A novel stratification scheme combined with internal arteries in CT imaging for guiding postoperative adjuvant transarterial chemoembolization in hepatocellular carcinoma: a retrospective cohort study.

BACKGROUND: Although postoperative adjuvant transarterial chemoembolization (PA-TACE) improves survival outcomes in a subset of patients with resected hepatocellular carcinoma (HCC), the lack of reliable biomarkers for patient selection remains a significant challenge. The present study aimed to evaluate whether computed tomography imaging can provide more value for predicting benefits from PA-TACE and to establish a new scheme for guiding PA-TACE benefits. METHODS: In this retrospective study, patients with HCC who had undergone preoperative contrast-enhanced computed tomography and curative hepatectomy were evaluated. Inverse probability of treatment weight was performed to balance the difference of baseline characteristics. Cox models were used to test the interaction among PA-TACE, imaging features, and pathological indicators. An HCC imaging and pathological classification (HIPC) scheme incorporating these imaging and pathological indicators was established. RESULTS: This study included 1488 patients [median age, 52 years (IQR, 45-61 years); 1309 male]. Microvascular invasion (MVI) positive, and diameter >5 cm tumors achieved a higher recurrence-free survival (RFS), and overall survival (OS) benefit, respectively, from PA-TACE than MVI negative, and diameter ≤5 cm tumors. Patients with internal arteries (IA) positive benefited more than those with IA-negative in terms of RFS ( P =0.016) and OS ( P =0.018). PA-TACE achieved significant RFS and OS improvements in HIPC3 (IA present and diameter >5 cm, or two or three tumors) patients but not in HIPC1 (diameter ≤5 cm, MVI negative) and HIPC2 (other single tumor) patients. Our scheme may decrease the number of patients receiving PA-TACE by ~36.5% compared to the previous suggestion. CONCLUSIONS: IA can provide more value for predicting the benefit of PA-TACE treatment. The proposed HIPC scheme can be used to stratify patients with and without survival benefits from PA-TACE.

Diffusion-weighted Imaging and Arterial Spin Labeling for Prediction of Cerebral Infarct Volume in Acute Atherothrombotic Stroke.

OBJECTIVES: This study aims to investigate the usefulness of diffusion-weighted imaging (DWI) and arterial spin labeling (ASL) for predicting final infarct volume in patients with acute atherothrombotic subtype cerebral infarction (AT-type stroke). METHODS: The data of 77 patients with AT-type stroke were retrospectively analyzed. ASL and DWI values of minimum apparent diffusion coefficient (min ADC), mean ADC (mean ADC), minimum cerebral blood flow (min CBF), and mean CBF (mean CBF) of the infarction lesions were measured. Changes in cerebral infarction volume (ΔVolume) were determined by DWI reexamination on the 7th day after onset. Correlations of ADC and CBF with Δ Volume were analyzed. Receiver operating characteristic (ROC) curve analysis was used to determine the usefulness of ADC and CBF values for predicting final infarct volume. RESULTS: There was a significant difference in the distribution of the ΔVolume in AT-type stroke (P<0.0001). The ADC and min CBF values were negatively correlated with the infarct ΔVolume (P<0.05); mean CBF and ΔCBF were not correlated with ΔVolume. When min ADC was ≤0.303 × 10-3 mm2/s, min CBF 1.5 ≤2.415 mL/100 g/min, or min CBF2.5 ≤4.25 mL/100 g/min, ΔVolume was likely to be large. The ROC curve showed the highest predictive value for min ADC and min CBF. CONCLUSION: Distinctive patterns of quantitative ADC and CBF can be used as a simple and rapid method for predicting change in infarction volume in AT-type stroke.

Evaluating the efficacy and microenvironment changes of HER2 + gastric cancer during HLX02 and Endostar treatment using quantitative MRI.

BACKGROUND AND OBJECTIVES: Trastuzumab is an important targeted drug for HER2-positive gastric cancer. The treatment efficacy of a more cost-effective and accessible trastuzumab biosimilar, HLX02, was not well investigated, especially when combined with antiangiogenic treatment. In addition, the tumour microenvironment detected by functional MRI was still unclear during treatment. This study attempts to evaluate the therapeutic effect of antiangiogenic agents combined with HLX02 in a HER2-positive gastric cancer xenograft model and to detect microenvironmental changes using intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI). MATERIALS AND METHODS: We subcutaneously injected MKN-45 human gastric cancer cells into BALB/C nude mice to establish a tumour model. Twenty-eight mice were divided into four groups and treated with saline (Group 1), Endostar (Group 2), trastuzumab biosimilar HLX02 (Group 3), or the combination of Endostar and HLX02 (Group 4). We then performed IVIM-DWI before and at different time points after treatment. HE, HER2, TUNEL, E-cadherin staining, and α-SMA and CD31 double-staining were used to confirm the pathological changes. RESULTS: Group 4 demonstrated the smallest tumour volume at the end of treatment. The D value in Group 4 increased more dramatically, with the highest value on Day 20, compared with the other groups. Perfusion-related parameters (D* and f values) in Groups 2 and 4 increased initially and reversed after Day 10. Group 4 showed the lowest CD31 and HER2 and the highest TUNEL- and E-cadherin-positive staining rates. The D value was positively correlated with TUNEL but negatively correlated with HER2 staining. The D* and f values had positive correlations with CD31 and E-cadherin expression and the vessel maturity index. CONCLUSIONS: The trastuzumab biosimilar drug HLX02 exhibited good treatment efficacy in HER2-positive gastric cancer, especially when combined with Endostar. IVIM-DWI can noninvasively monitor the process of vascular normalization and reflect the treatment effect early at the molecular level.

