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Background/aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) was recently proposed as an alternative disease concept to nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the prognosis of patients with biopsy-confirmed MASLD using data from a multicenter study., Methods: This was a sub-analysis of the Clinical Outcome Nonalcoholic Fatty Liver Disease (CLIONE) study that included 1,398 patients with NAFLD. Liver biopsy specimens were pathologically diagnosed and histologically scored using the NASH Clinical Research Network system, the FLIP algorithm, and the SAF score. Patients who met at least one cardiometabolic criterion were diagnosed with MASLD., Results: Approximately 99% of cases (n=1,381) were classified as MASLD. Patients with no cardiometabolic risk (n=17) had a significantly lower BMI than patients with MASLD (20.9 kg/m2 vs. 28.0 kg/m2, P<0.001), in addition to significantly lower levels of inflammation, ballooning, NAFLD activity score, and fibrosis stage based on liver histology. These 17 patients had a median follow-up of 5.9 years, equivalent to 115 person-years, with no deaths, liver-related events, cardiovascular events, or extrahepatic cancers. The results showed that the prognosis for pure MASLD was similar to that for the original CLIONE cohort, with 47 deaths and one patient who underwent orthotopic liver transplantation. The leading cause of death was extrahepatic cancer (n=10), while the leading causes of liver-related death were liver failure (n=9), hepatocellular carcinoma (n=8), and cholangiocarcinoma (n=4)., Conclusion: Approximately 99% of NAFLD cases were considered MASLD based on the 2023 liver disease nomenclature. The NAFLD-only group, which is not encompassed by MASLD, had a relatively mild histopathologic severity and a favorable prognosis. Consequently, the prognosis of MASLD is similar to that previously reported for NAFLD.

Objective: Liver stiffness measurements (LSMs) and controlled attenuation parameters (CAPs) obtained using vibration-controlled transient elastography (VCTE) are recognized non-invasive methods of assessing liver histology. The usefulness of CAP for predicting liver-related events (LREs: hepatocellular carcinoma, decompensation, bleeding varices) is not well understood worldwide. Our aim was to re-evaluate the cutoff values of LSM/CAP in Japan and to examine whether LSM/CAP can predict LRE., Methods: Japanese NAFLD patients (n = 403) who underwent both liver biopsy and VCTE were enrolled. We determined optimal cutoff values of LSM/CAP diagnoses for fibrosis stage and steatosis grade and investigated their clinical outcome based on LSM/CAP values., Results: The LSM cutoff values for F1 to F4 are 7.1, 7.9, 10.0 and 20.2 kPa, and the CAP cutoff values for S1 to S3 are 230, 282 and 320 dB/m. During a median follow-up of 2.7 y (range: 0.0-12.5 y), 11 patients developed LREs. The incidence of LREs in the LSM Hi (≥8.7) group was significantly higher than that in the LSM Lo (<8.7) group (p = 0.003), and the incidence in the CAP Lo (<295) group was higher than that in CAP Hi (≥295) group (p = 0.018). Considering LSM and CAP together, the risk of LRE was higher in the LSM Hi CAP Lo group than in the LSM Hi CAP Hi group (p = 0.03)., Conclusion: We set LSM/CAP cutoff values to diagnose liver fibrosis and steatosis in Japan. Our study determined that NAFLD patients with high LSM and low CAP values are at high risk for LREs., Competing Interests: Conflict of interest H.T. has received research funding from Astellas Pharma Company and AbbVie. T.K. has received honoraria from EA Pharma, Janssen Pharmaceuticals, Taisho Pharmaceutical Company and Otsuka Pharmaceutical Company. Atsushi Nakajima has received honoraria from EA Pharma, Mochida Pharmaceutical Company, Astellas Pharma Company, Kowa Company, Biofermin, Mylan EPD and Taisho Pharmaceutical Company and research funding from EA Pharma, Gilead Sciences Inc., Astellas, Biofermin, Asuka Company, Kowa Company and Mylan EPD. The remaining authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Background & Aims: There are no detailed reports of clinical outcomes in Asian patients with nonalcoholic fatty liver disease (NAFLD) who undergo liver biopsy. We aimed to investigate the clinical outcomes of a large cohort of Asian patients with biopsy-proven NAFLD and evaluate the specific effects of nonalcoholic steatohepatitis and fibrosis stage., Methods: This multicenter registry-based retrospective cohort study, called the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia, included 1398 patients., Results: The median follow-up period was 4.6 years (range, 0.3-21.6 years), representing a total of 8874 person-years of follow-up. During that time, 47 patients died, and 1 patient underwent orthotopic liver transplantation. The leading cause of death was nonhepatic cancer (n = 10). The leading causes of liver-related death were liver failure (n = 9), hepatocellular carcinoma (HCC) (n = 8), and cholangiocellular carcinoma (n = 4). During follow-up, 37 patients developed HCC, 31 developed cardiovascular disease, and 68 developed nonhepatic cancer (mainly breast, stomach, and colon/rectum). Among our cohort of patients with NAFLD, liver-specific mortality was 2.34/1000 person-years (95% confidence interval [CI], 1.52-3.58), overall mortality was 5.34/1000 person-years (95% CI, 4.02-7.08), and HCC incidence was 4.17/1000 person-years (95% CI, 3.02-5.75). Liver fibrosis was independently associated with liver-related events but not overall mortality., Conclusions: Liver-related mortality was the leading cause of mortality in Asian patients with biopsy-confirmed NAFLD. Although fibrosis stage was independently associated with liver-related events, it was not associated with overall mortality after adjusting for confounders, such as histologic features of steatohepatitis., (Copyright © 2023. Published by Elsevier Inc.)

