Ktrans Values Research Articles

Omega-3 fatty acids are associated with blood-brain barrier integrity in a healthy aging population.

In aging populations, omega‐3 polyunsaturated fatty acids (PUFAs) have been associated with better cognitive function, slower rates of cognitive decline, and lower risk of developing dementia. Animal studies have shown that diets rich in omega‐3 PUFAs reduce blood–brain barrier (BBB) disruption associated with aging, but this has yet to be observed in humans.Forty‐five healthy subjects (mean age, 76 years) were recruited and underwent cognitive assessment (verbal learning and memory, language, processing speed, executive function, and motor control) and measurement of PUFAs. Forty of the same subjects also underwent magnetic resonance imaging (MRI) to measure BBB integrity (K trans using dynamic contrast‐enhanced MRI).The long chain omega‐3 score (DHA+EPA) was negatively correlated with K trans values in the internal capsule, indicating higher omega‐3 levels were associated with greater BBB integrity in this region (r = –0.525, p = .004). Trends were observed for a positive correlation between the long chain omega‐3 score and both memory and language scores, but not with executive function, speed, or motor control. The omega‐6 score was not significantly correlated with any cognitive scores or K trans values.The significant correlations between long chain omega‐3 levels and BBB integrity provide a possible mechanism by which omega‐3 PUFAs are associated with brain health.

The diagnostic efficiency of the perfusion-related parameters in assessing the vascular disrupting agent (CA4P) response in a rabbit VX2 liver tumor model.

There are inconsistencies when concomitantly using dynamic contrast enhancement (DCE) and intravoxel incoherent motion (IVIM) to evaluate diagnostic efficiency. To evaluate the diagnostic efficiency of perfusion-related parameters in assessing the effect of Combretastatin-A4-phosphate (CA4P) in a rabbit VX2 liver tumor model using DCE and IVIM. Twenty rabbits implanted with VX2 tumors were included in the study. The perfusion-parameters of DCE (Ktrans and iAUC60) and IVIM (f and D*) were measured at baseline and 4 h after administration of CA4P. Subsequently, the rabbits were euthanized. Pre- and post-treatment perfusion parameters were analyzed using paired t-test. Correlation between the various perfusion parameters and correlation of perfusion parameters with microvascular density (MVD) were assessed using Pearson correlation analysis. The diagnostic efficiency was evaluated using receiver operating characteristic (ROC) curve analysis. All perfusion parameters (Ktrans, iAUC60, f and D*) showed significant decrease after 4 h of CA4P administration (all P < 0.001). Post-treatment perfusion parameters showed a moderate correlation with MVD (r = 0.663, r = 0.567, r = 0.685, r = 0.618, respectively; all P < 0.05). At baseline and after treatment, Ktrans values and iAUC60 showed correlation with f and D* (all P < 0.05). Concomitant use of perfusion parameters of DCE and IVIM showed the best diagnostic performance, which was slightly greater than that observed with individual application of DCE or IVIM (AUC = 0.915, 0.880, and 0.895, respectively). Although concomitant application of DCE and IVIM can slightly improve the diagnostic value in assessing the effect of CA4P, the values were relatively small.

Blood-brain barrier leakage and hemorrhagic transformation: The Reperfusion Injury in Ischemic StroKe (RISK) study.

In patients with acute ischemic stroke treated with reperfusion therapy we aimed to evaluate whether pretreatment blood-brain barrier (BBB) leakage is associated with subsequent hemorrhagic transformation (HT). We prospectively screened patients with acute ischemic stroke treated with intravenous thrombolysis and/or endovascular treatment. Before treatment, each patient received computed tomography (CT), CT angiography, and CT perfusion. We assessed pretreatment BBB leakage within the ischemic area using the volume transfer constant (Ktrans ) value. Our primary outcome was relevant HT, defined as hemorrhagic infarction type 2 or parenchymal hemorrhage type 1 or 2. We evaluated independent associations between BBB leakage and HT using logistic regression, adjusting for age, sex, baseline stroke severity, Alberta Stroke Program Early CT Score (ASPECTS)≥6, treatment type, and onset-to-treatment time. We enrolled 171 patients with available assessment of BBB leakage. The patients' mean (±SD) age was 75.5 (±11.8) years, 86 (50%) were men, and the median (interquartile range) National Institutes of Health Stroke Scale score was 18 (12-23). A total of 32 patients (18%) received intravenous thrombolysis, 102 (60%) underwent direct endovascular treatment, and 37 (22%) underwent both. Patients with relevant HT (N=31;18%) had greater mean BBB leakage (Ktrans 0.77 vs. 0.60; p=0.027). After adjustment in the logistic regression model, we found that BBB leakage was associated both with a more than twofold risk of relevant HT (odds ratio [OR]2.50; 95% confidence interval [CI]1.03-6.03 per Ktrans point increase; OR2.34; 95% CI1.06-5.17 for Ktrans values>0.63 [mean BBB leakage value]) and with symptomatic intracerebral hemorrhage (OR4.30; 95% CI1.13-13.77 per Ktrans point increase). Pretreatment BBB leakage before reperfusion therapy was associated with HT, and may help to identify patients at risk of HT.

Comparison between high-frequency irreversible electroporation and irreversible electroporation ablation of small swine liver: follow-up of DCE-MRI and pathological observations.