Dl-3-n-butylphthalide attenuates brain injury caused by cortical infarction accompanied by cranial venous drainage disturbance.

BACKGROUND: Cerebral venous disorder may have a harmful effect on ischaemic stroke; however, the underlying mechanism remains to be elucidated. Although Dl-3-n-butylphthalide is a multitarget agent for antiischaemic stroke, its neuroprotective role in brain ischaemia accompanied by brain venous disturbance remains unclear. In this study, we induced cerebral venous disturbance by the occlusion of bilateral external jugular veins (EJVs) to explore the potential mechanism of the adverse effects of cerebrovenous disorders in cerebral infarction and explore the protective effect of Dl-3-n-butylphthalide on cerebral infarction accompanied through cerebral venous disturbance. METHODS: Cerebral venous disturbance was induced in Sprague-Dawley rats through the permanent occlusion of bilateral EJVs, and cerebral ischaemic stroke was induced through the permanent occlusion of the right cortical branches of the middle cerebral artery. 2,3,5-triphenyltetrazolium chloride staining, MRI, Evans blue extravasation and behavioural test were performed to evaluate infarction volume, cerebral blood flow (CBF), blood-brain barrier (BBB) integrity and neurological function. Immunofluorescence staining and western blot analysis were performed to detect loss of neuron, endothelial cells, pericytes and tight junctions. RESULTS: Bilateral EJVs occlusion did not cause cerebral infarction; however, it increased the infarction volume compared with the simple middle cerebral artery occlusion (MCAO) group, accompanied by severe neuron loss, worse neurological function, lower CBF, increased EJVs pressure, exacerbated Evans blue extravasation and brain oedema, as well as attenuated angiogenesis. Dl-3-n-butylphthalide displayed a neuroprotective effect in rats with MCAO accompanied by EJVs occlusion by reducing neuron loss, accelerating CBF restoration, promoting angiogenesis and relieving BBB damage. CONCLUSION: Bilateral EJVs occlusion did not significantly affect normal rats but aggravated brain damage in the case of ischaemic stroke. Dl-3-n-butylphthalide treatment plays a neuroprotective role in rats with MCAO accompanied by EJVs occlusion, mainly due to the promotion of CBF restoration and BBB protection.

Deep convolutional neural network for preoperative prediction of microvascular invasion and clinical outcomes in patients with HCCs.

OBJECTIVES: We aimed to develop and validate a deep convolutional neural network (DCNN) model for preoperative prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) and its clinical outcomes using contrast-enhanced computed tomography (CECT) in a large population of candidates for surgery. METHODS: This retrospective study included 1116 patients with HCC who had undergone preoperative CECT and curative hepatectomy. Radiological (R), DCNN, and combined nomograms were constructed in a training cohort (n = 892) respectively based on clinicoradiological factors, DCNN probabilities, and all factors; the performance of each model was confirmed in a validation cohort (n = 244). Accuracy and the AUC to predict MVI were calculated. Disease-free survival (DFS) and overall survival (OS) after surgery were recorded. RESULTS: The proportion of MVI-positive patients was respectively 38.8% (346/892) and 35.7 % (87/244) in the training and validation cohorts. The AUCs of the R, DCNN, and combined nomograms were respectively 0.809, 0.929, and 0.940 in the training cohorts and 0.837, 0.865, and 0.897 in the validation cohort. The combined nomogram outperformed the R nomogram in the training (p < 0.001) and validation (p = 0.009) cohorts. There was a significant difference in DFS and OS between the R, DCNN, and combined nomogram-predicted groups with and without MVI (p < 0.001). CONCLUSIONS: The combined nomogram based on preoperative CECT performs well for preoperative prediction of MVI and outcome. KEY POINTS: • A combined nomogram based on clinical information, preoperative CECT, and DCNN can predict MVI and clinical outcomes of patients with HCC. • DCNN provides added diagnostic ability to predict MVI. • The AUCs of the combined nomogram are 0.940 and 0.897 in the training and validation cohorts, respectively.

Comparative Study of Multi-Delay Pseudo-Continuous Arterial Spin Labeling Perfusion MRI and CT Perfusion in Ischemic Stroke Disease.

