, and multiple statistical features from quantitative DCE-MRI parameters were obtained in the segmented tumor. t-test and receiver operating characteristic (ROC) curve analysis were performed for comparing the effect of removal of LBVs on parameters as well as on tumor grading. k-means clustering exhibited better accuracy and computational efficiency. Tumors, in particular high-grade gliomas (HGGs), showed a high contrast compared with normal tissues (relative % difference = 18.5%) on quantitative maps after the removal of LBVs. Statistical features (95th percentile values) of all parameters in the tumor region showed a statistically significant difference (p< 0.05) between with and without LBV maps. Similar results were obtained for the ROC curve analysis for differentiation between low-grade gliomas and HGGs. Moreover, after the removal of LBVs, the rCBV, rCBF, and Vp maps show better visualization of tumor regions.

Abstract TP25: Model-Free Dynamic Contrast-Enhanced MRI in Cerebral Small Vessel Disease: Test-Retest Reliability and Association With WMH Lesion Burden

Introduction: Dynamic contrast enhanced (DCE)-MRI has been used to study blood-brain barrier (BBB) disruption in cerebral small vessel disease (CSVD), but complex kinetic modeling of DCE MRI is sensitive to noise and is not robust in detecting subtle BBB impairments. In contrast, model-free DCE is simple and does not require arterial input function and complex computation. In this study, we aimed to evaluate the test-retest repeatability of model-free DCE and its association with white matter hyperintensity (WMH) burden. Methods: Patients with CSVD were recruited. DCE-MRI, FLAIR, and T1 MPRage scans were acquired. A subgroup of patients had two repeated DCE MRI scans with an average interval of 41 days. WMH segmentation was performed to obtain the relative volume of WMH (rVwmh). Ten subjects had DCE-MRI data in two sessions for test-retest repeatability analysis. DCE-MRI were acquired using a Siemens volumetric interpolated breath-hold examination (VIBE) gradient echo sequence with a temporal resolution of 49 seconds and an acquisition time of ~20 minutes. The wash-out slope (WOS), which indicates the rate of contrast agent leaving the tissue, was computed. Results: 64 patients (mean (SD) age = 68.6 (8.51), 37 females) with CSVD were studied. WOS demonstrated good test-retest repeatability for WM and GM with an intra-class correlation coefficient (ICC) of 0.626 and 0.671 in cerebrum WM and GM, respectively. WMH WOS has a significant negative correlation with rVwmh (r=-0.31; p&lt;0.02). Conclusions: A slow contrast wash-out (small WOS) is expected in the presence of BBB impairment. WMH burdens are associated with BBB impairments manifested by decreased WOS. WOS is computationally less intense and demonstrates good repeatability. It may offer an alternative to model-based DCE in evaluating BBB dysfunction in patients with CSVD.

Role of Dynamic Contrast-Enhanced MRI in Differentiation Between Malignant and Benign Cervical Lymph Nodes: A Case-Control Study

Background: Changes in signals and parameters of time-signal intensity curve (TIC) resulting from dynamic magnetic resonance imaging (MRI) have been considered for determining malignancy. However, the specific diagnostic criteria of TIC for detecting malignancy in various organs, such as lymph nodes, are not yet well-established. Objectives: This study aimed to evaluate the role of some TIC parameters in identifying malignant cervical lymph nodes. Patients and Methods: In this case-control study, patients with cervical lymphadenopathy were examined by dynamic contrast-enhanced MRI (DCE-MRI) before excisional biopsy. They were then divided into malignant and benign groups based on histopathology. Malignant patients were considered as the case group, while benign cases were considered as the control group. The TIC parameters included the signal intensity (SI) at 45 seconds, 90 seconds, 120 seconds, 5 minutes, and 10 minutes, as well as maximum signal intensity (SImax), the time at which the maximum signal intensity occurs (Tmax), the peak signal intensity (SI peak), and the time at which the peak signal intensity occurs (T peak). Additionally, the enhancement slope (ES), washout ratio (WR), and washout slope (WS) were evaluated at 5 and 10 minutes. Results: A total of 63 patients were enrolled in the study, including 31 (49.2%) patients with benign lymphadenopathies and 32 (50.8%) patients with malignant lymphadenopathies. Among the variables under study, significant differences were observed between the malignant (M) group and the benign (B) group in terms of the SI-5 min, SI-10 min, WR-5 min, WR-10 min, and WS-5 min (SI-5 min: 124.4 ± 145 (B) vs. 219.2 ± 93.8 (M), P = 0.003; SI-10 min: 109.9 ± 134.6 (B) vs. 188.9 ± 83.7 (M), P = 0.007; WR-5 min: 0.58 ± 0.38 (B) vs. 0.15 ± 0.13 (M), P &lt; 0.001; WR-10 min: 0.63 ± 0.36 (B) vs. 0.26 ± 0.17 (M), P &lt; 0.001; and WS-5 min: 0.93 ± 1.20 (B) vs. 1.40 ± 4.44 (M), P = 0.001). In the receiver operating characteristic (ROC) curve analysis, WS-5 min showed specificity of 29.1%, 75%, 90%, and 95% and sensitivity of 88.2%, 70.6%, 47.1%, and 47.1% at cutoff points of 0.1, 0.37, 0.57, and 0.66, respectively. Conclusion: The WR-5 min can be considered as a potential TIC index in DCE-MRI for the diagnosis of malignant cervical lymphadenopathies.