Background:High-frequency irreversible electroporation (H-FIRE) is a novel, next-generation nanoknife technology with the advantage of relieving irreversible electroporation (IRE)-induced muscle contractions. However, the difference between IRE and H-FIRE with distinct ablation parameters was not clearly defined. This study aimed to compare the efficacy of the two treatments in vivo.Methods:Ten Bama miniature swine were divided into two group: five in the 1-day group and five in the 7-day group. The efficacy of IRE and H-FIRE ablation was compared by volume transfer constant (Krans), rate constant (Kep) and extravascular extracellular volume fraction (Ve) value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), size of the ablation zone, and histologic analysis. Each animal underwent the IRE and H-FIRE. Temperatures of the electrodes were measured during ablation. DCE-MRI images were obtained 1, 4, and 7 days after ablation in the 7-day group. All animals in the two groups were euthanized 1 day or 7 days after ablation, and subsequently, IRE and H-FIRE treated liver tissues were collected for histological examination. Student's t test or Mann-Whitney U test was applied for comparing any two groups. One-way analysis of variance (ANOVA) test and Welch's ANOVA test followed by Holm-Sidak's multiple comparisons test, one-way ANOVA with repeated measures followed by Bonferroni test, or Kruskal-Wallis H test followed by Dunn's multiple comparison test was used for multiple group comparisons and post hoc analyses. Pearson correlation coefficient test was conducted to analyze the relationship between two variables.Results:Higher Ve was seen in IRE zone than in H-FIRE zone (0.14 ± 0.02 vs. 0.08 ± 0.05, t = 2.408, P = 0.043) on day 4, but no significant difference was seen in Ktrans or Kep between IRE and H-FIRE zones at all time points (all P > 0.05). For IRE zone, the greatest Ktrans was seen on day 7, which was significantly higher than that on day 1 (P = 0.033). The ablation zone size of H-FIRE was significantly larger than IRE 1 day (4.74 ± 0.88 cm2vs. 3.20 ± 0.77 cm2, t = 3.241, P = 0.009) and 4 days (2.22 ± 0.83 cm2vs. 1.30 ± 0.50 cm2, t = 2.343, P = 0.041) after treatment. Apoptotic index (0.05 ± 0.02 vs. 0.73 ± 0.06 vs. 0.68 ± 0.07, F = 241.300, P < 0.001) and heat shock protein 70 (HSP70) (0.03 ± 0.01 vs. 0.46 ± 0.09 vs. and 0.42 ± 0.07, F = 64.490, P < 0.001) were significantly different between the untreated, IRE and H-FIRE zones, but no significant difference was seen in apoptotic index or HSP70 between IRE and H-FIRE zone (both P > 0.05). Electrode temperature variations were not significantly different between the two zones (18.00 ± 3.77°C vs. 16.20 ± 7.45°C, t = 0.682, P = 0.504). The Ktrans value (r = 0.940, P = 0.017) and the Kep value (r = 0.895, P = 0.040) of the H-FIRE zone were positively correlated with the number of hepatocytes in the ablation zone.Conclusions:H-FIRE showed a comparable ablation effect to IRE. DCE-MRI has the potential to monitor the changes of H-FIRE ablation zone.

Combined dynamic contrast enhanced MRI parameter with clinical factors predict the survival of concurrent chemo-radiotherapy in patients with 2018 FIGO IIICr stage cervical cancer

PurposeCombined clinical prognostic factors and magnetic resonance imaging (MRI) parameters on predicting the prognosis after concurrent chemo-radiotherapy (CCRT)in patients with 2018 International Federation of Gynecology and Obstetrics (FIGO) IIICr stage patients. MethodsA total of 117 patients with cervical cancer (2018 FIGO stage IIICr) who underwent CCRT were enrolled from Dec.2014 to Jul.2017. 47 patients developed outcome events, including 32 recurrences and 15 deaths. Clinical and MR parameters of primary tumors were analyzed, including apparent diffusion coefficient (ADC) values (ADCmean, ADCmin, and ADCmax) and dynamic contrast-enhanced MRI (DCE-MRI) parameters (Ktrans, Kep, Ve) were recorded. The short diameters of visible lymph nodes in the MRI and enhanced computed tomography (CT) images were measured. Progression-free survival (PFS) was compared by Kaplan-Meier analysis and independent predictors were identified using cox regression analysis. ResultsThe median PFS was 35 months (6–68 month). The 1-year and 3-year PFS rates were was 90.4 %, 74.4 %, respectively. Multivariate analysis showed that 2018 FIGOIIIC2r stage (HR 2.701,95 %CI1.259to. 5.797; p = 0.011), Ktrans(HR 0.353;95 %CI 0.189 to 0.659; p = 0.001) and ADCmin (HR0.423,95 %CI0.229to0.783; p = 0.006) were highly correlated with poor PFS. ConclusionIn conclusion, we have identified IIIC2r stage, Ktrans value and ADCmin value as the most important factors in evaluating the survival rate and prognosis of patients with stage IIICr cervical cancer. For stage IIIC1r subgroup, Ktrans, ADCmin value and site of positive lymph node >2 were independent prognostic factors.

Differentiation between glioblastoma and primary CNS lymphoma: application of DCE-MRI parameters based on arterial input function obtained from DSC-MRI.

