The Clinical Impact of Hepatic Arterial Infusion Chemotherapy New-FP for Hepatocellular Carcinoma with Preserved Liver Function.

Background: Systemic treatments are recommended for advanced hepatocellular carcinoma (HCC) in preserved liver function. However, their effects are unsatisfactory in some tumor conditions, particularly macrovascular invasion (MVI) including major portal vein tumor thrombus (PVTT). We compared the efficacy of hepatic arterial infusion chemotherapy (HAIC) regimens New-FP and sorafenib for various tumor conditions in preserved liver function. Methods: We retrospectively collected the data of 1709 patients with HCC who were treated with New-FP or sorafenib. Survival was assessed after propensity score matching. Subgroup analyses were conducted: cohort 1 (no MVI or extrahepatic spread (EHS)), cohort 2 (MVI only), cohort 3 (EHS only), cohort 4 (MVI and EHS), and cohort 5 (major PVTT). Results: The New-FP group had a longer median survival time (MST) than the sorafenib in the whole analysis (18 vs. 9 months; p < 0.0001). New-FP demonstrated a longer MST compared with sorafenib in cohort 2 and cohort 4. In cohort 5, the MST of the New-FP group was 16 months, while that of sorafenib was 6 months (p < 0.0001). For major PVTT-HCC, the response rate of New-FP was 73.0%. The MST of patients who achieved complete response with New-FP was 59 months. Conclusions: HAIC using New-FP is promising for patients with MVI- and major PVTT-HCC in preserved liver function.

Survival Benefit of Hepatic Arterial Infusion Chemotherapy over Sorafenib in the Treatment of Locally Progressed Hepatocellular Carcinoma.

BACKROUND: Not all patients with hepatocellular carcinoma (HCC) benefit from treatment with molecular targeted agents such as sorafenib. We investigated whether New-FP (fine-powder cisplatin and 5-fluorouracil), a hepatic arterial infusion chemotherapy regimen, is more favorable than sorafenib as an initial treatment for locally progressed HCC. METHODS: To avoid selection bias, we corrected the data from different facilities that did or did not perform New-FP therapy. In total, 1709 consecutive patients with HCC initially treated with New-FP or sorafenib; 1624 (New-FP, n = 644; sorafenib n = 980) were assessed. After propensity score matching (PSM), overall survival (OS) and prognostic factors were assessed (n = 344 each). Additionally, the patients were categorized into four groups: cohort-1 [(without macrovascular invasion (MVI) and extrahepatic spread (EHS)], cohort-2 (with MVI), cohort-3 (with EHS), and cohort-4 (with MVI and EHS) to clarify the efficacy of each treatment. RESULTS: New-FP prolonged OS than sorafenib after PSM (New-FP, 12 months; sorafenib, 7.9 months; p < 0.001). Sorafenib treatment, and severe MVI and EHS were poor prognostic factors. In the subgroup analyses, the OS was significantly longer the New-FP group in cohort-2. CONCLUSIONS: Local treatment using New-FP is a potentially superior initial treatment compared with sorafenib as a multidisciplinary treatment in locally progressed HCC without EHS.

Regulation of transforming growth factor is involved in the efficacy of combined 5-fluorouracil and interferon alpha-2b therapy of advanced hepatocellular carcinoma.

Transforming growth factor-beta (TGF-ß) is critical in cancer cell invasion and metastasis. The effects of a treatment that targets TGF-ß using the combination of interferon alpha (IFNα)-2b and 5-fluorouracil (5-FU) are unknown. Here, we show that the serum levels of TGF-ß1 prior to the therapy correlate with increased maximum tumor diameter, which is significantly (p < 0.01) decreased after the combination therapy. 5-FU increased both the expression and secretion levels of TGF-ß1 in hepatoma cells, but not in normal hepatocytes. The combination of 5-FU and IFNα-2b synergistically affected cell death. However, a TGF-ß1 specific inhibitor did not affect the anti-tumor activity of 5-FU. 5-FU inhibited the phosphorylation of SMAD2 and reduced the total protein levels of SMAD2, SMAD4, and pINK4b. Conversely, 5-FU stimulated the phosphorylation of extracellular signal-regulated kinase (ERK)1/2. Accordingly, the protein levels of E-cadherin and claudin-1 were reduced in 5-FU-treated cells. The combination of 5-FU and IFNα-2b, and the inhibition of ERK1/2 by a specific inhibitor neutralized the effects of 5-FU on TGF-ß-related signaling molecules and restored their protein levels to those observed in the control. Interestingly, the phosphorylated protein levels of SMAD2 and the total protein levels of E-cadherin and p15INK4b were increased in 5-FU-stimulated HuH-7 cells, but not in Hep G2 cells. Our data suggest that the higher efficacy of the 5-FU and IFNα-2b combination therapy was associated with the regulation of TGF-ß expression, secretion, and the signals mediated by it.

