Japanese Hepatocellular Carcinoma Research Articles

Practicality of STAT3 Gene Polymorphisms and Sorafenib Trough Concentration as Biomarkers for Sorafenib-Induced Hand-Foot Skin Reaction in Hepatocellular Carcinoma

Introduction. The aim of this study was to evaluate the practicality of the signal transducer and activator of transcription (STAT) 3 polymorphisms as a predictive biomarker and sorafenib trough concentration as a monitoring biomarker for hand-foot skin reaction (HFSR) in patients with hepatocellular carcinoma (HCC). Methods. In total, 43 Japanese HCC patients were included. Sorafenib concentrations were measured, if possible, on days 8, 29, 35, and 57. The sorafenib concentration on day 8 (Cday8) was used for the analysis of HFSR occurring up to day 29. The median concentration for each patient (Cmedian) was used for HFSR occurring up to day 57 (study period). The STAT3 single nucleotide polymorphism (SNP) rs4796793 was determined using cell-free DNA extracted from plasma. Result. The Cday8 tended to be higher in the HFSR onset or grade ≥ 2 HFSR severity group than in the non-HFSR or grade ≤ 1 HFSR severity group. The Cmedian was significantly higher in the HFSR onset or grade ≥ 2 group than in the non-HFSR or grade ≤ 1 HFSR group. The Cmedian thresholds for predicting HFSR onset and severity were 3.62 μg/mL and 6.10 μg/mL, respectively. There was no association between STAT3 rs4796793 and HFSR onset or severity. In multivariate analysis, Cmedian values ≥ 3.62 μg/mL and >6.10 μg/mL were associated with the increased risk of HFSR onset (odds ratio: 16.6, p < 0.01) and severity (odds ratio: 15.7, p < 0.01), respectively. Conclusion. Monitoring of the sorafenib trough concentration may be practical for avoiding HFSR.

The Outcome of Salvage Liver Transplantation and Liver Resection for Recurrent Hepatocellular Carcinoma Using the 5-5-500 Rule, Japanese Extended Liver Transplantation Criteria for Hepatocellular Carcinoma

Liver transplantation (LT) for hepatocellular carcinoma (HCC) is limited to Child-Pugh class C patients according to the Japanese HCC treatment algorithm. However, extended criteria of LT for HCC, known as the 5-5-500 rule, were published in 2019. Hepatocellular carcinoma reportedly has a high recurrence rate after primary treatment. We hypothesized that the outcome of recurrent HCC would be improved if the 5-5-500 rule were adopted for patients with recurrent HCC. We, therefore, analyzed the outcomes of surgical treatment (liver resection [LR] and LT) for recurrent HCC using the 5-5-500 rule in our institute. Fifty-two patients younger than 70 years of age received surgical treatment for recurrent HCC using our institute's 5-5-500 rule from 2010 to 2019. We divided these patients into the LR and LT groups in the first study. The 10-year overall survival and re-recurrence-free survival were analyzed. The second study analyzed the risk factors of re-recurrence after surgical treatment for recurrent HCC. In the first study, the background characteristics of the 2 groups (LR and LT) showed no significant difference, except for age and Child-Pugh classification. There was no significant difference in the overall survival between groups (P=.35), but the re-recurrence-free survival in the LR group was significantly shorter than that in the LT group (P < .01). In the second study, the male sex and LR were risk factors of re-recurrence after surgical treatment for recurrent HCC. Child-Pugh's class did not contribute to re-recurrence. To improve the outcomes of recurrent HCC, LT is the better choice, regardless of the Child-Pugh class.

Association Between Renal Adverse Effects and Mortality in Patients With Hepatocellular Carcinoma Treated With Lenvatinib.