This study aimed to evaluate whether arterial input functions (AIFs) obtained from dynamic susceptibility contrast (DSC)-MRI (AIFDSC) improve the reliability and diagnostic accuracy of dynamic contrast-enhanced (DCE)-derived pharmacokinetic (PK) parameters for differentiating glioblastoma from primary CNS lymphoma (PCNSL) compared with AIFs derived from DCE-MRI (AIFDCE). This retrospective study included 172 patients with glioblastoma (n = 147) and PCNSL (n = 25). All patients had undergone preoperative DSC- and DCE-MRI. The volume transfer constant (Ktrans), volume of the vascular plasma space (vp), and volume of the extravascular extracellular space (ve) were acquired using AIFDSC and AIFDCE. The relative cerebral blood volume (rCBV) was obtained from DSC-MRI. Intraclass correlation coefficients (ICC) and ROC curves were used to assess the reliability and diagnostic accuracy of individual parameters. The mean Ktrans, vp, and ve values revealed better ICCs with AIFDSC than with AIFDCE (Ktrans, 0.911 vs 0.355; vp, 0.766 vs 0.503; ve, 0.758 vs 0.657, respectively). For differentiating all glioblastomas from PCNSL, the mean rCBV (AUC = 0.856) was more accurate than the AIFDSC-driven mean Ktrans, which had the largest AUC (0.711) among the DCE-derived parameters (p = 0.02). However, for glioblastomas with low rCBV (≤ 75th percentile of PCNSL; n = 30), the AIFDSC-driven mean Ktrans and vp were more accurate than rCBV (AUC: Ktrans, 0.807 vs rCBV, 0.515, p = 0.004; vp, 0.715 vs rCBV, p = 0.045). DCE-derived PK parameters using the AIFDSC showed improved reliability and diagnostic accuracy for differentiating glioblastoma with low rCBV from PCNSL. • An accurate differential diagnosis of glioblastoma and PCNSL is crucial because of different therapeutic strategies. • In contrast to the rCBV from DSC-MRI, another perfusion imaging technique, the DCE parameters for the differential diagnosis have been limited because of the low reliability of AIFs from DCE-MRI. • When we analyzed DCE-MRI data using AIFs from DSC-MRI (AIFDSC), AIFDSC-driven DCE parameters showed improved reliability and better diagnostic accuracy than rCBV for differentiating glioblastoma with low rCBV from PCNSL.

Blood Oxygenation Level Dependent Magnetic Resonance Imaging (MRI), Dynamic Contrast Enhanced MRI, and Diffusion Weighted MRI for Benign and Malignant Breast Cancer Discrimination: A Preliminary Experience.

Simple SummaryThe aim of the study is to combine blood oxygenation level dependent magnetic resonance imaging (BOLD-MRI), dynamic contrast enhanced MRI (DCE-MRI), and diffusion weighted MRI (DW-MRI) in differentiation of benign and malignant breast lesions. The results suggest that the combined use of DCE-MRI, DW-MRI and/or BOLD-MRI does not provide a dramatic improvement compared to the use of DCE-MRI features alone, in the classification of breast lesions. However, an interesting result was the negative correlation between R2* and D.Purpose. To combine blood oxygenation level dependent magnetic resonance imaging (BOLD-MRI), dynamic contrast enhanced MRI (DCE-MRI), and diffusion weighted MRI (DW-MRI) in differentiation of benign and malignant breast lesions. Methods. Thirty-seven breast lesions (11 benign and 21 malignant lesions) pathologically proven were included in this retrospective preliminary study. Pharmaco-kinetic parameters including Ktrans, kep, ve, and vp were extracted by DCE-MRI; BOLD parameters were estimated by basal signal S0 and the relaxation rate R2*; and diffusion and perfusion parameters were derived by DW-MRI (pseudo-diffusion coefficient (Dp), perfusion fraction (fp), and tissue diffusivity (Dt)). The correlation coefficient, Wilcoxon-Mann-Whitney U-test, and receiver operating characteristic (ROC) analysis were calculated and area under the ROC curve (AUC) was obtained. Moreover, pattern recognition approaches (linear discrimination analysis and decision tree) with balancing technique and leave one out cross validation approach were considered. Results. R2* and D had a significant negative correlation (−0.57). The mean value, standard deviation, Skewness and Kurtosis values of R2* did not show a statistical significance between benign and malignant lesions (p > 0.05) confirmed by the ‘poor’ diagnostic value of ROC analysis. For DW-MRI derived parameters, the univariate analysis, standard deviation of D, Skewness and Kurtosis values of D* had a significant result to discriminate benign and malignant lesions and the best result at the univariate analysis in the discrimination of benign and malignant lesions was obtained by the Skewness of D* with an AUC of 82.9% (p-value = 0.02). Significant results for the mean value of Ktrans, mean value, standard deviation value and Skewness of kep, mean value, Skewness and Kurtosis of ve were obtained and the best AUC among DCE-MRI extracted parameters was reached by the mean value of kep and was equal to 80.0%. The best diagnostic performance in the discrimination of benign and malignant lesions was obtained at the multivariate analysis considering the DCE-MRI parameters alone with an AUC = 0.91 when the balancing technique was considered. Conclusions. Our results suggest that the combined use of DCE-MRI, DW-MRI and/or BOLD-MRI does not provide a dramatic improvement compared to the use of DCE-MRI features alone, in the classification of breast lesions. However, an interesting result was the negative correlation between R2* and D.

18F-Trifluoromethylated D-Cysteine as a Promising New PET Tracer for Glioma Imaging: Comparative Analysis With MRI and Histopathology in Orthotopic C6 Models.

