E7386, a Selective Inhibitor of the Interaction between ß-Catenin and CBP, Exerts Antitumor Activity in Tumor Models with Activated Canonical Wnt Signaling.

The Wnt/ß-catenin signaling pathway plays crucial roles in embryonic development and the development of multiple types of cancer, and its aberrant activation provides cancer cells with escape mechanisms from immune checkpoint inhibitors. E7386, an orally active selective inhibitor of the interaction between ß-catenin and CREB binding protein, which is part of the Wnt/ß-catenin signaling pathway, disrupts the Wnt/ß-catenin signaling pathway in HEK293 and adenomatous polyposis coli (APC)-mutated human gastric cancer ECC10 cells. It also inhibited tumor growth in an ECC10 xenograft model and suppressed polyp formation in the intestinal tract of ApcMin /+ mice, in which mutation of Apc activates the Wnt/ß-catenin signaling pathway. E7386 demonstrated antitumor activity against mouse mammary tumors developed in mouse mammary tumor virus (MMTV)-Wnt1 transgenic mice. Gene expression profiling using RNA sequencing data of MMTV-Wnt1 tumor tissue from mice treated with E7386 showed that E7386 downregulated genes in the hypoxia signaling pathway and immune responses related to the CCL2, and IHC analysis showed that E7386 induced infiltration of CD8+ cells into tumor tissues. Furthermore, E7386 showed synergistic antitumor activity against MMTV-Wnt1 tumor in combination with anti-PD-1 antibody. In conclusion, E7386 demonstrates clear antitumor activity via modulation of the Wnt/ß-catenin signaling pathway and alteration of the tumor and immune microenvironments, and its antitumor activity can be enhanced in combination with anti-PD-1 antibody. SIGNIFICANCE: These findings demonstrate that the novel anticancer agent, E7386, modulates Wnt/ß-catenin signaling, altering the tumor immune microenvironment and exhibiting synergistic antitumor activity in combination with anti-PD-1 antibody.

Improved Visualization of Middle Ear Cholesteatoma with Computed Diffusion-weighted Imaging.

Computed DWI (cDWI) is a mathematical technique that calculates arbitrary higher b value images from at least two different lower b values. In addition, the removal of high intensity noise with image processing on cDWI could improve cholesteatoma-background contrast-to-noise ratio (CNR). In the present study, noise reduction was performed by the cut-off values of apparent diffusion coefficient (ADC) less than 0 and 0.4 × 10-3 s/mm2. The cholesteatoma to non-cholesteatoma CNR was increased using a noise reduction algorithm for clinical setting.

Diffusivity of intraorbital lymphoma vs. inflammation: comparison of single shot turbo spin echo and multishot echo planar imaging techniques.

PURPOSE: To compare the abilities of turbo spin-echo diffusion-weighted imaging (TSE DWI) and multi-shot echo planar DWI (MSh DWI) to discriminate orbital lymphoma from inflammatory lesions. MATERIALS AND METHODS: Twenty-nine patients with pathologically confirmed lymphomas and 39 patients with inflammation were imaged with a 3.0-T system. The apparent diffusion coefficient (ADC) of each lesion was measured. Signal intensities compared to normal grey matter on conventional imaging were also measured. RESULTS: The ADCs derived from the TSE DWI of the lymphomas (0.68 ± 0.14 × 10-3 mm2/s) were significantly lower than those of the inflammation cases (1.04 ± 0.39 × 10-3 mm2/s; p < 0.001). The ADCs derived from MSh DWI could not be used to separate the lymphomas from the inflammation (1.16 ± 0.43 × 10-3 mm2/s vs. 1.36 ± 0.48 × 10-3 mm2/s; p = 0.06). Conventional sequences also could not separate the lymphomas from the inflammation (p > 0.05). The ROC analysis showed the best diagnostic performance with ADCs derived from TSE DWI (the area under the curve: AUC = 0.831) followed by ADC derived from MSh DWI (AUC = 0.633). CONCLUSION: The ADCs derived from TSE DWI might help to differentiate orbital lymphomas from inflammation. KEY POINTS: • ADC of lymphoma was significantly lower than that of inflammation. • ADC derived from TSE DWI showed the best diagnostic performance. • This study was conducted by a 3-T MR scanner.

Differentiation of hypointense nodules on gadoxetic acid-enhanced hepatobiliary-phase MRI using T2 enhanced spin-echo imaging with the time-reversed gradient echo sequence: An initial experience.