Bimodal peaks of liver stiffness in a case of drug-induced liver injury.

A 69-year-old male complained of general fatigue and presented with elevation of liver enzymes without any cause of liver injury. We diagnosed him with hepatocellular drug-induced liver injury (DILI). Liver stiffness, which was evaluated according to the shear wave velocity (SWV) using virtual touch tissue quantification, was serially observed during hospitalization. A fast SWV was noted on the date of admission, indicating a "hard" degree of liver stiffness. The SWV gradually decreased until the 20th hospital day. However, the patient's liver enzymes again became elevated on the 20th hospital day, and the SWV simultaneously increased in association with a rise in the total bilirubin level. The laboratory data for the second peak of the SWV indicated mixed-type DILI; therefore, the patient's pathological state transitioned from the hepatocellular type to the mixed type. A liver biopsy performed before discharge revealed a state of recovery from acute inflammation without fibrotic changes. We conclude that the second peak of the SWV may be affected by the presence of intrahepatic cholestasis. We herein report the occurrence of bimodal peaks of liver stiffness in a patient with DILI. In such cases, each peak of liver stiffness may be the result of a different pathological mechanism, namely acute inflammation versus acute intrahepatic cholestasis. Although the detailed mechanisms underlying the development of liver stiffness due to intrahepatic cholestasis remain unclear, this case presented a limitation of virtual touch tissue quantification for evaluation of liver stiffness as fibrosis marker in the liver with intrahepatic cholestasis.

Efficacy of hepatic arterial infusion chemotherapy using 5-fluorouracil and systemic pegylated interferon α-2b for advanced intrahepatic cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma is categorized into intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). The prognosis of ICC is far worse than that of ECC. In this pilot trial, the efficacy of hepatic arterial infusion chemotherapy (HAIC) using 5-fluorouracil (5-FU) combined with subcutaneous administration of pegylated interferon (PEG-IFN) α-2b in patients with advanced ICC was evaluated. METHODS: The subjects were 20 advanced ICC patients treated using subcutaneous PEG-IFNα-2b (50-100 µg on day 1 of every week, for 4 weeks) and intra-arterial infusion of 5-FU (250 mg/day for 5 h on days 1-5 of every week, for 4 weeks). One treatment cycle lasted 4 weeks. Therapy was discontinued in patients with progressive disease (PD). For responses other than PD, treatment was repeated for ≥1 cycle. RESULTS: The objective early response rate was 60.0 %. Cumulative survival rates were 71.6 % at 6 months, 53.7 % at 12 months, 28.6 % at 18 months, and 14.3 % at 24 months. Median survival time was 14.6 months. All adverse reactions were controllable by temporary suspension of treatment. Serious complications and treatment-related deaths were not observed. CONCLUSIONS: The combination therapy of PEG-IFNα-2b and 5-FU for advanced ICC seems not to be worse than the results of the previous studies. Furthermore, most adverse effects are transient and well tolerated. Based on the present findings, this combination therapy may be useful for patients with advanced ICC as one of the therapeutic option.

Therapeutic efficacy of transarterial chemo-embolization with a fine-powder formulation of cisplatin for hepatocellular carcinoma.

