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Background: Validating the expanded criteria for living donor liver transplantation for hepatocellular carcinoma using national data is highly significant. The aim of this study was to evaluate the validity of the new Japanese criteria for living donor liver transplantation for hepatocellular carcinoma patients and identify factors associated with a poor prognosis using the Japanese national data set., Methods: The study population comprised patients who underwent living donor liver transplantation for hepatocellular carcinoma at 37 centres in Japan between 2010 and 2018. In a nationwide survey, the overall survival and recurrence-free survival rates were evaluated based on the new Japanese criteria for applying the 5-5-500 rule when extending the indication beyond the Milan criteria. Prognostic factors within the Japanese criteria were determined using the Cox proportional hazards model., Results: Patients within (485 patients) and beyond (31 patients) the Japanese criteria exhibited 5-year overall survival rates of 81% and 58% and 5-year recurrence-free survival rates of 77% and 48% respectively. Patients who met the Milan criteria, but not the 5-5-500 rule, had poorer outcomes. Multivariate analysis for 474 patients identified a neutrophil-to-lymphocyte ratio greater than or equal to 5 and a history of hepatectomy as independent risk factors., Conclusion: This nationwide survey confirms the validity of the Japanese criteria. The poor prognostic factors within the Japanese criteria include a neutrophil-to-lymphocyte ratio greater than or equal to 5 and previous hepatectomy., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Introduction: Current guidelines discourage the use of direct-acting antiviral (DAA) containing protease-inhibitor (PI) in advanced HCV cirrhosis. We aimed to compare the real-world tolerability of PI vs. non-PI DAA regimens in this population., Methods: We identified advanced cirrhosis patients treated with DAA from the REAL-C registry. The primary outcome was significant worsening or improvement in CPT or MELD scores following DAA treatment., Results: From the REAL-C registry of 15,837 patients, we included 1077 advanced HCV cirrhosis patients from 27 sites. 42% received PI-based DAA. Compared to non-PI group, the PI group was older, had higher MELD and higher percentage with kidney disease. Inverse probability of treatment weighting (IPTW; matching on age, sex, history of clinical decompensation, MELD, platelet, albumin, Asia site, Asian ethnicity, hypertension, hemoglobin, genotype, liver cancer, ribavirin) was used to balance the two groups. In the IPTW-matched cohorts, the PI and non-PI groups had similar SVR12 (92.9% vs. 90.7%, p = 0.30), similar percentages of significant worsening in CTP or MELD scores at posttreatment week 12 and 24 (23.9% vs. 13.1%, p = 0.07 and 16.5% vs. 14.6%, p = 0.77), and similar frequency of new HCC, decompensating event, and death by posttreatment week 24. In multivariable analysis, PI-based DAA was not associated with significant worsening (adjusted odds ratio = 0.82, 95% CI 0.38-1.77)., Conclusion: Tolerability and treatment outcomes were not significantly different in advanced HCV cirrhosis treated with PI-based (vs. non-PI) DAA up to CTP-B or MELD score of 15. Safety of PI-based DAA in those with CTP-C or MELD beyond 15 awaits further data., (© 2023. Asian Pacific Association for the Study of the Liver.)

Although liver regeneration has been extensively studied, the effects of bile-derived extracellular vesicles (bile EVs) on hepatocytes has not been elucidated. We examined the influence of bile EVs, collected from a rat model of 70% partial hepatectomy (PH), on hepatocytes. We produced bile-duct-cannulated rats. Bile was collected over time through an extracorporeal bile duct cannulation tube. Bile EVs were extracted via size exclusion chromatography. The number of EVs released into the bile per liver weight 12 h after PH significantly increased. Bile EVs collected 12 and 24 h post-PH, and after sham surgery (PH12-EVs, PH24-EVs, sham-EVs) were added to the rat hepatocyte cell line, and 24 h later, RNA was extracted and transcriptome analysis performed. The analysis revealed that more upregulated/downregulated genes were observed in the group with PH24-EVs. Moreover, the gene ontology (GO) analysis focusing on the cell cycle revealed an upregulation of 28 types of genes in the PH-24 group, including genes that promote cell cycle progression, compared to the sham group. PH24-EVs induced hepatocyte proliferation in a dose-dependent manner in vitro, whereas sham-Evs showed no significant difference compared to the controls. This study revealed that post-PH bile Evs promote the proliferation of the hepatocytes, and genes promoting cell cycles are upregulated in hepatocytes.