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Recently, the prognosis of NAFLD/NASH has been reported to be dependent on liver fibrosis degree. Liver biopsy remains the gold standard, but it has several issues that must be addressed, including its invasiveness, cost, and inter-observer diagnosis variability. To solve these issues, a variety of noninvasive tests (NITs) have been in development for the assessment of NAFLD progression, including blood biomarkers and imaging methods, although the use of NITs varies around the world. The aim of the Japan NASH NIT (JANIT) Forum organized in 2020 is to advance the development of various NITs to assess disease severity and/or response to treatment in NAFLD patients from a scientific perspective through multi-stakeholder dialogue with open innovation, including clinicians with expertise in NAFLD/NASH, companies that develop medical devices and biomarkers, and professionals in the pharmaceutical industry. In addition to conventional NITs, artificial intelligence will soon be deployed in many areas of the NAFLD landscape. To discuss the characteristics of each NIT, we conducted a SWOT (strengths, weaknesses, opportunities, and threats) analysis in this study with the 36 JANIT Forum members (16 physicians and 20 company representatives). Based on this SWOT analysis, the JANIT Forum identified currently available NITs able to accurately select NAFLD patients at high risk of NASH for HCC surveillance/therapeutic intervention and evaluate the effectiveness of therapeutic interventions., (© 2022. The Author(s).)

The prognosis of nonalcoholic fatty liver disease (NAFLD) patients depends on liver-related events (LREs), extrahepatic cancers, and major adverse cardiovascular events (MACEs). The fibrosis-4 (FIB-4) index is one of the most reliable and useful predictors of the degree of liver fibrosis. Recent studies have reported that the FIB-4 index is also useful for predicting LREs and MACEs in NAFLD patients. In the present study, we investigated the prognostic value of the FIB-4 index in NAFLD patients. A total of 506 biopsy-confirmed NAFLD patients from six hepatology centers in Japan from 2002 to 2013 were enrolled in this study. Of these NAFLD patients, 353 were available for more than 100 days of follow-up and did not exhibit events (LREs, extrahepatic cancers, MACEs) at the time of entry. The mean follow-up duration of all the subjects was 2716 ± 1621 days (102-7483 days). New LREs (hepatocellular carcinoma (HCC) ( n = 8), decompensation ( n = 11), bleeding varices ( n = 8)) developed in 18 patients. Twenty-four and twelve patients developed extrahepatic cancers and MACEs, respectively. The median FIB-4 index was 1.255; we divided our cohort into two groups according to this (FIB4 Low, FIB4 Hi). The incidence of HCC tended to be higher in FIB4 Hi ( n = 7) than in FIB4 Low ( n = 1). The incidence of LREs was significantly higher in FIB4 Hi ( n = 17) than in FIB4 Low ( n = 1). The incidence of extrahepatic cancers was significantly higher in FIB4 Hi ( n = 20) than in FIB4 Low ( n = 4); the incidence of MACEs was also significantly higher in FIB4 Hi ( n = 10) than in FIB4 Low ( n = 2). The FIB-4 index is a useful biomarker for predicting not only LREs but also extrahepatic cancers and MACEs.

Background and Aim: Older age, type 2 diabetes mellitus (T2DM), and obesity are known risk factors for liver-related events (LREs). We investigated the impacts of T2DM and obesity on LRE according to age in Japanese patients with non-alcoholic fatty liver disease (NAFLD)., Methods: We performed a subanalysis of a retrospective cohort study (CLIONE in Asia), including 1395 patients with biopsy-proven NAFLD. The median follow-up was 4.6 years., Results: The median age was 57 years, and 36.2% had T2DM. The median body mass index (BMI) was 27.4, and 28.5% were severely obese (BMI ≥ 30). During follow-up, 37 patients developed hepatocellular carcinoma (HCC), and 58 patients developed LRE. In patients younger than 65 years, advanced fibrosis (hazard ratio [HR] 7.69, P < 0.001) and T2DM (HR 3.37, P = 0.017) were HCC risk factors, and advanced fibrosis (HR 9.40, P < 0.001) and T2DM (HR 2.51, P = 0.016) were LRE risk factors. In patients 65 years and older, advanced fibrosis (HR 4.24, P = 0.010) and obesity (HR 4.60, P = 0.006) were HCC risk factors, and advanced fibrosis (HR 4.22, P = 0.002) and obesity (HR 4.22, P = 0.002) were LRE risk factors., Conclusion: Type 2 diabetes mellitus and obesity contributed to LRE in younger and older patients, respectively, along with advanced fibrosis. Therefore, controlling T2DM in patients younger than 65 years and controlling weight in patients 65 years and older could prevent LRE. The development of age-dependent screening and management strategies is necessary for patients with NAFLD., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