AIM: To evaluate the efficacy of transarterial chemoembolization (TACE) using a suspension of a fine-powder formulation of cisplatin (DDPH) in lipiodol (LPD) in the treatment of hepatocellular carcinoma (HCC). METHODS: The subjects were 262 HCC patients treated with TACE using a DDPH-LPD suspension. The DDPH-LPD suspension was prepared by mixing 50 mg of DDPH into 10 mL of LPD. TACE was repeated when treated lesions relapsed and/or new hepatic lesions were detected. These patients received additional TACE using the same agent. TACE was repeated until complete regression of the tumor was obtained. The primary efficacy endpoint of the current study was the objective early response rate. Secondary efficacy endpoints were progression-free survival (PFS) and overall survival. RESULTS: The objective early response rate was 43.6%. Cumulative PFS rates were 56.7% at 6 mo, 23.1% at 12 mo, 13.4% at 18 mo, and 10.5% at 24 mo. The median PFS was 6.6 mo. Cumulative survival rates were 90.6% at 6 mo, 81.9% at 12 mo, 70.5% at 24 mo, and 58.8% at 36 mo. Median survival time was 46.6 mo. All adverse reactions were controllable by temporary suspension of treatment. No serious complications or treatment-related deaths were observed. CONCLUSION: TACE using a suspension of DDPH in LPD may be a useful treatment for HCC.

Icteric acute hepatitis E with no response of immunoglobulin M class anti-hepatitis E virus antibody.

A 68-year-old Japanese man developed icteric acute hepatitis during periodic care after undergoing gastrectomy due to early gastric cancer. The routine serological markers for hepatitis A, B and C viruses were all negative. Although the liver enzymes spontaneously recovered without any specific therapy, cholestasis was relatively prolonged and successfully treated with prednisolone. Determination of serum hepatitis E virus (HEV) RNA revealed the transient infection of HEV, and both immunoglobulin (Ig)A and IgG class anti-HEV antibodies were detected after the disease onset, whereas those were negative when measured 3 weeks prior to the onset. In addition, the titer of serum IgA class antibody was associated with the clinical signs of hepatitis. In contrast, no IgM class antibody was detected throughout the course. This case suggests that screening only with IgM class antibody is not sufficient to detect acute HEV infection.

Therapeutic efficacy of combination therapy with intra-arterial 5-fluorouracil and systemic pegylated interferon α-2b for advanced hepatocellular carcinoma with portal venous invasion.

BACKGROUND: The prognosis of advanced hepatocellular carcinoma (HCC) remains poor, particularly among patients with portal vein tumor thrombosis (PVTT). This study evaluated the efficacy of combined 5-fluorouracil and pegylated interferon (PEG-IFN) α-2b in patients with advanced HCC. METHODS: Subjects comprised 59 HCC patients with PVTT treated using subcutaneous administration of PEG-IFNα-2b (50-100 µg on day 1 of each week for 4 weeks) and intra-arterial infusion of 5-fluorouracil (250 mg/d for 5 hours on days 1-5 of each week for 4 weeks). One treatment cycle lasted 4 weeks. The current therapy was discontinued in patients with progressive disease (PD). For responses other than PD, treatment was repeated for ≥1 cycle. The primary efficacy endpoint was the objective early response rate. Secondary efficacy endpoints were progression-free survival (PFS) and overall survival. RESULTS: Objective early response rate was 73.0%. Cumulative PFS rates were 67.4% at 6 months, 30.2% at 12 months, 25.9% at 18 months, and 20.7% at 24 months. Median PFS was 9.7 months. Cumulative survival rates were 82.4% at 6 months, 73.6% at 12 months, 52.8% at 24 months, and 44.0% at 36 months. Median survival time was 29.9 months. All adverse reactions were controllable by temporary suspension of treatment. Serious complications and treatment-related deaths were not observed. CONCLUSIONS: Although a prospective randomized controlled trial using a larger population of patients with advanced HCC is needed to evaluate combination therapy with 5-fluorouracil and PEG-IFNα-2b, this new combination therapy may be useful for patients with advanced HCC.

Conservative treatment of an aortoesophagial fistula after endovascular stent grafting for a thoracic aortic aneurysm.

BACKGROUND: Aortoesophageal fistula (AEF) is an uncommon condition that presents a problem in therapy because of the high rate of morbidity and mortality associated with its surgical management and the uniformly fatal outcome of medical treatment. In this article we describe a case of secondary AEF after endoluminal stent grafting of the thoracic aorta, which was observed by only conservative management and followed up for 14 months with no signs of recurrent hemorrhage or chronic mediastinitis. CASE REPORT: A 54-year old man with hepatocellular carcinoma (HCC) was admitted to our hospital because of tarry stool. He had a history of traumatic aneurysm, and undergone segmental replacement with a stent graft three years ago. After admission, Esophagogastroduodenoscopy and computed tomography identified AEF. He was treated conservatively, because his stage of HCC was advanced. Oral intake was prohibited, and the patient received proton pump inhibitors, intravenous hyperalimentation and antibiotics. Afterwards, no signs of hemorrhage were observed. Although oral intake was resumed after that, another bleeding event or development of mediastinitis was not observed. Subsequently, He was received chemotherapy for advanced HCC, and we observed downstaging of his advanced HCC. CONCLUSIONS: Although we observed 14 months survival in our case under conservative management of secondary AEF, it seems that the treatment of secondary AEF should do the operative management.