Malignant hepatic tumors (MHTs) in children are rare and account for approximately 5% of candidates for pediatric liver transplantation (LT) in Japan. We conducted a national survey of pediatric patients undergoing living donor LT for MHTs between October 1990 and April 2018. In total, 116 children underwent LT for MHTs during this study period: 100 hepatoblastomas (HBLs), 10 hepatocellular carcinomas (HCCs), and six other MHTs. The overall patient survival rate at 5 years was 81.3% for HBL, 60.0% for HCC, and 80.0% for other MHTs (P = 0.047). In patients with HBL, there was no significant difference in the 1- and 5-year patient survival rates between patients undergoing primary LT and those who received salvage LT for tumor recurrence (89.7%, 81.6% vs. 88.0%, 76%; P = 0.526). The 5-year overall survival rate after LT for HBL significantly improved from 63.2% in 1996-2008 to 89.8% in 2009-2018 (P = 0.018). The presence of lung metastasis before LT had no significant influence on the long-term survival (P = 0.742). Five patients with HCC died, including two who fell outside the Milan criteria. In conclusion, LT for pediatric MHTs, especially HBL, is a valuable treatment option for select patients., (© 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Background: Cure rates of hepatitis C virus (HCV) treatment with direct-acting antivirals (DAAs) for patients with active and inactive hepatocellular carcinoma (HCC) may differ, but well-controlled studies are limited. We aimed to evaluate DAA outcomes in a large East Asian HCV/HCC population compared with HCV/non-HCC patients., Methods: Using data from the Real-World Evidence from the Asia Liver Consortium (REAL-C) registry (Hong Kong, Japan, South Korea, and Taiwan), we used propensity score matching (PSM) to match HCC and non-HCC (1:1) groups for age, sex, cirrhosis, prior treatment, HCV genotype, treatment regimen, baseline platelet count, HCV RNA, total bilirubin, alanine aminotransferase, and albumin levels to evaluate DAA treatment outcomes in a large population of HCV/HCC compared with HCV/non-HCC patients., Results: We included 6081 patients (HCC, n = 465; non-HCC, n = 5 616) treated with interferon-free DAAs. PSM of the entire study population yielded 436 matched pairs with similar baseline characteristics. There was no statistically significant difference in the overall SVR rate of HCC (92.7%) and non-HCC (95.0%) groups. Rates of treatment discontinuation, adverse effects, and death were also similar between HCC and non-HCC groups. Among patients with HCC, those with active HCC had a lower SVR than inactive HCC cases (85.5% vs 93.7%; P = .03). On multivariable analysis, active HCC, but not inactive HCC, was significantly associated with lower SVR (OR, 0.28; P = .01) when compared with non-HCC., Conclusions: Active HCC but not inactive HCC was independently associated with lower SVR compared with non-HCC patients undergoing DAA therapy, although cure rate was still relatively high (85%) in active HCC patients., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Despite HCV cure, patients remain at risk for HCC, but risk factor data for HCC following SVR are limited for Asian patients., Methods: To address this gap, we analyzed 5814 patients (5646 SVR, 168 non-SVR) from the Real-World Evidence from the Asia Liver Consortium for HCV (REAL-C) who did not have HCC or a history of HCC at baseline (pre-DAA treatment) and did not develop HCC within 6 months of baseline. To assess the effect of SVR on HCC incidence, we used 1:4 propensity score matching [(PSM), age, sex, baseline cirrhosis, and baseline AFP] to balance the SVR and non-SVR groups., Results: In the PSM cohort (160 non-SVR and 612 SVR), the HCC incidence rate per 100 person years was higher in the non-SVR compared to the SVR group (5.26 vs. 1.94, p < 0.001). Achieving SVR was independently associated with decreased HCC risk (adjusted HR [aHR]: 0.41, p = 0.002). Next, we stratified the SVR cohort of 5646 patients to cirrhotic and noncirrhotic subgroups. Among cirrhotic SVR patients, aged ≥ 60, having an albumin bilirubin grade (ALBI) of 2 or 3 (aHR: 2.5, p < 0.001), and baseline AFP ≥ 10 ng/mL (aHR: 1.6, p = 0.001) were associated with higher HCC risk, while among the non-cirrhotic SVR group, only baseline AFP ≥ 10 ng/mL was significant (aHR: 4.26, p = 0.005)., Conclusions: Achieving SVR decreases HCC risk; however, among East Asians, patients with elevated pretreatment AFP remained at risk. Pretreatment AFP, an easily obtained serum marker, may provide both prognostic and surveillance value for HCC in East Asian patients who obtained SVR.

