A randomized study of cisplatin and 5-FU hepatic arterial infusion chemotherapy with or without adriamycin for advanced hepatocellular carcinoma.

PURPOSE: This multicenter, randomized, open-labeled, clinical trial evaluated the efficacy and safety of cisplatin/5-fluorouracil (5-FU) hepatic arterial infusion chemotherapy (CF-HAIC) versus adriamycin adding to CF-HAIC (ACF-HAIC) in advanced HCC patients. METHODS: Fifty-six patients with advanced HCC were randomized to two treatment groups: (1) CF-HAIC group [n = 29, 5-FU, 500 mg/m(2) on days 1-3, and cisplatin, 60 mg/m(2) on day 2] and (2) ACF-HAIC group [n = 27, adriamycin, 50 mg/m(2) on day 1, 5-FU, 500 mg/m(2) on days 1-3, and cisplatin, 60 mg/m(2) on day 2] every 4 weeks via an implantable port system. Primary efficacy endpoint was overall survival (OS). Treatment response and time to progression were secondary endpoints. RESULTS: Treatment response rates did not differ significantly between the two treatment groups. Time to progression (5.4 vs. 5.8 months, P = 0.863) and OS (11.1 vs. 8.8 months, P = 0.448) were not significantly different. When the factors affecting patient OS were analyzed, disease control rate [P < 0.001, HR 6.437 (95% CI 2.580-16.064)] was independently associated with OS. Age (≥60 years) and serum AFP level (≥200 ng/dL) also were significant factors for OS [P = 0.007, HR 4.945 (95% CI 1.543-15.850), P = 0.048, HR 2.677 (95% CI 1.010-7.095), respectively]. Grade 4 treatment-related toxicity and mortality was not observed in both groups. CONCLUSIONS: Although both HAIC regimens are safe and effective in patients with advanced HCC, HAIC adding adriamycin did not show delayed tumor progression and survival benefit compared to CF-HAIC in advanced HCC.

A study of the awareness of chronic liver diseases among Korean adults.

BACKGROUND/AIMS: Chronic liver disease is closely associated with lifestyle, and public enlightenment of the lifestyle factors is important in reducing prevalence of chronic liver disease. The KASL (Korean Association for the Study of the Liver) conducted a survey of basic information and epidemiological data regarding chronic liver diseases. METHODS: A survey of chronic liver disease involving a total of 2,794 respondents was conducted. The respondents included patients and their guardians, visitors for health check-ups, and online pollees who completed a questionnaire on the awareness of fatty liver or chronic liver disease. RESULTS: Of the entire cohort, 854 (39.7%) said they have had or still have fatty liver or an elevated transaminase level (>40 IU/L), but only 23.4% of the respondents had visited a hospital. It was found that 35% of healthy subjects and 45% of patients and their guardians misunderstood hepatitis B as the hereditary disesase. Furthermore, 26% of the subjects responded that patients with inactive hepatitis B do not require regular follow-up. While 17.9% answered that it is not too late to test for liver cancer when symptoms arise, 38.8% believed that liver transplant in liver cancer patients has a low success rate and is thus not recommended. CONCLUSIONS: Despite the inundation of information and widespread media advertising, the awareness of chronic liver disease is unsatisfactory among Korean adults. Systematic nationwide studies are needed to obtain data and information regarding the prevalence of chronic liver disease and patterns of use of the health-care system.

Association between acid suppressive therapy and spontaneous bacterial peritonitis in cirrhotic patients with ascites.

OBJECTIVE: Proton pump inhibitor (PPI) or histamine-2 receptor antagonist (H2RA) therapy may cause intestinal bacterial overgrowth and translocation. Therefore, acid suppressive therapy may increase the risk of spontaneous bacterial peritonitis (SBP) in cirrhotic patients with ascites. MATERIAL AND METHODS: A total of 176 cirrhotic patients with ascites who underwent diagnostic paracentesis between September 2004 and April 2009 were included in the analysis. Patients with gastrointestinal hemorrhage and/or antibiotic therapy within 2 weeks prior to hospital admission were excluded. SBP was defined as ≥250/mm(3) polymorphonuclear white blood cells with or without a positive culture from the ascitic fluid. Eighty-three patients (mean age 56.1 years, 63 males) had SBP and 93 (mean age 54.7 years, 75 males) did not. RESULTS: On the multivariate analysis, a Child-Pugh class C (OR = 2.890, 95% CI 1.443-5.786; p = 0.003), high MELD scores (≥ 20, OR = 3.540, 95% CI 1.155-10.849; p = 0.027), and PPI use (OR = 3.443, 95% CI 1.164-10.188; p = 0.025) were risk factors for SBP. H2RA was not associated with SBP. CONCLUSIONS: PPI use, as well as Child-Pugh class C and high MELD scores, was an independent risk factor for the development of SBP in cirrhotic patients with ascites. Further prospective studies are warranted to clarify this issue.