Benchtop proof of concept and comparison of iron- and magnesium-based bioresorbable flow diverters.

Bioresorbable flow diverters (BRFDs) could significantly improve the performance of next-generation flow diverter technology. In the current work, magnesium and iron alloy BRFDs were prototyped and compared in terms of porosity/pore density, radial strength, flow diversion functionality, and resorption kinetics to offer insights into selecting the best available bioresorbable metal candidate for the BRFD application. BRFDs were constructed with braided wires made from alloys of magnesium (MgBRFD) or iron (FeBRFD). Pore density and crush resistance force were measured using established methods. BRFDs were deployed in silicone aneurysm models attached to flow loops to investigate flow diversion functionality and resorption kinetics in a simulated physiological environment. The FeBRFD exhibited higher pore density (9.9 vs 4.3 pores/mm2) and crush resistance force (0.69 ± 0.05 vs 0.53 ± 0.05 N/cm, p = 0.0765, n = 3 per group) than the MgBRFD, although both crush resistances were within the range previously reported for FDA-approved flow diverters. The FeBRFD demonstrated greater flow diversion functionality than the MgBRFD, with significantly higher values of established flow diversion metrics (mean transit time 159.6 ± 11.9 vs 110.9 ± 1.6, p = 0.015; inverse washout slope 192.5 ± 9.0 vs 116.5 ± 1.5, p = 0.001; n = 3 per group; both metrics expressed as a percentage of the control condition). Last, the FeBRFD was able to maintain its braided structure for > 12 weeks, whereas the MgBRFD was almost completely resorbed after 5 weeks. The results of this study demonstrated the ability to manufacture BRFDs with magnesium and iron alloys. The data suggest that the iron alloy is the superior material candidate for the BRFD application due to its higher mechanical strength and lower resorption rate relative to the magnesium alloy.

Optimal length and temporal resolution of dynamic contrast-enhanced MR imaging for the differentiation between prostate cancer and normal peripheral zone tissue.

The value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in the detection of prostate cancer is controversial. There are currently insufficient peer reviewed published data or expert consensus to support routine adoption of DCE-MRI for clinical use. Thus, the objective of this study was to explore the optimal temporal resolution and measurement length for DCE-MRI to differentiate cancerous from normal prostate tissue of the peripheral zone of the prostate by non-parametric MRI analysis and to compare with a quantitative MRI analysis. Predictors of interest were onset time, relative signal intensity (RSI), wash-in slope, peak enhancement, wash-out and wash-out slope determined from non-parametric characterisation of DCE-MRI intensity-time profiles. The discriminatory power was estimated from C-statistics based on cross validation. We analyzed 54 patients with 97 prostate tissue specimens (47 prostate cancer, 50 normal prostate tissue) of the peripheral zone, mean age 63.8 years, mean prostate-specific antigen 18.9 ng/mL and mean of 10.5 days between MRI and total prostatectomy. When comparing prostate cancer tissue with normal prostate tissue, median RSI was 422% vs 330%, and wash-in slope 0.870 vs 0.539. The peak enhancement of 67 vs 42 was higher with prostate cancer tissue, while wash-out (-30% vs -23%) and wash-out slope (-0.037 vs -0.029) were lower, and the onset time (32 seconds) was comparable. The optimal C-statistics was 0.743 for temporal resolution of 8.0 seconds and measurement length of 2.5 minutes compared with 0.656 derived from a quantitative MRI analysis. This study provides evidence that the use of a non-parametric approach instead of a more established parametric approach resulted in greater precision to differentiate cancerous from normal prostate tissue of the peripheral zone of the prostate.

Distinguishing Brain Metastasis Progression From Radiation Effects After Stereotactic Radiosurgery Using Longitudinal GRASP Dynamic Contrast-Enhanced MRI.

