Routine image-enhanced endoscopic surveillance for metachronous esophageal squamous cell neoplasms in head and neck cancer patients.

BACKGROUND: Esophageal squamous cell neoplasms (ESCNs) are common second primary tumors in patients with head and neck cancer. Image-enhanced endoscopy (IEE) with Lugol chromoendoscopy or magnifying narrow-band imaging both increase the detection of early ESCNs. No evidence-based ESCN surveillance program for head and neck cancer patients without a history of synchronous ESCNs exists. We aimed to evaluate the performance of an IEE surveillance program with magnifying narrow-band imaging endoscopy and Lugol chromoendoscopy. METHODS: From April 2016, we routinely used IEE with magnifying narrow-band imaging and Lugol chromoendoscopy to evaluate patients with head and neck cancer history. All patients who were negative for ESCNs at the first surveillance endoscopy and received at least 2 IEEs through December 2019 were included. Demographic profiles, clinical data, cancer characteristics, IEE results and pathology reports were analyzed. RESULTS: A total of 178 patients were included. Only 4 patients (2.2%) developed metachronous ESCNs during follow-up, all of whom received curative resection treatment. The interval for the development of metachronous ESCNs was 477 to 717 days. In multivariate Firth logistic regression and Kaplan‒Meier survival curve analysis, Lugol's voiding lesion type C had an increased risk of esophageal cancer development (adjusted odds ratio = 15.71; 95% confidence interval, 1.33-185.87, p = 0.029). Eight patients died during the study period, and none of them had metachronous ESCNs. CONCLUSIONS: IEE with magnifying narrow-band imaging and Lugol chromoendoscopy is an effective surveillance program in head and neck cancer patients without a history of ESCNs. Annual surveillance can timely detect early ESCNs with low ESCN-related mortality.

Addition of Carvedilol to Gastric Variceal Obturation Does Not Decrease Recurrence of Gastric Variceal Bleeding in Patients With Cirrhosis.

BACKGROUND & AIMS: Gastric variceal bleeding (GVB) frequently recurs after hemostasis by gastric variceal obturation (GVO). We performed a multicenter, randomized controlled trial to determine the efficacy of carvedilol plus GVO in secondary prophylaxis of GVB. METHODS: We performed a prospective study of 121 patients with cirrhosis (ages 20-80 years) with GVB proven by endoscopy within 24 hours of bleeding and stable hemodynamics for at least 3 days after initial GVO. Patients were randomly assigned into a group that underwent repeated GVO (n = 61) or a group received repeated GVO plus carvedilol (n = 60). Recurrent GVB, upper gastrointestinal bleeding (UGIB), adverse events, and survival were compared between the groups. RESULTS: GVB recurred in 21 patients (34%) in the group that received repeated GVO and 14 patients (23%) in the group that received repeated GVO plus carvedilol (P = .18). Ascites (relative risk [RR], 2.69; 95% CI, 1.33-5.48; P = .006) and hepatoma (RR, 2.10; 95% CI, 1.03-4.28; P = .04) were associated with recurrent GVB. Twenty-nine patients (48%) in the group that received repeated GVO and 17 patients (28%) in the group that received repeated GVO plus carvedilol had recurrent UGIB (P = .03). Carvedilol (RR, 0.44; 95% CI, 0.24-0.80; P = .007) was associated with reduced risk of UGIB recurrence. Ascites (RR, 3.02; 95% CI, 1.59-5.73; P = .001) and hepatoma (RR, 2.07; 95% CI, 1.10-3.88; P = .02) were associated with recurrent UGIB. A higher proportion of patients in the group that received repeated GVO plus carvedilol (53%) had adverse events than the group that received repeated GVO (15%) (P < .001). Mean survival times were 21 ± 18 months in the group that received repeated GVO vs 25 ± 20 months in the group that received repeated GVO plus carvedilol (P = .30). CONCLUSION: In a randomized controlled trial, we found that addition of carvedilol to GVO did not decrease recurrence of GVB in patients with cirrhosis but was associated with decreased recurrence of UGIB. However, carvedilol plus GVO produced significantly more adverse events. Mean survival times did not differ significantly between groups. ClinicalTrials.gov no: NCT02504723.

Effects of Caffeine Treatment on Hepatopulmonary Syndrome in Biliary Cirrhotic Rats.