With the aging population, stroke has gradually become the leading cause of death and disability among adults. It is necessary to verify whether multi-delay pseudo-continuous arterial spin labeling (pCASL) MRI can be used as a standard neuroimaging protocol in the patients with ischemic stroke. We aimed to investigate the clinical utility of multi-delay pCASL for evaluating cerebral perfusion in ischemic stroke disease. Twenty-one ischemic stroke patients [18 men and 3 women; median age, 62 years (age range, 37-84 years)] were enrolled in this study. All patients underwent examinations, including the multi-delay pCASL protocol (using 6 PLDs between 1,000 and 3,500 ms) and computed tomography perfusion (CTP). The cerebral blood flow (CBF) and arterial transit time (ATT) maps were obtained by the multi-delay pCASL protocol, while CBF and mean transit time (MTT) maps were derived by CTP measurements. Based on the voxel level analysis, Pearson correlation coefficients were used to estimate the associations between the two modalities in the gray matter, white matter, and whole brain of each subject. Moderate to high positive associations between ASL-CBF and CTP-CBF were acquired by voxel-level-wise analysis in the gray matter, white matter, and whole brain of the enrolled patients (all P < 0.005), and the average Pearson correlation coefficients were 0.647, 0.585, and 0.646, respectively. Highly significant positive correlations between ASL-ATT and CTP-MTT were obtained by voxel-level-wise associations in the gray matter, white matter, and whole brain (all P < 0.005), and the average Pearson correlation coefficients were 0.787, 0.707, and 0.799, respectively. In addition, significant associations between ASL and CT perfusion were obtained in the gray, white matter and whole brain, according to the subgroup analyses of patient's age and disease stage. There is a correlation between perfusion parameters from multi-delay pCASL and CT perfusion imaging in patients with ischemic stroke. Multi-delay pCASL is radiation-free and non-invasive, and could be an alternative method to CT scans for assessing perfusion in ischemic stroke disease.

Monitoring Treatment Efficacy of Antiangiogenic Therapy Combined With Hypoxia-Activated Prodrugs Online Using Functional MRI.

OBJECTIVE: This study aimed to investigate the effectiveness of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) and blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) in monitoring tumor responses to antiangiogenic therapy combined with hypoxia-activated prodrugs (HAPs). MATERIALS AND METHODS: Establishing colon cancer xenograft model by subcutaneously injecting the HCT116 cell line into BALB/C nude mice. Twenty-four tumor-bearing mice were randomly divided into four groups and injected with bevacizumab combined with TH-302 (A), bevacizumab (B), TH-302 (C), or saline (D) on days 1, 4, 7, 10 and 13. Functional MRI was performed before and at 3, 6, 9, 12 and 15 days after treatment. Pathologic examinations, including HE staining, HIF-1α and CD31 immunohistochemical staining, and TUNEL and Ki-67 immunofluorescent staining, were performed after the last scan. RESULTS: At the end of the study, Group A showed the lowest tumor volume, followed by Groups B, C, and D (F=120.652, P<0.001). For pathologic examinations, Group A showed the lowest percentage of CD31 staining (F=73.211, P<0.001) and Ki-67 staining (F=231.170, P<0.001), as well as the highest percentage of TUNEL staining (F=74.012, P<0.001). Moreover, the D* and f values exhibited positive correlations with CD31 (r=0.868, P<0.001, and r=0.698, P=0.012, respectively). R2* values was positively correlated with HIF-1α (r=0.776, P=0.003). D values were positively correlated with TUNEL (r=0.737, P=0.006) and negatively correlated with Ki-67 (r=0.912, P<0.001). The standard ADC values were positive correlated with TUNEL (r=0.672, P=0.017) and negative correlated with Ki-67 (r=0.873, P<0.001). CONCLUSION: Anti-angiogenic agents combined with HAP can inhibit tumor growth effectively. In addition, IVIM-DWI and BOLD-MRI can be used to monitor the tumor microenvironment, including perfusion, hypoxia, cell apoptosis and proliferation, in a noninvasive manner.

Corrigendum: Comprehensive Evaluation of White Matter Damage and Neuron Death and Whole-Transcriptome Analysis of Rats With Chronic Cerebral Hypoperfusion.

[This corrects the article DOI: 10.3389/fncel.2019.00310.].

The Diagnostic Performance of Diffusion Kurtosis Imaging in the Characterization of Breast Tumors: A Meta-Analysis.

