Background/Aim: We evaluated the relationship of hepatic function with repeated transarterial catheter chemoembolization (TACE) and prognosis after sorafenib treatment in various patient cohorts. Methods: Study 1 comprised of 212 Barcelona clinic liver cancer stage-B (BCLC-B) HCC patients classified as Child-Pugh A (CP-A) and who had received repeated TACE treatments (r-TACE) (naïve:recurrence = 66:146). Study 2 comprised of 435 patients with unresectable HCC classified as CP-A in who sorafenib was introduced (naïve:recurrence = 37:398; CP score 5:6 = 282:153; macro-vessel invasion [MVI]+: extrahepatic metastasis [EHM]+ both negative = 124:226:143). Changes in hepatic function along with CP and albumin-bilirubin (ALBI) score/grade during r-TACE in Study 1, and prognosis after introducing sorafenib in Study 2 were evaluated. Results: Hepatic function worsened to CP-B in 9-14% with each TACE procedure, while 18-21% had a change of classification from ALBI-1 to ALBI-2. When the prognosis of patients with the best CP score of 5 was analyzed, those with ALBI-1 (n = 154) had a better outcome than those with ALBI-2 (n = 128) (MST 17.5 vs. 9.9 months; p = 0.01), while ALBI-1 (n = 43) patients also showed a better outcome than ALBI-2 (n = 34) patients with a CP score of 5 without MVI/EHM (MST: 17.5 vs. 10.0 months; p = 0.029). The Akaike's Information criterion for ALBI-grade (MST: grade 1 vs. 2 = 16.9 vs. 10.4 months; p = 0.001) was also better than that for CP (MST: score 5 vs. 6 = 14.4 vs. 10.5 months; p = 0.003) (3195.6 vs. 3197.5) in all 435 patients. Conclusion: The rate of patients with downgraded hepatic function during r-TACE, especially with regard to ALBI-grade, was not low. ALBI-grade was shown to be a better hepatic function assessment tool than CP in patients receiving sorafenib treatment. Strict judgment of TACE-refractory status in patients with unresectable HCC is needed to improve prognosis before downgrading the hepatic function.

Abstract. Metformin is a commonly used oral antihyperglycemic agent of the biguanide family. Recent studies suggest that metformin may reduce cancer risk and improve prognosis. However, the antitumor mechanism of metformin in several types of cancers, including hepatocellular carcinoma (HCC), has not been elucidated. The goal of the present study was to evaluate the effects of metformin on HCC cell proliferation in vitro and in vivo, and to study microRNAs (miRNAs) associated with the antitumor effect of metformin in vitro. We used the cell lines Alex, HLE and Huh7, and normal hepatocytes to study the effects of metformin on human HCC cells. In an in vivo study, athymic nude mice bearing xenograft tumors were treated with metformin or left untreated. Tumor growth was recorded after 4 weeks, and the expression of cell cycle-related proteins was determined. Metformin inhibited the proliferation of Alex, HLE and Huh7 cells in vitro and in vivo. Metformin blocked the cell cycle in G0/G1 in vitro and in vivo. This blockade was accompanied by a strong decrease of G1 cyclins, especially cyclin D1, cyclin E and cyclin-dependent kinase 4 (Cdk4). In addition, microRNA (miRNA) expression was markedly altered by the treatment with metformin in vitro and in vivo. In addition, various miRNAs induced by metformin also may contribute to the suppression of tumor growth. Our results demonstrate that metformin inhibits the growth of HCC, possibly by inducing G1 cell cycle arrest through the alteration of microRNAs.

