Celecoxib induces hepatic stellate cell apoptosis through inhibition of Akt activation and suppresses hepatic fibrosis in rats.

BACKGROUND AND AIMS: Activated hepatic stellate cells (HSCs) but not quiescent HSCs express cyclo-oxygenase-2 (COX-2), suggesting that the COX-2/prostanoid pathway has an active role in hepatic fibrogenesis. However, the role of COX-2 inhibitors in hepatic fibrogenesis remains controversial. The aim of this study was to investigate the antifibrotic effects of celecoxib, a selective COX-2 inhibitor. METHODS: The effects of various COX inhibitors-that is, ibuprofen, celecoxib, NS-398 and DFU, were investigated in activated human HSCs. Then, the antifibrotic effect of celecoxib was evaluated in hepatic fibrosis developed by bile duct ligation (BDL) or peritoneal thioacetamide (TAA) injection in rats. RESULTS: Celecoxib, NS-398 and DFU inhibited platelet-derived growth facor (PDGF)-induced HSC proliferation; however, only celecoxib (> or =50 microM) induced HSC apoptosis. All COX inhibitors completely inhibited prostaglandin E(2) (PGE(2)) and PGI(2) production in HSCs. Separately, PGE(2) and PGI(2) induced cell proliferation and extracellular signal-regulated kinase (ERK) activation in HSCs. All COX inhibitors attenuated ERK activation, but only celecoxib significantly inhibited Akt activation in HSCs. Celecoxib-induced apoptosis was significantly attenuated in HSCs infected with adenovirus containing a constitutive active form of Akt (Ad5myrAkt). Celecoxib had no significant effect on PPARgamma (peroxisome proliferator-activated receptor gamma) expression in HSCs. Celecoxib inhibited type I collagen mRNA and protein production in HSCs. Oral administration of celecoxib (20 mg/kg/day) significantly decreased hepatic collagen deposition and alpha-SMA (alpha-smooth muscle actin) expression in BDL- and TAA-treated rats. Celecoxib treatment significantly decreased mRNA expression of COX-2, alpha-SMA, transforming growth factor beta1 (TGFbeta1) and collagen alpha1(I) in both models. CONCLUSIONS: Celecoxib shows a proapoptotic effect on HSCs through Akt inactivation and shows antifibrogenic effects in BDL- and TAA-treated rats, suggesting celecoxib as a novel antifibrotic agent of hepatic fibrosis.

High prevalence of significant histology in asymptomatic chronic hepatitis B patients with genotype C and high serum HBV DNA levels.

Current treatment guidelines suggest that antiviral therapy be considered for chronic hepatitis B (CHB) patients with high viral load if a biopsy shows significant liver disease despite alanine aminotransferase (ALT) levels two times or less than the upper limit of normal (ULN). We evaluated the histological findings in CHB patients with high viral load and persistently normal or slightly elevated serum ALT levels. Between January 2003 and June 2006, 105 consecutive treatment-naive patients with CHB who underwent ultrasonography-guided percutaneous liver biopsy, had detectable serum HBV DNA (>10(5) copies/mL) in a direct hybridization assay and normal or slightly elevated serum ALT levels (≤2 × ULN) for at least 12 months were included in a prospective study. Histological assessment was based on the METAVIR scoring system. Significant histology was defined as fibrosis stage ≥F2 or necroinflammation grade ≥A2. Among the 105 CHB patients with high viral load and persistently normal or slightly elevated serum ALT levels for at least 12 months, significant fibrosis (F2-F4 fibrosis) was observed in 63 patients (60.0%) and the actual significant histology was found in 65 patients (61.9%). On multivariate analysis, serum ALT levels and age at which they entered the study were independent factors associated with significant histology. Odds ratios for significant histology increased progressively according to serum ALT levels and age. In conclusion, a large proportion of CHB patients with genotype C, high viral load and ALT ≤2 × ULN had significant liver disease on liver biopsy and should be considered for antiviral therapy.

Local radiotherapy for unresectable hepatocellular carcinoma patients who failed with transcatheter arterial chemoembolization.