Rationale and Objectives: Diffusion kurtosis imaging (DKI) is a promising imaging technique, but the results regarding the diagnostic performance of DKI in the characterization and classification of breast tumors are inconsistent among published studies. This study aimed to pool all published results to provide more robust evidence of the differential diagnosis between malignant and benign breast tumors using DKI. Methods: Studies on the differential diagnosis of breast tumors using DKI-derived parameters were systemically retrieved from PubMed, Embase, and Web of Science without a time limit. Review Manager 5.3 was used to calculate the standardized mean differences (SMDs) and 95% confidence intervals of the mean kurtosis (MK), mean diffusivity (MD), and apparent diffusion coefficient (ADC). Stata 12.0 was used to pool the sensitivity, specificity, and diagnostic odds ratio (DOR) as well as the publication bias and heterogeneity of each parameter. Fagan's nomograms were plotted to predict the post-test probabilities. Results: Thirteen studies including 867 malignant and 460 benign breast lesions were analyzed. Most of the included studies showed a low to unclear risk of bias and low concerns regarding applicability. Breast cancer showed a higher MK (SMD = 1.23, P < 0.001) but a lower MD (SMD = -1.29, P < 0.001) and ADC (SMD = -1.21, P < 0.001) than benign tumors. The MK (SMD = -1.36, P = 0.006) rather than the MD (SMD = 0.29, P = 0.20) or ADC (SMD = 0.26, P = 0.24) can further differentiate invasive ductal carcinoma from ductal carcinoma in situ. The DKI-derived MK (sensitivity = 90%, specificity = 88%, DOR = 66) and MD (sensitivity = 86% and specificity = 88%, DOR = 46) demonstrated superior diagnostic performance and post-test probability (65, 64, and 56% for MK, MD, and ADC) in differentiating malignant from benign breast lesions, with a higher sensitivity and specificity than the DWI-derived ADC (sensitivity = 85% and specificity = 83%, DOR = 29). Conclusion: The DKI-derived MK and MD demonstrate a comparable diagnostic performance in the discrimination of breast tumors based on their microstructures and non-Gaussian characteristics. The MK can further differentiate invasive ductal carcinoma from ductal carcinoma in situ.

Intravoxel Incoherent Motion Diffusion-Weighted Imaging for Quantitative Differentiation of Breast Tumors: A Meta-Analysis.

Objectives: The diagnostic performance of intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) in the differential diagnosis of breast tumors remains debatable among published studies. Therefore, this meta-analysis aimed to pool relevant evidence regarding the diagnostic performance of IVIM-DWI in the differential diagnosis of breast tumors. Methods: Studies on the differential diagnosis of breast lesions using IVIM-DWI were systemically searched in the PubMed, Embase and Web of Science databases in recent 10 years. The standardized mean difference (SMD) and 95% confidence intervals of the apparent diffusion coefficient (ADC), tissue diffusivity (D), pseudodiffusivity (D*), and perfusion fraction (f) were calculated using Review Manager 5.3, and Stata 12.0 was used to pool the sensitivity, specificity, and area under the curve (AUC), as well as assess publication bias and heterogeneity. Fagan's nomogram was used to predict the posttest probabilities. Results: Sixteen studies comprising 1,355 malignant and 362 benign breast lesions were included. Most of these studies showed a low to unclear risk of bias and low concerns regarding applicability. Breast cancer had significant lower ADC (SMD = -1.38, P < 0.001) and D values (SMD = -1.50, P < 0.001), and higher f value (SMD = 0.89, P = 0.001) than benign lesions, except D* value (SMD = -0.30, P = 0.20). Invasive ductal carcinoma showed lower ADC (SMD = 1.34, P = 0.01) and D values (SMD = 1.04, P = 0.001) than ductal carcinoma in situ. D value demonstrated the best diagnostic performance (sensitivity = 86%, specificity = 86%, AUC = 0.91) and highest post-test probability (61, 48, 46, and 34% for D, ADC, f, and D* values) in the differential diagnosis of breast tumors, followed by ADC (sensitivity = 76%, specificity = 79%, AUC = 0.85), f (sensitivity = 80%, specificity = 76%, AUC = 0.85) and D* values (sensitivity = 84%, specificity = 59%, AUC = 0.71). Conclusion: IVIM-DWI parameters are adequate and superior to the ADC in the differentiation of breast tumors. ADC and D values can further differentiate invasive ductal carcinoma from ductal carcinoma in situ. IVIM-DWI is also superior in identifying lymph node metastasis, histologic grade, and hormone receptors, and HER2 and Ki-67 status.

Evaluating the Treatment Efficacy of Nano-Drug in a Lung Cancer Model Using Advanced Functional Magnetic Resonance Imaging.