High-dose radiotherapy with intensity-modulated radiation therapy for advanced hepatocellular carcinoma.

AIMS AND BACKGROUND: We report the results of intensity-modulated radiotherapy for patients with advanced hepatocellular carcinoma who were not candidate for local ablative therapies, transarterial chemoembolization or hepatic arterial infusion chemotherapy. METHODS AND STUDY DESIGN: Between 2003 and 2008, 27 patients were treated with high-dose radiotherapy (median dose, 50.4 Gy). The equivalent sphere size of tumors was 11.4 ± 2.6 cm. Nineteen and 8 patients were Child-Pugh class A and B, respectively. Eighteen patients had thromboses in large veins. Six patients were treated with radiotherapy as the initial treatment modality, and 21 patients received other treatments before radiotherapy. RESULTS: The overall response rate was 44.4% (1 pathologic complete response and 11 partial responses). The primary failure pattern was intrahepatic disease progression. Until the last follow-up, the primary liver masses and vein thromboses did not progress in 63.6% and 60.0% of the patients, respectively. The median progression-free survival and overall survival after radiotherapy rate were 3 and 5 months, respectively. Based on univariate analyses, response, Child-Pugh classification, and vein thrombosis were significant factors for overall survival, and tumor response, tumor size, vein thrombosis, and multiplicity were significant factors for progression-free survival. Tumor response was the only significant prognostic factor for overall survival and progression-free survival based on multivariate analyses. CONCLUSIONS: Radiotherapy with intensity-modulated radiotherapy achieved a good response rate in patients with advanced hepatocellular carcinoma, and patients who had a good response lived longer than patients who did not have a good response.

Pathological complete remission of advanced hepatocellular carcinoma with main portal vein tumor thrombosis by hepatic arterial infusion chemotherapy.

Cures for advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) are rare and difficult. We report a case of pathologically confirmed complete remission of HCC induced by hepatic arterial infusion chemotherapy (HAIC). A 45-year-old male patient had a massive HCC in the right lobe of the liver and tumor thrombus in the right and main portal veins. He achieved a partial response after two cycles of HAIC with 5-fluorouracil (750 mg/m(2)) and cisplatin (25 mg/m(2)). After the completion of six cycles he received a curative partial hepatectomy, and histopathology revealed complete necrosis without any viable tumor cell. He was in good health at a 4-month follow-up. These results suggest that this regimen is a promising therapeutic modality for the treatment of advanced HCC with PVTT.

Risk assessment for the development of hepatocellular carcinoma: according to on-treatment viral response during long-term lamivudine therapy in hepatitis B virus-related liver disease.

BACKGROUND & AIMS: To assess the risk for the development of hepatocellular carcinoma (HCC) according to the underlying liver status and on-treatment viral response during long-term lamivudine therapy in patients with hepatitis B virus-related liver disease. PATIENTS AND METHODS: Between March 1997 and February 2005, a total of 872 patients were treated with lamivudine for more than one year. Between 1983 and 1998, a total of 699 patients were enrolled as historical controls. RESULTS: For patients with compensated cirrhosis, HCC occurred in 4.9% (5/103) of cases with sustained viral suppression (persistently <141,500 copies/ml), 11.8% (20/170) in cases with viral breakthrough, and 19.4% (7/36) in cases with a suboptimal response (persistently 141,500 copies/ml): the mean follow-up was 5.1+/-2.7, 5.4+/-2.3, and 3.7+/-1.8 years, respectively. For the control group, HCC developed in 25.0% (37/148) of the cases during a mean follow-up of 6.1+/-4.3 years. Thus, the annual incidence of HCC was 0.95%, 2.18%, 5.26%, and 4.10% in patients with sustained viral suppression, viral breakthrough, suboptimal response, and the control group, respectively. The cumulative incidence of HCC in patients with sustained viral suppression was significantly lower than in patients with a suboptimal response and the controls (p=0.002 and p=0.005, respectively). In patients without cirrhosis and with decompensated cirrhosis, the preventive effects of lamivudine on the development of HCC were not observed (p=0.446 and p=0.123, respectively). CONCLUSION: Lamivudine therapy reduced the incidence of HCC in patients with compensated cirrhosis when the viral suppression was sustained.

