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.

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.

Histopathological study of vascular changes after intra-arterial and intravenous injection of N-butyl-2-cyanoacrylate.

OBJECTIVE: To assess the histopathological vascular changes after injection of N-butyl-2-cyanoacrylate into the vessels of adult rabbits. METHODS: The animals used were 42 pure-blood New Zealand white rabbits weighing 2-3 kg. 0.2 mL cyanoacrylate with lipiodol was injected into the external jugular vein and femoral artery of each rabbit. Tissue specimens were obtained for histopathological study at 3 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 2 months and 3 months after injection. RESULTS: The vessels were obliterated immediately after the injection. The main manifestation of histopathology at 3 days to 2 weeks was an acute inflammatory reaction; this progressed to subacute vasculitis at 3 weeks and a chronic granulomatous foreign body reaction developed at 4 weeks. The glue mass essentially disappeared in 2-3 months, replaced by fibrotic tissue with partial vascular recanalization. At 3 weeks after injection, the elastic fibrils of the arterial wall proliferated distinctly, resulting in narrowing of the lumen with subsequent obliteration, whereas the venous wall still showed inflammation and necrosis without hyperplasia of elastic fibrils. Extrusion of glue was observed over 1-3 months in both arteries and veins and was obvious in the latter. CONCLUSIONS: The histopathological changes after injection of N-butyl-2-cyanoacrylate were similar in the arteries and the veins with the exception of hyperplasia of elastic fibrils in the arterial wall and inflammation and necrosis in the venous wall at 2-3 weeks. Glue extrusion was seen in both arteries and veins.

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.