Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging as a useful detection method for advanced primary biliary cirrhosis.

AIM: In primary biliary cirrhosis (PBC), damaged hepatocytes resulting from chronic cholestasis follow a compensatory mechanism that alters hepatobiliary transporter expression to reduce the accumulation of potentially toxic compounds such as bile acid. Organic anion transporter peptide 1B3 (OATP1B3), which transports agents such as gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), has reduced expression in the late stages of PBC. Therefore, we investigated the use of Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) as a useful detection method for the advanced staging of PBC. METHODS: Stage I-III PBC (non-liver cirrhosis [LC]-PBC, n = 12), stage IV (LC-PBC, n = 6), and non-PBC patients (control group, n = 4) were included in this study. We obtained liver tissue samples by percutaneous liver biopsy. Hepatic OATP1B3 expression was determined immunohistochemically, and OATP1B3 mRNA levels were assessed using real-time reverse transcription polymerase chain reaction. The relative enhancement (RE) in the hepatobiliary phase was calculated using the signal intensity of Gd-EOB-DTPA-enhanced MRI. RESULTS: Immunohistochemistry revealed markedly reduced expression of OATP1B3 in hepatocytes around the central vein in LC-PBC patients. Hepatic OATP1B3 mRNA expression in LC-PBC patients was significantly lower than that in non-LC-PBC patients (P < 0.05). The RE on MRI was significantly decreased in the LC-PBC group (0.33 ± 0.14) compared with the non-LC-PBC (0.91 ± 0.15, P < 0.01) and control (0.92 ± 0.20, P < 0.01) groups. CONCLUSION: Gd-EOB-DTPA-enhanced MRI may provide a useful detection method for liver disease in patients with LC-PBC.

Immunohistochemical demonstration of transferrin receptor 1 and 2 in human hepatocellular carcinoma tissue.

BACKGROUND/AIMS: Recent studies have confirmed that iron overload is involved not only in liver carcinogenesis, but in its progression. Results in studies using liver cancer cell lines have suggested a relationship between transferrin receptor (TfR) expression and liver carcinogenesis, but TfR expression has not yet been analyzed in human hepatocellular carcinoma (HCC) tissues. METHODOLOGY: We immunohistochemically assessed the expression of TfR1 and TfR2 in tumor tissues and adjacent non-tumorous liver tissues from 41 HCC patients who underwent partial hepatectomy. We evaluated uptake of iron in hepatocytes and HCC cells using iron staining. RESULTS: The expression TfR was significantly higher in HCC samples than in adjacent non-tumor tissue (p < 0.001). TfR expression was significantly related to serum alpha-fetoprotein (p < 0.05) and des-gamma carboxy prothrombin (p < 0.05) concentrations. We also found iron deposition in non-tumor tissue from 25 patients, but in only two HCC samples, consistent with findings that hepatocellular iron uptake decreases with liver carcinogenesis. CONCLUSIONS: We investigated the expression of TfR1 and TfR2 in human HCC tissues by immunohistochemistry, the first report demonstrating TfR2 expression immunohistochemically in human HCC. These results suggest that TfR is expressed in response to iron deficiency during liver carcinogenesis.

Why is radiofrequency ablation therapy applied for hepatocellular carcinoma up to 3 nodules and smaller than 3 cm in tumor size?

BACKGROUND/AIMS: Radiofrequency ablation (RFA) has been applied for hepatocellular carcinoma (HCC) up to 3 nodules, within 3 cm in size. However, the scientific rationale of the treatment criteria for RFA has not been well analyzed. We compared the number and size of tumors with recurrence rates and survival rates. METHODOLOGY: The study participants retrospectively were enrolled 625 consecutive cases of naïve HCC treated with RFA. We analyzed recurrence rates and survival of 472 for the patients with HCC ≤ 3 nodules, ≤ 3 cm in size (Group A), and 153 for the patients exceeding limits (Group B). RESULTS: Median follow-up was 2.97 years. The survival rate of Group A was significantly higher than that of Group B (5 years: 55.6% vs. 44.2%, 10 years: 27.4% vs. 15.7%; P<0.05). Multivariate analysis of predictors for prognostic factors demonstrated that meeting the RFA criteria, Child-Pugh score A, and lower levels of des-gamma carboxy prothrombin (DCP) were independent factors significantly affecting prognosis. CONCLUSIONS: The present study is the firstto elucidate the scientific rationale for RFA treatment criteria for HCC regarding tumor number and size. We confirmed that the RFA treatment criteria select patients who stand to gain the most from RFA.