Hepatic arterial infusion chemotherapy using high-dose 5-fluorouracil and cisplatin with or without interferon-alpha for the treatment of advanced hepatocellular carcinoma with portal vein tumor thrombosis.

OBJECTIVE: In this retrospective study, we assessed the efficacy of hepatic arterial infusion chemotherapy (HAIC) using high-dose 5-fluorouracil (5-FU) and cisplatin with or without interferon (IFN)-alpha for the treatment of advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis. MATERIAL AND METHODS: Fifty-two patients were included in the analysis. The patients were treated with 5-FU (750 mg/m(2)) and cisplatin (25 mg/m(2)) from Days 1 to 4. IFN-alpha was administered subcutaneously at a dose of 3 million units from Days 1 to 4, and then every other day for 24 days. Chemotherapy was repeated every 4 weeks. Thirty-one patients were treated with 5-FU, cisplatin and IFN-alpha (FPI group) and 21 were treated with 5-FU and cisplatin (FP group). RESULTS: An objective tumor response was achieved in six patients (19.4%) in the FPI group. In the FP group, 12 patients (57.1%) achieved an objective tumor response (p = 0.015). The cumulative survival rate was higher in the FP group than the FPI group, but this difference was not statistically significant (p = 0.353). The median survival time for the 18 responders was 14 months (range 4-25 months), and their 6, 12, and 24-month cumulative survival rates were 89%, 83%, and 25%, respectively. CONCLUSIONS: HAIC using high-dose 5-FU plus cisplatin achieved a good tumor response. Adding IFN-alpha did not show any additional beneficial effects in terms of tumor response rate or survival.

[Clinical characteristics of intrahepatic cholangiocarcinoma and prognostic factors in patients who received non-surgical treatment].

BACKGROUND/AIMS: This study was conducted to analyze the prognostic factors in patients with intrahepatic cholangiocarcinoma (ICC) who did not receive surgery. METHODS: Between August 1997 and November 2007, the medical records of 175 patients (mean age; 66 years, male/female 126/49), who were diagnosed as ICC, were reviewed retrospectively. RESULTS: Clonorchiasis and hepatolithiasis was found in 14.9%, and 6.3% of all patients, and no risk factors were identified in 77.8% of them. Surgical resection was performed in 29.1% (51 patients), chemotherapy +/- radiotherapy in 12.6% (22 patients), and palliative therapy in 58.3% (102 patients). The proportion of patients with stage I was 23.4% (41 patients). The prognostic factors in patients who did not receive surgery were alkaline phosphatase (ALP) and bilirubin levels by univariate and multivariate analysis. The median survival of patients with normal ALP and bilirubin levels was six months, whereas only one month in patients with elevated ALP and bilirubin levels (p<0.001). Tumor characteristics of patients with elevated bilirubin and ALP levels were infiltrative tumor, bile duct involvement, and very huge tumor. CONCLUSIONS: The prognostic factors of ICC in patients who did not receive surgery were ALP and bilirubin levels, but not lymph node metastasis.

[A case of peritoneal seeding from a ruptured hepatocellular carcinoma with direct invasion into the stomach causing gastrointestinal hemorrhage].

Hepatocellular carcinoma (HCC) rarely invades the gastrointestinal (GI) tract. It occurs in 0.7% to 2% of clinical HCC cases. Moreover, gastric invasion with GI hemorrhage via peritoneal seeding is very rare. We report the case of 67-year-old woman who had a history of HCC rupture and was admitted due to left upper quadrant abdominal pain. The patient was diagnosed with three omental metastatic masses and underwent hepatic segmentectomy and omental tumorectomy. Two months later, the patient had massive melena, and an esophagogastroduodenoscopy showed very large ulcerated friable mass on the gastric body. The histology was consistent with the diagnosis of metastatic HCC. The patient died from persistent GI hemorrhage 93 days after the admission. This case illustrates the very rare event of peritoneal seeding of a ruptured HCC causing direct invasion of the stomach, followed by GI hemorrhage.