Combination therapy of intra-arterial 5-fluorouracil and systemic pegylated interferon α-2b for advanced hepatocellular carcinoma.

BACKGROUND: This study evaluated the efficacy of combined 5-fluorouracil (5-FU) and pegylated interferon (PEG-IFN) α-2b in patients with advanced hepatocellular carcinoma (HCC). METHODS: Fifty patients with portal vein tumor thrombosis were enrolled. Of these, 21 patients were treated using subcutaneous administration of PEG-IFNα-2b and intra-arterial infusion of 5-FU (5-FU/PEG-IFN group), 12 patients were treated using intramuscular administration of IFNα-2b and intra-arterial infusion of 5-FU (5-FU/IFN group), and 17 patients received intra-arterial infusion chemotherapy with lipiodol-cisplatin (CDDP) suspension (CDDP group). RESULTS: The objective early response rate was significantly higher in the 5-FU/PEG-IFN group than in the 5-FU/IFN or CDDP groups (71.4 vs. 8.3% and 17.6%, respectively; P < 0.0001). Cumulative survival rates at 6 and 12 months were 83.8 and 77.8% in the 5-FU/PEG-IFN group, 60.8 and 16.2% in the 5-FU/IFN group, and 58.4 and 12.5% in the CDDP group, respectively. The cumulative survival rate was significantly higher in the 5-FU/PEG-IFN group than in the other 2 groups (P = 0.0272). Serious complications and treatment-related deaths were not observed in any of the 3 groups. CONCLUSION: Although a prospective randomized controlled trial using a larger population of patients with advanced HCC is needed to evaluate combination therapy with 5-FU and PEG-IFNα-2b, this new combination therapy may be useful for patients with advanced HCC.

Effects of branched-chain amino acid-enriched nutrient for patients with hepatocellular carcinoma following radiofrequency ablation: a one-year prospective trial.

BACKGROUND AND AIM: This prospective control study examined whether supplementation with branched-chain amino acid (BCAA)-enriched nutrients can help maintain and improve residual liver function and nutritional status in cirrhotic patients with hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA). METHODS: Subjects were 49 patients with hepatitis C-related HCC who underwent RFA. Two groups were formed: BCAA group (BCAA-enriched nutrient, aminoleban EN) and controls (standard diet only). Event-free survival rate, liver function tests, and Short Form (SF)-8 scores were evaluated in both groups before and one year after RFA. Energy metabolism using indirect calorimetry was measured before and after 3 months. RESULTS: Complete data were obtained from 35 patients (BCAA group, n = 20; controls, n = 15). Six events (death, recurrence of HCC, rupture of esophageal varices and liver failure) occurred during the observation period, but frequencies of these events did not differ between groups. Event-free survival rate tended to be higher in the BCA group than in controls. Among the parameters of liver function, serum albumin level was only significantly increased over 6 months, and remained at similar values for one year (P < 0.05). SF-8 scores for general health, physical functioning, and social functioning were significantly elevated in the BCAA group (P < 0.05). Non-protein respiratory quotient was significantly improved in the BCAA group (P < 0.01). CONCLUSION: Supplementation with BCAA-enriched nutrients for one year in cirrhotic patients with HCC after RFA therapy can perform safety and improve both nutritional state and quality of life.

Transcatheter arterial chemoembolization with a fine-powder formulation of cisplatin for hepatocellular carcinoma.