Pilot Study of Hepatic Arterial Infusion Chemotherapy with Interferon-beta and 5-fluorouracil: A New Chemotherapy for Patients with Advanced Hepatocellular Carcinoma.

BACKGROUND/AIMS: The present pilot study aimed to evaluate the safety and efficacy of hepatic arterial infusion chemotherapy (HAIC) with interferon-beta (IFN-ß) and 5-fluorouracil (5-FU) in patients with advanced hepatocellular carcinoma (HCC). METHODOLOGY: We studied 10 patients with advanced HCC and who were unresponsive to previous HAIC using low-dose 5-FU and cisplatin. The median age was 67 years. Eight patients had portal vein tumor thrombosis and four patients had extrahepatic metastasis. Using a drug delivery system, patients were treated with HAIC of IFN-ß (600 MIU/body, three times/week) and 5-FU (250 mg/body, five times/week). Chemotherapy was repeated consecutively for 2 weeks every 4 weeks. RESULTS: Six (60%) patients had a decrease in tumor markers alpha-fetoprotein (APP) or des-gamma-carboxy prothrombin (DCP). The median overall survival was 108 days and the 1-year survival rate was 10.0%. Univariate analysis showed two significant prognostic factors related to long-term survival for more than 60 days: a decrease in APP or DCP 4 weeks after treatment (P = 0.035) and no extra hepatic metastasis (P = 0.035). Severe hepatic injury was not observed. CONCLUSIONS: HAIC with IFN-ß and 5-PU exerts modest antitumor effects and poses no particular safety concerns. This may be a new promising strategy for treatment of advanced HCC.

Desmoplastic small round cell tumors in a young man.

A previously healthy 18-year-old man was admitted to our hospital with abdominal pain in September 2010. We performed a percutaneous biopsy of multiple intrahepatic masses. A diagnosis of desmoplastic small round cell tumors was confirmed based on the presence of a polyphenotypic immunoprofile (positivity for EMA, vimentin, cytokeratin, desmin and WT1) and characteristic EWS-WT1 gene fusion. Because the mass had invaded the mesentery and the disease had disseminated to liver, the patient received palliative chemotherapy with carboplatin, paclitaxel, vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide and irinotecan. The maximal response to the chemotherapy was a partial remission. The patient died 20 months after diagnosis.

3-Hydroxyl-3-methylglutaryl-coenzyme A reductase is up regulated in hepatocellular carcinoma associated with paraneoplastic hypercholesterolemia.

Hepatocellular carcinoma (HCC) is frequently associated with paraneoplastic hypercholesterolemia. However, cholesterol overproduction in HCC tissue has never been demonstrated. An aim of this study is to prove cholesterol overproduction in the HCC tissue of patients with paraneoplastic hypercholesterolemia. Six patients with HCC associated with paraneoplastic hypercholesterolemia and three control patients with HCC who did not have hypercholesterolemia were investigated regarding the expression of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase in HCC tissue by means of immunohistochemical technique. In HCC associated with paraneoplastic hypercholesterolemia, HMG-CoA reductase was clearly stained in cancer cells whereas surrounding non-tumorous hepatocytes showed only slight expression of HMG-CoA reductase. In contrast, HCC tissues derived from patients without paraneoplastic hypercholesterolemia showed only slight expression of HMG-CoA reductase whereas surrounding non-tumorous hepatocytes showed a clear expression of HMG-CoA reductase. We morphologically proved cholesterol overproduction in HCC tissue derived from patients with paraneoplastic hypercholesterolemia. Immunohistochemistry for HMG-CoA reductase thought to be useful in the diagnosis of paraneoplastic hypercholesterolemia.

Limitation of repeated radiofrequency ablation in hepatocellular carcinoma: proposal of a three (times) × 3 (years) index.