Differentiating brain metastasis progression from radiation effects or radiation necrosis (RN) remains challenging. Golden-angle radial sparse parallel (GRASP) dynamic contrast-enhanced MRI provides high spatial and temporal resolution to analyze tissue enhancement, which may differ between tumor progression (TP) and RN. To investigate the utility of longitudinal GRASP MRI in distinguishing TP from RN after gamma knife stereotactic radiosurgery (SRS). We retrospectively evaluated 48 patients with brain metastasis managed with SRS at our institution from 2013 to 2020 who had GRASP MRI before and at least once after SRS. TP (n = 16) was pathologically confirmed. RN (n = 16) was diagnosed on either resected tissue without evidence of tumor or on lesion resolution on follow-up. As a reference, we included a separate group of patients with non-small-cell lung cancer that showed favorable response with tumor control and without RN on subsequent imaging (n = 16). Mean contrast washin and washout slopes normalized to the superior sagittal sinus were compared between groups. Receiver operating characteristic analysis was performed to determine diagnostic performance. After SRS, progression showed a significantly steeper washin slope than RN on all 3 follow-up scans (scan 1: 0.29 ± 0.16 vs 0.18 ± 0.08, P = .021; scan 2: 0.35 ± 0.19 vs 0.18 ± 0.09, P = .004; scan 3: 0.32 ± 0.12 vs 0.17 ± 0.07, P = .002). No significant differences were found in the post-SRS washout slope. Post-SRS washin slope differentiated progression and RN with an area under the curve (AUC) of 0.74, a sensitivity of 75%, and a specificity of 69% on scan 1; an AUC of 0.85, a sensitivity of 92%, and a specificity of 69% on scan 2; and an AUC of 0.87, a sensitivity of 63%, and a specificity of 100% on scan 3. Longitudinal GRASP MRI may help to differentiate metastasis progression from RN.

Abstract 5980: Identification of pre-treatment tumor habitats for the prediction of neoadjuvant therapy response in triple negative breast cancer

Abstract Introduction: Triple negative breast cancer (TNBC) patients exhibit varied levels of response to neoadjuvant chemotherapy (NAC), with only 27-51% of patients achieving pathological complete response (pCR). This diverse response can be attributed in-part to heterogeneity of the tumor microenvironment, affecting therapeutic delivery and efficacy. Multiparametric magnetic resonance imaging (MRI) can be used to spatially resolve intratumoral heterogeneity into distinct tumor subregions, or habitats. We investigated whether MRI-derived tumor habitats identified prior to initiation of NAC were predictive of pathological response in TNBC patients. Methods: Women with stage II/III TNBC who received a pre-treatment (baseline) breast MRI and NAC at our institution (2012-2019) were retrospectively identified. Pathological response was determined at surgery, with pCR defined as no residual tumor within the breast or lymph nodes. Both diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI data were collected prior to initiation of NAC. The apparent diffusion coefficient (a measure of cell density) was calculated for each voxel from DW-MRI. Signal enhancement ratio, percent enhancement, and wash-out slope were calculated for each voxel from DCE-MRI, providing measures of vascularity. Hierarchical clustering of voxel data was used to identify tumor habitats, with each subregion labeled in terms of “high” or “low” vascularity and cellularity based on mean parameter values for the subregion. Tumor composition was quantified as percent tumor volume comprised by each habitat. Differences between pCR and non-pCR patients were assessed using Wilcoxon rank sum test, with p&amp;lt;0.05 considered significant. Results: 46 women with TNBC were retrospectively identified (median age: 48, range 31-77 yrs), of which 14 (30%) achieved pCR. No significant differences between pCR and non-pCR patients were observed in baseline tumor volume or longest diameter (p&amp;gt;0.05). Clustering analysis yielded four tumor habitats: low-vascularity low-cellularity (LV-LC), low-vascularity high-cellularity (LV-HC), high-vascularity low-cellularity (HV-LC), and high-vascularity high-cellularity (HV-HC). Patients who achieved pCR had significantly higher fraction of the HV-HC habitat at baseline (p=0.02). No significant differences were observed for other habitats. Discussion &amp; Conclusion: Our findings suggest multiparametric MRI can identify physiologically-distinct tumor habitats prior to NAC, which are predictive of response. A higher fraction of HV-HC habitat was associated with pCR, potentially suggestive of increased therapeutic delivery/sensitivity. Clinical translation of this approach would enable more specific characterizations of tumor heterogeneity and prediction of response, which could aid in personalizing regimens for optimal outcomes. Citation Format: Anum S. Kazerouni, Laura C. Kennedy, Shaveta Vinayak, Suzanne Dintzis, Habib Rahbar, Savannah C. Partridge. Identification of pre-treatment tumor habitats for the prediction of neoadjuvant therapy response in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5980.

Intracranial Pressure and Cerebral Hemodynamic Monitoring After Cardiac Arrest in Pediatric Pigs Using Contrast Ultrasound-Derived Parameters.