PURPOSE: The purpose of this study was to investigate the efficacy of local radiotherapy (RT) as a salvage treatment for unresectable hepatocellular carcinoma (HCC) patients who failed with transcatheter arterial chemoembolization (TACE). METHODS AND MATERIALS: Patients with unresectable HCC who had been treated with and eventually failed with TACE were eligible. The judgment of TACE failure was based on incomplete tumor filling of lipiodol-adriamycin mixture on either angiography or computed tomography (CT) scan. From January 1993 to December 1997, 27 patients were entered into this study. They had UICC Stage III (17) or IVA (10) disease, with a mean tumor size of 7.2 +/- 2.9 cm. Local RT was done, with a mean tumor dose of 51.8 +/- 7.9 Gy, in daily 1.8-Gy fractions using a 10- or 6-MV linear accelerator. Survival was calculated from both the diagnosis and the start of RT using the Kaplan-Meier method. RESULTS: An objective response was observed in 16 of 24 patients (66.7%) including 1 CR. Intrahepatic metastasis was noted outside the RT field in 10 patients (37.0%). Extrahepatic distant metastasis occurred in 4 patients. Survival rates at 1, 2, and 3 years were 85. 2%, 58.1%, and 33.2%, respectively, from the diagnosis and 55.9%, 35. 7%, and 21.4%, respectively, from the start of RT. The median survivals were 26 months from the diagnosis and 14 months from the start of RT. Acute toxicity involved alteration in liver function test (13 patients) and thrombocytopenia (2 patients). Subacute and chronic toxicity involved gastroduodenal ulcer (3 patients) and duodenitis (2 patients). There was no treatment-related death. CONCLUSION: In unresectable HCC patients who failed with TACE, local RT induced a substantial tumor response of 66.7%, with a 3-year survival rate of 21.4% and a median survival time of 14 months. Toxicity was significant but manageable. Although we do not know if there is survival benefit through this treatment, local RT in these patients seems to be valuable as a salvage for TACE-failed HCC.

Combined transcatheter arterial chemoembolization and local radiotherapy of unresectable hepatocellular carcinoma.

PURPOSE: The best prognosis in hepatocellular carcinoma (HCC) can be achieved with surgical resection; however, the number of resected cases are limited due to advanced lesions or associated liver disease. The purpose of this study was to investigate the efficacy and toxicity of a prospective trial of combined transcatheter arterial chemoembolization (TACE) and local radiotherapy (RT) in unresectable HCC. METHODS AND MATERIALS: Patients with histologically proven unresectable HCC due to either advanced lesions or associated cirrhosis were eligible. From March 1992 to August 1994, 30 patients were entered into this study. TACE was performed with Lipiodol (5 ml) and doxorubicin (Adriamycin ; 50 mg), followed by gelatin sponge particle (Gelfoam) embolization. Local RT was started within 7-10 days following TACE. Mean tumor dose was 44.0+/-9.3 Gy in daily 1.8 Gy fractions. Response was assessed by computerized tomography (CT) scan 4-6 weeks following completion of the treatment and then at 1-3-month intervals. Survival was calculated from the start of TACE using the Kaplan-Meier method. RESULTS: An objective response was observed in 19 patients, giving a response rate of 63.3%. Distant metastasis occurred in 10 patients, with 8 in the lung only and 2 in both lung and bone. Survival rates at 1, 2, and 3 years were 67%, 33.3%, and 22.2%, respectively. Median survival was 17 months. There were 6 patients surviving more than 3 years. Toxicity included transient elevation of liver function tests in all patients, fever in 20, thrombocytopenia in 4, and nausea and vomiting in 1. There was no treatment-related death. CONCLUSION: Combined TACE and local RT is feasible and tolerable. It gives a 63.3% response rate with median survival of 17 months. We feel that this regimen would be a new promising modality in unresectable HCC. Further study is required to compare the therapeutic efficacy of this regimen to TACE alone.

Combined treatment of radiotherapy and hyperthermia for unresectable hepatocellular carcinoma.

