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Background Conversion from sorafenib to regorafenib is primarily an evidence-based treatment strategy in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the safety and efficacy of sequential therapy with sorafenib and regorafenib in patients with advanced HCC by analysis of outcomes in clinical practice with the aim to complement phase III findings. Methods The medical records of patients with advanced HCC receiving regorafenib were retrieved to collect data on sorafenib administration at seven Japanese institutions. Radiological responses and adverse events were evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Common Terminology Criteria for Adverse Events version 4.0, respectively. Results Before March 2018, 44 patients were administered regorafenib for advanced HCC. The median sorafenib treatment duration was 8.4 months. The most common adverse events were similar to those reported by the RESORCE trial. The median overall survival (OS) was 17.3 months (95% confidence interval [CI] 11.4-22.9), and 17 of 37 patients (45.9%) discontinued regorafenib and received sequential systemic therapy after regorafenib. These patients had significantly longer OS than those who were treated by the best supportive care or sub-optimal therapy (not reached versus 8.7 months [95% CI 5.8-11.7]; P < 0.001). Conclusion The results based on Japanese clinical practices verified the tolerability of regorafenib in advanced HCC. Major regorafenib-associated adverse events were similar to those related to sorafenib. OS was significantly longer than expected, which might be associated with the sequential systemic therapies after regorafenib, mainly lenvatinib.

Background and Aims: Some follow-up studies of large regenerative nodules (LRNs) and dysplastic nodules (DNs) were reported previously. However, the pre-malignant potentiality of LRNs has remained controversial up to now. No LRNs showed malignant transformation in our previous study. We aimed to evaluate the pre-malignant potentiality of LRNs and DNs with a greater number of cases and longer follow-up periods., Methods: From 1982 to 2005, 1,500 consecutive nodular lesions up to 2 cm in diameter were subjected to US guided thin-needle biopsy in cirrhotic patients at Chiba University Hospital. Of these lesions, 68 LRNs in 60 cases and 20 DNs in 22 cases were followed up for more than 6 months without any anti-cancer therapy. The last US examination was in 2010. The total study period was 28 years. We analyzed the histological findings and the clinical data of all cases retrospectively. The outcome of the lesions was examined., Results: The mean follow-up period was 38.9 (16-119) months in LRNs and 31.9 (6-101 months) in DNs. Rate of nodule enlargement was higher in DNs (8/24 nodules, 33%) than LRNs (11/68 nodules, 16 %), (p = 0.0743, not significant). Rate of malignant transformation was also higher in DNs (10/24 nodules, 42%) than LRNs (9/68 nodules, 13%), (p = 0.0040, significant). The rate of disappearance in images was similar between LRNs and DNs., Conclusions: We should recognize LRN as low risk pre-malignant lesions whereas DNs as high risk lesions.

Advanced chronic hepatitis C patients with sustained virolological response by antivirals remain at risk for hepatocellular carcinoma (HCC). We investigated the incidence of HCC during and immediately after peginterferon-alfa-2a and ribavirin (RBV) treatment in patients with chronic hepatitis C in Japan. HCC was detected in 8 of 238 patients during and after these treatments (mean follow-up period: 572 ± 252 days). In conclusion, occurrence of HCC is not a rare event during and immediately after peginterferon-alfa-2a plus RBV treatment. In cases with cirrhosis, higher α-fetoprotein levels, old age, or a previous history of HCC treatment, clinicians should be especially alert for the possible development of HCC during and immediately after peginterferon-alfa-2a and RBV treatment. Clinicians should regularly check for the possible development of HCC even in chronic hepatitis C patients under treatment., (Copyright © 2011 S. Karger AG, Basel.)