Recent genetic analyses revealed genetic heterogeneity in hepatocellular carcinoma (HCC), although it remains unclear how genetic alterations contribute to the multistage progression of HCC, especially the early step from hypovascular liver nodules to hypervascular HCC. We conducted multiregional whole-genome sequencing on HCCs with a nodule-in-nodule appearance, consisting of inner hypervascular HCC surrounded by hypovascular HCC arising from a common origin, and identified point mutations, structural variations, and copy-number variations in each specimen. According to the genetic landscape of the inner and outer regions, together with the pathological and radiological findings, we examined the stepwise evolution of cancer cells from slow-growing HCC to rapid-growing HCC. We first demonstrated that most tumor cells consisting of hypovascular well-differentiated HCCs already harbored thousands of point mutations and even several structural variations, including chromosomal translocations and chromothripsis, as the trunk events. Telomerase reverse transcriptase (TERT)-associated aberrations, including promoter mutations, chromosomal translocation, and hepatitis B virus DNA integration, as well as abnormal methylation status, were commonly detected as the trunk aberrations, while various liver cancer-related genes, which differed in each case, had additionally accumulated in the inner dedifferentiated nodules. Further, differences in the trunk and branch mutational signatures suggested a multistep contribution to the mutagenesis in each case. In conclusion, genomic alterations associated with the TERT gene could be the key driver events to form the hypovascular HCC, and additional case-specific driver mutations accumulate during the progression phase, forming intra- and inter-tumoral heterogeneity, confirming the importance of genetic testing before targeting therapy. These data shed light on the process of multistep hepatocarcinogenesis and will be helpful toward investigating new therapeutic strategies for HCC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Hepatitis B virus (HBV) genotypes B (HBV/B) and C (HBV/C) are the most prevalent genotypes among Japanese patients with hepatitis. Reportedly, HBV/C infection has been associated with more severe disease progression, manifesting as developing cirrhosis and hepatocellular carcinoma (HCC), than HBV/B infection. However, no long-term studies have examined the development of HCC in HBV/B-infected patients in Japan. The aims of our study were to compare the incidence of HCC in HBV/B- or HBV/C-infected patients. A total of 241 patients were followed up among 295 hepatitis B surface antigen (HBsAg)-positive carriers. Genotypes of HBV were A in 1% (4/295), B in 61% (179/295), C in 37% (110/295) and D in 1% (2/295) patients, and 96% of HBV/B were infected with subgenotype Bj. The mean age at HCC diagnosis was significantly higher in HBV/B than in HBV/C (67.0 ± 10.0 vs 57.7 ± 8.0 years, P < 0.001). The value of FIB-4 index was significantly higher in HBV/B than in HBV/C (P < 0.01). The rate of HCC was higher in HBV/C than in HBV/B, and a significant difference was observed until the 20-year observation period (P = 0.048). However, thereafter, HCC associated with HBV/B increased, and no significant difference was observed between HBV/B and HBV/C. HCC development was consistently observed even in HBV/B infection, especially among elderly patients with advanced fibrosis compared with HBV/C. HBV/B-infected patients developed HCC later in life, and in the long term, we found no differences in incidence of HCC development rates between these two genotypes., (© 2019 John Wiley & Sons Ltd.)