The purpose of this study was to retrospectively investigate the feasibility of 11 C-choline PET, compared with 18 F-FDG PET, for the detection of hepatocellular carcinoma (HCC). Methods: A total of 16 HCC lesions in 12 patients were examined with both 11 Ccholine PET and 18 F-FDG PET. Tumor lesions were identified as areas of focally increased uptake, exceeding that of surrounding noncancerous liver tissue. For semiquantitative analysis, the tumor-to-liver (T/L) ratio was calculated by dividing the maximal standardized uptake value (SUV) in HCC lesions by the mean SUV in noncancerous liver tissue. Results: 11 C-choline PET showed a slightly higher detection rate than did 18 F-FDG PET for detection of HCC (63% vs. 50%, respectively), although this difference was not statistically significant. 11 C-choline PET had a better detection rate for moderately differentiated HCC lesions but not for those poorly differentiated (75% vs. 25%, respectively). In contrast, 18 F-FDG PET exhibited the opposite behavior, with corresponding detection rates of 42% and 75%, respectively. The mean 11 C-choline SUV and T/L ratio in moderately differentiated HCC lesions were higher than those in poorly differentiated HCC lesions. In contrast, the mean 18 F-FDG SUV and T/L ratio in poorly differentiated HCC were higher than those in moderately differentiated HCC. These differences, however, were also not statistically significant. Conclusion: 11 C-choline PET had a better detection rate for moderately differentiated HCC lesions but not for poorly differentiated HCC lesions, whereas 18 F-FDG PET produced the opposite result. 11 C-choline is a potential tracer to complement 18 F-FDG in detection of HCC lesions.

No abstract

Abstract. Although a number of studies have shown that vitamin K possesses antitumor activities on various neoplastic cell lines, there are few reports demonstrating in vivo antitumor effects of vitamin K, and the antitumor effect on colorectal cancer (CRC) remains to be examined. Therefore, antitumor effects of vitamin K on CRC were examined both in vitro and in vivo. Vitamins K2, K3 and K5 suppressed the proliferation of colon 26 cells in a dose-dependent manner, while vitamin K1 did not. On flow cytometry, induction of apoptosis by vitamins K2, K3 and K5 was suggested by population in sub-G1 phase of the cell cycle. Hoechst 33342 staining and a twocolor flow cytometric assay using fluorescein isothiocyanateconjugated annexin V and propidium iodide confirmed that vitamins K2, K3 and K5 induced apoptotic death of colon 26 cells. Enzymatic activity of caspase-3 in colon 26 cells was significantly up-regulated by vitamins K2, K3 and K5. The pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Aspfluoromethyl ketone, substantially prevented vitamin Kmediated apoptosis. In vivo study using syngeneic mice with subcutaneously established colon 26 tumors demonstrated that intravenous administration of vitamins K2, K3 and K5 significantly suppressed the tumor growth. The number of apoptotic tumor cells was significantly larger in the vitamin K-treated groups than in the control group. These results suggest that vitamins K2, K3 and K5 exerted effective antitumor effects on CRC in vitro and in vivo by inducing caspasedependent apoptotic death of tumor cells, suggesting that these K vitamins may be promising agents for the treatment of patients with CRC. IntroductionWorldwide, colorectal cancer (CRC) ranks third in cancer incidence after lung and breast, and is a major cause of cancer mortality (1). In 2000, there were 943,000 new cases diagnosed and 510,000 deaths worldwide, corresponding figures for Europe were 363,000 cases and 199,000 deaths (2). Although surgery alone is the standard approach in localized malignancy, approximately 50% of early-stage patients present disease relapse (3). Furthermore, approximately 30% of CRC is diagnosed when it is already at an advanced stage. There are also a considerable number of patients who cannot undergo surgery even at an early stage of the disease due to severe complications, such as chronic heart failure, chronic renal failure and chronic obstructive pulmonary diseases. Fluoropyrimidine-based chemotherapy is now considered the standard treatment for patients with inoperable CRC, but approximately 90% of patients do not respond to chemotherapy based on 5-fluorouracil (5-FU)/folinic acid (4). Thus, the development of new treatment modalities is necessary to improve the overall survival rate of patients with CRC.Vitamin K is an essential vitamin that was discovered as a fat-soluble anti-hemorrhagic agent. Vitamin K is also known as an obligatory cofactor in the post-translational γ-carboxylation of glutamic acid residues (5-8). Vitamin K-dependent proteins include prothrombin (fact...