Background/aims: To evaluate the therapeutic efficacy of percutaneous ethanol injection (PEI) for patients with < or = 3 lesions of small (< or = 3 cm diameter) hepatocellular carcinoma (HCC)., Methods: PEI was applied to 270 patients with small HCC as the first-line treatment option during a 20-year period., Results: (1) There was no treatment-related deaths, and only 2.2% of severe complications; (2) PEI induced a complete response of all HCCs according to CT evaluation performed within one month after the procedure, and the local recurrence rate at 3 years was 10%; (3) the overall 3- and 5-year survival rates after treatment were 81.6 and 60.3%, respectively, but the rates were higher, 87.3 and 78.3%, in Child A patients with a solitary tumor < or = 2 cm in diameter; (4) factors significantly influencing survival were liver function (P = 0.0033) and serum alpha-fetoprotein level (P = 0.0014), and (5) the recurrence rate at remote sites in the liver was lower in patients with HCC < or = 2 cm (P = 0.0395) and in those with a solitary HCC (P < 0.0001) according to Cox's proportional hazard model. (6) Radiofrequency ablation would not have been performed in approximately 25% of these patients., Conclusions: PEI is considered a reliable treatment for small HCC in terms of safety and efficacy.

Background: Metallothionein (MT), which is known to detoxify heavy metal ions, is considered to serve as a mechanism of resistance to platinum complex compounds. In the present study, MT expression in hepatocellular carcinoma (HCC) was immunohistologically investigated to clarify its relationship to clinical background factors and responsiveness to anticancer drugs., Methods: Specimens from 117 patients with HCC were immunohistologically studied, using a monoclonal anti-MT antibody. the percentage of MT-positive HCC (MT ratio) cells was determined, to evaluate the extent of staining with anti-MT antibody. Staining with an MT ratio of more than 50% was categorized as diffusely positive; an MT ratio of 5% to less than 50% was focally positive; and an MT ratio of less than 5% was negative. Twenty-two patients received repeated arterial infusion chemotherapy with carboplatin (CBDCA), a platinum-containing compound, and the MT expression was analyzed in relation to their chemotherapeutic response., Results: The ratio of MT-positive cells in HCC decreased with the degree of histological differentiation and also decreased with higher tumor stage. In patients treated with CBDCA, the ratio of MT-positive cells in responders was significantly lower than that in non-responders., Conclusions: MT expression decreases with the degree of histological differentiation and decreases with increasing tumor stage in HCC. In addition, MT expression may lower the antitumor effect of CBDCA.

We administered trientine hydrochloride, a drug used in the treatment of Wilson's disease, to patients with hepatocellular carcinoma after radical treatment with percutaneous ethanol injection or radiofrequency ablation, and examined its effect on the reduction of liver-tissue copper content. We enrolled 24 patients with 3 or fewer primary lesions of Child class A or B hepatocellular carcinoma with diameters of 3 cm or less who had undergone radical treatment with percutaneous ethanol injection or radiofrequency ablation. Trientine hydrochloride was orally administered in a single daily dose of 250 mg to 12 patients before a meal (at fasting, group 1) or at a total daily dosage of 750 mg, divided into 3 doses, to 12 patients (group 2). This study was a randomized between-groups comparative study of 12 weeks' duration. We used the particle-induced x-ray-emission method to determine liver-tissue mineral content. Urine copper and serum mineral levels were also measured, and transaminase levels were examined. Liver-tissue copper content decreased significantly, to 160.1 microg/g dry weight, after treatment, compared with the pretreatment level of 306.8 microg/g dry weight (P <.05). We detected no significant difference in iron or zinc content before and after treatment. The copper content was significantly reduced after treatment in both groups (P <.05). The urine copper level was significantly increased after 1 week of treatment but decreased thereafter. Serum copper levels were significantly reduced after treatment (P <.01). We detected no significant difference in transaminase level before and after treatment. Iron-deficiency anemia in 1 patient after 12 weeks' treatment was the only adverse reaction, and it was improved by the administration of an iron product. We noted no other overt adverse reactions. In patients with hepatocellular carcinoma, trientine hydrochloride therapy may significantly reduce copper content in liver tissue.