Eighty-four patients with unresectable primary hepatocellular carcinoma due either to locally advanced lesion or to association with liver cirrhosis were treated with combined radiotherapy and hyperthermia from April 1988 to January 1991. Purpose of this study was to assess thermometry, response rate, toxicity, and survival in those patients. External radiotherapy was given with a total of 30.6 Gy/3.5 wks. Hyperthermia was given twice a week with a total of 6 treatment sessions using an 8 MHz radiofrequency capacitive type heating machine. Each hyperthermia session was started within 30 min following radiotherapy and continued for 30-60 min. Thermal data were analysed with maximum, minimum, and average temperatures of the tumors. Thermal mapping was also done. In thermometry results, maximum, minimum, and average temperatures of the tumors were 41.9 +/- 1.3 degrees C, 39.9 +/- 1.0 degrees C, and 40.8 +/- 0.9 degrees C, respectively. The fraction over 40 degrees C was 73 +/- 32% with a wide variation from 15% to 100%. Among 67 assessable patients, 27 patients showed tumor regression of more than 50% of the original tumor volume (40.3% response rate). Symptomatic improvement was observed in 78.6% of the patients. Acute toxicities during the treatment were mostly acceptable local pain (51.2%) and local fat necrosis (13.1%). The actuarial 1-year, 2-year, and 3-year survival rates were 44.8%, 19.7%, and 15.6%, respectively. Median survival was 6 months. In view of acceptable toxicities and the current rate of survival, further evaluation of combined treatment of radiotherapy and hyperthermia for unresectable hepatocellular carcinoma is warranted.

Effect of anticancer drugs and desferrioxamine in combination with radiation on hepatoma cell lines.

Several anticancer chemotherapeutic agents (5-fluorouracil, adriamycin and cisplatinum) and desferrioxamine, an iron chelator, were tested with regard to cytotoxicity and to the combined effect on radiation induced cell killing using two human hepatoma cell lines (HepG2 and PLC/PRF/5). Survival fractions were measured by quantitative colorimetric assay (MTT assay) and dose-response curves were plotted. MTT assay could be successfully used in the assessment of radiosensitivity in addition to chemosensitivity, because a good linear relationship between optical densities and cell numbers was observed and cells approached exponential growth for the first 7 days of culture when 5 x 10(3) or less cells were inoculated per well in our study. Steepness of the final slope (D0), width of the shoulder (D0) and the extrapolation number (n) of radiation survival curves were 1061.72 rad, 226.43 rad and 1.25 respectively in HepG2 and 1091.38 rad, 268.42 rad and 1.29 respectively in PLC/PRF/5. After combining anticancer chemotherapeutic agents and desferrioxamine with radiation, the widths of the shoulders were decreased whereas sensitizer enhancement ratios were increased as the concentration of drugs increased in both cell lines. These results suggest that neither anticancer chemotherapeutic agents nor desferrioxamine enhance cell killing induced by radiation alone, but suggested the possibility that they inhibit the repair of radiation damage.

Liver involvement in multiple myeloma proven by peritoneoscopy--a case report.

Liver involvement in multiple myeloma has been known to be common in autopsied series. However, since its clinical significance is uncertain yet, invasive procedure confirming plasma cell infiltration of the liver has been rarely performed. We report a case with multiple myeloma which had plasma cell infiltration of a liver. A peritoneoscopic biopsy of the liver for the purpose of disclosing the nature of the aggravating liver function in a carrier of the hepatitis B virus showed infiltration of lymphoreticular cell which were identified later as lambda-light chain producing primitive plasma cells by immunohistochemical stain.

A large common bile duct stone migrated from the gallbladder through a cholecystohepaticodochal fistula: an unusual complication of Mirizzi syndrome type II.

Mirizzi syndrome with a biliobiliary fistula (Mirizzi syndrome type II) is a rare complication of a long-standing gallbladder stone disease. It is even rarer for a gallbladder stone to migrate through a biliobiliary fistula into the common duct. We encountered this interesting complication of Mirizzi syndrome type II in an 86 year-old female patient. A large gallbladder stone migrated into, and impacted into the distal common bile duct through a cholecystohepaticodochal fistula. The stone was resistant to mechanical lithotripsy and was treated with biliary endoprosthesis and oral bile acids.