AIM: To evaluate the efficacy of transcatheter arterial chemoembolization (TACE) using a suspension of a fine-powder formulation of cisplatin (DDPH) for hepatocellular carcinoma (HCC). METHODS: The study population was comprised of 164 patients who were treated by TACE alone. Of these patients, 76 underwent TACE using a suspension of DDPH in lipiodol (LPD) (DDPH group), and the remaining 88 underwent TACE with an emulsion of doxorubicin (ADM) with LPD (ADM group). We compared the DDPH group with the ADM group in terms of the objective early response rate, progression free survival (PFS) and overall survival (OS). RESULTS: The objective early response rate in the DDPH group was significantly higher than that in the ADM group (54% vs 24%, P < 0.001). The PFS rate in the DDPH group was also significantly higher than that in the ADM group (P < 0.001). Moreover, the OS in the DDPH group was significantly longer than that in the ADM group (P = 0.002). Although the incidence rate of nausea or vomiting in the DDPH group was higher than that in the ADM group, the ADM group showed a higher incidence rate of the adverse events of hepatic arterial damage and leucopenia. No other serious complications were observed in either group. CONCLUSION: We conclude that TACE using a suspension of DDPH in LPD could be a useful treatment for HCC.

Changes in liver function parameters after percutaneous radiofrequency ablation therapy in patients with hepatocellular carcinoma.

AIM: To evaluate changes in liver function parameters and risk factors 1 year after percutaneous radiofrequency ablation (RFA) therapy in patients with hepatocellular carcinoma (HCC). METHODS: Subjects in this retrospective study comprised 45 patients with HCC who underwent RFA therapy (RFA alone, n = 25; transcatheter arterial embolization therapy before RFA, n = 20) and showed no recurrence of HCC 1 year after RFA. Serial changes in serum total bilirubin, albumin, prothrombin time and Child-Pugh score (CPs) were evaluated before and after RFA. In addition, Cox proportional hazards regression analysis was used to clarify risk factors for aggravation of liver function after RFA therapy. RESULTS: Serum albumin levels showed a significant decrease from before (3.6 +/- 0.4 g/dL) to 12 months after RFA therapy (3.2 +/- 0.4 g/dL; P

[Three (3) cases of advanced hepatocellular carcinoma (HCC) treated successfully by transcatheter arterial chemoembolization (TACE) using lipiodol and a fine- powder formulated cisplatin (DH)].

Although great advances have been made in therapies for patients with hepatocellular carcinoma(HCC), the prognosis for advanced HCC remains poor because liver transplantation is not applicable. We report three(3)cases of HCC treated successfully by transcatheter arterial chemoembolization(TACE)using a suspension of Lipiodol and a fine powder formulation of cisplatin(DDPH). Case No. 1 was a 64-year-old man with multiple HCCs who had undergone several sessions of TACE using doxorubicin(ADM). During the course of the treatment, the HCC became intractable and residual tumors were observed repeatedly within a short period. He was then treated by TACE using DDPH instead of ADM. The tumor marker levels decreased in response to this treatment and no recurrence of HCC has been observed. Case No. 2 was a 71-year-old man who had been diagnosed with multiple HCCs in 2004. He was treated by TACE with ADM, but the procedure had to be repeated more than three(3)times due to residual tumors. Despite the treatment, the tumor grew gradually and a formation of tumor thrombus was observed in the inferior vena cava. Both the tumor and tumor thrombus reduced in size after TACE with DDPH. Case No. 3 was a 52-year-old man who had been monitored diabetes mellitus and chronic hepatitis at our hospital. Multiple HCCs were diagnosed in 2006. TACE with DDPH was performed as an initial therapy. The tumors shrank or disappeared in response to this treatment. These results propose that TACE with DDHP against advanced HCC is effective.

Evaluation of newly developed combination therapy of intra-arterial 5-fluorouracil and systemic pegylated interferon alpha-2b for advanced hepatocellular carcinoma with portal venous invasion: preliminary results.

AIM: Prognosis is extremely poor for advanced hepatocellular carcinoma (HCC) in patients with portal invasion. The present study evaluated the efficacy of combined intra-arterial 5-fluorouracil (5-FU) and systemic pegylated interferon (PEG-IFN)alpha-2b in patients with advanced HCC. METHODS: The subjects comprised nine HCC patients with portal vein thrombosis treated using subcutaneous administration of PEG-IFNalpha-2b (50-100 microg on day 1 of every week, for 4 weeks) and intra-arterial infusion of 5-FU (250 mg/day for 5 h on days 1-5 of every week, for 4 weeks). For four patients with hepatitis C virus (HCV) infection, oral administration of ribavirin (400-800 mg/day) was added. At the end of every cycle, response to therapy was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. RESULTS: Partial response (PR) was observed in seven of nine patients, with stable or progressive disease in the remaining two patients. Tumors were resectable in three patients displaying PR after treatment. Tumor markers decreased significantly after therapy. Serum HCV-RNA titers were markedly decreased and became undetectable in all patients with HCV infection. National Cancer Institute-Common Toxicity Criteria: version 3.0 (NCI-CTC) grade 3 thrombocytopenia was seen in one case at the end of treatment, but was resolved with cessation of treatment. Other adverse effects were manageable. CONCLUSION: Combination therapy with intra-arterial 5-FU and systemic PEG-IFNalpha-2b may be useful as a palliative treatment for patients with advanced HCC. A prospective controlled trial using a larger population of patients with advanced HCC is needed to evaluate this new combination therapy.