Aim: To study whether cancer cell differentiation in small hepatocellular carcinoma (HCC) can be assessed by computed tomography (CT) and magnetic resonance (MR) imaging., Methods: We retrospectively evaluated the relationship between cancer cell differentiation in 127 HCC 3 cm or less in diameter (113 patients) and CT and MR images. Images were reviewed in a consensus conference by three authors (SA, TY, and ME). Histopathological diagnosis of HCC was made from liver specimens obtained by sonographically guided biopsy., Results: The degree of histological differentiation of cancer cells was significantly different between HCC that were isodense with liver parenchyma in both artery-dominant and equilibrium phases in contrast-enhanced CT and tumors that were hyperdense in the artery-dominant phase and iso- or hypodense in the equilibrium phase (P = 0.0054), as well as tumors that were iso- or hypodense artery-dominant and hypodense equilibrium (P = 0.0002). Histological differentiation of lesions that were hyperintense in T1-weighted images and hypointense in T2-weighted images differed significantly from those with the opposite MR characteristics (P = 0.0122). In T1-weighted fat-suppression images and T2-weighted images, respectively, the degree of histological differentiation was significant between the hypointense/hyperintense and the hyperintense/hypointense patterns (P < 0.0001), as well as the hyperintense/isointense (P = 0.0296), the hyperintense/hyperintense (P = 0.0434), and the isointense/hyperintense (P = 0.0171). Using these differences an equation was developed that could determine with 76% accuracy whether the tumors were well or less-well differentiated., Conclusion: CT and MR imaging patterns were useful in predicting the degree of histological differentiation of cancer cells in HCC.

Background/aims: The aim of this study was to investigate the relationship between trace metals and the prevalence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis or hepatic cirrhosis caused by hepatitis C virus (HCV)., Methods: We measured the contents of copper, iron, and zinc in HCC tissue (n = 112), dysplastic nodules (n = 7), and liver parenchyma in patients with (n = 112) and without (n = 12; 7 with grade F3 fibrosis, 5 with grade F4 fibrosis) HCC. Metals were quantified in thin-needle biopsy specimens using the particle-induced X-ray emission method (PIXE)., Results: Copper level in liver parenchyma was higher in patients with HCC than in those without HCC (p < 0.01), while there was no such difference in hepatic iron. In patients with grade F4 fibrosis, copper content in the liver parenchyma was higher in the presence of HCC than in its absence (p < 0.05). Multiple regression analysis showed that the only factor significantly associated with the coexistence of HCC in HCV-positive patients with chronic liver disease was the copper level in the liver parenchyma., Conclusions: Hepatic copper overload may contribute to the development of HCC in HCV-positive patients with chronic hepatitis or cirrhosis., (Copyright 2003 S. Karger AG, Basel)

The aim of this study was to determine the metabolizing activities in the liver of patients with hepatocellular carcinoma (HCC). Thin-layer chromatography autoradioluminography was used to measure metabolizing activities. Succinate-producing activity (SPA) was used as an indicator of metabolizing activity of the tricarboxylic acid (TCA) cycle in mitochondria, and diazepam-N-demethylating activity (DZ-DA), diazepam-3-hydroxylating activity (DZ-HA) and tolbutamide-methyl-hydroxylating activity (TB-HA) as indicators of drug metabolizing activities by P-450. SPA and drug-metabolizing activity of HepG2 cells were examined to compare with those of human liver specimens. Liver biopsy specimens of 30 patients and surgical specimens of eight patients with HCC were studied. SPA of HepG2 cells was as high as that of human tumor tissue, and DZ-DA, DZ-HA and TB-HA were undetectable in HepG2 cells. SPA and DZ-HA of non-tumor tissue in biopsy samples were significantly higher than those in resected liver specimens (P < 0.05). In biopsy specimens, SPA was significantly higher in tumor tissue than in non-tumor tissue (P < 0.05), and DZ-DA, DZ-HA and TB-HA were significantly lower in tumor tissue (P < 0.01). SPA was significantly higher in large tumors (>/=30 mm) than in small tumors <30 mm (P < 0.05), and TB-HA was significantly lower in large tumors than in small tumors (P < 0.01). DZ-DA and TB-HA significantly decreased with the progression of the tumor differentiation (P < 0.05). In conclusion, HCC has increased metabolizing activities of the TCA cycle and decreased drug-metabolizing activities.