A case of flutamide-induced acute cholestatic hepatitis--a case report.

Flutamide, an oral nonsteroidal, antiandrogenic, anilid compound which inhibits the uptake and binding of androgens to nuclear receptors in the prostate, is used with or without LH-RH analogues for treatment of patients with metastatic carcinoma of the prostate. Clinically significant hepatotoxicities such as toxic hepatitis, cholestatic hepatitis, hepatic failure, and even death have rarely been reported in the English literature, but no case has been reported in Korea. A 75-year-old man with metastatic carcinoma of the prostate had taken flutamide (750 mg/day) for 7 months and suddenly developed jaundice and general weakness. The findings of blood chemistries were compatible with cholestatic hepatitis, but ultrasonography, viral marker and auto-antibody studies did not reveal any attributable causes. Histologic examination of a sono-guided liver biopsy only disclosed centrilobular cholestasis, nuclear glycogenosis and mild sinusoidal lymphocytic infiltration. Discontinuation of flutamide resulted in an almost full recovery of the patient's liver function in 2 months. We, herein, report a case of flutamide-induced acute choestatic hepatitis with a brief review of the literature.

Peritoneoscopic liver biopsy findings in asymptomatic chronic HBsAg carriers with normal liver function tests and no hepatomegaly.

Asymptomatic chronic HBsAg carriers with normal liver function tests are, in general regarded as having no liver pathology. Most of the histologic findings in asymptomatic chronic carriers have been reported from areas with low incidence of Hepatitis B virus (HBV) infection, such as North America and Western Europe. It is well known that there are many differences in HBV infection between low and high endemic areas, but there have been few reports on the histologic findings of asymptomatic chronic HBsAg carriers from endemic areas. The present study was undertaken in Korea which is one of the endemic areas for HBV infection and was designed to assess the prevalence of chronic liver disease by peritoneoscopic liver biopsy among asymptomatic chronic HBsAg carriers and to make a basis for the follow-up of asymptomatic chronic HBsAg carriers according to the results obtained. One hundred and ten asymptomatic HBsAg-positive carriers with normal liver function tests and no hepatomegaly were included in the study. Final diagnosis by peritoneoscopic liver biopsy revealed that of the 110 asymptomatic carriers only 27 (24.5%) had a histologically normal liver, while 51 (46.4%) had chronic liver diseases, and the remaining 32 (29.1%) had nonspecific histologic abnormalities (nonspecific reactive changes in 18 cases, cholestasis in 6 cases, and fatty change in 8 cases). Of the 51 patients with chronic liver diseases, 3 had liver cirrhosis, 4 chronic active hepatitis with cirrhosis, 11 chronic active hepatitis and 33 chronic persistent hepatitis. The frequency of liver cirrhosis and chronic active hepatitis with cirrhosis was significantly high in the over 30 years of age group (12.1%) than in the under 30 years of age group (0%; p = 0.011 by Fisher's exact test). In conclusion, 46.4% of the Korean asymptomatic chronic HBsAg carriers with normal liver function tests and no hepatomegaly had chronic liver disease. This finding contrasted with reports from low incidence areas of HBV infection. Our results suggest that in endemic areas, a liver biopsy should be considered to assess the status of liver disease in asymptomatic chronic HBsAg carriers even if liver function tests are normal and hepatomegaly is absent, and the result can be used as a basis for the follow-up of each asymptomatic chronic HBsAg carriers.

A case of paraesophageal hernia repaired by laparoscopic approach.