Lenvatinib, a multitargeted tyrosine kinase inhibitor, was recently approved for hepatocellular carcinoma (HCC) treatment in Japan; however, the association between proteinuria following lenvatinib administration in HCC patients and early mortality is unknown. This study aimed to examine the association between nephrotic-range proteinuria (NRP) and mortality and evaluated the risk factors for NRP among Japanese HCC patients treated with lenvatinib. We retrospectively analyzed 45 consecutive patients receiving lenvatinib from 2018-2019. Primary outcome was overall survival. Cox proportional hazards regression was used to evaluate the association between NRP and overall survival. Logistic regression analyses were used to identify NRP risk factors after lenvatinib initiation. The median age was 66 years, 56% were women, and 20% had pre-existing proteinuria. During a 1-year median follow-up, 24 died, and 5 developed NRP. Univariable logistic regression showed that pre-existing proteinuria was associated with higher NRP risk; however, the association was not significant after covariate adjustment. Following multivariable Cox analysis, NRP did not affect overall survival in advanced HCC patients receiving lenvatinib. Urinalysis findings should be monitored regularly in patients receiving lenvatinib because NRP incidence was comparable to that of prior studies. Identifying the predictors of NRP after lenvatinib initiation warrants further investigation.

Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following first-line sorafenib: Pooled efficacy and safety in Japanese patients across two global randomized phase III studies (REACH-2 and REACH).

320 Background: Ramucirumab (RAM), a human IgG1 monoclonal antibody, inhibits ligand activation of VEGFR2. REACH and REACH-2 were two global, randomized, double-blind, placebo (PBO)-controlled multicenter, phase III studies of RAM versus PBO in patients with HCC after prior sorafenib. REACH-2 confirmed RAM treatment benefit for patients with baseline AFP ≥ 400 ng/mL, consistent with results in a prespecified subgroup of patients in REACH with AFP ≥ 400 ng/mL. Methods: Other than AFP levels, study designs and eligibility for both studies were similar. All patients received RAM (8 mg/kg) I.V. or PBO every 14 days. Pooled analyses were performed to further support the assessments of efficacy and safety in Japanese patients with baseline AFP ≥ 400 ng/mL. Results: In total, 101 Japanese patients were pooled from REACH and REACH-2 (n = 61 RAM; n = 40 PBO). Pooled baseline patient characteristics were balanced between arms including baseline AFP and etiology. As in the individual studies, improvement in OS (median OS 10.78 vs 4.47 mo; HR 0.555; 95% CI 0.348, 0.885; p = .0124) was observed. Improvements in PFS (median PFS 3.88 vs 1.41 mo; HR 0.341; 95% CI 0.212, 0.550; p &lt; .0001), ORR (9.8% vs 2.5%, p = .1285), and disease control rate (67.2% vs 35.0%, p = .0035) were also observed. Consistent with individual study results, hypertension was the only grade 3 or higher adverse events of special interest among ≥ 5% patients that was more frequently observed in the RAM arm (13.1%) compared with the PBO arm (5.0%). Conclusions: Pooled analysis of two phase III trials of RAM as second-line treatment in patients with HCC following first-line sorafenib demonstrated a clinically meaningful benefit with a manageable safety profile in Japanese HCC patients with baseline AFP ≥ 400 ng/mL. Treatment benefits in OS observed in the Japanese subpopulation were consistent with the entire population (median OS 8.1 vs 5.0 mo; HR 0.694; p = .0002. Zhu AX et al., World GI 2018). Further analysis to characterize the Japanese patients compared to the non-Japanese population is planned. Clinical trial information: NCT01140347 (REACH), NCT02435433 (REACH-2).

Healthy human serum N-glycan profiling reveals the influence of ethnic variation on the identified cancer-relevant glycan biomarkers.