Comparing MRI and histopathology, this study aims to comprehensively explore the potential application of 18F-trifluoromethylated D-cysteine (S-[18F]CF3-D-CYS) in evaluating glioma by using orthotopic C6 glioma models. Sprague–Dawley (SD) rats (n = 9) were implanted with C6 glioma cells. Tumor growth was monitored every week by multiparameter MRI [including dynamic contrast-enhanced MRI (DCE-MRI)], [18F]FDG, S-[18F]CF3-D-CYS, and [18F]FDOPA PET imaging. Repeated scans of the same rat with the two or three [18F]-labeled radiotracers were investigated. Initial regions of interest were manually delineated on T2WI and set on the same level of PET images, and tumor-to-normal brain uptake ratios (TNRs) were calculated to semiquantitatively assess the tracer accumulation in the tumor. The tumor volume in PET and histopathology was calculated. HE and Ki67 immunohistochemical staining were further performed. The correlations between the uptake of S-[18F]CF3-D-CYS and Ki67 were analyzed. Dynamic S-[18F]CF3-D-CYS PET imaging showed tumor uptake rapidly reached a peak, maintained plateau during 10–30 min after injection, then decreased slowly. Compared with [18F]FDG and [18F]FDOPA PET imaging, S-[18F]CF3-D-CYS PET demonstrated the highest TNRs (P < 0.05). There were no significant differences in the tumor volume measured on S-[18F]CF3-D-CYS PET or HE specimen. Furthermore, our results showed that the uptake of S-[18F]CF3-D-CYS was significantly positively correlated with tumor Ki67, and the poor accumulated S-[18F]CF3-D-CYS was consistent with tumor hemorrhage. There was no significant correlation between the S-[18F]CF3-D-CYS uptakes and the Ktrans values derived from DCE-MRI. In comparison with MRI and histopathology, S-[18F]CF3-D-CYS PET performs well in the diagnosis and evaluation of glioma. S-[18F]CF3-D-CYS PET may serve as a valuable tool in the clinical management of gliomas.

DCE-MRI in Glioma, Infiltration Zone and Healthy Brain to Assess Angiogenesis: A\xa0Biopsy Study

PurposeTo explore the focal predictability of vascular growth factor expression and neovascularization using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in glioma.Methods120 brain biopsies were taken in vital tumor, infiltration zone and normal brain tissue of 30 glioma patients: 17 IDH(isocitrate dehydrogenase)-wildtype glioblastoma (GBM), 1 IDH-wildtype astrocytoma °III (together prognostic group 1), 3 IDH-mutated GBM (group 2), 3 anaplastic astrocytomas IDH-mutated (group 3), 4 anaplastic oligodendrogliomas and 2 low-grade oligodendrogliomas (together prognostic group 4). A mixed linear model evaluated the predictabilities of microvessel density (MVD), vascular area ratio (VAR), mean vessel size (MVS), vascular endothelial growth factor and receptors (VEGF-A, VEGFR‑2) and vascular endothelial-protein tyrosine phosphatase (VE-PTP) expression from Tofts model kinetic and model-free curve parameters.ResultsAll kinetic parameters were associated with VEGF‑A (all p < 0.001) expression. Ktrans, kep and ve were associated with VAR (p = 0.006, 0.004 and 0.01, respectively) and MVS (p = 0.0001, 0.02 and 0.003, respectively) but not MVD (p = 0.84, 0.74 and 0.73, respectively). Prognostic groups differed in Ktrans (p = 0.007) and ve (p = 0.004) values measured in the infiltration zone. Despite significant differences of VAR, MVS, VEGF‑A, VEGFR‑2, and VE-PTP in vital tumor tissue and the infiltration zone (p = 0.0001 for all), there was no significant difference between kinetic parameters measured in these zones.ConclusionThe DCE-MRI kinetic parameters show correlations with microvascular parameters in vital tissue and also reveal blood-brain barrier abnormalities in the infiltration zones adequate to differentiate glioma prognostic groups.

Enhancement degree of brain metastases: correlation analysis between enhanced T2 FLAIR and vascular permeability parameters of dynamic contrast-enhanced MRI.

To investigate the correlation between enhancement degrees of brain metastases on contrast-enhanced T2-fluid-attenuated inversion recovery (CE-T2 FLAIR) and vascular permeability parameters of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Thirty-nine patients with brain metastases were prospectively collected. They underwent non-enhanced T2 FLAIR, DCE-MRI, CE-T2 FLAIR, and contrast-enhanced three-dimensional brain volume imaging (CE-BRAVO). Quantitative parameters of DCE-MRI were evaluated for all lesions, which included volume transfer constant (Ktrans), rate constant (Kep), and fractional volume of the extracellular extravascular space (Ve). Contrast ratio (CR) and percentage increase (PI) values of all lesions on CE-T2 FLAIR were also measured. The tumor enhancement degree on CE-T2 FLAIR in relation to CE-BRAVO was visually classified as higher (group A), equal (group B), and lower (group C). A total of 82 brain metastases were evaluated, including 31 in group A, 19 in group B, and 32 in group C. The Ktrans and Kep were negatively correlated with the CR (ρ = - 0.551, p < 0.001 and ρ = - 0.708, p < 0.001, respectively) and PI (ρ = - 0.511, p < 0.001 and ρ = - 0.621, p < 0.001, respectively). The Ktrans and Kep of group A were significantly lower than those of group C (both p < 0.001). No significant difference was found in Ve among the groups (p = 0.327). The enhancement degree of brain metastases on CE-T2 FLAIR is negatively correlated with Ktrans and Kep values, which indicate that vascular permeability parameters may play an important role in explaining the difference in enhancement between CE-T2 FLAIR and CE-BRAVO. • The enhancement degree on CE-T2 FLAIR was negatively correlated with Ktrans and Kep values. • The vascular permeability of brain metastasis accounted for the difference in enhancement degree between CE-T2 FLAIR and CE-BRAVO. • CE-T2 FLAIR is useful for detecting brain metastases with mild disruption of the blood-brain barrier.