Hepatopulmonary syndrome (HPS) is a lethal complication of cirrhosis characterized by hypoxia and overt intrapulmonary shunting. In this study, we investigated the effect of caffeine in rats with common bile duct ligation (CBDL)-induced liver cirrhosis and HPS. CBDL rats were randomly allocated to receive caffeine or vehicle for 14 days. On the 28th day after CBDL, mortality rate, hemodynamics, liver, and renal biochemistry parameters and arterial blood gas analysis were evaluated. Lung and liver were dissected for the evaluation of inflammation, angiogenesis and protein expressions. In another series with parallel groups, the intrapulmonary shunting was determined. Caffeine significantly reduced portal pressure (caffeine vs. control: 10.0 ± 3.7 vs. 17.0 ± 8.1 mmHg, p < 0.05) in CBDL rats. The mortality rate, mean arterial pressure, biochemistry data and hypoxia were similar between caffeine-treated and control groups. Caffeine alleviated liver fibrosis and intrahepatic angiogenesis but intrapulmonary inflammation and angiogenesis were not ameliorated. The hepatic VEGF/Rho-A protein expressions were down-regulated but the pulmonary inflammation- and angiogenesis-related protein expressions were not significantly altered by caffeine. Caffeine did not reduce the intrapulmonary shunting, either. Caffeine has been shown to significantly improve liver fibrosis, intrahepatic angiogenesis and portal hypertension in cirrhotic rats, however, it does not ameliorate HPS.

Insulin reverses major portal hypertension-related derangements in rats with liver cirrhosis and diabetes.

Liver cirrhosis is accompanied by increased intrahepatic resistance and angiogenesis-related portosystemic collaterals formation. Diabetic patients suffer from abnormal vasoresponsiveness and angiogenesis that can be ameliorated by glucose control. However, the relevant presentation is not clear in those with cirrhosis and diabetes, in whom insulin is the treatment of choice. Liver cirrhosis was induced in Sprague-Dawley rats with common bile duct ligation (BDL) and sham rats were used as controls. Streptozotocin 60 mg/kg (STZ, i.p., to induce diabetes) or vehicle was injected. The rats received BDL and STZ injections were injected with insulin or vehicle. On the 29th day after the procedure, the groups were surveyed for (1) systemic and portal hemodynamics; (2) mesenteric vascular density; (3) severity of portosystemic collaterals; (4) hepatic resistance using in situ liver perfusion; (5) histology survey of mesentery and liver; and (6) mesentery angiogenesis- and liver fibrogenesis-related protein expressions. Compared with the cirrhotic rats, the cirrhotic diabetic rats had lower body weight, cardiac output, superior mesenteric arterial (SMA) resistance and portal venous (PV) resistance, and higher SMA and PV flow, which were mostly reversed by insulin. The cirrhotic diabetic rats also had increased mesenteric vascular density, and enhanced pERK, pAkt, VEGF, VEGFR2 protein expressions that were reversed by insulin. Insulin decreased the degree of shunting in the diabetic cirrhotic rats. Hepatic perfusion pressure and severity of liver fibrosis were not significantly influenced by diabetes and insulin treatment in the cirrhotic rats. In conclusion, diabetes aggravated hemodynamic derangements, mesenteric angiogenesis and collaterals in the cirrhotic rats, which were mostly ameliorated by insulin. Further clinical investigations are warranted.

Combination of albumin-bilirubin grade and platelets to predict a compensated patient with hepatocellular carcinoma who does not require endoscopic screening for esophageal varices.

BACKGROUNDS AND AIMS: There is no consensus on screening for high-risk esophageal varices (HRV) in patients with hepatocellular carcinoma (HCC). Here, we aimed to investigate the prevalence and risk factors of HRV in patients with HCC and to assess the combination of albumin-bilirubin grade and platelet count (ALBI-PLT score) for predicting compensated patients who do not need unnecessary endoscopic screening for HRV. METHODS: The ALBI-PLT score was calculated by adding the ALBI grade and points for platelet count (1 point if platelet count >150,000/mm3 and 2 points if ≤150,000/mm3). The predictive value of the ALBI-PLT score for HRV was analyzed in 887 compensated patients enrolled from October 2007 to April 2014 (study cohort). This was validated in 215 compensated patients from May 2014 to December 2015 (validation cohort). RESULTS: In the study cohort, the rates of HRV were 2.9% and 21.1% in compensated HCC patients with an ALBI-PLT score of 2 and >2, respectively. The negative predictive values of the ALBI-PLT score for predicting HRV were 97.1% and 98.1% in the study and validation cohorts, respectively. For compensated patients who did not receive endoscopic screening at the time of HCC diagnosis, the 5-year cumulative variceal hemorrhage rate was lower in patients with an ALBI-PLT score of 2 than in those with an ALBI-PLT score >2 (1.7% vs 9.1%, P = .007). CONCLUSION: In patients with HCC with compensated liver function, an ALBI-PLT score of 2 predicted a very low risk of HRV and variceal hemorrhage; therefore, endoscopic screening for esophageal varices is not recommended for these patients.

