Binhao Zhang

JNK inhibitor SP600125 enhances TGF-β-induced apoptosis of RBE human cholangiocarcinoma cells in a Smad-dependent manner.

Transforming growth factor β (TGF-β) signaling is pivotal for the progression of specific types of tumors at certain stages. However, the mechanism by which TGF-β is regulated by other factors remains unclear. In this study, the involvement of SP600125, an inhibitor of c-Jun N-terminal kinase (JNK), in TGF-β-induced apoptosis of the RBE human cholangiocarcinoma cell line was investigated. Exogenous TGF-β1 activated Smad and non‑Smad signaling pathways, including the JNK pathway in RBE cells, and induced apoptosis, which was inhibited by knockdown of Smad4 expression. SP600125 increased the TGF-β1‑induced phosphorylation of Smad2 and Smad3, which enhanced the TGF-β1‑induced transcriptional response and apoptosis in RBE cells. The effect of SP600125 on the transcriptional response and apoptosis was reduced by knockdown of Smad4 expression. In addition, TGF-β1‑induced apoptosis was abrogated using the pan-caspase inhibitor Z‑VAD-fmk. SP600125 promoted the TGF-β1‑induced caspase cleavage, while knockdown of Smad4 expression counteracted this effect. These results indicate that SP600125 enhances TGF-β-induced apoptosis of RBE cells through a Smad‑dependent pathway that involves Smad‑dependent caspase activation. SP600125 is hypothesized to be an ideal therapeutic candidate for treating human cholangiocarcinoma.

Hepatic Resection for Hepatocellular Carcinoma in Patients With Portal Hypertension: A Long-Term Benefit Compared With Transarterial Chemoembolization and Thermal Ablation

AbstractThe optimal treatment for hepatocellular carcinoma (HCC) in cirrhotic patients with portal hypertension (PHT) is still controversial. The objective of this study is to compare HCC patients with PHT treated with hepatic resection to those treated with transarterial chemoembolization (TACE) or thermal ablation.A series of 167 cirrhotic patients with HCC undergoing hepatic resection or TACE/ablation from 2001 to 2008 were retrospectively analyzed. Cirrhotic patients with HCC were divided into 3 groups: hepatic resection in HCC patients with PHT (PHT-R group, n = 58), without PHT (NPHT-R group, n = 67), and TACE or thermal ablation in HCC patients with PHT (PHT-O group, n = 42). The short-term and long-term outcomes of liver function, operative mortality and morbidity, and survival rate were compared.Baseline characteristics were similar among the 3 groups, except for patients in the PHT-R group had larger spleen (16.0 vs 11.4 cm, P = 0.001) and smaller tumor size (4.8 vs 7.1 cm, P = 0.001) in comparison with those in the NPHT-R group. The PHT-R group had better liver function compared with those in the PHT-O group (patients had Child–Turcotte–Pugh class B liver function: 5.2% vs 31%, P = 0.001). There was no significant difference of operative mortality and morbidity in all groups. The 1-, 3-, 5-year survival rates were 80.4%, 55.6%, and 28.1% in the PHT-R group; 79.1%, 64.2%, and 39.8% in the NPHT-R group (vs PHT-R, P = 0.313); and 60.7%, 24.4%, and 7.3% in the PHT-O group (vs PHT-R, P < 0.001).Hepatic resection shows better long-term results for cirrhotic HCC patients with PHT than TACE and thermal ablation.

Hepatocellular Carcinoma With Tumor Thrombus Occupying the Right Atrium and Portal Vein: A Case Report and Literature Review.

AbstractHepatocellular carcinoma (HCC) patients with tumor thrombus extended through the major hepatic veins and inferior vena cava into the right atrium (RA) are rare, and most cases are considered as the advanced stage with a poor prognosis.We report a case of HCC with a tumor thrombus extending into the RA and a tumor thrombus in the portal vein. A literature search for case reports was performed on PubMed.Compared with the published literature, our case is one of the youngest patients, but with the most advanced HCC that invades both the hepatic inflow and outflow vasculature. For this patient, we resected the tumor thrombus in the RA with the use of cardiopulmonary bypass, and then removed the tumor thrombus in the portal vein and ligated the left branch of portal vein. Because of insufficient remnant liver volume, microwave ablation and transcatheter arterial chemoembolization were performed to control the growth of HCC. The patient survived 6 months after surgery.This case suggests that for patients with extension of HCC into the RA and portal vein, surgery is a useful therapeutic modality, even in case that liver tumor cannot be resected.

Solitary perihepatic splenosis mimicking liver lesion: a case report and literature review.