Application of multiparametric MR imaging to predict the diversification of renal function in miR29a-mediated diabetic nephropathy

Diabetic nephropathy (DN) is one of the major leading cause of kidney failure. To identify the progression of chronic kidney disease (CKD), renal function/fibrosis is playing a crucial role. Unfortunately, lack of sensitivities/specificities of available clinical biomarkers are key major issues for practical healthcare applications to identify the renal functions/fibrosis in the early stage of DN. Thus, there is an emerging approach such as therapeutic or diagnostic are highly desired to conquer the CKD at earlier stages. Herein, we applied and examined the application of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and diffusion weighted imaging (DWI) to identify the progression of fibrosis between wild type (WT) and miR29a transgenic (Tg) mice during streptozotocin (STZ)-induced diabetes. Further, we also validate the potential renoprotective role of miR29a to maintain the renal perfusion, volume, and function. In addition, Ktrans values of DCE-MRI and apparent diffusion coefficient (ADC) of DWI could significantly reflect the level of fibrosis between WT and Tg mice at identical conditions. As a result, we strongly believed that the present non-invasive MR imaging platforms have potential to serveas an important tool in research and clinical imaging for renal fibrosis in diabetes, and that microenvironmental changes could be identified by MR imaging acquisition prior to histological biopsy and diabetic podocyte dysfunction.

Prognostic Prediction Based on Dynamic Contrast-Enhanced MRI and Dynamic Susceptibility Contrast-Enhanced MRI Parameters from Non-Enhancing, T2-High-Signal-Intensity Lesions in Patients with Glioblastoma.

ObjectiveFew attempts have been made to investigate the prognostic value of dynamic contrast-enhanced (DCE) MRI or dynamic susceptibility contrast (DSC) MRI of non-enhancing, T2-high-signal-intensity (T2-HSI) lesions of glioblastoma multiforme (GBM) in newly diagnosed patients. This study aimed to investigate the prognostic values of DCE MRI and DSC MRI parameters from non-enhancing, T2-HSI lesions of GBM.Materials and MethodsA total of 76 patients with GBM who underwent preoperative DCE MRI and DSC MRI and standard treatment were retrospectively included. Six months after surgery, the patients were categorized into early progression (n = 15) and non-early progression (n = 61) groups. We extracted and analyzed the permeability and perfusion parameters of both modalities for the non-enhancing, T2-HSI lesions of the tumors. The optimal percentiles of the respective parameters obtained from cumulative histograms were determined using receiver operating characteristic (ROC) curve and univariable Cox regression analyses. The results were compared using multivariable Cox proportional hazards regression analysis of progression-free survival.ResultsThe 95th percentile value (PV) of Ktrans, mean Ktrans, and median Ve were significant predictors of early progression as identified by the ROC curve analysis (area under the ROC curve [AUC] = 0.704, p = 0.005; AUC = 0.684, p = 0.021; and AUC = 0.670, p = 0.0325, respectively). Univariable Cox regression analysis of the above three parametric values showed that the 95th PV of Ktrans and the mean Ktrans were significant predictors of early progression (hazard ratio [HR] = 1.06, p = 0.009; HR = 1.25, p = 0.017, respectively). Multivariable Cox regression analysis, which also incorporated clinical parameters, revealed that the 95th PV of Ktrans was the sole significant independent predictor of early progression (HR = 1.062, p < 0.009).ConclusionThe 95th PV of Ktrans from the non-enhancing, T2-HSI lesions of GBM is a potential prognostic marker for disease progression.

Regional Differences in Blood-Brain Barrier Permeability in Cognitively Normal Elderly Subjects: A Dynamic Contrast-Enhanced MRI-Based Study.

ObjectiveThis study aimed to determine whether there are regional differences in the blood-brain barrier (BBB) permeability of cognitively normal elderly participants and to identify factors influencing BBB permeability with a clinically feasible, 10-minute dynamic contrast-enhanced (DCE) MRI protocol.Materials and MethodsThis IRB-approved prospective study recruited 35 cognitively normal adults (26 women; mean age, 64.5 ± 5.6 years) who underwent DCE T1-weighted imaging. Permeability maps (Ktrans) were coregistered with masks to calculate the mean regional values. The paired t test and Friedman test were used to compare Ktrans between different regions. The relationships between Ktrans and the factors of age, sex, education, cognition score, vascular risk burden, vascular factors on imaging, and medial temporal lobar atrophy were assessed using Pearson correlation and the Spearman rank test.ResultsThe mean permeability rates of the right and left hippocampi, as assessed with automatic segmentation, were 0.529 ± 0.472 and 0.585 ± 0.515 (Ktrans, × 10−3 min−1), respectively. Concerning the deep gray matter, the Ktrans of the thalamus was significantly greater than those of the putamen and hippocampus (p = 0.007, p = 0.041). Regarding the white matter, the Ktrans value of the occipital white matter was significantly greater than those of the frontal, cingulate, and temporal white matter (p < 0.0001, p = 0.0007, p = 0.0002). The variations in Ktrans across brain regions were not related to age, cognitive score, vascular risk burden, vascular risk factors on imaging, or medial temporal lobar atrophy in the study group.ConclusionOur study demonstrated regional differences in BBB permeability (Ktrans) in cognitively normal elderly adults using a clinically acceptable 10-minutes DCE imaging protocol. The regional differences suggest that the integrity of the BBB varies across the brains of cognitively normal elderly adults. We recommend considering regional differences in Ktrans values when evaluating BBB permeability in patients with neurodegenerative diseases.