OBJECTIVES: Nano-drug delivery system is an interesting field in precise cancer treatment, but few study has reported the microenvironmental changes after such treatment. This study aimed to detect the hemodynamic and microenvironmental changes in a lung cancer xenograft model after treated with doxorubicin (DOX) encapsulated by a cyclic arginine-glycine-aspartic acid polypeptide modified poly-(lactic-co-glycolic acid) nanosystem (cRGD-PLGA@DOX) using functional magnetic resonance imaging. MATERIALS AND METHODS: Thirty-two tumor-bearing mice were randomly divided into four groups. Group A was treated with 0.9% saline, Group B with 4 mg/kg of doxorubicin, Group C with 2 mg/kg of cRGD-PLGA@DOX, and Group D with 4 mg/kg of cRGD-PLGA@DOX. Intravoxel incoherent motion diffusion-weighed imaging (IVIM-DWI) and R2∗ mapping were performed, and D∗, f, D, and R2∗ values were obtained before and1, 2, and 3 weeks after treatment. They were sacrificed for pathological examination after examinations. RESULTS: The reconstructed cRGD-PLGA@DOX was homogeneous, well-dispersed, and spherical in shape, with an average size of 180 nm. Group D demonstrated the smallest tumor volume and highest tumor inhibition rate in 3 weeks. D value of Group B, C, and D manifested an upward trend in 3 weeks with the highest increase in Group D. D∗ values shared a similar increased trends with f values in Group A, B, and C in 3 weeks, except Group D. R2∗ value of Group A gradually increased in 3 weeks, but the trends were reversed in the treatment groups. D value was significantly negative with Ki-67 expression (r = -0.757, P < 0.001) but positive with TUNEL (r = 0.621, P < 0.001), and phosphate and tension homology deleted on chromosome ten (PTEN) staining (r = 0.57, P = 0.004). R2∗ value was closely correlated with HIF-1a (r = 0.721, P < 0.001). CONCLUSION: The nano-drug demonstrated an enhanced anti-tumor effect without the need of increased chemotherapeutic dosage. The tumor microenvironment such as cellular and perfusion changes during treatment can be non-invasively detected by two functional MRI including IVIM-DWI and R2∗ mapping.

Intravoxel Incoherent Motion Diffusion-Weighted Imaging Used to Detect Prostate Cancer and Stratify Tumor Grade: A Meta-Analysis.

Objectives: Intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) is a promising non-invasive imaging technique to detect and grade prostate cancer (PCa). However, the results regarding the diagnostic performance of IVIM-DWI in the characterization and classification of PCa have been inconsistent among published studies. This meta-analysis was performed to summarize the diagnostic performance of IVIM-DWI in the differential diagnosis of PCa from non-cancerous tissues and to stratify the tumor Gleason grades in PCa. Materials and Methods: Studies concerning the differential diagnosis of prostate lesions using IVIM-DWI were systemically searched in PubMed, Embase, and Web of Science without time limitation. Review Manager 5.3 was used to calculate the standardized mean difference (SMD) and 95% confidence intervals of the apparent diffusion coefficient (ADC), tissue diffusivity (D), pseudodiffusivity (D*), and perfusion fraction (f). Stata 12.0 was used to pool the sensitivity, specificity, and area under the curve (AUC), as well as publication bias and heterogeneity. Fagan's nomogram was used to predict the post-test probabilities. Results: Twenty studies with 854 patients confirmed with PCa were included. Most of the included studies showed a low to unclear risk of bias and low concerns regarding applicability. PCa showed a significantly lower ADC (SMD = -2.34; P < 0.001) and D values (SMD = -1.86; P < 0.001) and a higher D* value (SMD = 0.29; P = 0.01) than non-cancerous tissues, but no difference was noted with the f value (SMD = -0.16; P = 0.50). Low-grade PCa showed higher ADC (SMD = 0.63; P < 0.001) and D values (SMD = 0.80; P < 0.001) than the high-grade lesions. ADC showed comparable diagnostic performance (sensitivity = 86%; specificity = 86%; AUC = 0.87) but higher post-test probabilities (60, 53, 36, and 36% for ADC, D, D*, and f values, respectively) compared with the D (sensitivity = 82%; specificity = 82%; AUC = 0.85), D* (sensitivity = 70%; specificity = 70%; AUC = 0.75), and f values (sensitivity = 73%; specificity = 68%; AUC = 0.76). Conclusion: IVIM parameters are adequate to differentiate PCa from non-cancerous tissues with good diagnostic performance but are not superior to the ADC value. Diffusion coefficients can further stratify the tumor Gleason grades in PCa.

Application of IVIM-DWI in Detecting the Tumor Vasculogenic Mimicry Under Antiangiogenesis Combined With Oxaliplatin Treatment.

Objectives: This study aimed to detect the time window of vascular normalization during anti-vascular treatment using intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI). Simultaneously, we evaluated the tumor invasiveness and vasculogenic mimicry and performed synthetic assessment of treatment efficacy of angiogenesis inhibitor combined with conventional chemotherapy using IVIM-DWI. Materials and Methods: HCT116 cells were subcutaneously administered into the right flank of BALB/C nude mice to build a colon cancer xenograft model. Thirty-two tumor-bearing mice were randomly divided into four groups and intraperitoneally administered with normal saline (Group A or control group), bevacizumab (Group B), oxaliplatin monotherapy (Group C), and oxaliplatin combined with bevacizumab (Group D). The IVIM-DWI was performed on days 0, 3, 6, 9, 12, and 15 after the treatments. Another 51 tumor-bearing mice were included in the pathological examinations. α-Smooth muscle actin (SMA) and CD31 double-staining, periodic acid-Schiff (PAS) and CD31 double-staining, hematoxylin and eosin (HE), Ki-67, and E-cadherin staining were performed. The tumor growth and dynamic change of each parameter were noted. Results: The mice in Group D manifested the smallest tumor volume and highest tumor inhibition rate. Microvessel density was significantly decreased but accompanied by increased vasculogenic mimicry after antiangiogenic treatment. The trend was reversed by oxaliplatin treatment. Treated with bevacizumab, the vessel maturity index shared a similar trend with D * and f-values during days 3-12, which slowly increased from days 0 to 9 and then decreased briefly. D-value significantly correlated with vasculogenic mimicry and Ki-67, while D * and f-values showed positive correlations with microvessel density and E-cadherin, an indicator of epithelial-mesenchymal transition. Conclusion: Oxaliplatin performed an inhibited effect on vasculogenic mimicry. Bevacizumab can enhance the tumor chemotherapy through vascular normalization within a transient time period, which can be detected by IVIM-DWI. D * and f-values are able to predict the tumor invasiveness while D is superior in reflecting vasculogenic mimicry and Ki-67 expression during antitumor treatment.