Homocysteine deteriorates intrahepatic derangement and portal-systemic collaterals in cirrhotic rats.

In liver cirrhosis, the altered levels of vasoactive substances, especially endothelin-1 (ET-1) and nitric oxide (NO) lead to elevated intrahepatic resistance, increased portal-systemic collaterals and abnormal intra- and extra-hepatic vascular responsiveness. These derangements aggravate portal hypertension-related complications such as gastro-oesophageal variceal bleeding. Homocysteine, a substance implicated in cardiovascular diseases, has been found with influences on vasoresponsiveness and angiogenesis. However, their relevant effects in liver cirrhosis have not been investigated. In the present study, liver cirrhosis was induced by common bile duct ligation (BDL) in Sprague-Dawley rats. In acute study, the results showed that homocysteine enhanced hepatic vasoconstriction to ET-1 but decreased portal-systemic collateral vasocontractility to arginine vasopressin (AVP). Homocysteine down-regulated hepatic phosphorylated endothelial NO synthase (p-eNOS) and p-Akt protein expressions. Inducible NOS (iNOS) and cyclooxygenase (COX)-2 expressions were up-regulated by homocysteine in splenorenal shunt (SRS), the most prominent intra-abdominal collateral vessel. In chronic study, BDL or thioacetamide (TAA) rats received homocysteine or vehicle for 14 days. The results revealed that homocysteine increased hepatic collagen fibre deposition and fibrotic factors expressions in both BDL- and TAA-induced liver fibrotic rats. Portal-systemic shunting and expressions of mesenteric angiogenetic factors [vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), PDGF receptor ß (PDGFRß) and p-eNOS] were also increased in BDL rats. In conclusion, homocysteine is harmful to vascular derangements and liver fibrosis in cirrhosis.

Caffeine ameliorates hemodynamic derangements and portosystemic collaterals in cirrhotic rats.

UNLABELLED: Portal hypertension (PH), a pathophysiological derangement of liver cirrhosis, is characterized by hyperdynamic circulation, angiogenesis, and portosystemic collaterals. These may lead to lethal complications, such as variceal bleeding. Caffeine has been noted for its effects on liver inflammation, fibrogenesis, and vasoreactiveness. However, the relevant influences of caffeine in cirrhosis and PH have not been addressed. Spraque-Dawley rats with common bile duct ligation-induced cirrhosis or sham operation received prophylactic or therapeutic caffeine treatment (50 mg/kg/day, the first or 15th day since operation, respectively) for 28 days. Compared to vehicle (distilled water), caffeine decreased cardiac index, increased systemic vascular resistance, reduced portal pressure (PP), superior mesenteric artery flow, mesenteric vascular density, portosystemic shunting (PSS), intrahepatic angiogenesis, and fibrosis without affecting liver and renal biochemistry. The beneficial effects were reversed by selective adenosine A1 agonist N6-cyclopentyladenosine (CPA) or A2A agonist GCS21680. Both prophylactic and therapeutic caffeine treatment decreased portal resistance and PP in thioacetamide (200mg/kg, thrice-weekly for 8 weeks)-induced cirrhotic rats. Caffeine down-regulated endothelial nitric oxide synthase, vascular endothelial growth factor (VEGF), phospho-VEGFR2, and phospho-Akt mesenteric protein expression. Caffeine adversely affected viability of hepatic stellate and sinusoidal endothelial cells, which was reversed by CPA and GCS21680. On the other hand, caffeine did not modify vascular response to vasoconstrictors in splanchnic, hepatic, and collateral vascular beds. CONCLUSIONS: Caffeine decreased PP, ameliorated hyperdynamic circulation, PSS, mesenteric angiogenesis, hepatic angiogenesis, and fibrosis in cirrhotic rats. Caffeine may be a feasible candidate to ameliorate PH-related complications in cirrhosis.