Background: Hepatocellular carcinoma (HCC) recurrently develops in cirrhotic liver containing a number of regenerative nodules (RNs). However, the biological tumorigenic potential of RNs is still unclear. To uncover the molecular bases of tumorigenesis in liver cirrhosis, we investigated the genetic aberrations in RNs of cirrhotic tissues using next-generation sequencing., Methods: We isolated 205 RNs and 7 HCC tissues from the whole explanted livers of 10 randomly selected patients who had undergone living-donor liver transplantation. Whole-exome sequencing and additional targeted deep sequencing on 30 selected HCC-related genes were conducted to reveal the mutational landscape of RNs and HCCs., Results: Whole-exome sequencing demonstrated that RNs frequently harbored relatively high-abundance genetic alterations, suggesting a clonal structure of each RN in cirrhotic liver. The mutation signature observed in RNs was similar to those determined in HCC, characterized by a predominance of C>T transitions, followed by T>C and C>A mutations. Targeted deep sequencing analyses of RNs identified nonsynonymous low-abundance mutations in various tumor-related genes, including TP53 and ARID1A. In contrast, TERT promoter mutations were not detected in any of the RNs examined. Consistently, TERT expression levels in RNs were comparable to those in normal livers, whereas every HCC tissue demonstrated an elevated level of TERT expression., Conclusion: Analyses of RNs constructing cirrhotic liver indicated that a variety of genetic aberrations accumulate in the cirrhotic liver before the development of clinically and histologically overt HCC. These aberrations in RNs could provide the basis of tumorigenesis in patients with liver cirrhosis.

Primary hepatic neuroendocrine carcinoma (NEC) is rare, and its origin, clinical features, diagnosis and treatment have not been clarified. Primary mixed NEC and hepatocellular carcinoma (HCC) is even rarer and is divided into either combined type or collision type. We report a patient with the combined type of mixed NEC and HCC. A 72-year-old male was diagnosed with HCC and underwent hepatectomy because of the presence of two tumors in his liver. Histological examination demonstrated that one of the tumors had both NEC and HCC components. The transitional zone was noted in the immunohistological examination, and the tumor was determined to be the combined type of primary mixed NEC and HCC. This was the first description of an HCC component being found in an NEC-dominant area in a primary mixed NEC and HCC tumor. Three weeks after hepatectomy, an abdominal computed tomography scan showed extensive regional and para-aortic lymphadenopathy, and early relapse was suspected in the patient. The patient died 3 months after the operation despite treatment with combination chemotherapy. This report describes an unfavorable case and summarizes all the primary mixed NEC and HCC tumor cases that have been previously reported.

Aim: To clarify the characteristics of metabolite profiles in virus-related hepatocellular carcinoma (HCC) patients using serum metabolome analysis., Methods: The serum levels of low-molecular-weight metabolites in 68 patients with HCC were quantified using capillary electrophoresis chromatography and mass spectrometry. Thirty and 38 of the patients suffered from hepatitis B virus-related HCC (HCC-B) and hepatitis C virus-related HCC (HCC-C), respectively., Results: The main metabolites characteristic of HCC were those associated with glutathione metabolism, notably 13 γ-glutamyl peptides, which are by-products of glutathione induction. Two major profiles, i.e., concentration patterns, of metabolites were identified in HCC patients, and these were classified into two groups: an HCC-B group and an HCC-C group including some of the HCC-B cases. The receiver operating characteristic curve for the multiple logistic regression model discriminating HCC-B from HCC-C incorporating the concentrations of glutamic acid, methionine and γ-glutamyl-glycine-glycine showed a highly significant area under the curve value of 0.94 (95%CI: 0.89-1.0, P < 0.0001)., Conclusion: The serum levels of γ-glutamyl peptides, as well as their concentration patterns, contribute to the development of potential biomarkers for virus-related HCC. The difference in metabolite profiles between HCC-B and HCC-C may reflect the respective metabolic reactions that underlie the different pathogeneses of these two types of HCC.

Unlabelled: Hepatocellular cancer (HCC) is a highly treatment-refractory cancer and is also highly resistant to adverse cellular stress. Although cell behavior can be modulated by noncoding RNAs (ncRNA) within extracellular vesicles (EV), the contributions of long noncoding RNAs (lncRNAs) are largely unknown. To this end, the involvement and functional roles of lncRNAs contained within EVs during chemotherapeutic stress in human HCC were determined. Expression profiling identified a subset of lncRNAs that were enriched in tumor cell-derived vesicles released from two different cell lines. Of these, lincRNA-VLDLR (linc-VLDLR) was significantly upregulated in malignant hepatocytes. Exposure of HCC cells to diverse anticancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell-cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, subfamily G member 2), whereas overexpression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an EV-enriched lncRNA that contributes to cellular stress responses., Implications: These findings provide new insight into the role of EVs and demonstrate the capacity of lncRNAs to mediate chemotherapeutic stress response in HCC., (©2014 American Association for Cancer Research.)