Paraesophageal hernia comprises only 2 approximately 5% of all hiatal hernias but is prone to incarceration and strangulation. For this reason they must be recognized and repaired as expeditiously as possible. The laparoscopic approach has already been successfully applied to the repair of the more common sliding hiatal hernia and it seems reasonable to propose that the paraesophageal hernia, provided it is not complicated, might also be repaired by the laparoscopic technique. We present here a case of paraesophageal hernia which has been successfully repaired by the laparoscopic approach. A 73-year-old female suffering from postprandial fullness in the retrosternal area was diagnosed preoperatively with paraesophageal hiatal hernia with gastroesophageal acid reflux and was submitted for laparoscopic repair. The procedure entailed reduction of the hernia, mobilization of the esophagogastric junction with crural repair and partial fundoplication. At the 9th-month follow-up, the patient had remained asymptomatic and follow-up studies revealed no evidence of hernia or acid reflux. As a result of this favorable experience with minimal morbidity, early hospital discharge, and effective control of symptoms without adverse sequalae, laparoscopic repair can be considered as the curative and minimal invasive method in the management of paraesophageal hernia.

Oxidative stress effect on the activation of hepatic stellate cells.

Collagen is the most excessive extracellular matrix protein in hepatic fibrosis. Activated, but not quiescent, hepatic stellate cells (HSCs) have a high level of collagen and a smooth muscle actin (alpha SMA) expression. HSCs play a key role in the pathogenesis of hepatic fibrosis. We analyzed a mechanism leading to HSC activation by evaluating the role of oxidative stress and the expression of NFkB. In vitro study HSCs were proliferated (PCNA:2% vs 68%) and activated (alpha SMA: 5% vs 78%) by ascorbate/FeSO4, and HSCs activated by type I collagen were blocked (PCNA: 97% vs 4%, a SMA: 86% vs 9%) by a-tocopherol. In vivo study means of a SMA positive cells in liver at 400 x HPF were 48.3+/-5.2 and 15.2+/-1.8 and [3H]thymidine uptake of HSC was 529.2+/-284.8 cpm and 223.0+/-86.3 cpm in control and a-tocopherol treated group respectively at 32 hours after CCl4 injection. Nuclear extracts from activated, but not from quiescent, HSCs formed a complex with the NFkB cognate oligonucleotidesand alpha-tocopherol inhibited this bindings. This study indicates that oxidative stress plays an essential role through the induction of NFkB on HSC activation.

Spontaneous bowel perforation during the course of acute pancreatitis--a case report.

We recently experienced a case of spontaneous perforation of infected necrosis into the colon and duodenum during the course of acute pancreatitis in a 63 year-old male patient. Enteric perforations or fistulas in the setting of acute pancreatitis implicate severe underlying pathology and have substantial morbidity and mortality. In the meantime it has generally been accepted that infected pancreatic or peripancreatic necrosis should be managed surgically as soon as possible. Enteric perforations in the present case contributed to transient improvement of the patient's infection sign and condition, and thus an early operation was able to be avoided. Delayed surgical management resulted in complete recovery of the patient without postoperative morbidity. Herein we report an unusual complication of acute pancreatitis.

An ischemic skin lesion after chemoembolization of the right internal mammary artery in a patient with hepatocellular carcinoma.

A huge nodular hepatocellular carcinoma located at the anterior superior portion of the left lobe in a patient with hepatocellular carcinoma was treated with transcatheter arterial chemoembolization through the left hepatic artery. Three months later, however, there was a re-elevation of the serum alpha-fetoprotein level and evidence of a marginal recurrence at the left side of the previously embolized tumor was noted on the postembolization computed tomographic scan. Although the hepatic artery was intact in the second hepatic arteriography, we found that the right internal mammary artery was feeding the recurred hepatocellular carcinoma. This internal mammary artery was successfully treated with Lipiodol-transcatheter arterial chemoembolization. However, an ischemic lesion occurred in the skin of the anterior chest and abdominal wall several days after internal mammary artery embolization. We report here a very rare case of ischemic skin lesion on the anterior chest and abdominal wall following transcatheter arterial chemoembolization of the right internal mammary artery. This internal mammary artery was embolized because it had developed a collateral tumor feeding vessel following the initial chemoembolization of a hepatocellular carcinoma.

Dysphagia due to mediastinal tuberculous lymphadenitis presenting as an esophageal submucosal tumor: a case report.