Endothelin receptor blockers reduce shunting and angiogenesis in cirrhotic rats.

BACKGROUND: Angiogenesis plays a pivotal role in splanchnic hyperaemia and portosystemic collateral formation in cirrhosis. Endothelin-1 (ET-1), an endothelium-derived vasoconstrictor, has also been implicated in the pathogenesis of cirrhosis and portal hypertension. DESIGN: This study aimed to survey the influences of ET-1 in cirrhosis-related angiogenesis. Common bile duct ligation was performed on Spraque-Dawley rats to induce cirrhosis. Since the 14th day after the operation, rats randomly received distilled water (DW, control), bosentan [a nonselective ET receptor (ETR) blocker] or ambrisentan (a selective ETA R blocker) for 4 weeks. On the 43rd day, portal and systemic haemodynamics, liver biochemistry, portosystemic shunting degree, mesenteric vascular density, mRNA and/or protein expressions of relevant angiogenic factors were evaluated. RESULTS: In cirrhotic rats, bosentan significantly reduced portal pressure. Ambrisentan did not influence haemodynamics and liver biochemistry. Both of them significantly improved the severity of portosystemic collaterals and decreased the mesenteric vascular density. Compared with the DW-treated cirrhotic rats, splenorenal shunt and mesenteric inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), vascular endothelial growth factor mRNA expressions and mesenteric iNOS, COX2, VEGF, phospho-VEGF receptor 2, Akt and phospho-Akt protein expressions were down-regulated in both groups. CONCLUSIONS: In rats with liver cirrhosis, both nonselective and selective ETA R blockade ameliorate the severity of portosystemic shunting and mesenteric angiogenesis via the down-regulation of VEGF pathway and relevant angiogenic factors. ET receptors may be targeted to control the severity of portosystemic collaterals and associated complications in cirrhosis.

2'-Hydroxyflavanone ameliorates mesenteric angiogenesis and portal-systemic collaterals in rats with liver fibrosis.

BACKGROUND AND AIM: Portal-systemic collaterals lead to dreadful consequences in patients with cirrhosis. Angiogenesis participates in the development of liver fibrosis, hyperdynamic circulation, and portal-systemic collaterals. 2'-Hydroxyflavanone (2'-HF), one of the citrus fruits flavonoids, is known to have antiangiogenesis effect without adverse response. However, the relevant effects in liver fibrosis have not been surveyed. METHODS: Male Wistar rats received thioacetamide (TAA, 100 mg/kg tiw, i.p.) for 6 weeks to induce liver fibrosis. On the 29th to 42nd day, rats randomly received 2'-HF (100 mg/kg, qod, i.p.) or vehicle (corn oil). On the 43rd day, after hemodynamic measurements, the followings were surveyed: (i) severity of collaterals; (ii) mesenteric angiogenesis; (iii) mesenteric proangiogenic factors protein expressions; (iv) Mesenteric vascular endothelial cells apoptosis; and (v) Mesenteric expressions of proteins regulating apoptosis. RESULTS: Compared with the vehicle group, 2'-HF did not significantly change body weight, mean arterial pressure, heart rate, and portal pressure in TAA rats. 2'-HF significantly alleviated the severity of collaterals, but the mesenteric phospho-ERK, ERK, phospho-Akt, Akt, COX1, COX2, VEGF, and VEGFR-2 protein expressions were not altered. The apoptotic index of 2'-HF group was significantly higher and the mesenteric protein expressions of pro-apoptotic factors, NFkB 50, NFkB 65, Bax, phospho-p53, 17 kD cleaved caspase 3, and 17 kD casepase 3 were up-regulated. CONCLUSIONS: 2'-HF does not influence the hemodynamics but alleviated the severity of collaterals in rats with liver fibrosis and early portal hypertension. This is, at least partly, attributed to enhanced apoptosis of mesenteric vascular endothelial cells.

The Impact of Spironolactone on the Severity of Portal-Systemic Collaterals and Hepatic Encephalopathy in Cirrhotic Rats.