Resistance to adverse environmental conditions, such as hypoxia, contributes to the reduced efficacy of anticancer therapies and tumor progression. Although deregulated expression of many long noncoding RNA (lncRNA) occurs in human cancers, the contribution of such RNA to tumor responses to hypoxia are unknown. RNA expression profiling identified several hypoxia-responsive lncRNAs, including the long intergenic noncoding RNA, regulator of reprogramming (linc-RoR), which is also increased in expression in malignant liver cancer cells. Linc-RoR expression was increased in hypoxic regions within tumor cell xenografts in vivo. Tumor cell viability during hypoxia was reduced by small interfering RNA (siRNA) to linc-RoR. Compared with controls, siRNA to linc-RoR decreased phosphorylation of p70S6K1 (RPS6KB1), PDK1 and HIF-1α protein expression and increased expression of the linc-RoR target microRNA-145 (miR-145). Linc-RoR was highly expressed in extracellular RNA released by hepatocellular cancer (HCC) cells during hypoxia. Incubation with extracellular vesicle preparations containing extracellular RNA increased linc-RoR, HIF-1α expression and cell survival in recipient cells. These studies show that linc-RoR is a hypoxia-responsive lncRNA that is functionally linked to hypoxia signaling in HCC through a miR-145-HIF-1α signaling module. Furthermore, this work identifies a mechanistic role for the extracellular transfer of linc-RoR in intercellular signaling to promote cell survival during hypoxic stress.

Aims/hypothesis: Epidemiological studies have revealed that obesity and diabetes mellitus are independent risk factors for the development of non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma. However, the debate continues on whether insulin resistance as such is directly associated with NASH and liver tumourigenesis. Here, we investigated the incidence of NASH and liver tumourigenesis in Irs1 ( -/- ) mice subjected to a long-term high-fat (HF) diet. Our hypothesis was that hepatic steatosis, rather than insulin resistance may be related to the pathophysiology of these conditions., Methods: Mice (8 weeks old, C57Bl/6J) were given free access to standard chow (SC) or an HF diet. The development of NASH and liver tumourigenesis was evaluated after mice had been on the above-mentioned diets for 60 weeks. Similarly, Irs1 ( -/- ) mice were also subjected to an HF diet for 60 weeks., Results: Long-term HF diet loading, which causes obesity and insulin resistance, was sufficient to induce NASH and liver tumourigenesis in the C57Bl/6J mice. Obesity and insulin resistance were reduced by switching mice from the HF diet to SC, which also protected these mice against the development of NASH and liver tumourigenesis. However, compared with wild-type mice fed the HF diet, Irs1 ( -/- ) mice fed the HF diet were dramatically protected against NASH and liver tumourigenesis despite the presence of severe insulin resistance and marked postprandial hyperglycaemia., Conclusions/interpretation: IRS-1 inhibition might protect against HF diet-induced NASH and liver tumourigenesis, despite the presence of insulin resistance.

