Advances in Studies of Chiglitazar Sodium, a Novel PPAR Pan-Agonist, for the Treatment of Type 2 Diabetes Mellitus.

Chiglitazar sodium is a new peroxisome proliferator-activated receptor (PPAR) pan-agonist with independent intellectual property rights in China. It can treat type 2 diabetes mellitus and regulate metabolism by modestly activating PPARα, PPARγ, and PPARδ to improve insulin sensitivity, regulate blood glucose, and promote fatty acid oxidation and utilization. Chiglitazar sodium has a significant insulin-sensitizing effect and is advantageous in reducing fasting and postprandial blood glucose levels, particularly at the 48 mg dose in patients with concomitant high triglycerides in terms of blood glucose and triglyceride level control.

Long-term outcomes of combined radiofrequency ablation and multipronged ethanol ablation for the treatment of unfavorable hepatocellular carcinoma

PURPOSE: To evaluate the local efficacy, safety, and long-term outcomes of combined radiofrequency ablation (RFA) and multipronged ethanol ablation (EA) in the treatment of unfavorable hepatocellular carcinoma (HCC) and to determine the prognostic factors for survival. METHODS: Between August 2009 and December 2017, 98 patients with 110 unfavorable HCC nodules who underwent combined RFA and multipronged EA were retrospectively enrolled in the study. Unfavorable HCC was defined as a medium (3.1-5.0 cm) or large (5.1-7.0 cm) HCC nodule, a tumor located at a high-risk site, or a perivascular tumor. The treatment response, overall survival (OS), and recurrence-free survival (RFS) were analyzed. The Kaplan-Meier method and Cox proportional hazards regression model were used to evaluate the prognostic factors. RESULTS: Complete ablation was obtained in 80.9% (89/110) of the tumors after initial treatment. Major complications were observed in 3 (3.1%) patients. The cumulative incidence of local tumor progression (LTP) was 23.5% at five years, and no variable was found to be an independent predictive factor for LTP. The five-year OS and RFS rates were 41.9% and 34.0%, respectively. Multivariate analysis showed that the serum alpha-fetoprotein level, tumor size, presence of residual tumor after ablation, and extrahepatic metastases were significant prognostic factors for OS (P = 0.023, P = 0.030, P = 0.001, and P = 0.010, respectively). Tumor type and the number of tumors were predictive factors for RFS (P = 0.029 and P = 0.001, respectively). A perivascular tumor was not an independent predictive factor for OS or RFS. CONCLUSION: Combined RFA and multipronged EA is a safe and effective treatment for unfavorable HCC, especially for perivascular tumors.

Multiple-Electrode Switching-Based Radiofrequency Ablation vs. Conventional Radiofrequency Ablation for Single Early-Stage Hepatocellular Carcinoma Ranging From 2 to 5 Cm.

Purpose: To retrospectively compare the treatment outcome of multiple-electrode switching-based radiofrequency ablation (switching RFA) and the conventional RFA for early-stage hepatocellular carcinoma (HCC). Methods: A total of 122 patients with single early-stage HCC ranging from 2.1 to 5.0 cm received ultrasonography-guided percutaneous RFA as the first-line treatment. Seventy-one patients underwent switching RFA, and 51 underwent conventional RFA. Tumor response, major complication, local tumor progression (LTP), and overall survival (OS) were compared between the two groups. Log-rank tests and Cox regression models were used for univariate and multivariate analyses to identify predictors of LTP and OS. Results: The rate of initial local complete response rates were 100% (71/71) in the switching RFA group and 98.0% (50/51) in the conventional RFA group (P > 0.05). No major complication occurred in the switching RFA group, whereas two in the conventional RFA group. After a median follow-up period of 45.9 months (range, 9.8-60.0 months), the rates of LTP in the switching RFA and conventional RFA groups were 19.7% (14/71) and 41.2% (21/51), respectively. The cumulative LTP rates at 1, 3, and 5 years were 11.3, 20.5, and 20.5% for switching RFA and 17.6, 38.7, and 46.7% for conventional RFA, respectively (p < 0.001). Switching RFA was an independent factor associated with a lower LTP rate (p = 0.022). Five-year OS rates were 75.8% after switching RFA vs. 66.2% after conventional RFA (p = 0.363). Extrahepatic recurrence was a significant prognostic factor for OS in multivariable analysis. Conclusion: Compared with conventional RFA, switching RFA provides a high local tumor control for single early-stage HCC. An ongoing randomized trial might help to clarify the role of this approach for the treatment of HCC.

Supramolecular Photothermal Nanomedicine Mediated Distant Tumor Inhibition via PD-1 and TIM-3 Blockage.