We previously demonstrated that Mac-2 binding protein (M2BP) is a useful biomarker for nonalcoholic fatty liver disease (NAFLD), particularly NAFLD fibrosis prediction. In the present study, we investigated the prognostic value of M2BP in patients with NAFLD. A total of 506 patients with biopsy-confirmed NAFLD from 2002 to 2013 were enrolled in this study in Japan. Three hundred fifty-three of these patients with NAFLD were available for follow-up for more than 100 days and showed no liver-related events at the time of entry. Liver-related events were defined as hepatocellular carcinoma (HCC), decompensation, and gastroesophageal varices with variceal treatment. The mean follow-up duration of all the subjects was 2716 ± 1621 days (102-7483 days). Eighteen patients developed new liver-related events (HCC, 8; decompensation, 11; varices, 8). Nine patients developed cardiovascular disease (CVD), and 24 patients developed new cancers in other organs. The median serum M2BP level was 1.603 μg/mL, and we divided our cohort into two groups according to the serum M2BP level: M2BP low group (M2BP Low) and M2BP high group (M2BP Hi). The incidence of HCC was significantly higher in M2BP Hi (n = 8) than in M2BP Low (n = 0). The incidence of liver-related events was significantly higher in M2BP Hi (n = 16) than in M2BP Low (n = 2). The incidences of death, CVD events, and cancer in other organs were not different between the groups. Interestingly, the incidence of colorectal cancer was significantly higher in M2BP Hi (n = 5) than in M2BP Low (n = 0). Conclusion: M2BP is a useful biomarker to predict liver-related events, particularly HCC. Additionally, M2BP is a potential predictive biomarker of colorectal cancer development., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Non-alcoholic steatohepatitis (NASH), a severe form of non-alcoholic fatty liver disease (NAFLD), can progress to cirrhosis, hepatocellular carcinoma (HCC), and hepatic failure/liver transplantation. Indeed, NASH will soon be the leading cause of HCC and liver transplantation. Lifestyle intervention represents the cornerstone of NASH treatment, but it is difficult to sustain. However, no pharmacotherapies for NASH have been approved. Oxidative stress has been implicated as one of the key factors in the pathogenesis of NASH. Systematic reviews with meta-analyses have confirmed that vitamin E reduces transaminase activities and may resolve NASH histopathology without improving hepatic fibrosis. However, vitamin E is not recommended for the treatment of NASH in diabetes, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis. Nevertheless, vitamin E supplementation may improve clinical outcomes in patients with NASH and bridging fibrosis or cirrhosis. Further studies are warranted to confirm such effects of vitamin E and that it would reduce overall mortality/morbidity without increasing the incidence of cardiovascular events. Future clinical trials of the use of vitamin E in combination with other anti-fibrotic agents may demonstrate an additive or synergistic therapeutic effect. Vitamin E is the first-line pharmacotherapy for NASH, according to the consensus of global academic societies., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Liver fibrosis stage is one of the most important factors in stratifying the risk of developing hepatocellular carcinoma (HCC). We evaluated the usefulness of liver stiffness measured by magnetic resonance elastography (MRE) to stratify the risk of developing HCC in patients who underwent MRE before receiving direct-acting antivirals (DAAs) and subsequently achieved sustained virological response (SVR)., Methods: A total of 537 consecutive patients with persistent hepatitis C virus who underwent initial MRE before DAA therapy and achieved SVR were enrolled. Factors associated with HCC development were analyzed by univariate and multivariate Cox proportional hazards models., Results: Albumin-bilirubin score ≥ -2.60 (adjusted hazard ratio [aHR] 6.303), fibrosis-4 (FIB-4) score >3.25 (aHR 7.676), and MRE value ≥4.5 kPa (aHR 13.190) were associated with HCC development according to a univariate Cox proportional hazards model. A multivariate Cox proportional hazards model showed that an MRE value ≥4.5 kPa (aHR 7.301) was the only factor independently associated with HCC development. Even in patients with an FIB-4 score >3.25, the cumulative incidence rate of HCC development in those with an MRE value <4.5 kPa was significantly lower than that in patients with an MRE value ≥4.5 kPa., Discussion: Liver stiffness measured by MRE before DAA therapy was an excellent marker for predicting subsequent HCC development in patients with hepatitis C virus infection who achieved SVR. The same results were observed in patients with high FIB-4 scores., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background and Aim: The prevalence of hepatocellular carcinoma (HCC) associated with nonalcoholic fatty liver disease (NAFLD-HCC) is increasing. Unfortunately, NAFLD frequently develops into HCC without liver cirrhosis. Therefore, we investigated the clinical features of HCC in NAFLD patients without advanced fibrosis., Methods: We compared clinical characteristics, survival rates, and recurrence rates between 104 NAFLD-HCC patients diagnosed between January 2000 and December 2016, including 35 without (F0-2) and 69 with advanced fibrosis (F3-F4). Risk factors associated with survival and recurrence were evaluated., Results: In total, 66.3% of those diagnosed had advanced fibrosis, 58.8% in men and 80.5% in women (men vs women, P = 0.03). In NAFLD-HCC without advanced fibrosis, tumor size was significantly larger and liver histological activity was lower than those in patients with advanced fibrosis. Survival rates between the two groups did not differ. Among those achieving curative treatment, the recurrence rate was significantly lower in NAFLD-HCC without advanced fibrosis (P < 0.01). Risk factors of recurrence were male gender, lower serum albumin, and advanced fibrosis., Conclusions: In men, HCC tended to develop from NAFLD without advanced fibrosis. Although tumor size in NAFLD-HCC without advanced fibrosis is significantly larger, the recurrence rate is significantly lower. Surgical therapy should be strongly considered in these cases., (© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The genetic factors affecting the natural history of nonalcoholic fatty liver disease (NAFLD), including the development of nonalcoholic steatohepatitis (NASH) and NASH-derived hepatocellular carcinoma (NASH-HCC), are still unknown. In the current study, we sought to identify genetic factors related to the development of NAFLD, NASH, and NASH-HCC, and to establish risk-estimation models for them. For these purposes, 936 histologically proven NAFLD patients were recruited, and genome-wide association (GWA) studies were conducted for 902, including 476 NASH and 58 NASH-HCC patients, against 7,672 general-population controls. Risk estimations for NAFLD and NASH were then performed using the SNPs identified as having significant associations in the GWA studies. We found that rs2896019 in PNPLA3 [p = 2.3x10-31, OR (95%CI) = 1.85 (1.67-2.05)], rs1260326 in GCKR [p = 9.6x10-10, OR (95%CI) = 1.38(1.25-1.53)], and rs4808199 in GATAD2A [p = 2.3x10-8, OR (95%CI) = 1.37 (1.23-1.53)] were significantly associated with NAFLD. Notably, the number of risk alleles in PNPLA3 and GATAD2A was much higher in Matteoni type 4 (NASH) patients than in type 1, type 2, and type 3 NAFLD patients. In addition, we newly identified rs17007417 in DYSF [p = 5.2x10-7, OR (95%CI) = 2.74 (1.84-4.06)] as a SNP associated with NASH-HCC. Rs641738 in TMC4, which showed association with NAFLD in patients of European descent, was not replicated in our study (p = 0.73), although the complicated LD pattern in the region suggests the necessity for further investigation. The genetic variants of PNPLA3, GCKR, and GATAD2A were then used to estimate the risk for NAFLD. The obtained Polygenic Risk Scores showed that the risk for NAFLD increased with the accumulation of risk alleles [AUC (95%CI) = 0.65 (0.63-0.67)]., Conclusions: We demonstrated that NASH is genetically and clinically different from the other NAFLD subgroups. We also established risk-estimation models for NAFLD and NASH using multiple genetic markers. These models can be used to improve the accuracy of NAFLD diagnosis and to guide treatment decisions for patients.