[Long-term clevudine therapy in nucleos(t)ide-naïve and lamivudine-experienced patients with hepatitis B virus-related chronic liver diseases].

BACKGROUNDS/AIMS: Clevudine is an effective antiviral nucleoside analogue, but there are few data regarding its long-term effects, resistance, and safety. The aim of this study was to evaluate the long-term clinical efficacy of clevudine over a 1-year treatment period in nucleos(t)ide-naive and lamivudine-experienced chronic hepatitis B patients. METHODS: Nucleos(t)ide-naive (group A, n=196) and lamivudine-experienced (serum hepatitis B virus, HBV DNA >2,000 copies/mL without resistant mutants at the start of clevudine therapy, group B, n=75) patients were included in this study. Basic clinical characteristics including age, sex, the presence of cirrhosis, laboratory data, and hepatitis B surface antigen (HBeAg) positivity were similar between the two groups. Pretreatment serum levels of HBV DNA were 7.4 and 6.6 log(10) copies/mL (P<0.001). The mean treatment duration was 8 months for both groups (range for group A: 3-21 months; range for group B: 3-20 months). Genotypic analysis for resistant mutations in the reverse transcriptase of HBV was performed after viral breakthrough. RESULTS: After 1 year of therapy, 75.0% and 51.9% of groups A and B, respectively, had HBV DNA levels of <2,000 copies/mL (P=0.032), and HBeAg seroconversion rates were 16.9% and 16.7%, respectively. The rates of viral breakthrough at 1 year were 10.0% (8/80) and 44.4% (12/27), respectively (P<0.001). Proven sites of mutation of HBV DNA polymerase in naive patients were, for example, L80I, L180M, A181V/T, M204I and V207I. Ten patients complained of prominent fatigue and revealed elevated serum levels of aspartate aminotransferase (AST) and creatine phosphokinase (CPK). Two of these patients presented with severe myopathy from which they recovered completely after quitting clevudine. CONCLUSIONS: Clevudine is one of the recommended first-line medicines for the treatment of chronic hepatitis B, but it is not free from resistance, particularly in patients with a history of previous lamivudine treatment, but also in naive patients. Clevudine should be avoided in previously lamivudine-exposed patients. In addition, reelevation of serum AST and CPK levels is not a rare occurrence, and close observation and follow-up tests are essential.

S-1 and gemcitabine as an outpatient-based regimen in patients with advanced or metastatic pancreatic cancer.

OBJECTIVE: The standard beneficial chemotherapy proved for patients with pancreatic cancer is a regimen containing gemcitabine. Novel oral fluoropyrimidine, S-1, can be added to gemcitabine to improve the efficacy of chemotherapy and to provide better convenience for patients. We aimed to evaluate the efficacy and safety of S-1 plus gemcitabine combination chemotherapy as a first-line treatment in patients with locally advanced or metastatic pancreatic cancer. METHODS: Patients with histologically confirmed, bidimensionally measurable advanced/metastatic pancreatic cancer were eligible for the study. Chemotherapy consisted of S-1 (30 mg/m(2) p.o. bid from Day 1 to 14) and gemcitabine (1000 mg/m(2) on Days 8 and 15) every 3 weeks based on the results of a previously reported Phase I trial. Treatment was repeated until disease progression or unacceptable toxicity occurred. RESULTS: From January 2005 to August 2007, 22 patients were enrolled. Median age was 62 years (range, 50-73). Nineteen patients (86.3%) had metastases and of these, 11 patients (57.9%) had multiple liver metastases. The overall response rate was 27.3% (95% CI, 8.7-45.9), with a partial response in six patients, stable disease in nine (40.9%) and progressive disease in seven (31.8%). With a median follow-up of 25.4 months, the median time to progression and overall survival were 4.6 (95% CI, 2-7.2 months) and 8.5 months (95% CI, 6.8-10.1 months), respectively, and 1-year survival rate was 27.3%. S-1 plus gemcitabine was well tolerated. Grade 3/4 hematological adverse events were neutropenia (9.1/9.1%) and anemia (4.5/0%). Non-hematological adverse events were mainly gastrointestinal events. Twenty patients (91%) received chemotherapy on an outpatient basis. CONCLUSIONS: Combination chemotherapy of S-1 plus gemcitabine appears to be active and well tolerated as first-line treatment in patients with advanced/metastatic pancreatic cancer.