Supramolecular nanoparticles for photothermal therapy (PTT) have shown promising therapeutic efficacy in the primary tumor and great potential for turning the whole-body immune microenvironment from "cold" to "hot," which allows for the simultaneous treatment of the primary tumor and the metastatic site. In this work, we develop a liposome-based PTT nanoparticle through the self-assembly of FDA-approved intravenous injectable lipids and a photothermal agent, indocyanine green (ICG). The obtained ICG-liposome shows long-term storage stability, high ICG encapsulation efficiency (>95%), and enhanced near-infrared (NIR) light-triggered photothermal reaction both in vitro and in vivo. The ICG-liposome efficiently eradicated the primary tumor upon laser irradiation in two colon cancer animal models (CT26 and MC38) and promoted the infiltration of CD8 T cells to distant tumors. However, PTT from ICG-liposome shows only a minimal effect on the inhibition of distant tumor growth in long-term monitoring, predicting other immunosuppressive mechanisms that exist in the distant tumor. By immune-profiling of the tumor microenvironment, we find that the distant tumor growth after PTT highly correlates to compensatory upregulation of immune checkpoint biomarkers, including program death-1 (PD-1), T-cell immunoglobulin, and mucin domain-containing protein 3 (TIM-3), in tumor-infiltrating CD8 T cells. Based on this mechanism, we combine dual PD-1 and TIM-3 blockade with PTT in an MC38 tumor model. This combo successfully clears the primary tumor, generates a systemic immune response, and inhibits the growth of the distant tumor. The ICG-liposome-combined PD-1/TIM-3 blockade strategy sheds light on the future clinical use of supramolecular PTT for cancer immunotherapy.

Application of Contrast-Enhanced Ultrasound in the Diagnosis of Solid Pseudopapillary Tumors of the Pancreas: Imaging Findings Compared With Contrast-Enhanced Computed Tomography.

OBJECTIVES: The purpose of this study was to assess the characterization and usefulness of contrast-enhanced ultrasound (CEUS) for diagnosing solid pseudopapillary tumors of the pancreas (SPTP) and compare the enhancement patterns with contrast-enhanced computed tomography (CECT). METHODS: Forty-three SPTP lesions proved by pathologic findings in 42 patients examined with CEUS and CECT were included in this study. The enhancement characteristics and typical CEUS features of the tumors were investigated. These characteristics were compared according to lesion sizes. The enhancement patterns of CEUS were compared with CECT. RESULTS: The most common enhancement levels of SPTP in the early phase and late phase for CEUS were isoenhancement (19 of 43 [44.2%]) and hypoenhancement (32 of 43 [74.4%]), respectively. The 4 most common enhancement patterns were hypo-hypo (16 of 43 [37.2%]), iso-iso (11 of 43 [25.6%]), hyper-hypo (8 of 43 [18.6%]), and iso-hypo (8 of 43 [18.6%]) enhancement. For the 43 SPTP lesions, typical CEUS features such as lesion membrane, intralesional vessel, and intralesional compartmentalization enhancements were detected in 30 (69.8%), 27 (62.8%), and 10 (23.2%) cases. Compared with CECT, isoenhancement during the early phase and hypoenhancement during the late phase were the most common imaging characteristics of CEUS. CONCLUSIONS: Lesion membrane, intralesional vessel, and intralesional compartmentalization enhancements are typical CEUS features of SPTP, especially for large lesions (lesion size ≥3.0 cm). Isoenhancement during the early phase and hypoenhancement during the late phase are the most common imaging characteristics of CEUS and CECT, making CEUS a viable alternative diagnostic method that is noninvasive.

Percutaneous thermal ablation for the treatment of colorectal liver metastases and hepatocellular carcinoma: a comparison of local therapeutic efficacy.

AIM: This study aimed to compare the local therapeutic efficacy of percutaneous thermal ablation for colorectal liver metastases (CRLM) and hepatocellular carcinoma (HCC). METHODS: One hundred sixty-one CRLM nodules in 101 patients and 122 HCC nodules in 97 patients were treated with thermal ablation. Complications and local efficacy were retrospectively compared. RESULTS: Major complications were observed in two (2.0%) patients in the CRLM group and one (1.0%) in the HCC group (p = 1.000). The complete ablation (CA) rate of lesions ≤ 3 cm was lower in the CRLM group than in the HCC group (p = 0.018). After a mean follow-up period of 21.1 ± 20.7 months in the CRLM group and 22.1 ± 17.6 months in the HCC group, the local tumour progression (LTP) rate of lesions > 3 cm was higher in the CRLM group than in the HCC group (p = 0.036). The multivariate analysis revealed that only safety margin (≤ 0.5 cm/> 0.5 cm) was a significant predictor of LTP in both CRLM and HCC. CONCLUSIONS: To achieve better local tumour control, thermal ablation should be more aggressive for CRLM than for HCC, especially for large tumours in clinical.