Background: In Japan, the prevalence of hepatocellular carcinoma (HCC) associated with nonviral liver disease, especially with nonalcoholic fatty liver disease (NAFLD-HCC) and alcoholic liver disease (ALD-HCC), has been increasing. Clarification of the clinical features of NAFLD-HCC and ALD-HCC is needed. We performed a large retrospective multicenter survey to clarify the clinical course of these two types of HCC., Methods: Clinical characteristics, survival, and recurrence were examined in 532 patients with ALD-HCC and 209 patients with NAFLD-HCC who were diagnosed between January 2000 and December 2013., Results: The ALD-HCC patients were predominantly male and were younger than the patients with NAFLD-HCC. Lifestyle-related diseases were significantly more common in the NAFLD-HCC group, but the prevalence of cirrhosis was significantly higher in the ALD-HCC group. The histological diagnosis of NAFLD-HCC showed a gender difference (F4; 72.7 % in the females vs. 37.6 % in the males). The characteristic features of HCC including histology, survival rate, and recurrence rate were quite similar in the NAFLD-HCC and ALD-HCC groups: 5-year survival rates 49.1 vs. 43.7 %; 5-year recurrence rates 69.6 vs. 65.4 %, respectively. However, the risk factors for recurrence differed between the two groups: des-gamma-carboxy prothrombin was a risk factor in NAFLD-HCC and α-fetoprotein was a risk factor in ALD-HCC., Conclusions: Although the characteristic features underlying these two diseases are different, the two HCC groups showed a similar clinical course. The recurrence rates of the two HCC groups were relatively high. We found that critical tumor markers for recurrence differed between the two diseases.

Background: Type 2 diabetes mellitus (T2DM) is an established independent risk factor for hepatocellular carcinoma (HCC). T2DM is associated with non-alcoholic steatohepatitis (NASH), which is a major cause of non-HBV and non-HCV-related HCC; nevertheless, it has been difficult to identify those patients with T2DM who have a high risk of developing HCC. The aim of this study was to identify genetic determinants that predispose T2DM patients to HCC by genotyping T2DM susceptibility loci and PNPLA3., Methods: We recruited 389 patients with T2DM who satisfied the following three criteria: negative for HBs-Ag and anti-HCV Ab, alcohol intake <60 g/day, and history of T2DM >10 years. These patients were divided into two groups: T2DM patients with HCC (DM-HCC, n = 59) or those without HCC (DM-non-HCC, n = 330). We genotyped 51 single-nucleotide polymorphisms (SNPs) previously reported as T2DM or NASH susceptibility loci (PNPLA3) compared between the DM-HCC and DM-non-HCC groups with regard to allele frequencies at each SNP., Results: The SNP rs738409 located in PNPLA3 was the greatest risk factor associated with HCC. The frequency of the PNPLA3 G allele was significantly higher among DM-HCC individuals than DM-non-HCC individuals (OR 2.53, p = 1.05 × 10(-5)). Among individuals homozygous for the PNPLA3 G allele (n = 115), the frequency of the JAZF1 rs864745 G allele was significantly higher among DM-HCC individuals than DM-non-HCC individuals (OR 3.44, p = 0.0002)., Conclusions: PNPLA3 and JAZF1 were associated with non-HBV and non-HCV-related HCC development among Japanese patients with T2DM.

Epigenetic changes as well as genetic changes are mechanisms of tumorigenesis. We aimed to identify novel genes that are silenced by DNA hypermethylation in hepatocellular carcinoma (HCC). We screened for genes with promoter DNA hypermethylation using a genome-wide methylation microarray analysis in primary HCC (the discovery set). The microarray analysis revealed that there were 2,670 CpG sites that significantly differed in regards to the methylation level between the tumor and non-tumor liver tissues; 875 were significantly hypermethylated and 1,795 were significantly hypomethylated in the HCC tumors compared to the non‑tumor tissues. Further analyses using methylation-specific PCR, combined with expression analysis, in the validation set of primary HCC showed that, in addition to three known tumor-suppressor genes (APC, CDKN2A, and GSTP1), eight genes (AKR1B1, GRASP, MAP9, NXPE3, RSPH9, SPINT2, STEAP4, and ZNF154) were significantly hypermethylated and downregulated in the HCC tumors compared to the non-tumor liver tissues. Our results suggest that epigenetic silencing of these genes may be associated with HCC.