Primary carcinoid tumor of the liver: A case report.

A53-year-old woman was hospitalized with a hepatic tumor that had been detected on health-screening ultrasonography. Laboratory data showed no marked findings: HBs-Ag and HCV-Ab were negative, and levels of serum AFP, PIVKA-II, CEA, and CA 19-0 were within their normal ranges. Ultrasonogram showed a hyperechoic circle concentric with and inside of a hypoechoic mass in the right hepatic lobe. The tumor appeared isodense with the surrounding liver in unenhanced CT, but enhanced CT showed a low density mass. A celiac arteriogram revealed a hypervascular tumor. The resected tumor measured 20×15 mm. Microscopic findings showed a carcinoid tumor that was positive for Grimelius stain. Further examination of the lung, gastrointestinal tract, and other organs found no primary carcinoid tumor. The patient has been well and free from tumor of the liver or elsewhere for the 7 years since her operation. We therefore considered this lesion to have been a primary carcinoid tumor of the liver. Only 14 cases of this disease have ever been reported in Japan. This report includes a review of the literature on the imaging of this rare tumor.

Contrast-enhanced ultrasonography using levovist: Usefulness of diagnosis of small focal nodular hyperplasia lesions.

Differential diagnosis of focal nodular hyperplasia and hepatocellular carcinoma is clinically important because, while both are hypervascular tumors, they have vastly different prognoses. Because the spoke-wheel appearance is the primary characteristic of focal nodular hyperplasia, we attempted to detect this pattern in nodules smaller than 3 cm in diameter with contrast-enhanced ultrasonography using a contrast agent (Levovist). Four patients were examined with contrast-enhanced US: two of the patients were examined with Coded Harmonic Angio; the other two patients were examined with contrast-enhanced color and power Doppler US without harmonic imaging. Although the hepatic arteriogram showed the spoke-wheel appearance in only one tumor (diameter, 3 cm), contrast-enhanced US clearly demonstrated this characteristic in all four tumors, including three tumors that were less than 2 cm in diameter. Because it is noninvasive and can be carried out in an outpatient clinic, contrast-enhanced US is extremely useful for diagnosing small focal noduler hyperplasia lesions at sites that can be observed with US.

A novel prostaglandin E receptor subtype agonist, 0N0-4819, attenuates acute experimental liver injury in rats.

We evaluated the efficacy of ONO-4819, a newly developed agonist of a prostaglandin receptor subtype (EP4), on experimental model of acute liver injury in rats. Acute liver injury was induced by simultaneous intraperitoneal (i.p.) administration of D-galactosamine (GalN, 1 g/kg body weight) and lipopolysaccharide (LPS, 100 mg/kg body weight). The rats received a single intraperitoneal injection of ONO-4819 (0.2 mg/kg body weight) or physiological saline immediately after GalN/LPS administration. Submassive hepatic necrosis with marked elevation of serum total bilirubin, serum aspartate aminotransferase and serum alanine aminotransferase levels developed 24 h after GalN/LPS administration. The administration of ONO-4819 significantly inhibited the development of submassive hepatic necrosis and inhibited the elevation in levels of biochemical markers that indicate liver function. In addition, the apoptotic index of hepatocytes assessed by the TUNEL method was significantly lower in rats treated with ONO-4819 than in the control. Although serum levels of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and interleukin-8 (IL-8) were markedly elevated after GalN/LPS administration, ONO-4819 significantly inhibited the elevation of those of TNF-alpha and IFN-gamma but not that of IL-8. The beneficial effect of ONO-4819 for acute liver injury was similar at doses of 0.1, 0.05 and 0.01 mg/kg body weight. These results suggest that the EP4 agonist, ONO-4819, may have a protective effect against experimental liver injury in rats through the suppression of inflammatory cytokines.