Background: Intrahepatic and extrahepatic recurrence remains a significant problem for hepatocellular carcinoma (HCC). The aim of this study was to determine the usefulness of diffusion-weighted magnetic resonance imaging (DWI) for histological tumor grading and preoperative prediction of early HCC recurrence within 6 months of operation., Methods: A total of 44 patients who had undergone hepatic resection for HCC (50 nodules) were reviewed retrospectively. DWI was performed within 30 days before hepatectomy, and apparent diffusion coefficients (ADCs) were measured using 2 methods: mean ADC and minimum-spot ADC. Relationships between ADCs and histological differentiation and between ADCs and early recurrence of HCC were analyzed., Results: Mean ADC was significantly lower in poorly differentiated HCC (n=18, 1.07±0.15×10(-3) mm2/s) than in moderately differentiated HCC (n=29, 1.29±0.21×10(-3) mm2/s; P<.05). Minimum-spot ADC was significantly lower in poorly differentiated HCC (n=18, 0.69±0.19×10(-3) mm2/s) than in well-differentiated HCC (n=3, 1.15±0.10×10(-3) mm2; P<.01) or in moderately differentiated HCC (n=29, 0.98±0.18×10(-3) mm2/s; P<.0001). Of 34 patients who were able to be observed for >6 months after resection, 9 showed early recurrence. Minimum-spot ADC was significantly lower in patients with early recurrence (n=9, 0.64±0.24×10(-3) mm2/s) than in patients without early recurrence (n=25, 0.88±0.19×10(-3) mm2/s; P<.05). On multivariate analysis, minimum-spot ADC was a significant risk factor for early recurrence (P<.05)., Conclusion: Quantitative measurement of ADC of HCC with magnetic resonance diffusion weighted imaging is a promising functional imaging tool in the prediction of histological grade and early recurrence before treatment.

CD133 antigen has been used to identify cancer stem cells in several solid tumor types, including hepatocellular carcinomas (HCCs). The aim of this study was to investigate whether the expression and subcellular localization of CD133 correlated with the clinicopathological factors, recurrence, and survival in HCC patients. Tissue specimens from 136 HCC patients who underwent curative primary hepatectomy between 2000 and 2005 were collected and immunohistochemically analyzed for CD133 expression. Positive immunohistochemical results and subcellular localization of CD133 were determined, and the correlation between CD133 expression and clinicopathological factors of HCC patients were evaluated. CD133-positive tumor cells were observed in 30 (22.1%) cases. Cytoplasmic and membranous expressions were observed in 22 (16.2%) and 20 (14.7%) of the CD133-positive cases, respectively. Positive cytoplasmic expression of CD133 was found to be associated with the overall survival of HCC patients, especially in stage III and IVA HCC patients (p=0.0092). Univariate analysis revealed that pre-operative serum albumin, alpha-fetoprotein (AFP) levels, tumor size, portal venous invasion, and cytoplasmic CD133 expression were important risk factors in HCC. Multivariate analysis revealed that among the factors related to tumor aggressiveness, cytoplasmic expression of CD133 showed the most significant association with overall survival, although the difference was not statistically significant (p=0.0681). Cytoplasmic expression of CD133 was a significant risk factor for the overall survival of HCC patients. Patients with stage III and IVA HCC showing positive cytoplasmic expression of CD133 are more likely to have a worse prognosis.

We performed loss of heterozygosity (LOH) analysis on five chromosomal arms (1p, 3p, 9p, 10q, 17p) in hepatocellular carcinoma (HCC). Univariate analyses of 80 patients who underwent liver transplantation demonstrated significant correlations between cancer recurrence and the following variables: LOH on 3p26, LOH on 10q23, LOH on 17p13, tumor diameter > or = 5 cm, number of tumors > or = 4, histologic Grade 3, alpha-fetoprotein (AFP) > or = 400 ng/mL, American Joint Committee on Cancer (AJCC) pT classification, and portal invasion. Patients with LOH on 10q23 exhibited a significantly higher 3-year recurrence rate (38.9%vs 11.9%, P = 0.0009). Multivariate analysis identified LOH on 10q23, histologic Grade 3, tumor nodules > or = 4, and AFP > or = 400 ng/mL as the risk factors of advanced HCC recurrence. These results suggest that LOH on 10q23 is associated with metastatic recurrence of HCC.

Background/purpose: The applicability of the staging systems of hepatocellular carcinoma (HCC) to liver transplantation (LT) has not been fully evaluated. Therefore, we compared the HCC recurrence after LT as predicted by various staging systems, including the American Joint Committee on Cancer (AJCC) system 5th edition, the AJCC system 6th edition, the American Liver Tumor Study Group (ALTSG) system, and the Liver Cancer Study Group of Japan (LCSGJ) system., Methods: A total of 108 patients who had HCC were classified according to these systems. We compared cumulative recurrence curves, recurrence-free survival curves, and overall survival curves of the systems estimated by Kaplan-Meier method. We compared cumulative event rates among different stages with the log-rank test for each staging system., Results: The log-rank test showed that the cumulative recurrence rates were different among different stages with a statistical significance for the staging systems except for the AJCC 5th edition system. Cumulative recurrence curves by the AJCC 6th edition system and the LCSGJ system showed better visual separation than the other two systems. With respect to recurrence-free survival and overall survival, no staging systems showed significant discriminative power., Conclusions: The current AJCC tumor-node-metastasis staging and the LCSGJ system are superior in predicting HCC recurrence after LT.