We explore the correlation of contrast-enhanced ultrasound (CEUS) parameters to intracranial pressure (ICP) in a porcine experimental model of pediatric cardiac arrest. Eleven pediatric pigs underwent electrically induced cardiac arrest followed by cardiopulmonary resuscitation. ICP was measured using intracranial bolt monitor and CEUS was monitored through a cranial window. Various CEUS parameters were monitored at baseline, immediately post return of spontaneous circulation (ROSC), 1 hour-post ROSC, and 3 hours post-ROSC. There was significant ICP correlation with wash-out slope assessed by CEUS time intensity curve analysis at immediate post-ROSC. At 3 hours post-ROSC there was also significant negative correlation between ICP and peak enhancement which may be due to the evolution of anoxic injury. The use of CEUS in assessing disruption of cerebral hemodynamics and ICP post cardiac arrest will need future validation and comparison to other imaging modalities. The correlation between CEUS parameters and ICP may be due to the alterations in cerebral autoregulation that result from anoxic brain injury.

Abstract 2804: Impact of deformable registration methods for prediction of treatment response to neo-adjuvant chemotherapy in breast cancer

Abstract Purpose: This study aimed to evaluate the effect of the registration accuracy of several deformable registration methods on the predictive value of radiomic features to model recurrence-free survival (RFS) in patients undergoing neoadjuvant chemotherapy (NAC) for breast cancer. Methods: From the I-SPY 1 cohort, 130 patients had clinical data and imaging data from the first two visits available, including 38 events (death or recurrence). We computed voxel-wise kinetic maps (peak enhancement, wash-in slope, wash-out slope, and signal enhancement ratio) from both pre-treatment and early-treatment MR images. For each of six different deformable registration methods (ANTs, DRAMMS, ART, NiftyReg, NMI-FFD, and SSD-FFD), we calculated the transformation field and used it to warp the kinetic maps obtained from early treatment MR images. Using these, for each kinetic feature, for each registration method, the parametric response map (PRM) at each voxel computed the difference between the warped kinetic feature and the kinetic feature from the pre-treatment image. We extracted 104 radiomic texture features from each PRM kinetic map, using the CAPTK toolkit, applied principal component (PC) analysis to the 104-dimensional feature vector, and retained the first four PCs for modeling (one covariate for every 10 events). We modeled RFS via Cox proportional hazards, comparing eight models: 1) baseline covariates of age, race, and hormone receptor status (model F1); 2) the covariates in model F1 plus functional tumor volume at the early-treatment visit (FTV2) (model F2); 3-8) the covariates in F2 with the addition of the radiomic feature PCs derived from each registration method. We evaluated model predictive performance using the C-statistic, and model fit via Kaplan-Meier plots and the log-rank test. Results: The baseline model (model F1) provided a C-statistic of 0.54, and model F2 gave 0.66. Among the automated registration methods, the F2+ANTs model had the highest performance with a C-statistic of 0.72. F2+DRAMMS gave 0.70, followed by F2+NiftyReg (0.68), F2+NMI-FFD (0.67), and F2+SSD-FFD (0.67). F2+ART had the lowest performance with a C-statistic of 0.66. The Kaplan-Meier curve for model F2 (baseline + FTV2) gave p = 0.0013 for separation between patients above and below median hazard as compared to the model F1 (p = 0.31). Including FTV2 and radiomic features, all models yielded p &amp;lt; 0.001 except the F2+ART model. Conclusion: The radiomic features of PRM maps derived from warping the DCE-MRI kinetic maps using the ANTs registration method significantly improved early prediction of survival during NAC as compared to other registration methods. Citation Format: Snekha Thakran, Eric Cohen, Nariman Jahani, Susan P. Weinstein, Lauren Pantalone, Nola Hylton, David Newitt, Christos Davatzikos, Despina Kontos. Impact of deformable registration methods for prediction of treatment response to neo-adjuvant chemotherapy in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2804.

Dynamic Contrast-Enhanced MRI of Prostate Lesions of Simultaneous [68Ga]Ga-PSMA-11 PET/MRI: Comparison between Intraprostatic Lesions and Correlation between Perfusion Parameters.

Simple SummaryDynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is an important method to analyze the perfusion model of tumors, allowing noninvasive quantification of microvascular structure and function. Furthermore, simultaneous [68Ga]Ga-prostate-specific membrane antigen (PSMA)-11 positron emission tomography (PET)/MRI is currently the most advantageous way for assessing prostate cancer staging. Therefore, combining these two examinations helps to diagnose the lesions more comprehensively. Our study analyzes perfusion parameters between intraprostatic lesions and the correlation between perfusion parameters and [68Ga]Ga-PSMA-11 PET. This study highlights the significant effect of PSMA uptake on perfusion parameters.We aimed to retrospectively compare the perfusion parameters measured from dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) of prostate benign lesions and malignant lesions to determine the relationship between perfusion parameters. DCE-MRI was performed in patients with PCa who underwent simultaneous [68Ga]Ga-prostate-specific membrane antigen (PSMA)-11 positron emission tomography (PET)/MRI. Six perfusion parameters (arrival time (AT), time to peak (TTP), wash-in slope (W-in), wash-out slope (W-out), peak enhancement intensity (PEI), and initial area under the 60-s curve (iAUC)), and a semi-quantitative parameter, standardized uptake values maximum (SUVmax) were calculated by placing regions of interest in the largest area of the lesions. The DCE-MRI parameters between prostate benign and malignant lesions were compared. The DCE-MRI parameters in both the benign and malignant lesions subgroup with SUVmax ≤ 3.0 and SUVmax > 3.0 were compared. The correlation of DCE-MRI parameters was investigated. Malignant lesions demonstrated significantly shorter TTP and higher SUVmax than did benign lesions. In the benign and malignant lesions subgroup, perfusion parameters of lesions with SUVmax ≤ 3.0 show no significant difference to those with SUVmax > 3.0. DCE-MRI perfusion parameters show a close correlation with each other. DCE-MRI parameters reflect the perfusion characteristics of intraprostatic lesions with malignant lesions, demonstrating significantly shorter TTP. There is a moderate to strong correlation between DCE-MRI parameters. Semi-quantitative analysis reflects that malignant lesions show a significantly higher SUVmax than benign lesions.

