Mingyue Cai

Hepatocellular Carcinoma with Portal Vein Tumor Thrombus: Treatment with Transarterial Chemoembolization Combined with Sorafenib—A Retrospective Controlled Study

PURPOSE To determine the safety and efficacy of transarterial chemoembolization (TACE) combined with sorafenib (hereafter, TACE-sorafenib) in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). MATERIALS AND METHODS This study was approved by the institutional review board, and the requirement for informed consent was waived. The medical records of consecutive patients with HCC and PVTT who underwent TACE-sorafenib or TACE alone from January 2010 to December 2012 were retrospectively evaluated. Sorafenib (400 mg) was administered twice daily. Outcomes of patients who underwent TACE-sorafenib were compared with outcomes of patients who underwent TACE by using the Kaplan-Meier method according to types of PVTT: PVTT in the main portal vein (type A), PVTT in the first-order portal vein branch (type B), and PVTT in second- or lower-order portal vein branches (type C). RESULTS Ninety-one patients were included in the analysis; 46 patients underwent TACE-sorafenib and 45 underwent TACE. TACE-sorafenib showed significant survival benefits compared with TACE in patients with type B (median survival, 13 months vs 6 months; P = .002) or type C (median survival, 15 months vs 10 months; P = .003) PVTT. TACE-sorafenib and main PVTT were the independent prognostic factors for survival at uni- and multivariate analysis. Liver function after TACE-sorafenib worsened only in patients with main PVTT. Sorafenib-related adverse events of grade 3 or higher occurred in 16 patients (35%). CONCLUSION TACE-sorafenib side effects were acceptable, and this treatment may improve overall survival in patients with HCC with first-order or lower-branch PVTT when compared with patients who underwent TACE alone.

Portal Vein Thrombosis after Partial Splenic Embolization in Liver Cirrhosis: Efficacy of Anticoagulation and Long-term Follow-up

PURPOSE To investigate the treatment and long-term outcome of portal vein thrombosis (PVT) after partial splenic embolization (PSE). MATERIALS AND METHODS From January 2006 to December 2011, 145 patients with hypersplenism caused by cirrhotic portal hypertension underwent PSE. In 11 cases, PVT was detected 13-42 days after PSE. Among the 11 patients, 5 underwent anticoagulant therapy because of clinical symptoms, and 6 did not receive anticoagulation because they were symptom-free (4 patients) or experienced variceal bleeding (2 patients). The long-term follow-up data from these 11 patients were analyzed retrospectively. RESULTS The 11 patients with PVT had a mean splenic infarction ratio of 71.5%. The mean duration of follow-up was 37.6 months. During the follow-up period, none of the 5 patients who underwent anticoagulation developed variceal hemorrhage despite presenting with large esophagogastric varices. Four of the five patients achieved complete resolution of thrombosis, and one did not develop thrombus progression. However, among the 6 patients who did not undergo anticoagulation, 2 developed esophagogastric variceal hemorrhage secondary to thrombus progression, 3 developed cavernous transformation of the portal vein and variceal progression, and 1 had partial calcification of the thrombus. Two patients who had variceal bleeding or rebleeding underwent a transjugular intrahepatic portosystemic shunt. Complete recanalization of the portal vein was achieved after the procedures. CONCLUSIONS PVT is a severe, potentially fatal complication of PSE. Early detection of PVT and prompt anticoagulation are effective to avoid serious consequences of PVT.

Role of multi-detector computed tomography for biliary complications after liver transplantation

AIM To investigate the diagnostic performance of multi-detector computed tomography (MDCT) in detecting biliary complications after orthotopic liver transplantation (OLT). METHODS Eighty-three consecutive OLT recipients, who presented with clinical or biochemical signs of biliary complications, underwent MDCT examination. Two experienced radiologists assessed MDCT images in consensus to determine biliary complications. Final confirmation was based on percutaneous transhepatic cholangiography or endoscopic retrograde cholangiography in 58 patients, surgery in four patients, liver biopsy in 10, and clinical and sonography follow-up in 11 patients. RESULTS Biliary complications were eventually confirmed in 62 of 83 patients (74.7%), including anastomotic biliary strictures in 32, nonanastomotic biliary strictures in 21, biliary stones in nine (5 with biliary strictures), anastomotic bile leak in five, and biloma in six (all with nonanastomotic strictures, and 2 with biligenic hepatic abscess). Twenty-one patients had no detection of biliary complications. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of MDCT for detecting biliary strictures were 90.6%, 86.7%, 89.2%, 92.3% and 83.9%, respectively. For detecting biliary stones, anastomotic bile leak and biloma, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value of MDCT were all 100%. CONCLUSION MDCT is a useful screening tool for detecting biliary complications after OLT.