BackgroundMost glycomics studies have focused on understanding disease mechanisms and proposing serum markers for various diseases, yet the influence of ethnic variation on the identified glyco-biomarker remains poorly addressed. This study aimed to investigate the inter-ethnic serum N-glycan variation among US origin control, Japanese, Indian, and Ethiopian healthy volunteers.MethodsHuman serum from 54 healthy subjects of various ethnicity and 11 Japanese hepatocellular carcinoma (HCC) patients were included in the study. We employed a comprehensive glycoblotting-assisted MALDI-TOF/MS-based quantitative analysis of serum N-glycome and fluorescence HPLC-based quantification of sialic acid species. Data representing serum N-glycan or sialic acid levels were compared among the ethnic groups using SPSS software.ResultsTotal of 51 N-glycans released from whole serum glycoproteins could be reproducibly quantified within which 33 glycoforms were detected in all ethnicities. The remaining N-glycans were detected weakly but exclusively either in the Ethiopians (13 glycans) or in all the other ethnic groups (5 glycans). Highest abundance (p < 0.001) of high mannose, core-fucosylated, hyperbranched/hypersialylated N-glycans was demonstrated in Ethiopians. In contrast, only one glycan (m/z 2118) significantly differed among all ethnicities being highest in Indians and lowest in Ethiopians. Glycan abundance trend in Ethiopians was generally close to that of Japanese HCC patients. Glycotyping analysis further revealed ethnic-based disparities mainly in the branched and sialylated structures. Surprisingly, some of the glycoforms greatly elevated in the Ethiopian subjects have been identified as serum biomarkers of various cancers. Sialic acid level was significantly increased primarily in Ethiopians, compared to the other ethnicities.ConclusionThe study revealed ethnic-specific differences in healthy human serum N-glycome with highest abundance of most glycoforms in the Ethiopian ethnicity. The results strongly emphasized the need to consider ethnicity matching for accurate glyco-biomarker identification. Further large-scale study employing various ethnic compositions is needed to verify the current result.

Phase 1 studies of 3- and 6-peptide vaccine cocktail derived from GPC3, WDRPUH, and NEIL3 in patients with advanced hepatocellular carcinoma (HCC).

387 Background: Glypican 3 (GPC3), WD-Repeat-containing Protein Up-regulated in HCC (WDRPUH), and Nei Endonuclease VIII-Like 3 (NEIL3) are tumor antigens in HCC. We conducted two phase 1 multicenter open-label studies for advanced HCC: one to evaluate the HLA-A*24-restricted 3-epitope peptide vaccine cocktail named ONO-7268MX1 (MX1); the other to evaluate the HLA-A*24 and -A*02-restricted 6-epitope peptide vaccine cocktail named ONO-7268MX2 (MX2). Both vaccines contain epitope peptides derived from GPC3, WDRPUH, and NEIL3. MX1 and MX2 cover most of Japanese HCC patients (pts). Safety is the primary, and efficacy and immunological response are the exploratory objectives. Methods: Pts received SC MX1 or MX2 once weekly. In MX1 study, pts received each of 3 peptides at 0.3 mg (cohort 1), 1 mg (cohort 2), and 3 mg of GPC3, 1.1 mg of WDRPUH and 3 mg of NEIL3 (cohort 3). In MX2 study, pts received each of 6 peptides at 1 mg. Results: In MX1 study, 3, 8, and 7 pts with HLA-A*24 were enrolled to cohort 1, 2, and 3, respectively. In MX2 study, 14 pts (7 with HLA-A*24, 6 with HLA-A*02, and 1 with HLA-A*24/A*02) were enrolled. No dose limiting toxicities were observed in both studies. The most commonly related AEs were Grade 1/2 injection site reaction (erythema, induration, pain, and pruritus), 44.4% (8/18) in MX1 and 78.6% (11/14) in MX2. Grade 3-related AEs occurred only in MX2 study; neutrophil count decreased, white blood cell count decreased, and decreased appetite (each 1 patient). No grade 4-related AEs occurred in both studies. No response (CR or PR) were seen in both studies. In MX1 study, median and mean of PFS [range], median duration of SD were 2.8, 3.4 [0.5-16.8], 3.7 months respectively, in MX2 study those were 1.9 and 2.8 [0.4-8.3], 5.7 respectively. In both studies, some pts showed long disease control (≥6 months). For those pts, each peptide-specific Cytotoxic T Lymphocyte (CTL) responses were shown by the ELISPOT assay. Conclusions: MX1 and MX2 showed good tolerability. Both vaccines induced CTL responses which may be related to antitumor effect. In addition, some pts showed long disease control. These results implied the potential usefulness of these vaccines for the treatment of HCC. Clinical trial information: JapicCTI-121933 and JapicCTI-142477.