Assessing the Activity of Multidrug Resistance-Associated Protein 1 at the Lung Epithelial Barrier.

Multidrug resistance-associated protein 1 (adenosine triphosphate-binding cassette subfamily C member 1 [ABCC1]) is abundantly expressed at the lung epithelial barrier, where it may influence the pulmonary disposition of inhaled drugs and contribute to variability in therapeutic response. The aim of this study was to assess the impact of ABCC1 on the pulmonary disposition of 6-bromo-7-11C-methylpurine (11C-BMP), a prodrug radiotracer that is intracellularly conjugated with glutathione to form the ABCC1 substrate S-(6-(7-11C-methylpurinyl))glutathione (11C-MPG). Methods: Groups of Abcc1(-/-) rats, wild-type rats pretreated with the ABCC1 inhibitor MK571, and wild-type control rats underwent dynamic PET scans after administration of 11C-BMP intravenously or by intratracheal aerosolization. In vitro transport experiments were performed with unlabeled BMP on the human distal lung epithelial cell line NCI-H441. Results: The pulmonary kinetics of radioactivity significantly differed between wild-type and Abcc1(-/-) rats, but differences were more pronounced after intratracheal than after intravenous administration. After intravenous administration, lung exposure (area under the lung time-activity curve from 0 to 80 min after radiotracer administration [AUClung]) was 77% higher and the elimination slope of radioactivity washout from the lungs (kE,lung) was 70% lower in Abcc1(-/-) rats, whereas after intratracheal administration, AUClung was 352% higher and kE,lung was 86% lower in Abcc1(-/-) rats. Pretreatment with MK571 decreased kE,lung by 20% after intratracheal radiotracer administration. Intracellular accumulation of MPG in NCI-H441 cells was significantly higher and extracellular efflux was lower in the presence than in the absence of MK571. Conclusion: PET with pulmonary administered 11C-BMP can measure ABCC1 activity at the lung epithelial barrier and may be applicable in humans to assess the effects of disease, genetic polymorphisms, or concomitant drug intake on pulmonary ABCC1 activity.

Textural radiomic features and time-intensity curve data analysis by dynamic contrast-enhanced MRI for early prediction of breast cancer therapy response: preliminary data

BackgroundTo investigate the potential of semiquantitative time-intensity curve parameters compared to textural radiomic features on arterial phase images by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for early prediction of breast cancer neoadjuvant therapy response.MethodsA retrospective study of 45 patients subjected to DCE-MRI by public datasets containing examination performed prior to the start of treatment and after the treatment first cycle (‘QIN Breast DCE-MRI’ and ‘QIN-Breast’) was performed. In total, 11 semiquantitative parameters and 50 texture features were extracted. Non-parametric test, receiver operating characteristic analysis with area under the curve (ROC-AUC), Spearman correlation coefficient, and Kruskal-Wallis test with Bonferroni correction were applied.ResultsFifteen patients with pathological complete response (pCR) and 30 patients with non-pCR were analysed. Significant differences in median values between pCR patients and non-pCR patients were found for entropy, long-run emphasis, and busyness among the textural features, for maximum signal difference, washout slope, washin slope, and standardised index of shape among the dynamic semiquantitative parameters. The standardised index of shape had the best results with a ROC-AUC of 0.93 to differentiate pCR versus non-pCR patients.ConclusionsThe standardised index of shape could become a clinical tool to differentiate, in the early stages of treatment, responding to non-responding patients.

Savitzky-Golay filter based contrast-enhanced ultrasound quantification in hepatic tumors: Methodology and its correlation with tumor angiogenesis.