Hepatic resection after transarterial chemoembolization increases overall survival in large/multifocal hepatocellular carcinoma: a retrospective cohort study

To investigate the prognosis of transarterial chemoembolization (TACE) followed by hepatic resection (HR) in large/multifocal hepatocellular carcinoma (HCC), the medical records of consecutive HCC patients who underwent TACE between January 2006 and December 2010 were retrospectively analyzed. Patients who received TACE alone comprised the T group (61 patients), while those who received HR after TACE comprised the T+R group (49 patients). All the resections were successfully performed, and only one class V complication occurred. While liver function was altered from baseline within 1 week after HR, it recovered within 1 month. Overall survival (OS) of the T+R and T groups were compared, and sub-group analyses were performed based on baseline α-fetoprotein (AFP) levels, the reduction of AFP, and tumor response before HR. Overall survival (OS) in the T+R group was longer than in the T group (47.00 ± 2.87 vs. 20.00 ± 1.85 months, P < 0.001). OS in the T+R group with AFP reduction was less than 50%, and OS among those with a poor tumor response before HR did not differ from the T group (P > 0.05). These patients may not benefit from the combined treatment. Our findings suggest HR after TACE is safe and effective for large/multifocal HCC, and prolongs OS when compared to TACE alone.

Hepatocellular Carcinoma Cells Carrying a Multimodality Reporter Gene for Fluorescence, Bioluminescence, and Magnetic Resonance Imaging In Vitro and In Vivo.

RATIONALE AND OBJECTIVES The study aimed to evaluate the feasibility of imaging or tracking hepatocellular carcinoma cells by modifying these cells to carry a multimodality reporter gene, enabling fluorescence, bioluminescence, and magnetic resonance imaging (MRI) in vitro and in vivo. MATERIALS AND METHODS HepG2 cells were labeled with the enhanced green fluorescent protein (EGFP)/luciferase2/ferritin-the multimodality reporter gene (labeled HepG2 cells). The labeled and unlabeled HepG2 cells were cultured in vitro and then injected subcutaneously into mice as a hepatoma model in vivo. The expressions of EGFP, luciferase2, and ferritin in HepG2 cell suspensions and hepatoma model were investigated using fluorescence, bioluminescence, and MRI. RESULTS Individual HepG2 cells expressing EGFP were identified under blue laser excitation. The linear coefficient between the optical signal intensity of luciferase2 and the number of labeled cells was 0.993. MRI was used to distinguish the T2* signal of 2 × 107 cells/mL between the labeled (6.67 ± 1.88 ms) and unlabeled cells (10.66 ± 2.22 ms) (P = 0.034). In vivo, individual HepG2 cells expressing EGFP in frozen sections were observed. Labeled cells expressing luciferase2 have been detected since the second day after injection, and the bioluminescence increased with the tumor size. The T2* signal was significantly different between the labeled (6.04 ± 1.60 ms) and unlabeled cells (17.06 ± 2.17 ms) (P <0.001). CONCLUSIONS A multimodality reporter gene consisting of EGFP, luciferase2, and ferritin was successfully integrated into the HepG2 cell genome via a lentiviral vector and was highly expressed in the daughter cells. These cells could be detected by fluorescence, bioluminescence, and MRI in vitro and in vivo.

Early prediction of survival in hepatocellular carcinoma patients treated with transarterial chemoembolization plus sorafenib

AIM To identify clinical biomarkers that could early predict improved survival in patients with advanced-stage hepatocellular carcinoma (HCC) treated with transarterial chemoembolization combined with sorafenib (TACE-S). METHODS We retrospectively evaluated the medical records of consecutive patients with advanced-stage HCC who underwent TACE-S from January 2012 to December 2015. At the first follow-up 4-6 wk after TACE-S (median, 38 d; range, 33-45 d), patients exhibiting the modified Response Evaluation Criteria in Solid Tumors (mRECIST)-evaluated complete response, partial response, and stable disease were categorized as early disease control. At this time point, multiple variables were analyzed to identify the related factors affecting survival. RESULTS Ninety-five patients were included in this study, and 60 of these patients achieved early disease control, with an overall disease control rate (DCR) of 63.2%. Patients who got sorafenib at the first TACE (no previous TACE) and patients without portal vein tumor thrombus (PVTT) had a higher DCR than those who underwent previous TACE before TACE-S (72.4% vs 48.6%, P = 0.019) and those with PVTT (75.5% vs 50.0%, P = 0.010). Early disease control after TACE-S, no previous TACE, and no PVTT were the independent prognostic factors for survival in the uni- and multivariate analyses. CONCLUSION The first follow-up 4-6 wk after TACE-S can be used as the earliest time point to assess the response to TACE-S, and patients with mRECIST-evaluated early disease control, no previous TACE, and no PVTT had better survival.