PURPOSE: To optimize the flip angle (FA) of the T2 enhanced spin-echo imaging using the time reversed gradient echo (T2FFE) and evaluate its utility for differentiating hypointensity nodules in the hepatobiliary phase (HBP) of gadoxetic acid-enhanced (Gd-EOB) MRI. MATERIALS AND METHODS: First, FA optimization of the T2FFE in the HBP was investigated by comparing signal-to-noise ratio (SNR) among different FAs using phantoms. The liver-to-muscle contrast ratios (CRLiver-Muscle) and image quality among three FAs (20°, 50° and 80°) were compared using images of 10 patients. Next, the utility of the T2FFE with an optimized FA for differentiating hypointensity nodules in the HBP was assessed by comparing the lesion-to-liver contrast ratio (CRLesion-Liver) among cysts, hemangiomas, hepatocellular carcinomas, and metastatic tumors in 32 patients. RESULTS: SNR increased as FA increased, but leveled off at FAs of 50° and greater. The FA of 50° showed significantly better image quality scores than that of 80° (p<0.05). After employing an FA of 50°, the CRLesion-Liver value indicated that the T2FFE depicted benign lesions as hyperintense and most malignant lesions as hypointense in relation with the liver parenchyma (p<0.05). CONCLUSION: The T2FFE in the HBP of Gd-EOB-MRI is useful for differentiating benign and malignant liver lesions.

Image quality and diagnostic performance of free-breathing diffusion-weighted imaging for hepatocellular carcinoma.

AIM: To retrospectively evaluate the diagnostic performance of free-breathing diffusion-weighted imaging (FB-DWI) with modified imaging parameter settings for detecting hepatocellular carcinomas (HCCs). METHODS: Fifty-one patients at risk for HCC were scanned with both FB-DWI and respiratory-triggered DWI with the navigator echo respiratory-triggering technique (RT-DWI). Qualitatively, the sharpness of the liver contour, the image noise and the chemical shift artifacts on each DWI with b-values of 1000 s/mm2 were independently evaluated by three radiologists using 4-point scoring. We compared the image quality scores of each observer between the two DWI methods, using the Wilcoxon signed-rank test. Quantitatively, we compared the signal-to-noise ratios (SNRs) of the liver parenchyma and lesion-to-nonlesion contrast-to-noise ratios (CNRs) after measuring the signal intensity on each DWI with a b-factor of 1000 s/mm2. The average SNRs and CNRs between the two DWI methods were compared by the paired t-test. The detectability of HCC on each DWI was also analyzed by three radiologists. The detectability provided by the two DWI methods was compared using McNemar's test. RESULTS: For all observers, the averaged image quality scores of FB-DWI were: Sharpness of the liver contour [observer (Obs)-1, 3.08 ± 0.81; Obs-2, 2.98 ± 0.73; Obs-3, 3.54 ± 0.75], those of the distortion (Obs-1, 2.94 ± 0.50; Obs-2, 2.71 ± 0.70; Obs-3, 3.27 ± 0.53), and the chemical shift artifacts (Obs-1, 3.38 ± 0.60; Obs-2, 3.15 ± 1.07; Obs-3, 3.21 ± 0.85). The averaged image quality scores of RT-DWI were: Sharpness of the liver contour (Obs-1, 2.33 ± 0.65; Obs-2, 2.37 ± 0.74; Obs-3, 2.75 ± 0.81), distortion (Obs-1, 2.81 ± 0.56; Obs-2, 2.25 ± 0.74; Obs-3, 2.96 ± 0.71), and the chemical shift artifacts (Obs-1, 2.92 ± 0.59; Obs-2, 2.21 ± 0.85; Obs-3, 2.77 ± 1.08). All image quality scores of FB-DWI were significantly higher than those of RT-DWI (P < 0.05). The average SNR of the normal liver parenchyma by FB-DWI (11.0 ± 4.8) was not significantly different from that shown by RT-DWI (11.0 ± 5.0); nor were the lesion-to-nonlesion CNRs significantly different (FB-DWI, 21.4 ± 17.7; RT-DWI, 20.1 ± 15.1). For all three observers, the detectability of FB-DWI (Obs-1, 43.6%; Obs-2, 53.6%; and Obs-3, 45.0%) was significantly higher than that of RT-DWI (Obs-1, 29.1%; Obs-2, 43.6%; and Obs-3, 34.5%) (P < 0.05). CONCLUSION: FB-DWI showed better image quality and higher detectability of HCC compared to RT-DWI, without significantly reducing the SNRs of the liver parenchyma and lesion-to-nonlesion CNRs.

Optimization and Clinical Feasibility of Free-breathing Diffusion-weighted Imaging of the Liver: Comparison with Respiratory-Triggered Diffusion-weighted Imaging.