Savitzky-Golay filter is a digital filter used in data smoothing, we introduced a contrast-enhanced ultrasound (CEUS) quantification software based on the filter (SGCQ). To explore the methodology of analyzing hepatic tumors hemodynamics applying SGCQ software and the correlation between SGCQ parameters and hepatocellular carcinoma (HCC) angiogenesis. Nighty-seven right-lobe located hepatic mass cases (15 females and 82 males, mean age 58±10y, mean lesion size: 39.9±11.6 mm) underwent CEUS scan preoperatively and had a final diagnosis of HCC (n = 52) or colorectal cancer metastatic liver tumors (MLT, n = 45) were included. CEUS was carried out using a 1-5 MHz convex probe. The CEUS clips were recorded and analyzed off-line to obtain the parameters. The parameters were analyzed by 3 observers separately to investigate inter-observer variability. Parameters were compared between tumor and adjacent liver and between different tumors. Immunohistochemistry was used to evaluate the microvessel density (MVD) of HCC, and the correlation between the parameters and MVD was analyzed. Intraclass correlation coefficient (ICC) of all parameters were greater than 0.75 except wash-in slope (a3) and time to peak (TTP) of adjacent liver. The parameters of a3, wash-out slope (a2), perfusion time (PT) and area under the curve (AUC) were significantly different between HCC and liver. The a2, a3, AUC, PT and enhanced intensity (EI) were significantly different between MLT and liver. AUC, a2, a3, da1 and dPI were significantly different between HCC and MLT. AUC, a2 and EI correlated with MVD. SGCQ software quantification have good consistency among three observers, the parameters of SGCQ can display the hemodynamics of HCC and MLT and the difference between them. AUC and EI can serve as useful biomarkers in tumor angiogenesis evaluation.

Imaging P-Glycoprotein Induction at the Blood-Brain Barrier of a β-Amyloidosis Mouse Model with 11C-Metoclopramide PET.

P-glycoprotein (ABC subfamily B member 1, ABCB1) plays an important role at the blood-brain barrier (BBB) in promoting clearance of neurotoxic β-amyloid (Aβ) peptides from the brain into the blood. ABCB1 expression and activity were found to be decreased in the brains of Alzheimer disease patients. Treatment with drugs that induce cerebral ABCB1 activity may be a promising approach to delay the build-up of Aβ deposits in the brain by enhancing clearance of Aβ peptides from the brain. The aim of this study was to investigate whether PET with the weak ABCB1 substrate radiotracer 11C-metoclopramide can measure ABCB1 induction at the BBB in a β-amyloidosis mouse model (APP/PS1-21 mice) and in wild-type mice. Methods: Groups of wild-type and APP/PS1-21 mice aged 50 or 170 d underwent 11C-metoclopramide baseline PET scans or scans after intraperitoneal treatment with the rodent pregnane X receptor activator 5-pregnen-3β-ol-20-one-16α-carbonitrile (PCN, 25 mg/kg) or its vehicle over 7 d. At the end of the PET scans, brains were harvested for immunohistochemical analysis of ABCB1 and Aβ levels. In separate groups of mice, radiolabeled metabolites of 11C-metoclopramide were determined in plasma and brain at 15 min after radiotracer injection. As an outcome parameter of cerebral ABCB1 activity, the elimination slope of radioactivity washout from the brain (kE,brain) was calculated. Results: PCN treatment resulted in an increased clearance of radioactivity from the brain as reflected by significant increases in kE,brain (from +26% to +54% relative to baseline). Immunohistochemical analysis confirmed ABCB1 induction in the brains of PCN-treated APP/PS1-21 mice with a concomitant decrease in Aβ levels. There was a significant positive correlation between kE,brain and ABCB1 levels in the brain. In wild-type mice, a significant age-related decrease in kE,brain was found. Metabolite analysis showed that most radioactivity in the brain comprised unmetabolized 11C-metoclopramide in all animal groups. Conclusion:11C-metoclopramide can measure ABCB1 induction in the mouse brain without the need to consider an arterial input function and may find potential application in Alzheimer disease patients to noninvasively evaluate strategies to enhance the clearance properties of the BBB.

Measurement of cerebral ABCC1 transport activity in wild-type and APP/PS1-21 mice with positron emission tomography

Previous data suggest a possible link between multidrug resistance-associated protein 1 (ABCC1) and brain clearance of beta-amyloid (Aβ). We used PET with 6-bromo-7-[11C]methylpurine ([11C]BMP) to measure cerebral ABCC1 transport activity in a beta-amyloidosis mouse model (APP/PS1-21) and in wild-type mice aged 50 and 170 days, without and with pretreatment with the ABCC1 inhibitor MK571. One hundred seventy days-old-animals additionally underwent [11C]PiB PET scans to measure Aβ load. While baseline [11C]BMP PET scans detected no differences in the elimination slope of radioactivity washout from the brain (kelim) between APP/PS1-21 and wild-type mice of both age groups, PET scans after MK571 pretreatment revealed significantly higher kelim values in APP/PS1-21 mice than in wild-type mice aged 170 days, suggesting increased ABCC1 activity. The observed increase in kelim occurred across all investigated brain regions and was independent of the presence of Aβ plaques measured with [11C]PiB. Western blot analysis revealed a trend towards increased whole brain ABCC1 levels in 170 days-old-APP/PS1-21 mice versus wild-type mice and a significant positive correlation between ABCC1 levels and kelim. Our data point to an upregulation of ABCC1 in APP/PS1-21 mice, which may be related to an induction of ABCC1 in astrocytes as a protective mechanism against oxidative stress.