Safety and effectiveness of sorafenib in Japanese patients with hepatocellular carcinoma in daily medical practice: interim analysis of a prospective postmarketing all-patient surveillance study.

BackgroundSorafenib was approved for treatment of unresectable hepatocellular carcinoma (HCC) in Japan in 2009. A prospective postmarketing all-patient surveillance (PMS) study was requested by Japanese authorities to confirm safety and effectiveness of sorafenib in Japanese HCC population.MethodsPatients with unresectable HCC treated with sorafenib were followed up for 12 months. Data on patient demographic characteristics, treatment status, clinical outcome, and adverse events (AEs) were collected.ResultsThis interim analysis included 1109 and 1065 patients evaluable for safety and effectiveness, respectively. Most patients (83.4 %) received the recommended initial dose of 400 mg twice daily. After a follow-up of 12-months, 89.8 % had discontinued treatment, most because of AEs (44.5 %) or progression (33.8 %). The most common drug-related adverse events (DRAE) were hand-foot skin reaction (51.4 %), liver dysfunction (26.4 %), diarrhea (25.1 %), and hypertension (21.6 %). The median overall survival (OS) was 348 days [95 % confidence interval (CI) 299–389 days], and the median duration of treatment was 87 days (95 % CI 78–98 days). Multivariate analyses identified baseline prognostic factors for longer OS, including female sex, low Child-Pugh score, Eastern Cooperative Oncology Group performance status 0, tumor stage I/II/III, low aspartate aminotransferase level, high hemoglobin level, hepatitis C and history of surgical resection.ConclusionsIn general, the safety and effectiveness findings in this PMS were consistent with findings from previous clinical studies. Sorafenib was well tolerated and clinically useful for Japanese patients.Clinical trial registration number: NCT01411436Electronic supplementary materialThe online version of this article (doi:10.1007/s00535-016-1173-5) contains supplementary material, which is available to authorized users.

A phase I study of GC33 in Japanese patients with advanced hepatocellular carcinoma (HCC).

235 Background: Glypican-3 (GPC3) belongs to a family of cell-surface heparan sulfate proteoglycans and is specifically expressed in HCC. In this phase I study, we examined the safety, tolerability, and pharmacokinetics of GC33, a recombinant, humanized monoclonal antibody against GPC3, in Japanese patients (pts) with advanced HCC. Methods: This study was a 3+3 design for dose escalation to determine the maximum tolerated dose (MTD) of GC33 given intravenously at 5, 10, and 20 mg/kg weekly. Key eligibility criteria included histological or cytological confirmation of HCC, ECOG PS ≤ 1, Child-Pugh A or B, adequate organ function, and tumor tissues available for GPC3 immunohistochemistry. Results: Thirteen pts were enrolled at 3 dose levels: median age=65 years (range 48-78), M/F=12/1, ECOG PS 0/1=9/4, HBV/HCV=4/8, liver cirrhosis +/-=8/5, Child-Pugh A (5-6)/B (7) =10/3. All pts received prior systemic therapy including sorafenib. Treatment was well tolerated at all dose levels without DLT, and MTD was not reached. The most common AEs were lymphocyte count decrease (77%), Natural Killer cell count decrease (77%), C-reactive protein increase (69%) and pyrexia (62%). Grade 3 AEs (≥ 2 pts) were lymphocyte count decrease (23%), blood pressure increase (23%) and platelet count decrease (15%). Infusion reactions were seen in 62% of pts and medically manageable. Anti-GC33 antibody was not detected in any of the patients. PK analysis of GC33 showed a half-life of 4 to 7 days and dose proportional for AUC after the first dose. Trough concentrations reached a steady state after 4 to 6 doses. Twelve out of 13 biopsied tumor specimens showed immunoreactivity with mouse GC33 antibody. There was no CR or PR, but 7 SD and 3 of them had SD for more than 5 months before progression (all with GPC3 expression). Conclusions: GC33 was well-tolerated up to 20 mg/kg weekly in Japanese HCC pts with Child-Pugh A or B liver cirrhosis and potentially beneficial to GPC3+ HCC. A randomized phase II study of GC33 monotherapy as 2nd line therapy in advanced HCC pts is currently ongoing. Clinical trial information: JapicCTI-101255.