Medium or Large Hepatocellular Carcinoma: Sorafenib Combined with Transarterial Chemoembolization and Radiofrequency Ablation

Purpose To determine the safety and efficacy of sorafenib combined with transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) (hereafter, S-TACE-RFA) in patients with medium or large (range, 3.1-7.0 cm in diameter) hepatocellular carcinoma (HCC). Materials and Methods This retrospective study evaluated the medical records of consecutive patients with medium or large HCC who underwent S-TACE-RFA or combined TACE and RFA (hereafter, TACE-RFA) from January 2010 to December 2014. Sorafenib was started 3-5 days after TACE, and RFA was performed 1-2 weeks after TACE. Treatment complications, recurrence-free survival (RFS), and overall survival (OS) in patients who underwent S-TACE-RFA were compared with those in patients who underwent TACE-RFA. Results Of the 174 patients who underwent S-TACE-RFA or TACE-RFA, 106 who met the eligibility criteria were included in this study. Among them, 40 underwent S-TACE-RFA and 66 underwent TACE-RFA. The patients who underwent S-TACE-RFA had longer RFS (median, 24.0 vs 10.0 months; P = .04) and better OS (median, 63.0 vs 36.0 months, P = .048) than those who underwent TACE-RFA. S-TACE-RFA and α-fetoprotein level were independent prognostic factors for survival in uni- and multivariable analyses. The rate of complications in patients who underwent S-TACE-RFA was similar to that in patients who underwent TACE-RFA (22.5% vs 18.2%, P = .59). Conclusion S-TACE-RFA resulted in longer RFS and better OS than did TACE-RFA in patients with medium or large HCC.

Andrographolide Ameliorates Liver Fibrosis in Mice: Involvement of TLR4/NF-κB and TGF-β1/Smad2 Signaling Pathways

Liver fibrosis is characterized by activated hepatic stellate cells (HSC) and extracellular matrix accumulation. Blocking the activation of HSC and the inflammation response are two major effective therapeutic strategies for liver fibrosis. In addition to the long history of using andrographolide (Andro) for inflammatory disorders, we aimed at elucidating the pharmacological effects and potential mechanism of Andro on liver fibrosis. In this study, liver fibrosis was induced by carbon tetrachloride (CCl4) and the mice were intraperitoneally injected with Andro for 6 weeks. HSC cell line (LX-2) and primary HSC were also treated with Andro in vitro. Treatment of CCl4-induced mice with Andro decreased the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), Sirius red staining as well as the expression of α smooth muscle actin (α-SMA) and transforming growth factor- (TGF-) β1. Furthermore, the expression of Toll-like receptor (TLR)4 and NF-κB p50 was also inhibited by Andro. Additionally, in vitro data confirmed that Andro treatment not only attenuated the expression of profibrotic and proinflammatory factors but also blocked the TGF-β1/Smad2 and TLR4/NF-κB p50 pathways. These results demonstrate that Andro prevents liver inflammation and fibrosis, which is in correlation with the inhibition of the TGF-β1/Smad2 and TLR4/NF-κB p50 pathways, highlighting Andro as a potential therapeutic strategy for liver fibrosis.

Amelioration of cirrhotic portal hypertension by targeted cyclooxygenase-1 siRNA delivery to liver sinusoidal endothelium with polyethylenimine grafted hyaluronic acid

Portal hypertension (PH), a leading cause of mortality in cirrhosis, lacks effective clinical therapeutic strategies. The increased thromboxane A2 (TXA2), derived primarily from the upregulation of cyclooxygenase-1 (COX-1) in cirrhotic liver sinusoidal endothelial cells (LSECs), is responsible for hepatic endothelial dysfunction and PH. Thus, blocking the COX-1 pathway in cirrhotic LSECs may benefit the treatment of PH. In this study, hyaluronate-graft-polyethylenimine (HA-PEI) was synthesized for the targeted delivery of COX-1 siRNA to LSECs. Compared to non-targeted PEI, HA-PEI mediated much more efficient siRNA delivery, which resulted in potent targeted gene silencing in LSECs. In vivo, HA-PEI notably increased the accumulation of siRNA along the sinusoidal lining of the liver, inhibited over-activation of the COX-1/TXA2 pathway in LSECs, and successfully reduced portal pressure in cirrhotic mice. These results highlight the potential of HA-PEI complexed siRNA to serve as a LSECs-specific nanomedical system for effective gene therapy in PH.