Blood-brain barrier dysfunction significantly correlates with serum matrix metalloproteinase-7 (MMP-7) following traumatic brain injury

ObjectivesTo determine if radiological evidence of blood brain barrier (BBB) dysfunction, measured using Dynamic Contrast Enhanced MRI (DCE-MRI), correlates with serum matrix metalloproteinase (MMP) levels in traumatic brain injury (TBI) patients, and thereby, identify a potential biomarker for BBB dysfunction. Patients and Methods20 patients with a mild, moderate, or severe TBI underwent a DCE-MRI scan and BBB dysfunction was interpreted from KTrans. KTrans is a measure of capillary permeability that reflects the efflux of gadolinium contrast into the extra-cellar space. The serum samples were concurrently collected and later analysed for MMP-1, −2, −7, −9, and −10 levels using an ELISA assay. Statistical correlations between MMP levels and the KTrans value were calculated. Multiple testing was corrected using the Benjamin–Hochberg method to control the false‐discovery rate (FDR). ResultsSerum MMP-1 values ranged from 1.5 to 49.6 ng/ml (12 ± 12.7), MMP-2 values from 58.3 to 174.1 ng/ml (109.5 ± 26.7), MMP-7 from 1.5 to 31.5 ng/mL (10 ± 7.4), MMP-9 from 128.6 to 1917.5 ng/ml (647.7 ± 749.6) and MMP-10 from 0.1 to 0.6 ng/mL (0.3 ± 0.2). Non-parametric Spearman correlation analysis on the data showed significant positive relationship between KTrans and MMP-7 (r = 0.55, p < 0.01). Correlations were also found between KTrans and MMP-1 (r = 0.74, p < 0.0002) and MMP-2 (r = 0.5, p < 0.025) but the actual MMP values were not above reference ranges, limiting the interpretation of results. Statistically significant correlations between KTrans and either MMP-9 or −10 were not found. ConclusionThis is the first study to show a correlation between DCE measures and MMP values in patients with a TBI. Our results support the suggestion that serum MMP-7 may be considered as a peripheral biomarker quantifying BBB dysfunction in TBI patients.

Multiparameter MRI and Clinical Factors for Predicting Early Response to Chemoradiotherapy in Cervical Cancer.

HomeRadiology: Imaging CancerVol. 3, No. 1 PreviousNext Research HighlightsFree AccessMultiparameter MRI and Clinical Factors for Predicting Early Response to Chemoradiotherapy in Cervical CancerSanaz Javadi, Vikas KundraSanaz Javadi, Vikas KundraSanaz JavadiVikas KundraPublished Online:Jan 29 2021https://doi.org/10.1148/rycan.2021209038MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked InEmail Take-Away Points■ Major Focus: To assess a combination of multiparametric MRI with clinical prognostic factors for predicting treatment outcomes in patients with cervical cancer.■ Key Result: Pretreatment individual multiple MRI parameters (diffusion coefficient, volume transfer constant, and extravascular extracellular space) and stage were found to be independent prognostic factors for prediction. Combining multiple MRI parameters, multiparametric MRI biomarkers, and their combination with clinical stage can parse categories favorable, intermediate, and unfavorable for recurrence after chemoradiotherapy.■ Impact: Further assessment of this combination is warranted for improving prediction of treatment responses in patients with cervical cancer.Cervical cancer is the fourth most common cause of cancer-related mortality in women globally. Chemoradiotherapy is the treatment of choice for locally advanced cervical cancer. Early prediction of treatment response could provide a window of opportunity to modify therapy if needed. Clinical prognostic factors alone have limitations in prediction of early response. A few studies have shown functional imaging methods, including PET and diffusion-weighted MRI, can predict recurrence and response to treatment in patients with cervical cancer (1–3). Zheng et al studied this topic further by combining pre- and posttreatment MRI parameters (intravoxel incoherent motion [IVIM], dynamic contrast-enhanced [DCE] MRI, and apparent diffusion coefficient [ADC]) with clinical prognostic factors (squamous cell carcinoma antigen, tumor stage, histologic type, and lymphadenopathy) to predict response to chemoradiotherapy in patients with cervical cancer.The study included 85 patients with pathologically proven cervical cancer that was greater than 1 cm who had no prior history of chemotherapy or radiation therapy and underwent pre- and posttreatment MRI. The latter was used to assess recurrence using Response Evaluation Criteria in Solid Tumors. Treatment included a combination of external beam radiotherapy, high-dose-rate intracavitary brachytherapy, and concurrent cisplatin chemotherapy. One month after completion of chemoradiotherapy, 40% of patients had residual disease. Patients with residual disease had higher stage but no other differences in clinical prognostic factors.Higher pretreatment ADC, IVIM diffusion-related coefficient (D), and DCE volume of extravascular extracellular space per unit volume of tissue (Ve), as well as lower IVIM perfusion-related parameter (f) and DCE volume transfer constant from blood plasma to the extravascular extracellular space (Ktrans) values were seen in tumors with residual disease on univariate analysis. The authors suggest that higher pretreatment ADC and D values may identify tumor necrosis, whereas high Ve, lower f value, and lower Ktrans may reflect poorer blood supply with decreased drug delivery and hypoxia causing resistance to radiation therapy.Multivariate analysis showed sensitivity and specificity of MRI parameters for predicting posttreatment residual tumor as 82% and 65% for D, 67% and 90% for Ktrans, and 82% and 71% for Ve, respectively. Combining these MRI parameters, the sensitivity and specificity for predicting residual disease were 91% and 90%, respectively. MRI parameters and International Federation of Gynecology and Obstetrics (FIGO) stage together produced 85% sensitivity and 96% specificity. MRI parameters with and without FIGO stage segregated patients into favorable, intermediate, and unfavorable categories for residual tumor recurrence. The study suggests that the combination of multiparametric MRI and clinical stage can predict response to treatment in cervical cancer.Highlighted ArticleZheng X, Guo W, Dong J, Qian L. Prediction of early response to concurrent chemoradiotherapy in cervical cancer: Value of multi-parameter MRI combined with clinical prognostic factors. Magn Reson Imaging 2020;72:159–166. doi: https://doi.org/10.1016/j.mri.2020.06.014