Differentiating the lung lesions using Intravoxel incoherent motion diffusion-weighted imaging: a meta-analysis.

BACKGROUND AND OBJECTIVES: The diagnostic performance of intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) in the differential diagnosis of pulmonary tumors remained debatable among published studies. This study aimed to pool and summary the relevant results to provide more robust evidence in this issue using a meta-analysis method. MATERIALS AND METHODS: The researches regarding the differential diagnosis of lung lesions using IVIM-DWI were systemically searched in Pubmed, Embase, Web of science and Wangfang database without time limitation. Review Manager 5.3 was used to calculate the standardized mean difference (SMD) and 95% confidence intervals of apparent diffusion coefficient (ADC), tissue diffusivity (D), pseudo-diffusivity (D*), and perfusion fraction (f). Stata 12.0 was used to pool the sensitivity, specificity, and area under the curve (AUC), as well as publication bias and heterogeneity. Fagan's nomogram was used to predict the post-test probabilities. RESULTS: Eleven studies with 481 malignant and 258 benign lung lesions were included. Most include studies showed a low to unclear risk of bias and low concerns regarding applicability. Lung cancer demonstrated a significant lower ADC (SMD = -1.17, P < 0.001), D (SMD = -1.02, P < 0.001) and f values (SMD = -0.43, P = 0.005) than benign lesions, except D* value (SMD = 0.01, P = 0.96). D value demonstrated the best diagnostic performance (sensitivity = 89%, specificity = 71%, AUC = 0.90) and highest post-test probability (57, 57, 43 and 43% for D, ADC, f and D* values) in the differential diagnosis of lung tumors, followed by ADC (sensitivity = 85%, specificity = 72%, AUC = 0.86), f (sensitivity = 71%, specificity = 61%, AUC = 0.71) and D* values (sensitivity = 70%, specificity = 60%, AUC = 0.66). CONCLUSION: IVIM-DWI parameters show potentially strong diagnostic capabilities in the differential diagnosis of lung tumors based on the tumor cellularity and perfusion characteristics, and D value demonstrated better diagnostic performance compared to mono-exponential ADC.

Evaluation of abnormal iron distribution in specific regions in the brains of patients with Parkinson's disease using quantitative susceptibility mapping and R2* mapping.

The primary aim of the present study was to evaluate abnormal iron distribution in specific regions of the brains in patients with Parkinson's disease (PD) using quantitative susceptibility mapping (QSM) and R2* mapping, and to compare the diagnostic performances of QSM and R2* mapping in differentiating patients with PD with that in normal controls. A total of 25 patients with idiopathic PD and 28 sex-and age-matched normal controls were included in the present study and their brains investigated using a 3T scanner. Magnetic resonance imaging techniques, namely, QSM and R2* mapping, were applied to generate susceptibility and R2* values. The differences in susceptibility and R2* values in deep grey matter nuclei between patients with PD and the normal controls were compared using independent samples t-tests. The abilities of QSM and R2* mapping to classify patients with PD and normal controls were analyzed using receiver operating characteristic curves. Correlation analyses between imaging parameters (e.g. susceptibility and R2* values) and clinical feature (disease severity assessed using the Hoehn and Yahr score) were performed. The intra-class correlation coefficient (ICC) for susceptibility (ICC=0.977; P<0.001) and R2* (ICC=0.945; P<0.001) values between two neuro-radiologists were >0.81, showing excellent inter-rater agreement. The susceptibility values were significantly increased in the substantia nigra (SN) and red nucleus, but were decreased in the putamen of patients with PD compared with that in the corresponding brain regions of normal controls. However, increased R2* values were observed only in the SN in patients with PD. QSM showed higher sensitivity and specificity compared with R2* mapping to separate the patients with PD from the normal controls. There were no significant correlations between the susceptibility/R2* values and clinical features in all targeted regions of the brains in patients with PD. In conclusion, both QSM and R2* mapping are feasible to calculate the iron levels in human brains, and QSM provides a more sensitive and accurate method to assess regional abnormal iron distribution in patients with PD.