Impaired Post‐Occlusive Reoxygenation and Reperfusion in the Lower Legs of PAD Patients

Peripheral arterial disease (PAD) is a systemic atherosclerotic vascular disease that leads to demand ischemia and impaired mitochondrial function in the lower legs. Identifying the extent of non‐exercise related convective and diffusive oxygen transport impairments is important in furthering our understanding of microvascular impairments in this population.PurposeThe aim of this study was to determine the extent of reperfusion and reoxygenation impairments in the medial gastrocnemius (MG) and soleus (SOL) muscles of PAD patients.MethodsA novel functional MRI (fMRI) sequence was employed to simultaneously assess tissue perfusion, T2* relaxation time (used as an index of tissue oxygenation), and venous oxygen saturation (SvO2) in 3 patients with symptomatic PAD and 3 healthy age‐matched controls. Collecting these three parameters in a single scan was achieved by interleaving a gradient‐recalled‐echo (GRE) sequence into the post‐labeling‐delay of a pulsed‐arterial‐spin‐labeling sequence (total acquisition time of about 3.2 seconds). FMRI data were continuously collected during a reactive hyperemia protocol that consisted of a 2‐minute baseline, a 5‐minute period of occlusion, and a 5‐minute period of reactive hyperemia. Occlusion pressures ranged between 185 mmHg and 200 mmHg as tolerated by the subjects. Complete occlusion was verified in all subjects. Region of interest analyses were performed on the MG and SOL muscles of each subject. Perfusion and T2* were first converted to a delta score (AU), and then analyzed for peak responses (relative to baseline), time‐to‐peak (TTP, relative to end‐occlusion), and the slope of recovery. SvO2, expressed as a percentage of oxygen (%), responds in a biphasic pattern to reactive hyperemia. Specifically, SvO2 initially decreases (termed “washout”) upon cuff release, followed by a recovery that often surpasses baseline values. Accordingly, the peaks and slopes of washout and recovery are reported for SvO2. All variables were compared between groups using independent samples t‐tests.ResultsResults indicated that MG T2* TTP was longer (+40.5±11.1 seconds, t=−3.6, P=0.02), SOL peak perfusion was attenuated (−98.9±29.5 AU, t=3.3, P=0.02), and the slope of SvO2 washout was less steep in PAD patients compared to controls (−1.3±0.3, t=3.4, P=0.02). PAD patients also tended to exhibit a longer MG T2* recovery slope (0.07±0.02, t=2.6, P=0.057), and lower MG peak perfusion (−26.0±9.8 AU, t=2.6, P=0.057) compared to controls.ConclusionsThese data suggest that reperfusion and oxygenation responses to post‐occlusive reactive hyperemia are blunted and delayed in lower legs of PAD patients. More importantly, this highlights the severity of microvascular dysfunction in this population.Support or Funding InformationThis research was supported NIH P01 HL134609 (PI‐Sinoway).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging as a Diagnostic Tool in the Assessment of Tumour Angiogenesis in Urinary Bladder Cancer

PurposeThe aim of study is to assess the role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and correlation with tumour angiogenesis in evaluation of urinary bladder cancer. Material and MethodsThe study included 81 patients with recent presumed diagnosis of bladder tumour or who came for follow up after management of histopathologically proven bladder cancer. All had DCE-MRI with time–signal intensity curve. The radiologic results then correlated with the histopathologic results using both haematoxylin and eosin stain and immuno-histochemical staining for localization and evaluation of CD34 immunoreactivity as a detector for the microvessel density (MVD) and tumour angiogenesis. ResultsSeventy-one cases were pathologically proven to be malignant: 41 cases (58%) showed type III time–signal intensity curve (descending); 22 cases (31%) showed type II (plateau); and 8 cases (11%) showed type I (ascending) curve. The sensitivity of DCE-MRI in stage T1 bladder tumour was 80%; in stage T2, it was (90.9%); and in stage T3, it was (96.9%). Overall accuracy of DCE-MRI in tumour staging was 89.5% and P = .001 (significant). Values more than the cutoff value = 76.13 MVD are cystitis with sensitivity (90%), specificity (91%), and P value is .001, which is statistically highly significant. ConclusionThere is a strong positive association between DCE-MRI (staging and washout slope of the time–signal intensity curve) with histopathologic grade, tumour stage, and MVD in bladder cancer. So, DCE-MRI can be used as reliable technique in preoperative predictions of tumour behavior and affect the planning of antiangiogenetic therapy.