PURPOSE: We compared the image quality of free-breathing diffusion-weighted imaging (FB-DWI) to that of respiratory-triggered DWI (RT-DWI) after proper optimization. MATERIALS AND METHODS: Three healthy subjects were scanned to optimize magnetic resonance (MR) parameters of FB-DWI to improve image quality, including spatial resolution, image noise, and chemical shift artifacts. After this optimization, we scanned 32 patients with liver disease to assess the clinical feasibility of the optimized FB-DWI. Of the 32 patients, 14 had a total of 28 hepatocellular carcinomas (HCCs), four had a total of 15 metastatic liver tumors, and the other 14 had no tumor. Qualitatively, we compared the image quality scores of FB-DWI with those of RT-DWI with the Wilcoxon signed-rank test. Quantitatively, we compared the signal-to-noise ratios (SNRs) of the liver parenchyma, lesion-to-nonlesion contrast-to-noise ratios (CNRs) and apparent diffusion coefficient (ADC) values of the liver parenchyma and liver tumor by the paired t-test. RESULTS: The average scores of image quality for sharpness of liver contour, image noise, and chemical shift artifacts were significantly higher for FB-DWI than RT-DWI (P < 0.05). SNRs, CNRs, and ADC values of the liver parenchyma and tumors did not differ significantly between the 2 DWI methods. CONCLUSION: Compared with RT-DWI, the optimized FB-DWI provided better spatial resolution, fewer artifacts, and comparable SNRs, lesion-to-nonlesion CNRs, and ADC values.

Improvement of T1 contrast in whole-brain black-blood imaging using motion-sensitized driven-equilibrium prepared 3D turbo spin echo (3D MSDE-TSE).

We demonstrated a new scheme for performing the T1-enhanced whole-brain black-blood imaging pulse sequence using motion-sensitized driven-equilibrium prepared 3-dimensional (3D) turbo spin echo (MSDE-TSE) with anti-driven-equilibrium post pulse. The use of an anti-driven-equilibrium pulse considerably improved the T1 contrast of MSDE-TSE black-blood images. This sequence can be used for whole-brain 3D volumetric T1-weighted black-blood imaging and may improve the accuracy of anatomical localization for certain brain lesions.

Quantification of myocardial iron deficiency in nonischemic heart failure by cardiac T2* magnetic resonance imaging.

The aim of this study was to use T2* cardiac magnetic resonance (CMR) imaging to quantify myocardial iron content in patients with heart failure (HF) and to investigate the relation between iron content, cardiac function, and the cause of HF. CMR data were analyzed from 167 patients with nonischemic and 31 with ischemic HF and 50 patients with normal ventricular function. Short-axis T2* imaging was accomplished using 3-T scanner and multiecho gradient-echo sequence. Myocardial T2* value (M-T2*) was calculated by fitting the signal intensity data for the mid-left ventricular (LV) septum to a decay curve. Patients with nonischemic HF were categorized into patients with LV ejection fraction (LVEF) <35% or ≥35%. The relation between nonischemic HF with LVEF <35% and the risk for major adverse cardiac events was analyzed by multivariate logistic regression analysis using M-T2* and HF biomarkers. M-T2* was significantly greater for patients with nonischemic HF (LVEF <35%: 29 ± 7 ms, LVEF ≥35%: 26 ± 5 ms) than for patients with normal LV function (22 ± 3 ms, p <0.0001) or ischemic HF (22 ± 4 ms, p <0.001). The odds ratio was 1.21 for M-T2* (p <0.0001) and 1.0015 for brain natriuretic peptide (p <0.0001) in relation to nonischemic HF with LVEF <35%. Furthermore, this value was 0.96 for systolic blood pressure (p = 0.012) and 1.02 for M-T2* (p = 0.03) in relation to the risk for major adverse cardiac events in patients with nonischemic HF. In conclusion, T2* CMR demonstrated the robust relation between myocardial iron deficiency and nonischemic HF. M-T2* is a biomarker that can predict adverse cardiac function in patients with nonischemic HF.

Whole-brain black-blood imaging with magnetization-transfer prepared spin echo-like contrast: a novel sequence for contrast-enhanced brain metastasis screening at 3T.

