A multicenter, randomized, double-blind trial comparing the efficacy and safety of TUDCA and UDCA in Chinese patients with primary biliary cholangitis.

AIM: Tauroursodeoxycholic acid (TUDCA) is a taurine conjugated form of ursodeoxycholic acid (UDCA) with higher hydrophility. To further evaluate the efficacy and safety of TUDCA for primary biliary cholangitis (PBC), we performed this study on Chinese patients. METHODS: 199 PBC patients were randomly assigned to either 250 mg TUDCA plus UDCA placebo or 250 mg UDCA plus TUDCA placebo, 3 times per day for 24 weeks. The primary endpoint was defined as percentage of patients achieving serum alkaline phosphatase (ALP) reduction of more than 25% from baseline. RESULTS: At week 24, 75.97% of patients in the TUDCA group and 80.88% of patients in the UDCA group achieved a serum ALP reduction of more than 25% from baseline (P = 0.453). The percentage of patients with serum ALP levels declined more than 40% following 24 weeks of treatment was 55.81% in the TUDCA group and 52.94% in the UDCA group (P = 0.699). Both groups showed similar improvement in serum levels of ALP, aspartate aminotransferase, and total bilirubin (P > 0.05). The proportion of patients with pruritus/scratch increased from 1.43% to 10.00% in UDCA group, while there's no change in TUDCA group (P = 0.023). Both drugs were well tolerated, with comparable adverse event rates between the 2 groups. CONCLUSIONS: TUDCA is safe and as efficacious as UDCA for the treatment of PBC, and may be better to relieve symptoms than UDCA.

Application of dsRNA in cancer immunotherapy: current status and future trends.

Cancer cells create a microenvironment that prevents tumor rejection by the host's immune system. The activation of pattern recognition receptors (PRRs) can elicit an innate immune response and guide the adaptive immune response to overcome this. dsRNA analogs can trigger TLR3, RIG-I, MDA5, NLRP3 and several other PRRs to induce not only robust immune response against cancer but also programmed cell death. This review focuses on the signal pathways activated by dsRNA and examines examples of their clinical application in cancer treatment.

Antiviral therapy delays esophageal variceal bleeding in hepatitis B virus-related cirrhosis.

AIM: To investigate the effect of antiviral therapy with nucleoside analogs in hepatitis B virus (HBV)-related cirrhosis and esophageal varices. METHODS: Eligible patients with HBV-related cirrhosis and esophageal varices who consulted two tertiary hospitals in Beijing, China, the Chinese Second Artillery General Hospital and Chinese PLA General Hospital, were enrolled in the study from January 2005 to December 2009. Of 117 patients, 79 received treatment with different nucleoside analogs and 38 served as controls. Bleeding rate, change in variceal grade and non-bleeding duration were analyzed. Multivariate Cox proportional hazard regression was used to identify factors related to esophageal variceal bleeding. RESULTS: The bleeding rate was decreased in the antiviral group compared to the control group (29.1% vs 65.8%, P < 0.001). Antiviral therapy was an independent factor related to esophageal bleeding in multivariate analysis (HR = 11.3, P < 0.001). The mean increase in variceal grade per year was lower in the antiviral group (1.0 ± 1.3 vs 1.7 ± 1.2, P = 0.003). Non-bleeding duration in the antiviral group was prolonged in the Kaplan-Meier model. Viral load rebound was observed in 3 cases in the lamivudine group and in 1 case in the adefovir group, all of whom experienced bleeding. Entecavir and adefovir resulted in lower bleeding rates (17.2% and 28.6%, respectively) than the control (P < 0.001 and P = 0.006, respectively), whereas lamivudine (53.3%) did not (P = 0.531). CONCLUSION: Antiviral therapy delays the progression of esophageal varices and reduces bleeding risk in HBV-related cirrhosis, however, high-resistance agents tend to be ineffective for long-term treatment.

Low incidence of complications from endoscopic gastric variceal obturation with butyl cyanoacrylate.