Liver cirrhosis and portal hypertension are accompanied by portal-systemic collaterals formation and lethal complications. Angiogenesis participates in the development of collaterals. Spironolactone is an aldosterone receptor antagonist used to control fluid overload in cirrhotic patients although recent studies suggest that it also inhibits angiogenesis. This study investigated the effect of spironolactone on abnormal angiogenesis and portal-systemic collaterals in cirrhosis. Liver cirrhosis was induced in Sprague-Dawley rats by common bile duct ligation (BDL), and sham-operated rats were the controls. The BDL and sham rats received spironolactone (20 mg/kg/d, oral gavage) or vehicle from day 15 to 28 after the operations. Spironolactone did not influence the portal and systemic hemodynamic, and the renal and hepatic biochemistry data, but it significantly ameliorated hepatic fibrosis, portal-systemic shunting, and mesenteric angiogenesis. Plasma vascular endothelial growth factor (VEGF) levels and the mesenteric protein expression of VEGF and phosphor-vascular endothelial growth factor receptor 2 (VEGFR-2) decreased in the spironolactone group. Spironolactone did not affect motor activity or plasma ammonia levels. The down-regulation of VEGF pathway participates, albeit partly, in the antiangiogenic effect of spironolactone. Thus, spironolactone treatment in patients with liver cirrhosis may provide additional benefits aside from ascites control.

The ability of 17 ß-estradiol to attenuate intrahepatic vasoconstriction to endothelin-1 in female rats is lost in cirrhosis.

BACKGROUND AND RATIONALE: The control of Endothelin-1 (ET-1)-mediated intrahepatic vasoconstriction in cirrhosis is beneficial for the alleviation of relevant complications. Cirrhosis is accompanied by hypogonadism and altered sex hormone status. Besides, sex hormones have vasoactive effects, but it is unknown if they influence vascular function in cirrhosis. This study aimed to investigate the roles of sex hormones in hepatic vascular reactions to ET-1 in cirrhosis. Liver cirrhosis was induced in Spraque-Dawley male and female rats with common bile duct ligation (BDL). Sham-operated (Sham) rats were controls. On the 43rd day after operations, intrahepatic vascular concentration-response curves to ET-1 were obtained with the following preincubatioins: 1) vehicle; 2) 17ß-estradiol; 3) progesterone; 4) testosterone. Livers from sham and BDL rats were dissected for real-time polymerase chain reaction analysis of estrogen, progesterone and testosterone receptors. RESULTS: Compared with sham males perfused with vehicle, sham females presented higher perfusion pressure changes to ET-1 which was reversed only by 17 ß-estradiol. In cirrhosis, compared with males, 17 ß-estradiol no longer attenuated vascular responsiveness to ET-1 in females. In females, BDL rats had lower hepatic estrogen receptor α(ERßα) mRNA expression than that in sham rats. CONCLUSIONS: The sham females showed a stronger intrahepatic vascular constrictive effect to ET-1 than sham males, which could be reversed by 17ß-estradiol. However, the influence of 17 ß-estradiol was lost in cirrhotic females, which may be attributed, at least partly, to intrahepatic ER α down-regulation in females with cirrhosis.

Green tea polyphenol decreases the severity of portosystemic collaterals and mesenteric angiogenesis in rats with liver cirrhosis.

Abnormal angiogenesis in liver cirrhosis often leads to severe complications such as variceal haemorrhage and encephalopathy. Furthermore, splanchnic angiogenesis elevates portal pressure, in which angiogenic factors play pivotal roles. GTP (green tea polyphenol) extracted from Camellia sinensis has anti-angiogenic properties, but the effects on the parameters described above in cirrhosis have not been investigated. The aim of the present study was to determine the effects of GTP in cirrhosis and to investigate the underlying mechanism. Liver cirrhosis was induced in Spraque-Dawley rats by common BDL (bile duct ligation). They randomly received GTP or DW (distilled water, vehicle) for 28 days, then haemodynamic parameters, portosystemic shunting, mesenteric window vascular density, intrahepatic angiogenesis, liver fibrosis, plasma VEGF (vascular endothelial growth factor) concentration, mesenteric angiogenic factor and receptor protein expression, and serum and mesenteric oxidative stress parameters were assessed. Compared with the DW group, GTP significantly decreased portosystemic shunting, liver fibrosis, intrahepatic angiogenesis, mesenteric window vascular density, VEGF concentration and down-regulated the mesenteric HIF (hypoxia-inducible factor)-1α, VEGF and phospho-Akt expression. In conclusion, GTP ameliorates the severity of portosystemic shunting and mesenteric angiogenesis via the suppression of HIF-1α, Akt activation and VEGF. GTP appears to be an appropriate agent in controlling portal hypertension-related complications via anti-angiogenesis.