Cellular mechanisms of hepatocyte growth factor-mediated urokinase plasminogen activator secretion by MAPK signaling in hepatocellular carcinoma.

AIMS AND BACKGROUND: The hepatocyte growth factor, its receptor c-Met, and urokinase-type plasminogen mediate various cellular responses on activation, including proliferation, survival, invasion, and metastasis. The regulatory mechanisms for the proliferation and the particular invasive phenotypes of hepatocellular carcinoma are not yet fully understood. In order to clarify the intracellular downstream signal for hepatocyte growth factor/c-Met signaling in tumor progression and metastasis in hepatoma, we determined the effects of a specific MEK1 inhibitor (PD 098059) and a p38 kinase inhibitor (SB 203580) on hepatocyte growth factor-mediated cell proliferation and urokinase-type plasminogen expression in hepatoma cell lines (HepG2 and Hep3B). RESULTS: Hepatocyte growth factor treatment induced the phosphorylation of ERK and p38 kinase in a dose-dependent manner, resulting in an early peak of phosphorylation at 3 to 10 min, which then rapidly decreased to a near basal level. Pretreatment with PD 098059 reduced hepatocyte growth factor-mediated cell proliferation and urokinase-type plasminogen secretion. In contrast, SB 203580 pretreatment enhanced cell proliferation and urokinase-type plasminogen secretion due to induction of ERK phosphorylation. Treatment with PD 098059 and SB 203580 resulted in a decrease in phospho-ERK activity. Stable expression of dominant negative-MEK1 in HepG2 cells showed a decrease in hepatocyte growth factor-mediated urokinase-type plasminogen secretion. CONCLUSIONS: Such results suggest that interaction of an MEK/ERK and a p38 kinase might be critical in intrahepatic invasion and metastasis of human hepatoma cells.

[A case of severe hypophosphatemia related to adefovir dipivoxil treatment in a patient with liver cirrhosis related to hepatitis B virus].

Adefovir dipivoxyl (ADV) effectively suppresses hepatitis B virus (HBV) replication but exhibits nephrotoxicity with severe hypophosphatemia when administered at a high dosage. This is the first report of severe hypophosphatemic osteomalacia induced by ADV at 10 mg/day. A 42-year-old man with HBV-related chronic liver disease presented with generalized bone pain, especially in the left ankle. He had been taking ADV for more than 1.5 years following a clinical breakthrough due to lamivudine-resistant HBV. Aggravating severe hypophosphatemia and elevated serum alkaline phosphatase levels with high bone fraction had been noted after 6 months of ADV therapy. Bone densitometry, simple bone X-rays, and a whole-body bone scan demonstrated osteoporosis and multiple areas with hot uptake, especially in the left ankle. All the image findings and symptoms improved after correcting the hypophosphatemia.

An adult case of glycogen storage disease type IIIa.

Glycogen storage disease type III (GSD III) is a very rare disorder caused by a deficiency in the activities of glycogen debranching enzymes (amylo-1-6-glucosidase and 4-alpha-glucanotransferase). GSD III is characterized by the accumulation of abnormal glycogen in the liver and skeletal muscle. The primary clinical manifestations are hepatomegaly, fasting hypoglycemia, and hyperlipidemia in infants. We report a rare case of GSD III in an adult. A 52-year-old woman presented to our clinic due to dyspnea on exertion, severe general weakness, and hepatomegaly. Hypertrophic cardiomyopathy was diagnosed based on echocardiogram findings. The microscopic findings of liver and skeletal muscle biopsies were consistent with the diagnosis of GSD. DNA analysis prompted by clinical and pathologic findings led to a definitive diagnosis of GSD IIIa. Diet therapy with cornstarch was started, and the patient was followed closely. This represents the first reported case of GSD IIIa diagnosed in an adult in Korea.