Differentiation of spinal metastases originated from lung and other cancers using radiomics and deep learning based on DCE-MRI

PurposeTo differentiate metastatic lesions in the spine originated from primary lung cancer and other cancers using radiomics and deep learning, compared to traditional hot-spot ROI analysis. MethodsIn a retrospective review of clinical spinal MRI database with a dynamic contrast enhanced (DCE) sequence, a total of 61 patients without prior cancer diagnosis and later confirmed to have metastases (30 lung; 31 non-lung cancers) were identified. For hot-spot analysis, a manual ROI was placed to calculate three heuristic parameters from the wash-in, maximum, and wash-out phases in the DCE kinetics. For each case, the 3D tumor mask was generated by using the normalized-cut algorithm. Radiomics analysis was performed to extract histogram and texture features from three DCE parametric maps. Deep learning was performed using these maps as inputs into a conventional convolutional neural network (CNN), as well as using all 12 sets of DCE images into a convolutional long short term memory (CLSTM) network. ResultsFor hot-spot ROI analysis, mean wash-out slope was 0.25 ± 10% for lung metastases and −9.8 ± 12.9% for other tumors. CHAID classification using a wash-out slope of −6.6% followed by wash-in enhancement ratio of 98% achieved a diagnostic accuracy of 0.79. Radiomics analysis using features representing tumor heterogeneity only reached the highest accuracy of 0.71. Classification using CNN achieved a mean accuracy of 0.71 ± 0.043, whereas a CLSTM improved accuracy to 0.81 ± 0.034. ConclusionsDCE-MRI machine-learning analysis methods have potential to predict lung cancer metastases in the spine, which may be used to guide subsequent workup for confirmed diagnosis.

Assessment of liver cirrhosis for patients with Child's A classification before hepatectomy using dynamic contrast-enhanced MRI

To determine the feasibility of semi-quantitative haemodynamic parameters derived from dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) to assess liver fibrosis. Seventy-five patients with Child's A classification (males/females=24/51; average age, 58 years; range, 30-80 years) received DCE-MRI 3 days prior to hepatectomy. Semi-quantitative haemodynamic parameters, including the wash-in slope, wash-out slope, and time-to-peak, were calculated from DCE-MRI data. Liver fibrosis of the resected non-tumour liver was graded pathologically from F0 (no fibrosis) to F6 (cirrhosis) in the regions corresponding to those assessed by DCE-MRI. The wash-out slope showed higher interobserver and intra-observer reliabilities than the wash-in slope and time-to-peak. There was a significant positive correlation between the wash-out slope and pathological grade of fibrosis (Spearman's correlation coefficient: r=0.5331, p<0.0001). The area under the receiver operating characteristic curve was 0.8066 when using the wash-out slope to differentiate cirrhosis (grade F6) from non-cirrhosis (grades F0-5). Using the cut-off point that maximised specificity, the sensitivity was 62.07%, specificity was 91.30%, positive predictive value was 81.81%, negative predictive value was 79.25%, and accuracy was 80%. The wash-out slope derived from DCE-MRI might be potentially useful in assessing liver cirrhosis in patients with Child's A classification before hepatectomy.

Ventilation distribution as a contributor to the functional exercise capacity in patients with systemic sclerosis-associated interstitial lung disease without pulmonary hypertension.

Phenotypic differences have been described between patients with systemic sclerosis (SSc)-associated interstitial lung disease (ILD) and SSc-associated pulmonary hypertension, including performance differences in the 6-min walk test (6MWT). Moreover, the correlations between the 6MWT and traditional pulmonary function tests (PFTs) are weak, indicating the need to search for new parameters that explain exercise performance. Thus, our objective was to evaluate the impact of ventilation distribution heterogeneity assessed by the nitrogen single-breath washout (N2SBW) test and peripheral muscle dysfunction on the exercise capacity in patients with SSc-ILD and limited involvement of the pulmonary parenchyma. In this cross-sectional study, 20 women with SSc-ILD and 20 matched controls underwent PFTs (including spirometry, diffusing capacity for carbon monoxide (DLco), and the N2SBW test) and performed the 6MWT and knee isometric dynamometry. The 6-min walking distance (6MWD, % predicted) was strongly correlated with the phase III slope of the single-breath nitrogen washout (phase III slopeN2SBW) (r=−0.753, P<0.0001) and reasonably correlated with the forced vital capacity (FVC) (r=0.466, P=0.008) and DLco (r=0.398, P=0.011). The peripheral oxygen saturation (SpO2) during exercise was not significantly correlated with any of the pulmonary or muscle function parameters. The phase III slopeN2SBW was the only predictive variable for the 6MWD, whereas quadriceps strength and FVC/DLco were predictive variables for SpO2. Ventilation distribution heterogeneity is one factor that contributes to a lower 6MWD in SSc-ILD patients. In addition, muscle dysfunction and abnormal lung diffusion at least partly explain the decreased SpO2 of these patients.