The Diagnostic Performance of DCE-MRI in Evaluating the Pathological Response to Neoadjuvant Chemotherapy in Breast Cancer: A Meta-Analysis.

Background: Neoadjuvant chemotherapy (NAC) is commonly utilized in preoperative treatment for local breast cancer, and it gives high clinical response rates and can result in pathologic complete response (pCR) in 6-25% of patients. In recent years, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been increasingly used to assess the pathological response of breast cancer to NAC. In present analysis, we assess the diagnostic performance of DCE-MRI in evaluating the pathological response of breast cancer to NAC. Materials and Methods: A systematic search in PubMed, the Cochrane Library, and Web of Science for original studies was performed. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess the methodological quality of the included studies. Patient, study, and imaging characteristics were extracted, and sufficient data to reconstruct 2 × 2 tables were obtained. Data pooling, heterogeneity testing, forest plot construction, meta-regression analysis and sensitivity analysis were performed using Stata version 12.0 (StataCorp LP, College Station, TX). Results: Eighteen studies (969 patients with breast cancer) were included in the present meta-analysis. The pooled sensitivity and specificity of DCE-MRI were 0.80 (95% confidence interval [CI]: 0.70, 0.88) and 0.84 (95% [CI]: 0.79, 0.88), respectively. Meta-regression analysis found no significant factors affecting heterogeneity. Sensitivity analysis showed that studies that set pathological complete response (pCR) (n = 14) as a responder showed a tendency for higher sensitivity compared with those that set pCR and near pCR together (n = 5) as a responder (0.83 vs. 0.72), and studies (n = 14) that used DCE-MRI to early predict the pathological response of breast cancer had a higher sensitivity (0.83 vs. 0.71) and equivalent specificity (0.80 vs. 0.86) compared to studies (n = 5) that assessed the response after NAC completion. Conclusion: Our results indicated that DCE-MRI could be considered an important auxiliary method for evaluating the pathological response of breast cancer to NAC and used as an effective method for dynamically monitoring the efficacy during NAC. DCE-MRI also performed well in predicting the pCR of breast cancer to NAC. However, due to the heterogeneity of the included studies, caution should be exercised in applying our results.

Diagnostic Performance of Diffusion Tensor Imaging for Characterizing Breast Tumors: A Comprehensive Meta-Analysis.

Rationale and Objectives: Controversy still exists on the diagnosability of diffusion tensor imaging (DTI) for breast lesions characterization across published studies. The clinical guideline of DTI used in the breast has not been established. This meta-analysis aims to pool relevant evidences and evaluate the diagnostic performance of DTI in the differential diagnosis of malignant and benign breast lesions. Materials and Methods: The studies that assessed the diagnostic performance of DTI parameters in the breast were searched in Embase, PubMed, and Cochrane Library between January 2010 and September 2019. Standardized mean differences and 95% confidence intervals of fractional anisotropy (FA), mean diffusivity (MD), and three diffusion eigenvalues (λ1, λ2, and λ3) were calculated using Review Manager 5.2. The pooled sensitivity, specificity, and area under the curve (AUC) were calculated with a bivariate model. Publication bias and heterogeneity between studies were also assessed using Stata 12.0. Results: Sixteen eligible studies incorporating 1,636 patients were included. The standardized mean differences indicated that breast cancers had a significantly higher FA but lower MD, λ1, λ2, and λ3 than those of benign lesions (all P < 0.05). Subgroup analysis indicated that invasive breast carcinoma (IBC) had a significantly lower MD value than that of ductal carcinoma in situ (DCIS) (P = 0.02). λ1 showed the best diagnostic accuracy with pooled sensitivity, specificity, and AUC of 93%, 92%, and 0.97, followed by MD (AUC = 0.92, sensitivity = 87%, specificity = 83%) and FA (AUC = 0.76, sensitivity = 70%, specificity = 70%) in the differential diagnosis of breast lesions. Conclusion: DTI with multiple quantitative parameters was adequate to differentiate breast cancers from benign lesions based on their biological characteristics. MD can further distinguish IBC from DCIS. The parameters, especially λ1 and MD, should attract our attention in clinical practice.

Dl-3-n-Butylphthalide Reduces Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion Through GDNF/GFRα1/Ret Signaling Preventing Hippocampal Neuron Apoptosis.