BACKGROUND & AIMS: Endoscopic variceal obturation with tissue adhesive is used to control gastric variceal bleeding. We investigated the prevalence of serious complications from this therapy. METHODS: We performed a retrospective analysis of complications that occurred in 753 patients with gastric variceal hemorrhages who were hospitalized in 2 tertiary referral hospitals. All patients received N-butyl-2-cyanoacrylate as therapy for endoscopic variceal obturation. RESULTS: Complications occurred in 51 patients. Thirty-three patients experienced rebleeding because of early-onset (within 3 months) extrusion of the N-butyl-2-cyanoacrylate glue cast (4.4%), 10 patients developed sepsis (1.3%), and 5 patients developed distant embolisms (0.7%; 1 pulmonary, 1 brain, and 3 splenic). One patient had major gastric variceal bleeding after endoscopic variceal obturation (0.1%), 1 developed a large gastric ulcer (0.1%), and 1 had mesentery hematoma, hemoperitoneum, and infection in the abdominal cavity (0.1%). The complication-related mortality was 0.53% (3 deaths from sepsis and 1 death from rebleeding after early-onset glue cast extrusion). CONCLUSIONS: The occurrence of complications after endoscopic variceal obturation with N-butyl-2-cyanoacrylate in gastric varices treatment is rare.

Grp78 promotes the invasion of hepatocellular carcinoma.

BACKGROUND: Glucose regulated protein 78 (Grp78) is involved in the invasion and metastasis in many human cancers including gastric cancer, breast cancer, prostate cancer. But the role of Grp78 in the invasion of human hepatocellular carcinoma has not been reported. In this article, we examined if Grp78 was associated with the invasion of hepatocellular carcinoma and explored the possible underlying mechanism. METHODS: The Grp78 and FAK expression levels in 44 patients with hepatocellular carcinoma were examined using immunohistochemistry. Grp78 overexpressing SMMC7721 cells were established by pcDNA3.1 (+)-Grp78 transfection and screened by G418. Grp78 and FAK levels in Grp78 overexpressing cells were down-regulated by siRNA transfection. The invasion status of tumor cells was evaluated by transwell assay in vitro, and chick embryo metastasis model in vivo. Cell spreading was determined by cell spreading assay, and quantitatively measured by Orisis software HUG. Grp78, pY397 FAK, pY576/577 FAK and FAK levels were detected by western blot. RhoA activity was detected by GST pulldown assay. The distribution of actin cytoskeleton was observed by fluorescent staining. RESULTS: Grp78 expression levels in 44 patients with hepatocellular carcinoma were negatively correlated with tumor grading, and positively correlated with portal invasion and intra-hepatic invasion. Overexpression of Grp78 in SMMC7721 cells promoted the invasion of cancer cells in vitro and in vivo, and this increase in tumor cell invasion was blocked by Grp78 siRNA knockdown. Our results also revealed that overexpression of Grp78 in SMMC7721 cells accelerated the process of cell spreading and promoted lamellipodia formation. Further analysis showed that overexpression of Grp78 in SMMC7721 cells increased pY397 and pY576/577 levels of FAK. Grp78 siRNA knockdown decreased FAK activation and activity. Our results also revealed that Grp78 overexpression in SMMC7721 cells decreased RhoA-GTP level, and Grp78 siRNA knockdown rescued RhoA-GTP level in Grp78 overexpressing cells, indicating Grp78 inhibited RhoA activity in hepatocellular carcinoma cells. Furthermore, overexpression of Grp78 in SMMC7721 cells increased phospho-p190RhoGAP level. FAK siRNA knockdown in Grp78 overexpressing cells reversed phospho-p190RhoGAP level. These data suggested that Grp78 inhibited RhoA activity by up-regulated phospho-p190RhoGAP level and Grp78 mediated p190RhoGAP phosphorylation is FAK dependent. CONCLUSION: Grp78 promoted the invasion of hepatocellular carcinoma both in vitro and in vivo. Overexpression of Grp78 in hepatocellular carcinoma cells enhanced the activation and activity of FAK which negatively regulated Rock kinase activity by promoting the phosphorylation of p190RhoGAP.

Study of glue extrusion after endoscopic N-butyl-2-cyanoacrylate injection on gastric variceal bleeding.