Objective: To compare 8-detector row helical computed tomography (CT) findings with histopathology in patients with hepatocellular carcinoma (HCC) who had undergone living-donor liver transplantation (LDLT)., Materials and Methods: This institutional review board-approved prospective study was performed between February 12, 2003 and November 12, 2004; of the 78 candidates for LDLT due to HCC who underwent preoperative multidetector CT (MDCT), 48 transplant recipients met our criteria and in 41 of them, HCCs were diagnosed with <15 lesions on MDCT; these patients represented the study population. Results of preoperative CT were correlated with histopathological results after 5-mm sagittal slicing of the explanted liver. Following the injection of contrast medium (2 ml/kg body weight of 300 mg I/ml), triple-phase contrast-enhanced images were obtained. CT was performed using the following parameters: detector row configuration, 8 x 1 mm, reconstruction interval, 1 mm, 200 mA s and 120 kVp. Image analysis was performed in consensus by three abdominal radiologists using 1-mm-thick slices with 0.5-mm overlap with paging as well as multiplanar reformatting (MPR; i.e. axial, coronal and sagittal images)., Results: A total of 134 HCCs were identified by pathological examination. The mean lesion size was 21 mm. Sensitivity, positive predictive value and accuracy for HCC detection were 87, 96 and 84% for all lesions, respectively, and 99, 100 and 97% for lesions >1 cm, respectively, but only 46, 76 and 41% for tumors <1 cm, respectively (n = 28). There were 12 false-negative lesions but only 5 false-positive findings., Conclusion: MDCT combined with the paging method and MPR images is very effective in the detection of HCCs >1 cm in diameter with a very low false-positive rate., (Copyright 2008 S. Karger AG, Basel.)

In the present study, the results of living donor liver transplantation (LDLT) for 125 hepatocellular carcinoma (HCC) patients were analyzed to determine optimal criteria exceeding the Milan criteria (MC) but still with predictably good outcomes. On the basis of pretransplant imaging studies, 70 patients met the MC, and 55 patients did not. Patients who exceeded the MC but presented with

Activation-induced cytidine deaminase (AID) plays a role as a genome mutator in activated B cells, and inappropriate expression of AID has been implicated in the immunopathological phenotype of human B-cell malignancies. Notably, we found that the transgenic mice overexpressing AID developed lung adenocarcinoma and hepatocellular carcinoma (HCC), suggesting that ectopic expression of AID can lead to tumorigenesis in epithelial tissues as well. To examine the involvement of AID in the development of human HCC, we analyzed the AID expression and its correlation with mutation frequencies of the p53 gene in liver tissues from 51 patients who underwent resection of primary HCCs. The specific expression, inducibility by cytokine stimulation and mutagenic activity of AID were investigated in cultured human hepatocytes. Only trace amounts of AID transcripts were detected in the normal liver; however, endogenous AID was significantly upregulated in both HCC and surrounding noncancerous liver tissues with underlying chronic hepatitis or liver cirrhosis (p < 0.05). Most liver tissues with underlying chronic inflammation with endogenous AID upregulation already contained multiple genetic changes in the p53 gene. In both hepatoma cell lines and cultured human primary hepatocytes, the expression of AID was substantially induced by TGF-beta stimulation. Aberrant activation of AID in hepatocytes resulted in accumulation of multiple genetic alterations in the p53 gene. Our findings suggest that the aberrant expression of AID is observed in human hepatocytes with several pathological settings, including chronic liver disease and HCC, which might enhance the genetic susceptibility to mutagenesis leading to hepatocarcinogenesis.