Application of T1 Map Information Based on Synthetic MRI for Dynamic Contrast-Enhanced Imaging: A Comparison Study with the Fixed Baseline T1 Value Method.

ObjectiveFor an accurate dynamic contrast-enhanced (DCE) MRI analysis, exact baseline T1 mapping is critical. The purpose of this study was to compare the pharmacokinetic parameters of DCE MRI using synthetic MRI with those using fixed baseline T1 values.Materials and MethodsThis retrospective study included 102 patients who underwent both DCE and synthetic brain MRI. Two methods were set for the baseline T1: one using the fixed value and the other using the T1 map from synthetic MRI. The volume transfer constant (Ktrans), volume of the vascular plasma space (vp), and the volume of the extravascular extracellular space (ve) were compared between the two methods. The interclass correlation coefficients and the Bland-Altman method were used to assess the reliability.ResultsIn normal-appearing frontal white matter (WM), the mean values of Ktrans, ve, and vp were significantly higher in the fixed value method than in the T1 map method. In the normal-appearing occipital WM, the mean values of ve and vp were significantly higher in the fixed value method. In the putamen and head of the caudate nucleus, the mean values of Ktrans, ve, and vp were significantly lower in the fixed value method. In addition, the T1 map method showed comparable interobserver agreements with the fixed baseline T1 value method.ConclusionThe T1 map method using synthetic MRI may be useful for reflecting individual differences and reliable measurements in clinical applications of DCE MRI.

Cognitive improvement effect of gintonin might be associated with blood-brain barrier permeability enhancement: dynamic contrast-enhanced MRI pilot study.

Along with the multiple neuroprotective effect, recent studies suggest that gintonin might increase the blood brain barrier permeability. We evaluated the effect of gintonin on the vascular permeability changes in different brain segments, using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). In this 8-week, randomized, open label pilot study, ten participants with subjective memory impairment but preserved cognitive function assigned to gintonin-enriched fraction (GEF) 300 mg/day or placebo groups. Korean versions of the Alzheimer's disease assessment scale (ADAS-K) and DCE-MRI parameters including Ktrans and Vp in different brain segments were evaluated at baseline and at 8 weeks after treatment. Nine participants completed the study protocol. No adverse events occurred during the observation period for 8 weeks in both groups. Following gintonin administration, increment trends of the brain permeability that did not reach a statistical significance were observed in the left hippocampus (Ktrans and Vp, both, p = 0.062), left thalamus and in left putamen (Ktrans, p = 0.062), and left insula and right amygdala (Vp, p = 0.062), but not in the control placebo group. The increment of the Ktrans value in the left thalamus from the baseline was highly correlated with the change of the ADAS scores (r = −0.900, p = 0.037). Gintonin might enhance the blood-brain barrier (BBB) permeability in the brain structures involved in cognitive functions. Further efficacy exploration for the synergistic effect of gintonin's BBB permeability enhancement to its other cognitive enhancing mechanisms are warranted.Trial RegistrationClinical Research Information Service Identifier: KCT0003418

Closed-loop trans-skull ultrasound hyperthermia leads to improved drug delivery from thermosensitive drugs and promotes changes in vascular transport dynamics in brain tumors.