AbstractHepatic splenosis, one type of manifestation of ectopic spleen tissue, is rarely reported. It cannot be distinguished from hepatic malignancies because of lack of significant radiological features. By means of this case report and 31 literature reviews, potential treatment modalities concerning clinical diagnostics, patients management could be discussed.The report presents the case of a 33-year-old man with a liver lesion. Finally, after a mini-incision laparotomy, the lesion was resected and the diagnosis confirmed it as hepatic splenosis. A literature search for case reports published between January 1, 1900, and August 1, 2014, was performed on PubMed.Approximately 80% (27/34) of patients diagnosed with hepatic splenosis had a history of splenectomy. The mean time interval between splenectomy and hepatic splenosis detection was 25 (1.5–47) years. The median size of reported hepatic splenosis is 30 mm in diameter. Technetium-99m-labeled heat denatured red-blood-cells scintigraphy or superparamagnetic iron oxide-enhanced magnetic resonance imaging is now considered to be the optimal method of diagnosing splenosis.Hepatic splenosis requires no treatment in most cases. Operation should be performed if it is accompanied by hypersplenism in hematological diseases. When the diagnosis remains unclear, further biopsy or laparoscopy is recommended. If hepatic splenosis is confirmed, careful follow-up is beneficial.

Perioperative antiviral therapy improves safety in patients with hepatitis B related HCC following hepatectomy

INTRODUCTION Hepatectomies may exacerbate chronic hepatitis B in patients with high hepatitis B viral (HBV) DNA levels, and could result in hepatic insufficiency. Antiviral treatment is effective for suppressing HBV virus loads. This study investigated whether perioperative antiviral therapy is warranted for resection of hepatocellular carcinoma (HCC) with concurrent HBV infections. METHODS Patients with HBV-related HCC (n = 112) who underwent major liver resection were retrospectively divided into two groups based on treatment with perioperative antiviral therapy (antiviral group) (n = 72) or absence of antiviral treatment (control group) (n = 40). RESULTS Exacerbation of chronic hepatitis B occurred in 6 patients of the control group (15.0%). The prevalence of hepatic insufficiency in the antiviral group and control group were 1.4% (1/72) and 12.5% (5/40), respectively (p < 0.05). Five of them (4.5%) developed hepatic encephalopathy and 3 of them (2.7%) developed hepatorenal syndrome. The control group had significantly higher morbidity (75.0% vs. 34.7%, p < 0.01) than the antiviral group. The control group had significantly higher levels of postoperative alanine aminotransferase (ALT) and serum bilirubin than the antiviral group. CONCLUSION Perioperative antiviral treatment improves patient safety by decreasing morbidity and speeding recovery of postoperative liver function for HBV-related major HCC resection.

Surgical treatment of hepato-pancreato-biliary disease in China: the Tongji experience

Hepato-pancreato-biliary (HPB) tumors are common in China. However, these tumors are often diagnosed at intermediate/ advanced stages because of the lack of a systemic surveillance program in China. This situation creates many technical challenges for surgeons and increases the incidence of postoperative complications. Therefore, Dr. Xiao-Ping Chen has made many important technical improvements, such as Chen’s hepatic portal occlusion method, the anterior approach for liver resection of large HCC tumors, the modified technique of Belghiti’s liver-hanging maneuver, inserting biliary-enteric anastomosis technique, and invaginated pancreaticojujunostomy with transpancreatic U-sutures. These techniques are simple, practical, and easy to learn. Owing to these advantages, complicated surgical procedures can be simplified, and the curative effects are greatly improved. These improved techniques have been widely applied in China and will benefit many additional patients. In this review, we introduce our experience of surgically treating intermediate/advanced hepatocellular carcinoma (HCC), hilar cholangiocarcinoma (HC), and pancreatic carcinoma, mainly focusing on technical innovations established by Dr. Chen in HPB surgery.

Selective Inflow Occlusion Technique Versus Intermittent Pringle Maneuver in Hepatectomy for Large Hepatocellular Carcinoma: A Retrospective Study.

AbstractSelective inflow occlusion (SIO) maneuver preserved inflow of nontumorous liver and was supposed to protect liver function. This study aims to evaluate whether SIO maneuver is superior to Pringle maneuver in patients undergoing partial hepatectomy with large hepatocellular carcinomas (HCCs).Between January 2008 and May 2012, 656 patients underwent large HCC resections and were divided into 2 groups: intermittent Pringle maneuver (IP) group (n = 336) and SIO group (n = 320). Operative parameters, postoperative laboratory tests, and morbidity and mortality were analyzed.In comparison to the IP maneuver, the SIO maneuver significantly decreased intraoperative blood loss (473 vs 691 mL, P = 0.001) and transfusion rates (11.3% vs 28.6%, P = 0.006). The rate of major complication between the 2 groups was comparable (22.6% vs 18.8%, P = 0.541). Patients with moderate/severe cirrhosis, total bilirubin > 17 &mgr;mol/L, or HBV DNA> = 104 copy/mL in SIO group resulted in lower major complication rates.The SIO maneuver is a safe and effective technique for large HCC resections. In patients with moderate/severe cirrhosis, total bilirubin > 17 &mgr;mol/L, or HBV DNA> = 104 copy/mL, the SIO technique is preferentially recommended.