Objective: In this study, we scored the hepatic parenchymal echo patterns as the coarse score (CS) analyzed with a neural network in cirrhosis patients and calculated the variations in CS as the coefficient of variation, and evaluate their usefulness as predictor of the development of hepatocellular carcinoma (HCC)., Methods: The relationship between the degree of variation in CS and histopathological findings was assessed in 10 autopsied livers fixed in formalin. The degree of intrahepatic variation in CS was calculated as the coefficient of variation of CS (CVCS). Irregular regeneration of liver cells in autopsied livers was classified into two categories, slight and severe. A total of 56 cirrhosis patients were prospectively followed to evaluate the predictors of HCC., Results: A significant positive correlation was observed between CVCS and the coefficient of variation of the diameter of the regenerative nodules. Coefficient variation of nodule diameter and CVCS in patients in whom irregular regeneration was severe were significantly higher than those in patients in whom irregular regeneration was mild (p < 0.05). Concerning the relationship between hepatitis virus markers and CS or CVCS, CVCS was significantly higher in those who were hepatitis C virus antibody positive and those who were hepatitis B surface antigen negative (p < 0.01). Using a combination of CS and CVCS, the incidence of HCC, as determined by the Kaplan-Meier method, was significantly higher in patients whose CS was > or = 1.5 and CVCS was > or = 15%, as compared with that in patients whose CS was <1.5 and CVCS was <15% (p < 0.01) and whose CS was > or = 1.5 and CVCS was <15% (p < 0.05). Multivariate analysis of the predictors for HCC using the Cox's proportional hazards model showed a significant correlation between the risk of development of HCC and CVCS, CS and serum alpha-fetoprotein level., Conclusions: CVCS and CS can be calculated from liver echo patterns and are useful for identifying a high-risk group for HCC., (Copyright 2002 S. Karger AG, Basel)

Objective: We examined the detectability of small hepatocellular carcinomas (HCCs) and the factors that affect hyperintensity of small HCC on T1-weighted images (T1W) by using T1-weighted fat-suppressed images (T1FS)., Methods: Thirty-nine HCCs (29 patients) measuring 30 mm or less were enrolled. The mean size of HCCs was 21.0+/-4.9 mm. Spin-echo T1W, T2-weighted images (T2W), and T1FS were obtained using a 1.5 T system. We evaluated the detectability in each sequence by receiver-operating-characteristic (ROC) analysis and the tumor-to-hepatic parenchyma contrast-to-noise ratio (CNR), the variance in the detectability among all interpreters with each sequence, and the presence or absence of improvement in the detectability by interpreting T1FS in addition to conventional T1W plus T2W. The contents of fat, copper, and iron in histologically diagnosed HCCs showing hyperintensity on both T1W and T1FS were measured. For determination of heavy metals, we used a particle induced X-ray emission analytical instrument., Results: ROC analyses revealed that T1FS were superior to T1W and T2W in detecting small HCCs (0.900+/-0.017 for T1FS, 0.859+/-0.019 for T1W, and 0.745+/-0.030 for T2W). The detectability by interpreting T1FS in addition to conventional T1W plus T2W was improved (0.931+/-0.013 for the conventional images and 0.973+/-0.008 for the conventional images plus T1FS, P<0.001). The detected lesions on T1FS demonstrated favorable CNR values. The copper content in the cancer and the ratio of the copper content in the cancer to that in the non-cancerous tissue were 275.4+/-219.0 microg/g dry weight, 6.9+/-5.5 in HCCs showing hyperintensity on both T1W and T1FS. Both were significantly higher (P<0.05)., Conclusion: T1FS showed excellent sensitivity and specificity in detecting small HCCS irrespective of the experience of interpreters. The use of T1FS suggested the involvement of copper might be one of the factors in hyperintensity of HCCs on T1W.