Cannabinoid receptor 2 agonist ameliorates mesenteric angiogenesis and portosystemic collaterals in cirrhotic rats.

UNLABELLED: Angiogenesis in liver cirrhosis leads to splanchnic hyperemia, increased portal inflow, and portosystemic collaterals formation, which may induce lethal complications, such as gastroesophageal variceal hemorrhage and hepatic encephalopathy. Cannabinoids (CBs) inhibit angiogenesis, but the relevant influences in cirrhosis are unknown. In this study, Spraque-Dawley rats received common bile duct ligation (BDL) to induce cirrhosis. BDL rats received vehicle, arachidonyl-2-chloroethylamide (cannabinoid receptor type 1 [CB(1) ] agonist), JWH-015 (cannabinoid receptor type 2 [CB(2) ] agonist), and AM630 (CB(2) antagonist) from days 35 to 42 days after BDL. On the 43rd day, hemodynamics, presence of CB receptors, severity of portosystemic shunting, mesenteric vascular density, vascular endothelial growth factor (VEGF), VEGFR-1, VEGFR-2, phospho-VEGFR-2, cyclooxygenase (COX)-1, COX-2, and endothelial nitric oxide synthase (eNOS) expressions as well as plasma VEGF levels were evaluated. Results showed that CB(1) and CB(2) receptors were present in left adrenal veins of sham rats, splenorenal shunts (the most prominent intra-abdominal shunts) of BDL rats, and mesentery of sham and BDL rats. CB(2) receptor was up-regulated in splenorenal shunts of BDL rats. Both acute and chronic JWH-015 treatment reduced portal pressure and superior mesenteric arterial blood flow. Compared with vehicle, JWH-015 significantly alleviated portosystemic shunting and mesenteric vascular density in BDL rats, but not in sham rats. The concomitant use of JWH-015 and AM630 abolished JWH-015 effects. JWH-133, another CB(2) agonist, mimicked the JWH-015 effects. JWH-015 decreased mesenteric COX-1, COX-2 messenger RNA expressions, and COX-1, COX-2, eNOS protein expressions. Furthermore, JWH-015 decreased intrahepatic angiogenesis and fibrosis. CONCLUSIONS: CB(2) agonist alleviates portal hypertension (PH), severity of portosystemic collaterals and mesenteric angiogenesis, intrahepatic angiogenesis, and fibrosis in cirrhotic rats. The mechanism is, at least partly, through COX and NOS down-regulation. CBs may be targeted in the control of PH and portosystemic collaterals.

Effects of simvastatin on the portal-systemic collateral vascular response to endothelin-1 and shunting degree in portal hypertensive rats.

OBJECTIVE: Endothelin-1 (ET-1) exerts vasoconstrictive effect on portal-systemic collateral vascular bed of portal hypertensive rats. Statins are lipid-lowering agents with nitric oxide (NO)-related vasodilatory effects. Considering NO-associated vascular hyporesponsiveness to vasoconstrictors and shunting formation in portal hypertension, this study investigated the effects of simvastatin on 1) the portal-systemic collateral vascular responsiveness to ET-1 and 2) the portal-systemic shunting degree. MATERIALS/METHODS: Portal hypertension was induced by partial portal vein ligation (PVL) in Sprague-Dawley rats. Simvastatin (20 mg/kg/day) or distilled water (control) was randomly administered by oral gavage since 2 days prior to until 7 days after PVL. Systemic and portal hemodynamics were measured on the 8th day. In another series, collateral perfusion with Krebs solution at different flow rates was performed to get flow-pressure curves which serve as an index of shunting degree. To survey the direct vascular effect, PVL rats randomly underwent preincubation with 1) Krebs solution, that is, the control group; or Krebs solution plus 2) simvastatin; 3) simvastatin + N (ω)-nitro-L-arginine (NNA, a NO synthase inhibitor); 4) simvastatin + indomethacin (a cyclooxygenase inhibitor), followed by ET-1 to evaluate the collateral vascular responsiveness. RESULTS: Chronic simvastatin treatment significantly reduced portal pressure. The flow-pressure curves were similar between two groups. Simvastatin preincubation reduced collateral perfusion pressure changes to ET-1 (p < 0.05), which were partially reversed by NNA (p < 0.05), but not by indomethacin. Conclusions. Chronic simvastatin treatment significantly improved portal hypertension. The effect was at least partially exerted by decreased portal-systemic collateral vascular resistance through NO-mediated vascular hyporesponsiveness. The severity of portal-systemic collaterals was not influenced by simvastatin.