Recent Trends of Japanese Hepatocellular Carcinoma due to HCV in Aging Society

The mean age of hepatocellular carcinoma (HCC) patients has increased (=65 years old). We want to identify the recent trend of the clinical features of HCC patients due to hepatitis C virus (HCV) (HCV-HCC). From 2000 to 2009, 855 naive HCC patients were admitted. HCV-HCC patients were divided into two groups, first period group (2000-04, n=270) and second period group (2005-09, n=343) and the clinical features of HCV-HCC were investigated. There was no difference in gender, TNM stage and percentages of HCV-HCC between the periods. On the other hand, the ratio of HCV-HCC patients with worse liver function (Child-Pugh B or C), elderly (=75 years old) and the population of patients treated with low invasive radiofrequency ablation were increased (30.0% to 42.0%, 17.2% to 35.8% and 25.1% to 36.2%, respectively; p<0.01). The 1y-, 3y- and 5y-survival rate of HCV-HCC did not show differences (82.1%, 60.5% and 44.7% vs. 81.8%, 56.9% and 37.7%, respectively; p=0.219). The ratio of aged HCV-HCC as well as HCV-HCC patients with worse liver function was increased. The less invasive treatment for HCC in these patients and the quick anti-viral treatment for HCV patients should be considered to avoid occurrence of HCC in Japan.

Hepatocellular carcinoma in non‐alcoholic steatohepatitis: Growing evidence of an epidemic?

The incidence of hepatocellular carcinoma in non-viral-related chronic liver disease has gradually increased in Japan. Obesity and diabetes mellitus type 2 have been established as a significant risk factor for hepatocellular carcinoma (HCC) by epidemiologic observations and experimental studies. The risks of these factors for HCC are likely conferred by two factors: the increased risk for development of non-alcoholic steatohepatitis (NASH) and the carcinogenic potential of themselves. Hepatocellular carcinoma in NASH is difficult to evaluate because histological diagnosis is required for diagnosis of NASH, which can lead selection bias. Furthermore, end-stage NASH is in effect "burned-out" NASH, for which the diagnosis of NASH cannot be made any more. At all events, previous studies on the etiology of Japanese HCC showed that non-alcoholic fatty liver disease accounts for 1-5% of all HCC (male predominant, median age 72 years). They have high prevalences of obesity and/or diabetes mellitus type 2 and 10-75% of the HCC arose from non-cirrhotic livers. HCC in NASH may be of multicentric origin, similar to HCC based on viral hepatitis. Regular screening for HCC is extremely important especially in cirrhotic NASH patients and recurrence should be warned. In western and Asian countries, the prevalence of non-alcoholic fatty liver disease in the general population is increasing dramatically. Therefore, there is an urgent need to elucidate pathogenesis and clinical features of HCC in NASH. In this review we summarize current concepts for HCC in NASH.

Features of hepatocellular carcinoma in cases with autoimmune hepatitis and primary biliary cirrhosis