AIM: To investigate glue extrusion after endoscopic N-butyl-2-cyanoacrylate injection on gastric variceal bleeding and to evaluate the long-term efficacy and safety of this therapy. METHODS: A total of 148 cirrhotic patients in our hospital with esophagogastric variceal bleeding (EGVB) were included in this study. N-butyl-2-cyanoacrylate was mixed with lipiodol in a 1:1 ratio and injected as a bolus of 1-3 mL according to variceal size. Patients underwent endoscopic follow-up the next week, fourth week, second month, fourth month, and seventh month after injection and then every 6 mo to determine the cast shape. An abdominal X-ray film and ultrasound or computed tomographic scan were also carried out in order to evaluate the time of variceal disappearance and complete extrusion of the cast. The average follow-up time was 13.1 mo. RESULTS: The instantaneous hemostatic rate was 96.2%. Early re-bleeding after injection in 9 cases (6.2%) was estimated from rejection of adhesive. Late re-bleeding occurred in 12 patients (8.1%) at 2-18 mo. The glue cast was extruded into the lumen within one month in 86.1% of patients and eliminated within one year. Light erosion was seen at the injection position and mucosa edema in the second week. The glue casts were extruded in 18 patients (12.1%) after one week and in 64 patients (42.8%) after two weeks. All kinds of glue clumping shapes and colors on endoscopic examination were observed in 127 patients (86.1%) within one month, including punctiform, globular, pillar and variform. Forty one patients (27.9%) had glue extrusion after 3 mo and 28 patients (28.9%) after six months. The extrusion time was not related to the injection volume of histoacryl. Obliteration was seen in 70.2% (104 cases) endoscopically. The main complication was re-bleeding resulting from extrusion. The prognosis of the patients depended on the severity of the underlying liver disease. CONCLUSION: Endoscopic injection of cyanoacrylate is highly effective for gastric varices bleeding. The glue clump shape is correlated with anatomic structure of vessels. The time of extrusion was not related to dosage of the glue.

[Intestinal intraepithelial lymphocytes in cirrhosis: experiment with rats].

OBJECTIVE: To investigate the phenotypes of T lymphocytes in the intestinal epithelium in cirrhosis. METHODS: Forty Wistar rats were randomly divided into 2 groups: cirrhosis group (n = 25) undergoing subcutaneous injection of 40% carbon tetrachloride twice a week for 10-12 weeks to establish cirrhosis models, and control group (n = 15). Twelve weeks later the rats were killed with their levers taken out. The T lymphocytes in the intestinal epithelium were isolated and labeled with mouse anti-rat CD3, CD4 and CD8 monoclonal antibody, Flow cytometry was performed. RESULTS: The number of intestinal intraepithelial lymphocytes of the cirrhosis group was (3.4 +/- 1.1) x 10(5)/cm, significantly higher than that of the control group [(2.3 +/- 0.5) x 10(5)/cm, P < 0.05]. The proportion of CD3(+) cells of the cirrhosis group were (76 +/- 8)%, not significantly different from that of the control group [(80 +/- 6)%, P > 0.05]. There were no significant different between two group (P > 0.05). The proportion of CD4(+)CD8(+) subpopulation of the cirrhosis group was (6.9 +/- 3.3)%, significantly higher than that of the control group [(3.7 +/- 1.8)%, P < 0.05]. The proportion of CD4(+)CD8(-) subpopulation of the cirrhosis group was (6.9 +/- 3.0)%, significantly higher than that of the control group [(4.4 +/- 1.4)%, P < 0.05]. CONCLUSION: There were alterations of the immune barrier function in cirrhosis. The increase of the proportion of CD4(+)CD8(+) subpopulation may be associated with the increases of the number of intestinal bacteria.

Treatment of gastric varices by endoscopic sclerotherapy using butyl cyanoacrylate: 10 years' experience of 635 cases.

BACKGROUND: Gastric varices (GV) are life-threatening for patients with portal hypertension. Endoscopic injection with butyl cyanoacrylate (BC), the mainstay of the therapy for GV, has been reported to be effective for hemostasis of bleeding varices, but its efficacy in the obliteration of GV and impact on the survival of patients still needs clarification. Here we summarized our experience of 10 years' practice to evaluate the efficacy and safety of endoscopic therapy using BC for GV patients. METHODS: From January 1997 to April 2006, GV cases treated with endoscopic injection using BC were collected. The "sandwich method" and the "modified sandwich method" were used to inject BC intravascularly. Retrograde analysis was made on the data of treatment and follow-up. RESULTS: A total of 635 GV cases treated with endoscopic injection using BC were collected, most of them (90.2%) suffered from post-hepatitis cirrhosis. Emergency hemostasis was achieved in 139 out of 146 sessions (95.2%). Complications occurred in 32 cases (5.2%), including hemorrhage due to early expulsion of tissue glue (3.1%), septicemia (1%) and ectopic thrombosis (0.5%), such as spleen infarction. Endoscopic follow-up in 503 patients showed complete disappearance (76.9%), collapse (17.3%) or remnants (5.8%) of gastric varices. A total of 550 patients were followed up clinically for 3 to 115 months. Of these patients, 44 had recurrent bleeding (8.0%) and 44 died from hepatic failure, recurrent bleeding, hepatic carcinoma or other causes. The longest survival was 115 months, with a median survival of 25 months. Survival rates at 1, 2, 3, 4 and 5 year were 95%, 92%, 90%, 83% and 81%, respectively. CONCLUSIONS: Endoscopic sclerotherapy with BC is effective for the hemostasis of bleeding GV, as well as obliteration of GV which contributes to less rebleeding and better survival. The modified sandwich method may be useful to minimize ectopic embolism, which we speculated to result from excess iodized oil.