BACKGROUND AND AIM: Percutaneous radiofrequency ablation (RFA) has been shown to be a highly effective treatment for hepatocellular carcinoma (HCC). We investigated the controllability of HCC and explored the algorithm of therapeutic strategy for HCC in patients who met the RFA criteria. METHODS: We enrolled 472 patients with HCC who met the RFA criteria (≤ 3 nodules, ≤ 3 cm) and underwent RFA for initial therapy. Patients who underwent repeated RFA were evaluated retrospectively when HCC exceeded the RFA criteria, or the functional hepatic reserve progressed to Child-Pugh grade C. RESULTS: Overall survival rates were: 1 year, 96%; 3 years, 79%; and 5 years, 56%. In 5 years, 14% of patients progressed to Child-Pugh grade C. Meanwhile, 47% of patients exceeded the RFA criteria. Annually, 8% of patients deviated from the RFA criteria. The percentage of patients who were able to receive RFA significantly decreased at the fourth session compared with up to the third session. The survival rates decreased at the rate of 7% annually until the third year after the initial RFA. Afterwards, it shifted to a decrease at the rate of 12% annually. In a multivariate analysis, the presence of hepatitis C virus infection and the existence of a single tumor were identified as significant independent factors contributing to probabilities exceeding the RFA criteria. CONCLUSIONS: HCC was controlled by RFA up to three RFA treatments and 3 years from the initial therapy. On this basis, we propose a "three (times) × 3 (years) index" for considering a shift from RFA to other treatment modalities.

Late-evening snack with branched-chain amino acids improves liver function after radiofrequency ablation for hepatocellular carcinoma.

AIM: This prospective study was designed to examine whether consumption of a branched-chain amino acid (BCAA)-enriched nutrient mixture as a late-evening snack (LES) helps maintain and/or improve liver functioning in liver cirrhosis (LC) patients who have undergone radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). METHODS: An equal number (10) of 30 LC patients who had undergone RFA for HCC was randomly assigned to a standard diet group (control) group, a morning BCAA (M-BCAA) administration group, or a LES with BCAA (LES-BCAA) administration group. Liver function testing was performed and Child-Pugh scores (CPS) calculated for each group to assess the improvement at 1, 4 and 12 weeks post-RFA. RESULTS: Compared to the control and M-BCAA groups, the LES-BCAA group experienced a rapid and significant improvement in albumin and total serum bilirubin levels and in CPS that began during the initial post-RFA period. These results indicate that LES with BCAA supplementation significantly improved the CPS of the LES-BCAA group at 4 and 12 weeks post-RFA. Although no patients experienced serious adverse effects, two patients who had been diagnosed with diabetes mellitus before undergoing RFA required blood sugar management to improve glycemic control and one subject withdrew due to supplement-induced vomiting. CONCLUSION: LES with BCAA supplementation significantly and rapidly improves liver functioning and CPS in LC patients who have undergone RFA for HCC. Control of blood sugar levels is necessary when calorie-containing BCAA is administrated to LC patients with impaired glucose tolerance.

Systemic chemotherapy using carboplatin and 5-fluorouracil for extrahepatic metastasis of hepatocellular carcinoma.

BACKGROUND/AIMS: We have evaluated the effectiveness of systemic chemotherapy for patients with extrahepatic metastasis from hepatocellular carcinoma. METHODOLOGY: We examined the background, survival rates, median survival time and side effects of 15 cases in which systemic chemotherapy using carboplatin and 5-fluorouracil was done (chemotherapy group) and 59 cases in which chemotherapy was not done (non-chemotherapy group) out of a total of 74 cases of patients with extrahepatic metastasis from hepatocellular carcinoma. RESULTS: The prognoses of the 15 chemotherapy cases and the 59 non-chemotherapy cases were as follows: 66.0%, 33.3%, 20.0% at 6 months, 12 months, 18 months respectively for the chemotherapy cases and 44.0%, 18.2%, 7.1% respectively for the non-chemotherapy cases. Median survival periods were 10.7 months for the chemotherapy group and 5.1 months for the non-chemotherapy group. A significantly better prognosis of survival (p=0.037) was identified in the chemotherapy group and no serious side effects were observed. CONCLUSIONS: The present research preceded the approval of sorafenib. This systemic combination chemotherapy will provide an extended survival prognosis and is thus considered to be comparatively safe and effective in those patients.