A patient with hemodialysis-related hyperammonemic encephalopathy: a delayed presentation of congenital arterioportal fistulas.

We present a 32-year-old woman who developed hyperammonemic encephalopathy during hemodialysis. She was rather well before 2009 when receiving peritoneal dialysis due to chronic interstitial nephritis. Due to a refractory peritonitis, the treatment was shifted to hemodialysis in January 2009. About 1 year later, she was found with consciousness disturbance during hemodialysis then admitted to the hospital because of hyperammonemia (165 µg/dl). During hospitalization, the patient's abdominal Doppler sonography showed a hepatofugal flow in the portal trunk while the hepatic artery angiography demonstrated multiple intrahepatic arterioportal fistulas. Her general condition was improved after the treatment of lactulose and hepatic artery embolization. With the occurrence of arterioportal fistulas induced portal hypertension, we speculated that the portal-systemic shunt was enhanced during hemodialysis because of venous hypotension which then resulted in the transient hyperammonemia. To the best of our knowledge, this is the first patient who developed hemodialysis- related hyperammonemic encephalopathy due to multiple arterioportal fistulas.

The influence of sorafenib on hepatic encephalopathy and the mechanistic survey in cirrhotic rats.

BACKGROUND: Sorafenib, a multikinase inhibitor that inhibits angiogenesis and carcinogenesis, has been used for patients with advanced hepatocellular carcinoma. However, sporadic cases have been reported with the development of hepatic encephalopathy (HE) after sorafenib treatment, mostly in those with cirrhosis. Liver function impairment, portal-systemic collaterals and brain oxidative stress participate in the pathogenesis of HE. The study therefore aimed to investigate the potential influences of sorafenib on HE and the relevant risk factors in cirrhotic rats. METHODS: Liver cirrhosis was induced in Spraque-Dawley rats with common bile duct ligation (CBDL). CBDL rats received sorafenib 1 mg/kg/day or distilled water (DW) via oral gavage since the 15th day post surgery for 2 weeks. On the 28th day, after motor activities measurements, mean arterial pressure, portal pressure and heart rate were checked. Thereafter, cerebral cortex and cerebellum were dissected for oxidative stress study and blood was collected for liver biochemistry survey. RESULTS: Sorafenib significantly reduced portal pressure (22%) and collateral shunting degree (15%) in cirrhotic rats. Alanine transaminase, aspartate transaminase, total bilirubin and ammonia were similar in sorafenib- and DW-treated groups. Motor activities were not significantly altered by sorafenib. In cerebrum, the oxidant and antioxidant substances activities were not significantly different between the two groups, whereas they were divergent in cerebellum and hippocampus. CONCLUSION: By surveying three main aspects involved in the pathogenesis of HE, this study demonstrates that sorafenib does not increase the risk of HE in cirrhotic rats.

Use of U-Net Convolutional Neural Networks for Automated Segmentation of Fecal Material for Objective Evaluation of Bowel Preparation Quality in Colonoscopy.

Background: Adequate bowel cleansing is important for colonoscopy performance evaluation. Current bowel cleansing evaluation scales are subjective, with a wide variation in consistency among physicians and low reported rates of accuracy. We aim to use machine learning to develop a fully automatic segmentation method for the objective evaluation of the adequacy of colon preparation. Methods: Colonoscopy videos were retrieved from a video data cohort and transferred to qualified images, which were randomly divided into training, validation, and verification datasets. The fecal residue was manually segmented. A deep learning model based on the U-Net convolutional network architecture was developed to perform automatic segmentation. The performance of the automatic segmentation was evaluated on the overlap area with the manual segmentation. Results: A total of 10,118 qualified images from 119 videos were obtained. The model averaged 0.3634 s to segmentate one image automatically. The models produced a strong high-overlap area with manual segmentation, with 94.7% ± 0.67% of that area predicted by our AI model, which correlated well with the area measured manually (r = 0.915, p < 0.001). The AI system can be applied in real-time qualitatively and quantitatively. Conclusions: We established a fully automatic segmentation method to rapidly and accurately mark the fecal residue-coated mucosa for the objective evaluation of colon preparation.