Pancreatic encephalopathy and Wernicke encephalopathy in association with acute pancreatitis: a clinical study.

AIM: To investigate clinical characteristics and therapy of pancreatic encephalopathy (PE) and Wernicke encephalopathy (WE). METHODS: In a retrospective study of 596 patients with acute pancreatitis (AP), patients with PE were compared to those with WE in regards to history, clinical manifestation, diagnosis, treatment and outcome. RESULTS: There were 93 patients with severe acute pancreatitis (SAP). Encephalopathies were discovered in 10 patients (1.7%). Six patients with PE all developed in SAP (6.5%), and three of them died (3% of SAP, 50% of PE). Four patients with WE developed in AP (0.7%), and two of them died (0.3% of AP, 50% of WE). Two patients with WE were treated with parenteral thiamine and survived. Global confusions were seen in all patients with encephalopathy. Ocular abnormalities were found. Conjugate gaze palsies were seen in 1 of 6 (16.7%) patients with PE. Of 4 patients with WE, one (25%) had conjugate gaze palsies, two (50%) had horizontal nystagmus, three (75%) had diplopia, and one (25%) had myosis. Ataxia was not seen in all patients. None of patients with WE presented with the classic clinical triad. CSF examinations for 2 patients with WE showed lightly-increased proteins and glucose. CT and MRI of the brain had no evidence of characteristic abnormalities. CONCLUSION: PE occurs in early or reiteration stage of SAP, and WE in restoration stage of SAP/AP. Ocular abnormalities are the hallmarks of WE, and horizontal nystagmus is common. It is difficult to diagnose earlier an encephalopathy as PE or WE, as well as differentiate one from the other. Long fasting, hyperemesis and total parenteral nutrition (TPN) without thiamine are main causes of thiamine deficiency in the course of pancreatitis.

Reversibility of experimental rabbit liver cirrhosis by portal collagenase administration.

The regression of cirrhosis is associated with increased intrahepatic collagenolytic enzyme activity. We investigated whether collagenase supplementation via portal vein infusion can retard cirrhosis development and/or reverse cirrhosis. In all, 35 rabbits were initially assigned to study. However, because of high surgical mortality and infection, only 15 animals completed study. Four normal controls (group I) received olive oil subcutaneously (SC) for 12 weeks followed by normal saline portal perfusion for 12 weeks. Four (group II) received CCl(4) SC for 6 weeks followed by portal vein collagenase, 6 mg twice weekly, plus SC CCl(4) for 6 additional weeks and then killed. Four rabbits (group III) received CCl(4) SC for 12 weeks and then 6 mg of collagenase portally for 12 weeks, while three control rabbits (group IV) received CCl(4) for 12 weeks followed by saline for 12 weeks. After 12 weeks of CCl(4), liver hydroxyproline content of collagenase-treated group II (361.1+/-106.6 microg/g) was significantly reduced compared with group III+IV that had not yet received collagenase (589.0+/-162.9 microg/g; P<0.05). In the main comparison, hydroxyproline content of collagenase-treated group III (177.5+/-35.6 microg/g) was significantly decreased compared with saline-treated controls (446.3+/-150.1 microg/g; P<0.01). Further, liver histology showed complete regression of cirrhosis in the collagenase-treated animals. No toxicity of liver, kidney, lung, brain or heart was observed histologically. Anaphylaxis occurred in 2/35 original animals (one fatal). In conclusion, this study provides 'proof of principle' that collagenase portal administration can retard cirrhosis development and speed regression of established cirrhosis in the rabbit CCl(4) model. Potential application to humans is premature, but feasible, if these findings are confirmed in additional animal studies.

Intraductal ultrasonography and endoscopic retrograde cholangiography in diagnosis of extrahepatic bile duct stones: a comparative study.