To characterize the clinical features of hepatocellular carcinoma (HCC) associated with autoimmune liver disease, we critically evaluated the literature on HCC associated with autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). A systematic review of the literature was conducted using the Japana Centra Revuo Medicina database which produced 38 cases of HCC with AIH (AIH-series) and 50 cases of HCC with PBC (PBC-series). We compared the clinical features of these two sets of patients with the general Japanese HCC population. On average, HCC was more common in men than in women with AIH or PBC. While many patients underwent chemolipiodolization (CL) or transcatheter arterial embolization (TAE) (AIH-series: P = 0.048 (vs operation), P = 0.018 (vs RFA, PEIT); PBC-series: P = 0.027 (vs RFA, PEIT), others refused therapeutic interventions [AIH-series: P = 0.038 (vs RFA, PEIT); PBC-series: P = 0.003 (vs RFA, PEIT)]. Liver failure was the primary cause of death among patients in this study, followed by tumor rupture. The survival interval between diagnosis and death was fairly short, averaging 14 +/- 12 mo in AIH patients and 8.4 +/- 14 mo in PBC patients. We demonstrated common clinical features among Japanese cases of HCC arising from AIH and PBC.

T1934 Recent Clinical Features in Japanese Hepatocellular Carcinoma with Alcoholic Liver Disease

T1934 Recent Clinical Features in Japanese Hepatocellular Carcinoma with Alcoholic Liver Disease

Comparison of Survival between Anatomic and Non-Anatomic Liver Resection in Patients with Hepatocellular Carcinoma: Significance of Surgical Margin in Non-Anatomic Resection

Aims: Anatomic resection, i.e., systematic removal of a liver segment confined by portal branches, is theoretically effective in eradicating intrahepatic metastasis of hepatocellular carcinoma (HCC). The procedure may reduce tumour recurrence and enhance survival of HCC patients. To determine the significance of anatomic resection for HCC patients, we retrospectively conducted a comparative analysis between anatomic (AR) and non-anatomic liver resection (NAR) in 113 Japanese HCC patients with a solitary tumour, a tumour located within one segment, absence or invasion of distal to second order branches of the portal vein, and absence or invasion of peripheral branches of the hepatic vein. Methods: Patients were divided into two groups, AR group (n = 49) and NAR group (n = 64). Results: The prevalence of liver damage Grade B in the NAR group was significantly greater than in the AR group (p < 0.05). Tumour-free and overall survival following liver resection was not significantly different between AR and NAR groups. In the NAR group, tumour-free and overall survival in patients with tumour exposure at the surgical margin was significantly lower than with a surgical margin greater than 0 mm (not exposed) (p < 0.05). Survival between the AR and NAR groups without tumour exposure at the surgical margin was similar.Conclusions: Anatomic resection is the theoretical aim. In HCC patients with impaired liver functions, limited liver resection without tumour exposure may provide longer tumour-free and overall survival.

Phase I study of sorafenib in Japanese patients with hepatocellular carcinoma

Sorafenib is an orally active multikinase inhibitor that targets serine and threonine, and tyrosine kinases that are involved in tumor-cell signal transduction and tumor angiogenesis. This phase I trial was conducted to evaluate the pharmacokinetics (PK), safety, and preliminary efficacy of sorafenib in Japanese patients with hepatocellular carcinoma (HCC) with underlying liver dysfunction. Patients with unresectable HCC, Child-Pugh status A or B, and adequate organ functions were treated. A single dose of sorafenib was administered, followed by a 7-day wash-out period, after which patients received either sorafenib 200 mg (cohort 1) or 400 mg (cohort 2) twice daily. The PK were investigated after a single dose and during steady state. The efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors. A total of 27 patients were evaluated for PK, safety, and efficacy. Although both area under the concentration-time curve for 0-12 h and maximal concentration at steady state were slightly lower in Child-Pugh B patients than in Child-Pugh A patients, the difference was not considered to be clinically relevant. Common adverse drug events included elevated lipase, amylase, rash or desquamation, diarrhea, and hand-foot skin reaction. A dose-limiting toxicity of hand-foot skin reaction was observed in one patient (cohort 2). Among the 24 patients evaluable for tumor response, one patient (4%) achieved a partial response, 20 (83%) had stable disease, and three (13%) had progressive disease. Sorafenib demonstrated a favorable tolerability and safety profile in Japanese HCC patients. Moreover, promising preliminary antitumor activity has been observed. Finally, there were no clinically relevant differences in PK between Child-Pugh A and B patients.