Liver failure after transarterial chemoembolization for patients with hepatocellular carcinoma and ascites: incidence, risk factors, and prognostic prediction.

BACKGROUND: Transarterial chemoembolization (TACE) is widely used in patients with hepatocellular carcinoma (HCC). Post-TACE liver failure may occur, especially in patients with poor hepatic reserve. Ascites is often present in patients with HCC with coexisting cirrhosis. This study investigated the incidence, risk factors, and prognostic predictors in patients with HCC and ascites receiving TACE. METHODS: A total of 614 patients with HCC were enrolled and analyzed. Liver failure was defined as an increase of serum bilirubin level (≥2.0 mg/dL), increasing or newly developed ascites, or hepatic encephalopathy within 2 weeks of TACE. RESULTS: Ascites that were present in 100 (16.2%) patients at study entry, independently predicted a poor prognosis in the Cox proportional hazard model [relative risk (RR)=1.75, P=0.004]. Post-TACE liver failure occurred in 17 (17.3%) of 98 patients with HCC who had ascites and long-term follow-up. Child-Turcotte-Pugh class B (odds ratio=10.1, P=0.038) and post-TACE gastrointestinal bleeding (odds ratio=10.86, P=0.006) were independent risk factors associated with liver failure in the multivariate analysis. Of the 17 patients with post-TACE liver failure, 16 (94%) died within the first year of treatment. Liver failure (RR: 2.13, P=0.029), serum α-fetoprotein level >51 ng/mL (RR=2.0, P=0.013) and poor performance status (RR: 2.17, P=0.003) independently predicted a poor prognosis in patients with ascites receiving TACE. CONCLUSIONS: Preexisting ascites increases the mortality in patients with HCC receiving TACE. In patients with HCC and ascites, Child-Turcotte-Pugh class B and gastrointestinal bleeding are associated with liver failure after TACE. Post-TACE liver failure is a common event and predicts a decreased survival in patients with HCC and ascites.

Magnifying endoscopy with narrow-band image for diagnosing diffuse type of gastric antral vascular ectasia in cirrhotic patients.

OBJECTIVE: Gastric antral vascular ectasia (GAVE) and portal hypertensive gastropathy (PHG) can cause gastrointestinal bleeding in cirrhotic patients. Distinguishing diffuse-type GAVE and severe PHG is important but difficult by conventional endoscopy and endoscopic biopsy. The aim of this study is to evaluate the value of magnifying endoscopy with narrow-band image for diagnosing diffuse-type GAVE in cirrhotic patients. METHODS: From January 2010 to December 2013, cirrhotic patients with diffuse red spots of stomach in suspicion of diffuse-type GAVE on conventional endoscopy in a tertiary medical center were included. The detection of diffuse red spots on magnifying endoscopy with narrow-band image (NBI) was classified into ring-pattern which suggested GAVE and mosaic-pattern which suggested non-GAVE. The golden diagnosis of GAVE was based on histological criteria of GAVE score ≥3 by any one of two endoscopic sessions. RESULTS: Total 27 cirrhotic patients were included. Twenty-two patients reached the diagnosis of GAVE and five patients were diagnosed of non-GAVE by histology. The diagnostic rate of conventional endoscopy was 81.5% (22/27). The positive rate of initial endoscopic biopsy was 77.2%. On magnifying endoscopy with NBI, the sensitivity, specificity, positive, negative predicted rate and accuracy of ring-pattern for the diagnosis of GAVE were 100, 90, 96.4, 100 and 97.3%. Kappa coefficient of inter-observer agreement for differentiating the ring and mosaic-pattern was 0.92. CONCLUSIONS: The efficacy and accuracy of magnifying endoscopy with NBI for diagnosing diffuse-type GAVE in cirrhotic patients have been demonstrated. It can avoid repeated endoscopy to confirm diagnosis and obviate the invasive biopsy in cirrhotic patients.