BACKGROUND: Intraductal ultrasonography (IDUS) is highly accurate in detection of extrahepatic bile duct stones. This study was to compare the accuracy of IDUS and endoscopic retrograde cholangiography (ERC) in the diagnosis of extrahepatic bile duct stones. METHODS: Thirty patients suspected of extrahepatic bile duct stones on B ultrasonography, CT, or MRI were enrolled for study. ERC was performed using a Fujinon duodenoscope (ED-410XT, ED-410Xu), then IDUS was done by inserting a Fujinon microprobe (PL2220-15) through the endoscopic biopsy channel to detect the extrahepatic bile duct. Finally stones in the extrahepatic bile duct were detected and extracted by endoscopic sphincterotomy (EST). RESULTS: Among the 30 patients, 26 were diagnosed as having cholelithiasis accurately through ERC. In one patient the stone detected by ERC was really floccule. Misdiagnosis happened in 2 patients with extrahepatic bile duct stones. So the overall accuracy and sensitivity of ERC in the diagnosis of extrahepatic bile duct stones were 86.7% (26/30) and 92.9% (26/28) respectively. In contrast, IDUS showed the results of diagnosis were in consistent with those of EST stone extraction. Its accuracy and sensitivity in the diagnosis of extrahepatic bile duct stones were 100% (30/30) and 100% (28/28) respectively. CONCLUSION: IDUS which is superior to ERC in diagnosing extrahepatic bile duct stones can avoid the visual error of ERC.

The effect of sclerotherapy of bleeding esophageal variceal on survival of cirrhotic patients.

OBJECTIVE: To investigate the effect of various factors in sclerotherapy of cirrhotic esophageal variceal bleeding (CEVB) on the prognosis, model of survival was established. METHODS: Kaplan-Meier analysis was applied in patients with CEVB treated by sclerotherapy from April 1987 to June 2000 to evaluate the survival, with follow-up data of survival and 29 selected factors of prognosis. Risk factors were identified with Cox's Proportional Hazard Model. RESULTS: Cox's model shows that Child grading and outcome of varices are two factors that significantly influence the prognosis and survival. Survival of 1, 3 and 5 year for the entire group is 93.29%, 85.24% and 74.27%, respectively. Survival of 1 year for patients of Child grade A, B and C is 98.88%, 95.97% and 82.32%, respectively, and survival of 5 year is 91.42%, 78.35% and 49.48%, respectively, with significant difference in survival curves. Outcome of esophageal varices is labeled with elimination, basically elimination, degree I, degree II and degree III, and survival of 1 year is 96.08%, 93.94%, 85.84%, 85.00% and 53.85%, respectively, survival of 5 year is 81.45%, 67.76%, 72.89%, 61.59% and 35.90%, respectively, with significant difference in survival curves. In patients of Child grade C with outcome of elimination or basically elimination, 1 year survival is 88.24%, and 2 year survival is 77. 98% approximately 83.63%. Survival curves of stratified groups are tended to converge after 50 months. CONCLUSIONS: Sclerotherapy for CEVB is an effective therapy to arrest emergent bleeding and prevent rebleeding. For patients of Child grade C,survival can also be prolonged, so it is advisable to take active measures. Repeat of sclerotherapy after about 4 years may be necessary. Sclerotherapy can significantly prolong the survival.

Experience in sclerotherapy for esophagogastric variceal bleeding.

OBJECTIVE: To evaluate the efficacy of endoscopic variceal sclerotherapy (EVS) for esophago gastric variceal bleeding. METHODS: A retrospective analysis was made on 1010 patients with esophagogastric variceal bleeding who underwent sclerotherapy, among whom there were 834 patients with cirrhosis, 160 with hepatocarcinoma, 12 with Budd-Chiari syndrome and 4 with congenital liver fibrosis. Totally, 3203 sessions of sclerotherapy were performed, including 602 sessions of emergency sclerotherapy and 2601 of selective surgery. The average number of sessions of sclerotherapy for the initial treatment in 710 cirrhosis patients who received continuous sclerotherapy was 3.2 +/- 1.1 times. Follow-up was done in 579 cirrhosis patients for 3-157 months, with an average period of 42.5+/- 32.8 months. RESULTS: The rate of emergency hemostasis in the whole group was 97.0%. The rate of complications was 13.4%, and the mortality rate was 1.8%. The rate of complete eradication and basically complete eradication of esophagogastric varices in cirrhosis patients was 84.1%. The late rebleeding rate was 23.7%, and the survival rates were 95.8% +/- 0.8%, 86.1% +/- 1.6%, 74.5% +/- 2.4%, 53.6% +/- 3.8% at 1, 3, 5 and 10 years, respectively, according to Kaplan-Meier analysis. CONCLUSION: EVS is an important method for the treatment of esophagogastric variceal bleeding.