Mediastinal tuberculous lymphadenitis is rare in adults, and it is even rarer for dysphagia to be the presenting symptom of mediastinal tuberculous lymphadenitis. Mediastinal tuberculous lymphadenitis with esophageal symptoms has been presented as esophageal ulceration, mucosal or submucosal mass with ulceration, fistula or sinus formation, extrinsic compression, or displacement of the esophagus. An exaggerated form of extrinsic compression may be presented as a submucosal tumor, radiologically or endoscopically. A barium esophagography of a 34 year-old woman with painful dysphagia revealed a large submucosal tumor-like mass on the mid-esophagus. The symptom was spontaneously improved over a 3-week period together with reduction of the mass size. A computed tomography of the chest disclosed an enlarged subcarinal lymph node and histologic examination of the specimen obtained by thoracoscopic biopsy brought about a diagnosis of tuberculosis. We herein report a case of mediastinal tuberculosis with unusual manifestations.

Radiological response predicts survival following transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma.

BACKGROUND: It remains unclear whether initial compact lipiodol uptake after transarterial chemoembolisation (TACE) is associated with improved survival in patients with hepatocellular carcinoma (HCC). AIM: To reveal the clinical relevance of compact lipiodolisation after TACE. METHODS: We studied 490 patients with unresectable HCC who had first been treated with TACE. Compact lipiodolisation was defined as the absence of an arterial enhancing lesion, reflecting complete lipiodol uptake, as assessed by dynamic computed tomography (CT) 1 month after treatment. The rate of initial compact lipiodolisation was analysed according to multiplicity and size of tumour, and survival of patients who achieved compact lipiodolisation was compared to that of patients who did not. RESULTS: Of the 490 patients, 409 (83.5%) were in Child-Pugh class A and 81 (16.5%) in class B. The rate of initial compact lipiodolisation in single HCCs was higher than that in multinodular HCCs (33.7% vs. 14.6%, P < 0.001). Among single HCCs, the rate of compact lipiodolisation in tumours ≤5, 5-10 and >10 cm was 46.6%, 13.6%, and 0% respectively. The 1-, 3- and 5-year survival rates of patients with compact uptake were 92.7%, 70.7% and 52.4% compared to 60.8%, 28.0% and 16.9% in patients with noncompact lipiodolisation. Multivariate analysis revealed that Child-Pugh class, alpha-fetoprotein level, tumour node metastasis stage, portal vein thrombosis and initial compact lipiodolisation were independent predictors of survival. CONCLUSIONS: Initial compact lipiodol uptake after transarterial chemoembolisation is associated with improved survival in patients with unresectable hepatocellular carcinoma. Accordingly, initial complete lipiodolisation should be considered a relevant therapeutic target.

Pharmacokinetics of oltipraz and its major metabolite (RM) in patients with liver fibrosis or cirrhosis: relationship with suppression of circulating TGF-beta1.

Oltipraz is a potential candidate drug for the treatment of liver fibrosis (LF) and liver cirrhosis (LC). The pharmacokinetics of oltipraz and its major rearranged metabolite (7-methyl-6,8-bis(methylthio)H-pyrrolo[1,2-a]pyrazine (RM)) were evaluated after single-dose (30-90 mg) and multiple-dose (60 mg b.i.d. or 90 mg q.d. for 24 weeks) oral administration of oltipraz to patients with LF or LC. Oltipraz was safe and well tolerated in both studies. In the single-dose study, the area under the plasma concentration-time curve (AUC), peak plasma concentration (C(max)), and terminal half-life (t(1/2)) of oltipraz as well as the AUC of its RM were dose dependent. Oltipraz was rapidly absorbed; the time to reach C(max) (T(max)) was 2-4 h. The conversion of oltipraz to RM was also rapid and substantial (AUC of RM from time 0 to the last measured concentration (AUC(last, RM))/AUC(last, oltipraz), 42-61%). In the multiple-dose study, the level of transforming growth factor-beta1 (TGF-beta1) (a blood fibrosis marker) was suppressed at steady-state plasma concentrations of approximately 20-60 ng/ml of oltipraz or of approximately 60-140 ng/ml of oltipraz plus RM. Overall, the pharmacokinetics, safety, and efficacy of oltipraz suggest that it may be helpful in the treatment of patients with LF or LC, at an optimal dosing regimen.