Hepatocyte growth factor promotes cell survival by phosphorylation of BAD in gastric cancer cells.

Hepatocyte growth factor (HGF) is one of the survival factors with a potent ability to promote cell survival by inhibiting apoptosis. However, the mechanism by which HGF inhibits apoptosis is not completely understood. To explore the genes associated with stomach cancer cell survival by HGF, we used cDNA microarray technology and selected 26 genes up- or downregulated in NUGC-3 cells during HGF treatment. Among them, BAD was confirmed to be upregulated at the RNA and protein levels by HGF treatment. We investigated the effect of BAD induced by HGF on cell survival. HGF treatment inhibited apoptosis induced by BAD overexpression and enhanced BAD phosphorylation. Pretreatment of NUGC-3 cells with PI3K inhibitors, LY 294002, decreased HGF-induced BAD phosphorylation on Ser136 whereas an MEK inhibitor, PD 98059, decreased BAD phosphorylation on Ser112. In conclusion, increases in BAD levels as well as BAD phosphoryation by HGF might contribute to HGF-mediated cell survival in NUGC-3 cells.

[Comparison of therapeutic results between combination therapy of peginterferon alpha-2a plus ribavirin and interferon alpha-2b plus ribavirin according to treatment duration in patients with chronic hepatitis C].

BACKGROUND/AIMS: This study compared the efficacy and safety of combined peginterferon alfa (PEG-IFN) and ribavirin with that of combined interferon alpha (IFN-alpha) and ribavirin, according to the treatment duration in Korean patients with chronic hepatitis C. METHODS: Medical records of 86 patients treated with PEG-IFN and ribavirin (mean age, 50.7 years; males/females, 57/29; genotypes 1/2, 59/27) and 134 patients treated with IFN-alpha and ribavirin (mean age, 50.9 years; males/females 74/60; genotypes 1/2, 79/55) were reviewed. Ribavirin was administered at doses of 600-1,200 mg and 600-800 mg in patients with genotypes 1 and 2, respectively. RESULTS: Sustained virological responses (SVRs) were evident in 68.4% and 41.7% of genotype 1 patients treated for 48 weeks in the PEG-IFN and IFN-alpha groups, respectively (P=0.021), and in 94.1% and 64.9% of genotype 2 patients treated for 24 weeks (P=0.026). Some genotype 1 patients treated for 24 weeks in the PEG-IFN group, who all exhibited negative HCV PCR results at week 12, showed an SVR of 87.5% (7/8). CONCLUSIONS: The rate of SVRs in Korean patients with chronic hepatitis C was higher for combined PEG-IFN and ribavirin than for combined IFN-alpha and ribavirin. Further study is needed to clarify the outcome of short-term therapy in patients with a rapid or early virological response.

[Comparison of clinical outcome between patients continuing and discontinuing lamivudine therapy in acute exacerbation after viral breakthrough during lamivudine therapy in chronic hepatitis B].

BACKGROUNDS/AIMS: Continuation of lamivudine therapy is controversial for patients with chronic hepatitis B when viral breakthrough occurs. Moreover, the effect of continuous lamivudine therapy is unknown in patients with acute exacerbation after viral breakthrough. We assessed clinical course of acute exacerbation after viral breakthrough in patients who continued and discontinued lamivudine therapy. METHODS: Medical records of 109 patients with viral breakthrough during lamivudine therapy were reviewed. Of 40 patients with acute exacerbation (ALT level > 5 x ULN), adefovir dipivoxil was unavailable in 38 patients. These 38 patients (mean age 42.6 years; male/female, 34/6) were divided into continuation (n=21) and discontinuation (n=17) groups. Clinical courses of the 2 groups were compared. RESULTS: During follow-up period (mean, 27 months; range, 6-60 months), ALT levels decreased to < 2 x ULN in 11 patients (52%) of continuation group and 9 patients (53%) of discontinuation group, varied from 2 x to 5 x ULN in 9 (43%) and 5 (29%), respectively, and increased to > 5 x ULN in 1 (5%) and 3 (18%), respectively, with no statistical significance (P=.417). CONCLUSIONS: When acute exacerbation of ALT levels occurs after viral breakthrough during lamivudine administration in patients with compensated chronic hepatitis B, continuation of lamivudine may have no advantage over discontinuation.