Background: Optimal indications for living donor liver transplantation (LDLT) for patients with hepatocellular carcinoma (HCC) have yet not been established. The aim of the present study was to determine optimal criteria including categories outside the Milan criteria (MC) and still with a predictably good outcome., Patients and Methods: Between February 1999 and December 2007, 136 patients with HCC underwent LDLT. Based on preoperative imaging studies, 74 patients met the MC and 62 did not., Results: Overall patient survival rate at 5 years was 70%. Patients who exceeded MC but presented with

Living donor liver transplantation (LDLT) has evolved to represent an important surgical strategy for patients with hepatocellular carcinoma (HCC). However, due to disadvantages, including donor risks and higher rates of perioperative complications, LDLT has been considered as a second-line treatment in Japan. The present study retrospectively evaluated clinical outcomes for 93 patients with HCC who underwent LDLT at our institute, including 44 patients who exceeded Milan criteria (MC). A total of 73 patients (78%) displayed a history of previous treatment for HCC using various nontransplant methods. Median follow-up was 24 months (range, 1-76 months). At 4 years after LDLT, overall patient survival rate was 64%, with similar rates for within-MC and over-MC groups (68% vs. 59%, respectively; P = 0.6548). However, cumulative recurrence rate was significantly higher in the over-MC group than in the within-MC group (35% vs. 15%, P = 0.0190). Regarding history of conventional treatment for HCC before LDLT, patients who had received only 1-2 previous treatments showed significantly lower recurrence rates than patients with > or =3 treatments (9% vs. 37%, P = 0.0411). In conclusion, LDLT may constitute an optional treatment with a chance of cure for patients with otherwise uncontrolled disease. However, repeated nontransplant treatments for recurrent HCC prior to LDLT may increase the risk of recurrence and impair the survival advantages conferred by LDLT.

A 68-year-old man presented with multiple hepatocellular carcinoma, which was considered to be unresectable at the first admission in January 1994. Pathological diagnosis was made by biopsy of the one lesion among them. From January 1994 to December 1997, 10 transarterial chemoembolizations and six percutaneous ethanol injection therapies were performed on the tumours in the cirrhotic liver. In February 1998 the tumour situated in the right lobe began to increase in size. The maximum tumour diameter was 6.3 cm measured by computed tomography (CT). In the beginning of May 1998 moderate ascites was present and mild hepatic encephalopathy was noticed. The patient was in the terminal stage of hepatocellular carcinoma and no further treatment was possible at that time. However, serum alpha-fetoprotein and protein induced by vitamin K absence or antagonist II dramatically decreased in June 1998. The CT scan also showed that the tumour had completely regressed without specific treatment. In February 1999 a new biopsy-proven hepatocellular carcinoma, 2 cm in diameter, developed in the lateral segment of the liver. It was well treated by percutaneous ethanol injection therapy. The patient was alive in good condition without any symptoms or tumour recurrence in June 1999. It was concluded that a rare case of spontaneous regression of hepatocellular carcinoma had occurred.

Background and Study Aims: The indications for laparoscopic microwave coagulation therapy (LMCT) for hepatocellular carcinoma (HCC) have not yet been adequately evaluated. This study investigated the value of LMCT in the treatment of HCC., Patients and Methods: Forty-three patients with liver cirrhosis (including five patients in Child Pugh grade C), with 56 HCC lesions, were enrolled in the study. When dynamic computed tomography (CT) showed a loss in HCC enhancement characteristics and a low concentration area after LMCT, a lesion was judged to have undergone complete necrosis., Results: The rate of complete necrosis for lesions measuring 40 mm or less was significantly higher (P<0.01) than for those measuring 41 mm or more. The rate of complete necrosis for lesions located on the liver surface, excluding those located close to the gallbladder or in contact with the diaphragm, was also significantly higher (P<0.01) than for those situated deep within the liver. The outcome for lesions of 40 mm or less was favorable. Intra-abdominal hemorrhage occurred in two patients, pneumothorax in three, and hepatic infarction in one, all associated with LMCT. However, these patients did not suffer any sequelae of clinical significance., Conclusions: This study suggests that there is a strong indication for LMCT for HCCs measuring 40 mm or less in diameter and those located on the liver surface even if they are as large as 50 mm, but not for those located close to the gallbladder or in contact with the diaphragm. LMCT appears to be applicable in patients with impaired liver function.