EVI1 (ecotropic viral integration site 1) is one of the most aggressive oncogenes associated with myeloid leukemia. We investigated DNA copy number aberrations in human hepatocellular carcinoma (HCC) cell lines using a high-density oligonucleotide microarray. We found that a novel amplification at the chromosomal region 3q26 occurs in the HCC cell line JHH-1, and that MECOM (MDS1 and EVI1 complex locus), which lies within the 3q26 region, was amplified. Quantitative PCR analysis of the three transcripts transcribed from MECOM indicated that only EVI1, but not the fusion transcript MDS1-EVI1 or MDS1, was overexpressed in JHH-1 cells and was significantly upregulated in 22 (61%) of 36 primary HCC tumors when compared with their non-tumorous counterparts. A copy number gain of EVI1 was observed in 24 (36%) of 66 primary HCC tumors. High EVI1 expression was significantly associated with larger tumor size and higher level of des-γ-carboxy prothrombin, a tumor marker for HCC. Knockdown of EVI1 resulted in increased induction of the cyclin-dependent kinase inhibitor p15(INK) (4B) by transforming growth factor (TGF)-β and decreased expression of c-Myc, cyclin D1, and phosphorylated Rb in TGF-β-treated cells. Consequently, knockdown of EVI1 led to reduced DNA synthesis and cell viability. Collectively, our results suggest that EVI1 is a probable target gene that acts as a driving force for the amplification at 3q26 in HCC and that the oncoprotein EVI1 antagonizes TGF-β-mediated growth inhibition of HCC cells., (© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

A 44-year-old female was referred to our hospital with a complaint of abdominal fullness. Computed tomography(CT) showed multiple liver masses and a huge ovarian tumor. Colonoscopy revealed a type 4 advanced cancer in the sigmoid colon. She was diagnosed with unresectable liver and ovarian metastases from advanced sigmoid colon cancer, for which we were obliged to select chemotherapy. As the first line, FOLFOX was applied and performed for 6 cycles, followed by FOLFOX plus bevacizumab(BV)for 5 cycles. While no deterioration of liver and ovarian metastases was observed during the course of those chemotherapy regimens, the patient developed a considerable level of acute sensorimotor neuropathic symptoms associated with oxaliplatin-induced peripheral neurotoxicity, forcing us to replace FOLFOX plus BV with FOLFIRI plus BV. Three cycles of FOLFIRI plus BV, however, turned out to be progressive disease with deterioration of liver and ovarian metastases. Since her oxaliplatin-induced neurotoxicity was improved, a regimen of FOLFOX plus BV was once again applied to her for 3 cycles, which failed to prevent her from having a progressive disease. The sequencing of K-RAS genes from the biopsy specimens of sigmoid colon cancer revealed an expression of a wild-type K-RAS. Thus, an addition of panitumumab to FOLFOX was made. Surprisingly, after 3 cycles of the chemotherapy regimen over 3 months, a significant reduction in the size of liver and ovarian metastases was observed. Her sense of abdominal fullness was apparently reduced and was even lower than what it was at admission. Panitumumab has great potential for effective treatment of patients with unresectable stage IV colorectal cancer, even after having acquired resistance to prior chemotherapy regimens.

Background & Aims: Nonalcoholic steatohepatitis (NASH) can progress to hepatocellular carcinoma (HCC). We aimed to characterize the clinical features of NASH patients with HCC., Methods: In a cross-sectional multicenter study in Japan, we examined 87 patients (median age, 72 years; 62% male) with histologically proven NASH who developed HCC. The clinical data were collected at the time HCC was diagnosed., Results: Obesity (body mass index ≥25 kg/m(2)), diabetes, dyslipidemia, and hypertension were present in 54 (62%), 51 (59%), 24 (28%), and 47 (55%) patients, respectively. In nontumor liver tissues, the degree of fibrosis was stage 1 in 10 patients (11%), stage 2 in 15 (17%), stage 3 in 18 (21%), and stage 4 (ie, liver cirrhosis) in 44 (51%). The prevalence of cirrhosis was significantly lower among male patients (21 of 54, 39%) compared with female patients (23 of 33, 70%) (P = .008)., Conclusions: Most patients with NASH who develop HCC are men; the patients have high rates of obesity, diabetes, and hypertension. Male patients appear to develop HCC at a less advanced stage of liver fibrosis than female patients., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background/aims: Pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (1CTP) is a sensitive serum marker for metastatic bone carcinomas and may also be associated with invasiveness of various carcinomas. To clarify the significance of 1CTP in hepato-biliary pancreas malignancies, we examined the relationship between clinicopathological features and serum level of 1CTP., Methodology: The subjects were 75 patients who underwent surgical resections including 27 patients with liver carcinomas, 15 with extra-hepatic biliary carcinomas, 14 pancreatic carcinomas and 19 benign diseases., Results: 1CTP level tended to be higher in the malignant diseases than in benign diseases but this difference was not significant (p = 0.065). Compared to benign adenoma, 1CTP level in the malignant diseases was significantly higher (p = 0.049). 1CTP level tended to be higher in patients with cholangitis compared to those with no inflammation or benign tumors (p = 0.065). 1CTP was not correlated with any tumor markers. 1CTP was not associated with node status and vascular infiltrations. 1CTP level tended to be lower in patients with poor differentiation., Conclusions: Serum level of 1CTP might be a predictive marker for hepatobiliary pancreas malignancies but also reflects the degree of co-existing cholangitis.

To achieve complete resection of metastatic colonic carcinoma in the liver and lung, thoracolaparotomy-assisted simultaneous resection was attempted in a 60-year-old male patient who had previously undergone sigmoidectomy for primary sigmoid colon carcinoma. A solitary liver metastasis was observed in segment 7 and a solitary lung metastasis was located in segment 6 of the right lower lung. Simultaneous resection was attempted and, in the left lateral position, a thoraco-laparotomy with oblique incision was made in the right seventh intercostal space. Both tumors could be palpated under a good operative view. A partial hepatectomy was performed followed by a segmental resection of the lung. A chest drainage tube was inserted for two postoperative days. The patient had no remarkable complications including pulmonary complication after surgery and was discharged at day 20 post-operation. For metastatic tumors simultaneously located in the right subphrenic part of the liver and the lower part of the right lung, thoraco-laparoscopy-assisted complete resection is a safe and useful option to achieve curative treatment.