In contrast-enhanced (CE) brain metastasis screening, coexistence of enhanced blood vessel suppression and higher tumor-to-parenchyma contrast may improve radiologists' performances in detecting brain metastases compared with conventional sequences. In this study, we propose a new scheme, allowing both suppression of blood signals and improvement of tumor-to-parenchyma contrast, using motion-sensitized driven equilibrium prepared 3D low-refocusing flip-angle turbo spin echo (TSE) ("magnetization transfer prepared spin echo"-like contrast volume examination: MATLVE) for brain metastasis screening at 3.0 T, and we compare MATLVE to conventional three-dimensional (3D)-gradient recalled echo (GRE) and 3D-TSE sequences. With the use of MATLVE, the signal intensity of CE blood decreased substantially. Furthermore, the contrast ratio of tumor-to-white matter was significantly higher than in either conventional 3D-GRE or 3D-TSE. MATLVE can be used for 3D volumetric post-CE black-blood imaging, and it may be effective in detecting small brain metastases by selectively enhancing tumor signals while suppressing blood signals.

Reevaluation of T2-weighted fast field echo (T2FFE): application to rapid volumetric black-blood imaging.

T2-fast field echo (T2FFE) sequence is a rapid T2-weighted steady state free precession sequence, but has not become a widely utilized MR-imaging strategy because of its low signal-to-noise ratio and high sensitivity to motion. These effects have seriously limited the clinical use of T2FFE and therefore T2FFE has not been used for routine clinical studies. Nevertheless, in this study, we have investigated the possibility of clinical application by re-optimization of the T2FFE on the current MRI systems. Our purpose in this study was to explore the sensitivity of T2FFE to flow spins using a flow phantom and a contrast optimization/comparison with 2D turbo spin-echo (TSE) T2-weighted images, and to evaluate its feasibility in volunteers and patients. This study demonstrated that the T2FFE sequence achieves rapid 3D T2-weighted black-blood imaging while minimizing the impact of motion using a low flip angle under the shortest repetition time and the shortest echo time conditions. Furthermore, 3D T2FFE with use of an optimal flip angle (30°-40°) can provide contrast equivalent to that of 2D TSE T2-weighted images. This proposed T2FFE sequence might be promising for numerous clinical applications.

A cost-sensitive extension of AdaBoost with markov random field priors for automated segmentation of breast tumors in ultrasonic images.

PURPOSE: A cost-sensitive extension of AdaBoost based on Markov random field (MRF) priors was developed to train an ensemble segmentation process which can avoid irregular shape, isolated points and holes, leading to lower error rate. The method was applied to breast tumor segmentation in ultrasonic images. METHODS: A cost function was introduced into the AdaBoost algorithm that penalizes dissimilar adjacent labels in MRF regularization. The extended AdaBoost algorithm generates a series of weak segmentation processes by sequentially selecting a process whose error rate weighted by the cost is minimum. The method was tested by generation of an ensemble segmentation process for breast tumors in ultrasonic images. This was followed by a active contour to refine the extracted tumor boundary. RESULTS: The segmentation performance was evaluated by tenfold cross validation test, where 300 carcinomas, 50 fibroadenomas, and 50 cysts were used. The experimental results revealed that the error rate of the proposed ensemble segmentation was two-thirds the error rate of the segmentation trained by AdaBoost without MRF. By combining the ensemble segmentation with a geodesic active contour, the average Jaccard index between the extracted tumors and the manually segmented true regions was 93.41%, significantly higher than the conventional segmentation process. CONCLUSION: A cost-sensitive extension of AdaBoost based on MRF priors provides an efficient and accurate means for the segmentation of tumors in breast ultrasound images.

Discrimination of breast tumors in ultrasonic images using an ensemble classifier based on the AdaBoost algorithm with feature selection.

This paper proposes a novel algorithm to estimate a log-compressed K distribution parameter and presents an algorithm to discriminate breast tumors in ultrasonic images. We computed a total of 208 features for discrimination, including those based on a parameter of a log-compressed K-distribution, which quantifies the homogeneity of the echo pattern in the tumor, but is influenced by compression parameters in the ultrasonic device. The proposed algorithm estimates the parameter of the log-compressed K-distribution in a manner free from this influence. To quantify irregularities in tumor shape, pattern-spectrum-based features were newly developed in this paper. The discrimination process uses an ensemble classifier trained by a multiclass AdaBoost learning algorithm (AdaBoost.M2), combined with a sequential feature-selection process. A 10-fold cross-validation test validated the performance, and the results were compared with those of a Mahalanobis distance-based classifier and a multiclass support vector machine. A total of 200 carcinomas, 50 fibroadenomas, and 50 cysts were used in the experiments. This paper demonstrates that the combination of a classifier trained by AdaBoost.M2 and features based on the estimated parameter of a log-compressed K-distribution, as well as those of the pattern spectrum, are useful for the discrimination of tumors.