Hippocampal neuron death is a key factor in vascular dementia (VD) induced by chronic cerebral hypoperfusion (CCH). Dl-3-n-butylphthalide (NBP) is a multiple-effects drug. Therefore, the potential molecular mechanisms underlying CCH and its feasible treatment should be investigated. This study had two main purposes: first, to identify a potential biomarker in a rat model of CCH induced VD using antibody microarrays; and second, to explore the neuroprotective role of NBP at targeting the potential biomarker. Glial cell line-derived neurotrophic factor (GDNF)/GDNF family receptor alpha-1 (GFRα1)/receptor tyrosine kinase (Ret) signaling is altered in the hippocampus of CCH rats; however, NBP treatment improved cognitive function, protected against hippocampal neuron apoptosis via regulation of GDNF/GFRα1/Ret, and activated the phosphorylation AKT (p-AKT) and ERK1/2 (p-ERK1/2) signaling. We also found that 1 h oxygen-glucose deprivation (OGD) followed by 48 h reperfusion (R) in cultured hippocampal neurons led to downregulation of GDNF/GFRα1/Ret. NBP upregulated the signaling and increased neuronal survival. Ret inhibitor (NVP-AST487) inhibits Ret and downstream effectors, including p-AKT and p-ERK1/2. Additionally, both GDNF and GFRα1 expression are markedly inhibited in hippocampal neurons by coincubation with NVP-AST487, particularly under conditions of OGD/R. GDNF/GFRα1/Ret signaling and neuronal viability can be maintained by NBP, which activates p-AKT and p-ERK1/2, increases expression of Bcl-2, and decreases expression of Bax and cleaved caspase-3. The current study showed that GDNF/GFRα1/Ret signaling plays an essential role in the CCH induced VD. NBP was protective against hippocampal neuron apoptosis, and this was associated with regulation of GDNF/GFRα1/Ret and AKT/ERK1/2 signaling pathways, thus reducing cognitive impairment.

Comprehensive Evaluation of White Matter Damage and Neuron Death and Whole-Transcriptome Analysis of Rats With Chronic Cerebral Hypoperfusion.

BACKGROUND/AIMS: Chronic cerebral hypoperfusion (CCH) is induced by chronic deficit of brain perfusion, contributes to a persistent or progressive cognitive dysfunction, which is characterized by diverse neuropathological manifestations. There are currently no effective medications available. White matter damage (WMD) and cortical neuron death may be caused by CCH, which are related to cognitive impairment, while the underlying molecular mechanisms remain unclear. In the study, a database of the transcriptome level was built to determine potential biomarkers in cortex of CCH. METHODS: CCH was induced in male Sprague-Dawley rats by permanent occlusion of the bilateral common carotid arteries. Rats were randomly divided into three groups: Sham-operated group (n = 24), the 4th and 8th week of CCH groups (total = 56, n = 28 for each group). Cognitive function was evaluated using the Morris water maze task. WMD and neuron damage were detected using diffusion tensor imaging and histological analysis, respectively. Western blotting analysis of various markers was used to examine neuronal death. Whole-transcriptome microarray was performed to assess mRNA, circRNA, and lncRNA expression profiles at 4th and 8th weeks after CCH. Diversified bioinformatic tools were performed to analyze and predict the key biological processes and signaling pathways of differentially expressed RNAs and co-expressed potential target genes. Co-expression networks of mRNA-circRNA-miRNA and lncRNA-mRNA were constructed. RESULTS: Compared to the sham group, cognitive impairment, disintegration of white matter, blood-brain barrier damage and neuron death were induced by CCH. Neuron death including apoptosis and necroptosis might occur in the cortex of CCH. We constructed the regulatory networks of whole-transcriptomic including differentially expressed mRNAs, circRNAs, and lncRNAs, and related biological functions and pathways involved in neurological disease, cell death and survival, energy and metabolism, et al. Our results also indicated that Cyr61 mRNA may play a role in the CCH-related cortical neuronal death. CONCLUSION: WMD and cortical neuronal death are worthy of attention in the pathogenesis of CCH. Additionally, the present results provide potential evidence at the whole-transcription level for CCH, offering candidate biomarkers and therapeutic targets.

Prostaglandin E1 Alleviates Cognitive Dysfunction in Chronic Cerebral Hypoperfusion Rats by Improving Hemodynamics.

Compensatory vascular mechanisms can restore cerebral blood flow (CBF) but fail to protect against chronic cerebral hypoperfusion (CCH)-mediated neuronal damage and cognitive impairment. Prostaglandin E1 (PGE1) is known as a vasodilator to protect against ischemic injury in animal models, but its protective role in CCH remains unclear. To determine the effect of PGE1 on cerebral hemodynamics and cognitive functions in CCH, bilateral common carotid artery occlusion (BCCAO) was used to mimic CCH in rats, which were subsequently intravenously injected with PGE1 daily for 2 weeks. Magnetic resonance imaging, immunofluorescence staining and Morris water maze (MWM) were used to evaluate CBF, angiogenesis, and cognitive functions, respectively. We found that PGE1 treatment significantly restored CBF by enhancing vertebral artery dilation. In addition, PGE1 treatment increased the number of microvascular endothelial cells and neuronal cells in the hippocampus, and decreased the numbers of astrocyte and apoptotic cells. In the MWM test, we further showed that the escape latency of CCH rats was significantly reduced after PGE1 treatment. Our results suggest that PGE1 ameliorates cognitive dysfunction in CCH rats by enhancing CBF recovery, sustaining angiogenesis, and reducing astrocyte activation and neuronal loss.