Maximum Value Measured by 2-D Shear Wave Elastography Helps in Differentiating Malignancy from Benign Focal Liver Lesions.

The goal of the work described here was to evaluate the diagnostic efficacy of 2-D shear wave elastography (2-D SWE) in differentiating malignancy from benign focal liver lesions (FLLs). The maxima, minima, means and the standard deviations of 2-D SWE measurements, expressed in kilopascals (Emax, Emin, Emean, ESD), were obtained for 221 patients with 229 FLLs. Receiver operating characteristic curve analysis was performed to evaluate the diagnostic performance of 2-D SWE. The Mann-Whitney U-test was used to assess inter-group differences. Emax, Emin, Emean and ESD were significantly higher in the 164 malignant lesions than in the 65 benign lesions (p < 0.001). For identification of malignant FLLs, the areas under receiver operating characteristic curves for Emax, Emin, Emean and ESD were 0.920, 0.710, 0.879 and 0.915, respectively. Emax was 96.21 ± 35.40 for 19 intrahepatic cholangiocarcinomas and 90.32 ± 54.71 for 35 liver metastatic lesions, which were significantly higher than 61.83 ± 28.87 for 103 hepatocellular carcinomas (p < 0.0001 and p = 0.0237). Emax was 38.72 ± 18.65 for 15 focal nodular hyperplasias, which was significantly higher than 20.56 ± 10.74 for 37 hemangiomas (p = 0.0009). The Emax values for adjacent liver parenchyma of hepatocellular carcinomas and intrahepatic cholangiocarcinomas were significantly higher than those for the other three lesion types (p < 0.005). In conclusion, Emax values of FLLs and adjacent liver parenchyma could help in differentiating malignant from benign FLLs.

Impact factors and the optimal parameter of acoustic structure quantification in the assessment of liver fibrosis.

The aims of the present study are to assess the impact factors on acoustic structure quantification (ASQ) ultrasound and find the optimal parameter for the assessment of liver fibrosis. Twenty healthy volunteers underwent ASQ examinations to evaluate impact factors in ASQ image acquisition and analysis. An additional 113 patients with liver diseases underwent standardized ASQ examinations, and the results were compared with histologic staging of liver fibrosis. We found that the right liver displayed lower values of ASQ parameters than the left (p = 0.000-0.021). Receive gain experienced no significant impact except gain 70 (p = 0.193-1.000). With regard to different diameter of involved vessels in regions of interest, the group ≤2.0 mm differed significantly with the group 2.1-5.0 mm (p = 0.000-0.033) and the group >5.0 mm (p = 0.000-0.062). However, the region of interest size (p = 0.438-1.000) and depth (p = 0.072-0.764) had no statistical impact. Good intra- and inter-operator reproducibilities were found in both image acquisitions and offline image analyses. In the liver fibrosis study, the focal disturbance ratio had the highest correlation with histologic fibrosis stage (r = 0.67, p < 0.001). In conclusion, the testing position, receive gain and involved vessels were the main factors in ASQ examinations and focal disturbance ratio was the optimal parameter in the assessment of liver fibrosis.

Shear wave elastography versus real-time elastography on evaluation thyroid nodules: a preliminary study.

OBJECTIVE: To comparatively evaluate shear wave elastography (SWE) and real-time elastography (RTE) in distinguishing malignant from benign thyroid nodules. METHODS: 49 patients with 64 focal thyroid nodules were enrolled and underwent SWE and RTE before surgery. SWE elasticity indices (mean, minimum and maximum value of 2-mm region of interest) of nodules were measured. For RTE, elastograms were assessed by Rago criteria and nodules with scores of 4 or 5 were classified as suspicious for malignancy. Surgery histopathologic results were adopted as diagnostic standard. RESULTS: Of the 64 nodules, 19 were papillary thyroid carcinomas and 45 were benign. SWE indices were significantly higher in malignant than benign nodules (P<0.05). Areas under the ROC curves (AUC) of SWE parameters were 0.840, 0.831 and 0.788, which were not significantly different from that of RTE showed as 0.880 (P=0.148-0.482). When the most accurate cut-off, 38.3kPa for mean value was applied to predict malignancy, the diagnostic specificity, sensitivity, accuracy, positive predictive value and negative predictive value of SWE and RTE were 68.4% versus 79.0%, 86.7% versus 84.4%, 81.3% versus 78.1%, 68.4% versus 64.7% and 86.7% versus 83.3%, respectively (P=0.683-1.000). CONCLUSION: SWE as a promising tool can be performed in differentiating thyroid nodules with comparable results to RTE.