Background/aims: A new prognostic staging system, the SLiDe (S, stage; Li, liver damage; De, des-gamma-carboxy prothrombin) score was recently proposed. We examined 207 HCC patients following hepatic resection to determine the usefulness of this staging system for HCC patients after surgery., Methodology: Disease-free and overall survival rates were calculated according to the Kaplan-Meier method, and differences between groups were tested for significance using the log-rank test., Results: Regarding disease-free survival, there were no significant differences in survival between SLiDe score 0 vs 1, between score 2 vs 3, and between score 4 vs 5. There were significant differences between 0-1 vs 2-3 (p < 0.01) and between 2-3 vs 4-5 (p < 0.01). Regarding overall survival, there were no significant differences in survival between score 0 vs 1, between score 2 vs 3, and between score 4 vs 5. There were significant differences between 0-1 vs 2-3 (p < 0.05) and between 2-3 vs 4-5 (p < 0.01)., Conclusions: The SLiDe score, a staging system that combines tumor factors, a tumor marker and hepatic function, might be a better predictor of prognosis in HCC patients who have undergone hepatic resection.

Hepatocellular carcinoma (HCC) patients often have esophagogastric varices due to portal hypertension by chronic hepatitis or cirrhosis. Surgical treatment for gastric varices is necessary when the patient undergoes hepatic resection for HCC, simultaneously. We examined the clinical demographics, surgical records and outcome in 7 patients undergoing both hepatectomy and Hassab's operation (=decongestion of upper gastric veins and splenectomy) between 1994 and 2007. All patients had HCC, including chronic injured liver diseases. Preoperative liver functions were well preserved in all patients. Right hepatectomy was performed in two patients and limited resections in 5. Three patients had postoperative complications and the in-hospital death by hepatic failure was observed in one. Four patients had tumor recurrence within one year and 3 were dead, while, two patients had long-term survival with or without recurrence of HCC. Following Hassab's operation, gastric varices dramatically disappeared. Portal hypertension and hypersplenism were significantly improved. Simultaneous operation with Hassab's procedure and hepatectomy is useful and can be safely performed in HCC patients with gastric varices.

Background/purpose: Large liver tumors often expand and severely compress intrahepatic vessels. In cases of the trisectionectomy for such tumors, however, it is difficult to adequately expose the transection planes. The liver hanging maneuver (LHM) is a useful technique for hemihepatectomy and an adequate transection plane might be also required in trisectionectomy., Methods: LHM procedure is basically followed by the Belghiti's method. A nasogastric tube was used for hanging. At the hepatic hilum, the tube was placed between the liver and Glisson's pedicle., Results: We report here the application of LHM for right and left trisectionectomy in patients with a large hepatoma in two cases. In case of a right trisectionectomy for a large tumor compressing the umbilical Glisson's pedicle, an adequate transection plane was obtained using the LHM because the resected and remnant livers rotated to the other side upon lifting the tube during transection. In case of a left trisectionectomy for a large hepatic tumor compressing the right hepatic vein, an adequate transection plane along the right hepatic vein was obtained using LHM as well., Conclusions: LHM is a useful surgical application for right and left trisectionectomy in patients with large liver tumors compressing the cut plane.

In anatomical resection of the liver, transection of the hepatic vein or Glisson's pedicle is necessary. We examined the surgical records and outcome of 25 patients who underwent hepatectomy. An endovascular stapler with 35 and 60 mm staples was used for transection of the hepatic vein or Glisson's pedicle, and hepatic parenchyma including vessels. Surgery included also left lateral sectorectomy in 6 patients, right lateral sectorectomy in one, right hepatectomy in 12, left hepatectomy in two and trisegmentectomy in 4. Endovascular stapling was used for transection of hepatic veins (n=25) in all patients and Glisson's pedicle (n=8). No failure of firing occurred during cutting. Injury of an aberrant bile duct occurred in one patient, but none suffered bleeding or bile leakage from the transected parts. Vascular transection using vascular stapler could be performed safely and rapidly during anatomical hepatic resection.

Background and Objectives: There is no appropriate grading system for prediction of survival of patients with metastatic liver cancer (MLC) from colorectal carcinoma. We propose the modified grading system for MLC from the present Japanese system., Methods: We compared predictive accuracies of survival of 121 Japanese MLC patients of five systems, including clinical risk score (CRS) proposed by Memorial-Sloan-Kettering-Cancer-Center, original H-number (OHN) by Japanese Society for Cancer of the Colon and Rectum, revised H-number (RHN) and Grade by the same society (GJSCCR), and our modified Grade (MGJSCCR) based on OHN and presence of primary lymph node metastasis., Results: Univariate analysis showed that discrimination of both disease-free and overall survival rates was significant for CRS, OHN and MGJSCCR (P < 0.05) but not for RHN and GJSCCR. Multivariate analysis showed CRS and MGJSCCR as the best systems for predicting disease-free and overall survival according to disease stage, for which Akaike information criteria (AIC) value was the lowest (423.7 and 313.9, hazard ratio 1.73 and 1.47, respectively for CRS, 423.9 and 313.5, hazard ratio 1.75 and 1.69, respectively for MGJSCCR; P < 0.05)., Conclusions: The simpler system of MGJSCCR is a better predictive grading system of prognosis of MLC patients who had undergone hepatic resection., ((c) 2008 Wiley-Liss, Inc.)

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.