Effective drug delivery in brain tumors remains a major challenge in oncology. Although local hyperthermia and stimuli-responsive delivery systems, such as thermosensitive liposomes, represent promising strategies to locally enhance drug delivery in solid tumors and improve outcomes, their application in intracranial malignancies remains unexplored. We hypothesized that the combined abilities of closed-loop trans-skull Magnetic Resonance Imaging guided Focused Ultrasound (MRgFUS) hyperthermia with those of thermosensitive drugs can alleviate challenges in drug delivery and improve survival in gliomas.Methods: To conduct our investigations, we first designed a closed loop MR-guided Focused Ultrasound (MRgFUS) system for localized trans-skull hyperthermia (ΔT < 0.5 °C) in rodents and established safety thresholds in healthy mice. To assess the abilities of the developed system and proposed therapeutic strategy for FUS-triggered chemotherapy release we employed thermosensitive liposomal Dox (TSL-Dox) and tested it in two different glioma tumor models (F98 in rats and GL261 in mice). To quantify Dox delivery and changes in the transvascular transport dynamics in the tumor microenvironment we combined fluorescent microscopy, dynamic contrast enhanced MRI (DCE-MRI), and physiologically based pharmacokinetic (PBPK) modeling. Lastly, to assess the therapeutic efficacy of the system and of the proposed therapeutic strategy we performed a survival study in the GL261 glioma bearing mice.Results: The developed closed-loop trans-skull MRgFUS-hyperthermia system that operated at 1.7 MHz, a frequency that maximized the brain (FUS-focus) to skull temperature ratio in mice, was able to attain and maintain the desired focal temperature within a narrow range. Histological evidence (H&E and Nissl) suggests that focal temperature at 41.5 ± 0.5 °C for 10 min is below the threshold for tissue damage. Quantitative analysis of doxorubicin delivery from TSLs with MRgFUS-hyperthermia demonstrated 3.5-fold improvement in cellular uptake in GL261 glioma mouse tumors (p < 0.001) and 5-fold increase in delivery in F98 glioma rat tumors (p < 0.05), as compared to controls (TSL-Dox-only). Moreover, PBPK modeling of drug transport that was calibrated using the experimental data indicated that thermal stress could lead to significant improvement in the transvascular transport (2.3-fold increase in the vessel diffusion coefficient; P < 0.001), in addition to promoting targeted Dox release. Prospective experimental investigations with DCE-MRI during FUS-hyperthermia, supported these findings and provided evidence that moderate thermal stress (≈41 °C for up to 10 min) can promote acute changes in the vascular transport dynamics in the brain tumor microenvironment (Ktrans value for control vs. FUS was 0.0097 and 0.0148 min-1, respectively; p = 0.026). Crucially, survival analysis demonstrated significant improvement in the survival in the TSL-Dox-FUS group as compared to TSL-Dox-only group (p < 0.05), providing supporting evidence on the therapeutic potential of the proposed strategy.Conclusions: Our investigations demonstrated that spatially controlled thermal stress can be attained and sustained in the mouse brain, using a trans-skull closed-loop MRgFUS system, and used to promote the effective delivery of chemotherapy in gliomas from thermosensitive drugs. This system also allowed us to conduct mechanistic investigations that resulted in the refinement of our understanding on the role of thermal stress in augmenting mass and drug transport in brain tumors. Overall, our study established a new paradigm for effective drug delivery in brain tumors based on closed-loop ultrasound-mediated thermal stress and thermosensitive drugs.

Blood-Brain Barrier Leakage Is Increased in Parkinson's Disease.

BackgroundBlood–brain barrier (BBB) disruption has been noted in animal models of Parkinson’s disease (PD) and forms the basis of the vascular hypothesis of neurodegeneration, yet clinical studies are lacking.ObjectiveTo determine alterations in BBB integrity in PD, with comparison to cerebrovascular disease.MethodsDynamic contrast enhanced magnetic resonance images were collected from 49 PD patients, 15 control subjects with cerebrovascular disease [control positive (CP)] and 31 healthy control subjects [control negative (CN)], with all groups matched for age. Quantitative maps of the contrast agent transfer coefficient across the BBB (Ktrans) and plasma volume (vp) were produced using Patlak analysis. Differences in Ktrans and vp were assessed with voxel-based analysis as well as in regions associated with PD pathophysiology. In addition, the volume of white matter lesions (WMLs) was obtained from T2-weighted fluid attenuation inversion recovery (FLAIR) images.ResultsHigher Ktrans, reflecting higher BBB leakage, was found in the PD group than in the CN group using voxel-based analysis; differences were most prominent in the posterior white matter regions. Region of interest analysis confirmed Ktrans to be significantly higher in PD than in CN, predominantly driven by differences in the substantia nigra, normal-appearing white matter, WML and the posterior cortex. WML volume was significantly higher in PD compared to CN. Ktrans values and WML volume were similar in PD and CP, suggesting a similar burden of cerebrovascular disease despite lower cardiovascular risk factors.ConclusionThese results show BBB disruption in PD.

Dynamic contrast-enhanced magnetic resonance imaging in correlation with tongue cancer stages.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) plays a significant role in tumor stage as it can be used to measure tissue perfusion and permeability of tumors. To investigate the relationships between both quantitative and semi-quantitative variables obtained from DCE-MRI and tongue cancer stages. Mean values of Ktrans, enhancement ratio (ER), wash-in slope (slope), and the 95th percentile (95%) values of the distribution for Ktrans, ER, and slope values (Ktrans (95%), ER (95%), and slope (95%), respectively) were calculated for 53 patients with tongue cancers (American Joint Committee on Cancer 8th Edition stage group: 10 in stages I and II, 14 in stage III, 21 in stage IVa, and eight in stage IVb as determined by histopathologic assessment). The relationship between tumor staging and each of the six DCE-MRI parameters was assessed separately using ordinal logistic regression. The logistic regression analysis revealed that both mean and 95th percentile values of Ktrans were significantly and positively correlated with tongue cancer stage (P < 0.01). More aggressive tumor stages had larger kinetic parameter. Moreover, the semi-quantitative parameters, such as ER (95%) and slope (95%), may be more significant predictors for evaluating tongue cancer stages than the mean ER and mean slope. Both quantitative and semi-quantitative imaging biomarkers are useful for evaluating the stages of tongue cancer, and the indices obtained from DCE-MRI were positively correlated with the tumor stages. These parameters have the potential to non-invasively evaluate the stages of tongue cancer in the clinical setting.