Sorafenib suppresses the rapid progress of hepatocellular carcinoma after insufficient radiofrequency ablation therapy: an experiment in vivo.

BACKGROUND: Radiofrequency ablation (RFA) is a widely applied treatment for hepatocellular carcinoma (HCC), but insufficient RFA can promote rapid progression of the residual tumor through the hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor A (VEGFA) pathway. Although sorafenib has been successfully applied to advanced HCC, the use of sorafenib in residual tumor cells after RFA has rarely been tested. PURPOSE: To evaluate the potential role of sorafenib as an adjunct to RFA to reduce the recurrence rate after insufficient RFA. MATERIAL AND METHODS: Xenograft tumors of SMMC 7721 were created by subcutaneously inoculating nude mice with hepatoma cells (5 × 10(6) cells per mouse). Fourteen days after inoculation, all mice were divided into three groups (control group [sham puncture], RFA group, and RFA combined with sorafenib treatment group) with six mice in each group. Each group was given a different treatment procedure. After treatment, the volume of the tumors was calculated from the resected specimens. The mRNA and protein expression of HIF-1α and VEGFA was quantified by real-time PCR and immunohistochemistry analysis. The micro-vessel density (MVD) was determined by CD34 immunohistochemistry. RESULTS: Real-time PCR and immunohistochemistry analysis showed that, compared to the RFA group, HIF-1α and VEGFA expression were significantly decreased in the group that received RFA combined with sorafenib treatment (P < 0.05). By comparing the control group with the RFA group, we found that insufficient RFA promoted HIF-1α and VEGFA expression (P < 0.05). Similar results were obtained for MVD expression. Additionally, the combination of RFA with sorafenib therapy resulted in a synergistic reduction in tumor growth compared to insufficient RFA and sham puncture (P < 0.05). CONCLUSION: Sorafenib was able to inhibit the expression of HIF-1α and VEGFA, and sorafenib was able to increase time to recurrence when used as an adjunct to RFA.

Development and evaluation of lipid microbubbles targeted to alpha(v)beta(3)-integrin via biotin-avidin bridge.

This work was to report preparation and quality control of targeted microbubbles (MB(t)) via biotin-avidin bridge, specifically verification of the "biotin-avidin-biotin" sandwich structure. (1) Lipid microbubbles filled with sulphur hexafluoride were produced by sonication and compared with commercially available microbubbles. (2) MB(t) were produced via biotin-avidin bridge. Specifically, the "biotin-avidin-biotin" sandwich structure on the surface of MB(t) was verified in vitro using fluorescence. (3) Adhesion of alpha(v)beta(3)-integrin targeted MB(t) (MB(αvß3)) to human umbilical vein endothelial cells (HUVECs) was tested using the parallel plate flow chamber (PPFC). "Biotin-avidin" is a reliable method to attach molecular probe onto the surface of microbubbles.

The application value of contrast-enhanced ultrasound in the differential diagnosis of pancreatic solid-cystic lesions.

OBJECTIVE: To retrospectively determine the accuracy of baseline ultrasound (BUS) and of contrast-enhanced ultrasound (CEUS) in the differential diagnosis of pancreatic solid-cystic lesions. METHODS: Fifty-four pancreatic solid-cystic lesions in 52 patients were examined with BUS and CEUS, two different seniority radiologists read the images independently, Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic value of BUS and CEUS in the diagnosis of benign or malignant pancreatic solid-cystic lesions, the diagnostic consistency between different seniority radiologists was evaluated by Kappa statistics. RESULTS: Among the 54 lesions, there were pancreatic cyst five cases, pancreatic pseudocyst twenty cases, pancreatic cystadenoma eight cases, pancreatic cystadenocarcinoma seven cases, intraductal papillary mucinous neoplasm of pancreas (IPMN) three cases, pancreatic carcinoma combined liquefied six cases, solid-pseudopallary tumor of pancreas (SPTP) three cases, pancreatic myopericytoma one case, pancreatic lymphangioma one case. After ROC analysis, the areas under the ROC curve (Az) were 0.752 by BUS, 0.928 by CEUS to resident radiologist, and 0.896 by BUS, 0.954 by CEUS to staff radiologist. The correct diagnosis rate of specific disease was 42.6% by BUS, 64.8% by CEUS to staff radiologist (P<0.05), and 33.3% by BUS, 53.7% by CEUS to resident radiologist (P<0.05). The interobserver agreement in CEUS is higher than that in BUS, the Kappa value was 0.889 ± 0.062 and 0.428 ± 0.126 respectively. CONCLUSION: Compared with BUS, CEUS can significantly enhance the diagnostic rate of pancreatic solid-cystic lesions.