Development of evidence‐based clinical guidelines for the diagnosis and treatment of hepatocellular carcinoma in Japan

The Clinical Practice Guidelines for Hepatocellular Carcinoma (HCC), the first evidence-based guidelines for the treatment of HCC in Japan, were compiled by an expert panel supported by the Japanese Ministry of Health, Labour, and Welfare. This set of guidelines covers six research fields: prevention, diagnosis and surveillance, surgery, chemotherapy, transarterial chemoembolization, and percutaneous local ablation therapy. A systematic review of the English medical literature on HCC was performed, and a total of 7192 publications were extracted, mainly from MEDLINE (1966-2002). After the second selection, 334 articles were adopted for the guidelines to form 58 pairs of research questions and recommendations. For the users' convenience, practical algorithms for the surveillance and treatment of HCC were also created, which were based on evidence from the selected articles forthe guidelines and modified according to the current status of medical practice in Japan, where liver resection for HCC is regarded as safe with less than 1% mortality and cadaveric donors for liver transplantation are extremely difficult to obtain. The formation of the guidelines and the outline of their contents are described. The Japanese HCC guidelines may be useful in decision making at every clinical step, both for patients and physicians. Although the main users of these guidelines are assumed to be Japanese physicians, the accumulated evidence and interpretation in the guidelines may attract universal attention.

Clinicopathological characteristics of patients with hepatocellular carcinoma after hepatectomy: Relationship with status of viral hepatitis

Viral hepatitis may modulate the status of liver dysfunction, tumor biology, and postoperative course in patients with hepatocellular carcinoma (HCC). To determine the characteristics of HCC in different types of viral hepatitis, we conducted a comparative analysis of clinicopathological features and outcomes in 243 Japanese HCC patients following hepatic resection. Patients were divided into four groups; non-B-non-C group, hepatitis B (HBV) group, hepatitis C (HCV) group, and co-infection with HB, and HC (HBCV) group. Liver function was worst and prevalence of cirrhosis was highest in HBCV group than in compare to HBV and non-B-non-C group. The prevalence rates of intrahepatic metastasis, tumor vascular involvement, and low curability in HBCV group were higher than in the other groups. Uncontrolled ascites and hepatic failure were significantly more common in HBCV group than other groups. The disease-free and overall survival rates of non-B-non-C group were better than those of the other groups; both survival rates were the worst in HBCV group than the other groups. HCC patients with co-infection of HBV and HCV had poorer liver function and more advanced tumors compared with the other groups. This might explain the poor prognosis of such patients.

Aging of patients with hepatitis C virus-associated hepatocellular carcinoma: Long-term trends in Japan

The incidence of hepatocellular carcinoma (HCC) in Japan has been increasing. The aim of the present study was to analyze epidemiological changes in Japanese HCC patients. A total of 463 patients with HCC diagnosed at our hospital between 1982 and 2001 were recruited for this study. Cohorts of patients with HCC were categorized into intervals of five years. The number of HBV- and HCV-associated HCC cases had decreased and increased in 1987-1991, respectively, and thereafter reached a plateau. The mean age of patients at diagnosis of HCV-associated HCC showed a steady significant increase from 60 to 68 years of age during the period, suggesting that these findings were associated with a shift toward an older-age group that had the highest rate of HCV infection. The mean age of patients with other types of HCC did not significantly change during the period. Since it is known that the prevalence of HCV infection in young Japanese persons is low and that the incidence of HCV infection is very low at present, our findings may indicate that the prevalence of HCC will decline in Japan, an advanced country with regard to HCV-associated HCC, in the near future.