Background/aims: Recently, early detection of liver tumors has been possible with improvement of various imaging techniques, and practical selection of imaging is clinically necessary to distinguish metastatic liver carcinoma (MLC) from colorectal carcinoma., Methodology: We retrospectively examined the diagnostic accuracy of enhanced computed tomography (eCT) and super paramagnetic iron oxide particles magnetic resonance imaging (SPIO-MRI) for 110 MLC lesions in 47 patients who underwent hepatic resection at a single Japanese cancer institute between 2000 and 2006. Sensitivity and positive predictive value (PPV) of both imaging techniques in comparison with resected specimens were analyzed. Fourteen cases were synchronous liver metastasis, which were resected simultaneously., Results: On a per patient basis, both eCT and SPIO-MRI showed a sensitivity of 85.1% (40 of 47 patients) and PPV was 100%, respectively. On a per lesion basis, a sensitivity of SPIO-MRI (98/110 lesions; 89%) tended to be higher than that of eCT (92 of 110 lesions; 84%), but not statistically different (p=0.32). PPV of SPIO-MRI (98 of 99 lesions; 99%) was not different from that of eCT (92 of 93; 99%). Twelve lesions in 7 patients that were not detected by both imaging methods were small lesions. PPV for liver cyst and non-timorous lesions was 99% by both imaging methods. Two liver cysts could be clearly diagnosed by SPIO-MRI only., Conclusions: We found no superiority of diagnosis with SPIO-MRI, which may not be conceptually useful for preoperative screening for MLC from colorectal carcinomas. SPIO-MRI may be useful to detect non-cancerous lesions as an adjuvant diagnostic tool with eCT.

Aim: To elucidate the relationship between the microvessel count (MVC) by CD34 analyzed by immunohistochemical method and prognosis in hepatocellular carcinoma (HCC) patients who underwent hepatectomy based on our preliminary study., Methods: We examined relationships between MVC and clinicopathological factors in 128 HCC patients. The modified Japan Integrated Staging score (mJIS) was applied to examine subsets of HCC patients., Results: Median MVC was 178/mm(2), which was used as a cut-off value. MVC was not significantly associated with any clinicopathologic factors or postoperative recurrent rate. Lower MVC was associated with poor disease-free and overall survivals by univariate analysis (P = 0.039 and P = 0.087, respectively) and lower MVC represented an independent poor prognostic factor in disease-free survival by Cox's multivariate analysis (risk ratio, 1.64; P = 0.024), in addition to tumor size, vascular invasion, macroscopic finding and hepatic dysfunction. Significant differences in disease-free and overall survivals by MVC were observed in HCC patients with mJIS 2 (P = 0.046 and P = 0.0014, respectively), but not in those with other scores., Conclusion: Tumor MVC appears to offer a useful prognostic marker of HCC patient survival, particularly in HCC patients with mJIS 2.

Anatomic resection is theoretically effective in eradicating intrahepatic metastasis of hepatocellular carcinoma (HCC). In patients who undergo a larger volume of hepatectomy or who have hepatic dysfunction, the extent of hepatectomy is limited to avoid postoperative hepatic failure. In the present case, a limited anatomic resection according to Couinaud's segment was performed because of the large volume of the right hemi-liver. A 62-year-old male was found to have a 12-cm HCC in segments 5, 6 and 7, with alcoholic liver disease. The total liver function was Child-Pugh grade A, as indocyanine green retention rate at 15 minutes (ICGR15) was 12%. The resected liver volume of right hemihepatectomy estimated by CT volumetry was 72% and the permitted resected volume based on Takasaki's formula applying ICGR15 was 65%. As the portal branches of segment 8 was free from HCC involvement and the estimated volume of segments 5, 6 and 7 was 51%, we scheduled anatomic resection of these segments to secure remnant liver function. Under Pringle's maneuver, hepatic transection on the border between right and left liver was performed and the right paramedian Glisson's pedicle was exposed in the first step. Branches of segment 5 were divided and the border between segments 5 and 8 was confirmed. Then, the right lateral sector was resected and the right hepatic vein draining segment 8 was secured. Postoperative course was satisfactory and the patient was free from tumor relapse for 16 months after hepatectomy. Under a balance between tumor location and hepatic functional reserve, anatomic resection would be necessary for the treatment of HCC patients.

Background/aims: In advanced cancers of hepatobiliary and pancreatic lesions, major vascular resection and reconstruction are necessary to accomplish curative resection, which may provide better patient outcomes., Methodology: Surgical records, morbidity and mortality, and prognosis were examined in patients with combined vascular resection. Thirty-six patients underwent 18 hepatectomies and 18 pancreatectomies., Results: In 18 patients who underwent hepatic resection, the resected vessels were the portal vein (PV) in 10, vena cava or hepatic vein in 9 and right hepatic artery (RHA) in 3. An artificial graft was used in 2 to replace the vena cava. Vascular bypass was performed in 5 patients. Morbidity was due to biliary stricture in 1 patient and adult respiratory distress syndrome in another who died during hospital stay. Fourteen (82%) had cancer recurrence, of whom 12 died of cancer, one died of other disease, and 2 survived cancer-free. The 5-year survival was 28%. In 18 patients who underwent pancreatectomy, resected vessels were PV in 18 and RHA in 1. An artificial graft was used in 3 and vascular passive bypass was performed in 6. One patient died of sepsis after total pancreatectomy during hospital stay. Eleven (64%) had cancer recurrence, of whom 11 died of cancer, 2 died of other disease, and 4 survived cancer-free. The 3-year survival was 27%., Conclusions: Complete surgical resection (R0) combined with main vascular resection could be safely performed in many patients with disease of the hepatobiliary and pancreas, which achieved longer survival in some patients even in the advanced stage.