Molecular characterization of pro-metastatic functions of β4-integrin in colorectal cancer

The β4-integrin subunit has been implicated in development and progression of several epithelial tumor types. However, its role in metastases of colorectal cancer (CRC) remains elusive. To study CRC metastasis, we generated a highly invasive, metastatic cell line MC38-LM10 (LM10) by passaging mouse CRC MC38 cells ten times, using a splenic injection model of liver metastasis. Affymetrix microarray analyses of LM10 and MC38 cell lines and their corresponding liver metastases generated a gene signature for CRC metastasis. This signature shows strong upregulation of β4-integrin in LM10 cells and corresponding metastases. Upregulation of β4-integrin in highly aggressive LM10 cells is associated with increased migration, invasion, and liver metastases. Furthermore, stable knockdown of β4-integrin in human CRC SW620 cells reduces Bcl-2 expression, increases apoptosis, and decreases invasion, tumorigenicity, and liver metastasis, thus resulting in significantly increased survival of mice (hazard ratio = 0.32, 95% confidence interval = 0.15-0.66, P<0.01). Patients with CRC tumors display higher β4-integrin levels in stages 1-4 and significantly lower survival rate. Collectively, β4-integrin plays a critical role in CRC progression, invasion, and metastasis, suggesting that it could be a potential therapeutic target for CRC patients.

A 4 and a half years old boy with mesenchymal hamartomas in the left lateral lobe of the liver: A case report and literature review

Rationale: Mesenchymal hamartomas of the liver is one type of rare liver tumor. Patient concerns: Mesenchymal hamartomas of the liver (MHL) is rarely reported in the left lobe of the liver in children who are more than 2 years old. It is difficult to distinguish it from liver lesions such as hepatoblastoma in children, and hepatocellular carcinoma and focal nodular hyperplasia in adults. In addition, it is hard to correctly diagnose it without pathological examination. Diagnoses: Mesenchymal hamartomas of the liver. Interventions: This patient underwent an operation assisted by the Da Vinci surgical system and the tumor was completely resected. Outcomes: No tumor recurrence or metastasis was observed 14 months after operation. Lessons: MHL is a benign tumor that is difficult to diagnose due to the lack of specific clinical symptoms and signs. The management of MHL remains controversial. To achieve a good long-term outcome, complete resection of MHL is recommended.

Animal and cellular models of hepatocellular carcinoma bone metastasis: establishment and characterisation

AbstractBackgroundAn increasingly high occurrence of bone metastases in hepatocellular carcinoma (HCC) patients highlights the importance of fundamental research on HCC bone metastasis, which has been limited in its success due to the lack of a model system.PurposeEstablishment of animal and cellular models of HCC bone metastasis and discovery of HCC bone metastasis-related genes.MethodsLuciferase-transfected HCC cell lines HCCLM3, MHCC97H, and SMMC-7721 were used to inoculate nude mice intracardially. Formation of bone metastases was examined by bioluminescence imaging, SPECT, and pathology study. Metastatic cells in bone were isolated and subcultured. Differences between bone metastatic cells and their parental cells were studied by in vitro/in vivo assays.ResultsMouse model of HCC bone metastasis was successfully established. Injected tumour cells formed metastases in the skull, the spine, the hind limbs, and the sternum, causing osteolytic lesions via act of MMP-1 and recruitment of osteoclasts. Four bone metastatic cell lines were extracted from HCCLM3-inoculated mice and were demonstrated to exhibit a much stronger ability to form bone metastases as well as other phenotypes, including enhanced in vitro migration/invasion and colony formation. Moreover, the expression of PTHrP, MMP-1, and CTGF was significantly elevated in bone metastatic cells compared to parental HCC cells. ConclusionThe nude mouse model and bone metastatic cell lines together provide an effective simulation of HCC bone metastasis. This model system will become powerful tool with which to explore the mechanisms and therapies of HCC bone metastasis. Additionally, PTHrP, MMP-1, and CTGF are candidate genes related to HCC bone metastasis.