Hepatic Iron Overload Induces Hepatocellular Carcinoma in Transgenic Mice Expressing the Hepatitis C Virus Polyprotein

Despite the evidence of hepatic iron overload in patients with chronic hepatitis C, it remains unknown if iron overload is related to hepatocarcinogenesis in this condition. The aim of this study was to determine whether iron overload contributes to development of hepatocellular carcinoma (HCC) in transgenic mice expressing the hepatitis C virus (HCV) polyprotein. Male C57BL/6 transgenic mice expressing the HCV polyprotein and nontransgenic littermates were fed an excess-iron diet or control diet. Mice in each group were assessed for altered liver morphology and function and the development of liver tumors. Hepatic iron concentrations in mice fed the excess-iron diet were comparable to those of patients with chronic hepatitis C. There was no inflammation in transgenic and nontransgenic livers. Compared with mice in 3 other groups, transgenic mice fed the excess-iron diet showed marked hepatic steatosis including the centrilobular microvesicular type, ultrastructural alterations of the mitochondria and decreased degradation activity of fatty acid at 6 months, and greater hepatic content of lipid peroxidation products and 8-hydroxy-2'-deoxyguanosine at 12 months after initiation of feeding. The number of proliferating hepatocytes was significantly increased in mice fed the excess-iron diet but was not different between transgenic and nontransgenic mice. Hepatic tumors including HCC developed in 5 of 11 (45%) transgenic mice fed the excess-iron diet but not in mice in other groups at 12 months after initiation of feeding. Iron overload induces mitochondrial injury and increases the risk of HCC development in transgenic mice expressing the HCV polyprotein.

Modified Japan Integrated Staging is currently the best available staging system for hepatocellular carcinoma patients who have undergone hepatectomy

We previously reported the effectiveness of the modified Cancer of the Liver Italian Program (CLIP) score in hepatocellular carcinoma (HCC) staging. To determine the best predictive staging system for HCC patients, we conducted a comparative analysis of prognosis using multivariate analysis in 230 Japanese HCC patients following hepatic resection. We compared overall survival as predicted by different staging systems: the tumor node metastasis (TNM) system by the Liver Cancer Study Group of Japan, the Japan Integrated Staging (JIS) score (Japanese TNM and Child-Pugh classification), the modified JIS score using liver damage grade, the CLIP score, and our modified CLIP score using protein induced by vitamin K absence or the antagonist II (PIVKA-II). By a univariate analysis the PIVKA-II level (cut-off level, 400 mAU/ml) was significantly associated with patient survival (P = 0.031); however, alpha-fetoprotein level was not related to survival. Liver damage grade was significantly associated with patient survival (P = 0.039), although Child-Pugh classification was not related to survival. Univariate analysis showed that prediction of survival, according to disease stage, was better with the modified JIS score than with the TNM system, CLIP, modified CLIP, or JIS score. Multivariate analysis showed the modified JIS score showed the best ability to predict overall survival according to disease stage (Hazard ratio, 1.77; P = 0.002), and its Akaike information criteria statistic was the lowest (634.3). The modified JIS score, a staging system that combines tumor factors and hepatic function, is a better predictor of prognosis than other systems in HCC patients who have undergone hepatic resection.

Absence of PIK3CA hotspot mutations in hepatocellular carcinoma in Japanese patients

A recent study revealed that the p110alpha (PIK3CA), catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is somatically mutated in many types of cancer. For example, PIK3CA is mutated in an estimated 35.6% of hepatocellular carcinoma (HCC) cases. To measure the frequency of PIK3CA hotspot mutations in Japanese HCC patients, exons 9 and 20 of the PIK3CA gene were sequenced in 47 clinical HCC samples. Contrary to expectations, no hotspot mutations were found any of the HCC samples. In addition, we found abnormally migrating waves near the end of exon 9 in the PCR chromatograms from 13 of the 47 samples. PCR amplification and subsequent cloning and sequencing revealed that these chromatograms contained two distinct sequences, the wild-type p110alpha sequence and a different sequence found on human chromosome 22q11.2, the Cat Eye Syndrome region, which contains a putative pseudogene of PIK3CA. These abnormally migrating waves were also found in noncancerous liver tissue, indicating that this was not a result of HCC-associated mutations. Therefore, it is likely that the percentage of hotspot mutations in the PIK3CA gene of Japanese HCC patients is lower than was previously reported.