Background/aims: In advanced hepatocellular carcinoma (HCC) with vascular involvement of major vessels, patients have a poor prognosis after surgical treatment., Methodology: Patient outcomes after surgical resection and the usefulness of adjuvant chemotherapy were examined in 12 patients with major hepatic vessel involvement who underwent hepatectomy with combined resection of major blood vessels., Results: The main portal vein was resected in 8 patients, the inferior vena cava in 3, hilar bile duct in 2 and hepatic artery in 1. Eleven patients underwent hemihepatectomy and 1 underwent segment 4 and 5 resection. The portal branch was repaired by venoplasty. The vena cava wall was repaired by suture closure. The hepatic artery was replaced by end-to-end anastomosis. The bile duct was repaired by Roux-en-Y hepaticojejunostomy. Although 2 patients had biliary leakage, there were no postoperative complications in 10 patients. The tumor recurrence rate was 83% in the early period and cancer death within 1 year was observed in 6 (50%), while 3 with tumor recurrence survived for more than 2 years and 2 survived without recurrence. In 233 HCC patients who underwent hepatectomy, 10 patients including 2 present cases received adjuvant chemotherapy at the time of tumor recurrence and 2 had complete responses. While in 11 patients receiving chemotherapy without resection, the response rate using Gemcitabine (66%) was higher than that using low dose Cisplatin plus 5-Fluorouracil (22%)., Conclusions: Complete surgical resection combined with main vascular resection could be safely performed in most advanced stage HCC patients and adjuvant chemotherapy in the early period after resection would be necessary, which may achieve longer survival in some patients even in the advanced stage.

Aim: To compare the prognosis of patients who underwent hepatectomy and ablation using the modified Japan Integrated Staging score (mJIS)., Methods: We examined the clinicopathologic records and patient outcomes in 278 HCC patients including 226 undergoing hepatectomy and 52 undergoing ablation therapy., Results: Cirrhosis was more frequent in the ablation group. Tumor size, number and presence of vascular invasion were significantly higher in the operation group compared to the ablation group. The local recurrence rate adjacent to treated lesions was significantly higher in the ablation group compared to the operation group (P < 0.05). The 3- and 5-year survival rates in the ablation and the operation group were 66% and 78%, and 50% and 63%, respectively, but not significantly different. Over 50% survival rates were observed in patients with a mJIS score of 0-2 in both groups. However, survival rates with a score of 3-5 in both groups were significantly lower., Conclusion: According to the mJIS system, both local treatments could be selected for patients with a score of 0-2. However, for patients with a score more than 3, liver transplantation might be a better option in patients with HCC.

Background and Objectives: Viral hepatitis may modulate the status of liver dysfunction, tumor biology, and postoperative course in patients with hepatocellular carcinoma (HCC)., Methods: 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., Results: 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., Conclusions: 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.

Background/aims: To predict the risk of liver dysfunction associated complications after hepatectomy, we evaluated perioperative parameters in patients after hepatectomy., Methodology: We examined 185 consecutive patients who underwent hepatectomy for liver tumors. Background liver was normal liver in 73 patients, chronic viral hepatitis in 49, cirrhosis in 46 and icteric liver in 17. Postoperative complications associated liver dysfunction (long-term ascites, intraabdominal infection and hepatic failure) occurred in 70 (38%) patients., Results: Univariate analysis identified 9 significant parameters associated with postoperative complications (resected volume > or = 50%, intraoperative bleeding volume > or = 1500 mL, liver activity at 15 min by technetium-99m galactosyl human serum albumin scintigraphy of < 0.85, alanine aminotransferase > or = 80 IU/L, total cholesterol < 150 mg/dL, prothrombin activity [PT] < 80%, Liver Damage grade B, histopathological activity index [HAI] of > or = 8 and hyaluronic acid [HA] of > or = 150 ng/mL). Multivariate logistic regression analysis identified resected volume, intraoperative bleeding, PT and HA levels as four significant independent predictors of post-hepatectomy complication with odds ratios of 7.0, 4.4, 7.5, and 5.4, respectively., Conclusions: Preoperative assessment and correction of abnormal PT and HA, careful evaluation of resected volume and attempt to reduce intraoperative bleeding are important to avoid postoperative hepatic complications.

To achieve complete ablation of liver cancer in the hepatic dome, thoracoscopy-assisted radiofrequency ablation was attempted in three patients. Under general anesthesia and left lateral position, a thoracoport site was placed in the 6th intercostal space and a small thoracotomy was placed in the 7th intercostal space. In all three cases, the liver cancer was located in the hepatic dome of segment 7/8 and the tumor could not be fully observed on the lung echogram. In Case 1, saline was infused into the thoracic cavity under thoracoscopic observation and percutaneous ablation was safely performed. In Cases 2 and 3, the right diaphragm was opened, guided by ultrasonography, and the electrode was inserted into this working space via the thoracotomy site. At day 7, complete ablation was confirmed by computed tomography. All patients recovered and were discharged after a short hospital stay without severe complications. Tumor recurrence has not been observed in any patient at this stage. For liver cancer located in the right subphrenic dome of the liver, thoracoscopy-assisted ablation is a safe and useful option particularly in patients with poor hepatic function.

Background: 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., Methods: 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)., Results: 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)., Conclusions: 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.

A long-term follow-up study was performed to identify the natural course of chronic HCV carriers with persistently normal serum ALT level (PNAL; < or =30 U/L) and to clarify the effect of interferon therapy on the inhibition of the development of hepatocellular carcinoma (HCC) in chronic hepatitis C patients with elevated ALT levels. One hundred twenty-nine HCV carriers with PNAL underwent liver biopsy, 69 were followed for more than 5 years, and 35 underwent serial liver biopsies. We included 1246 chronic hepatitis C patients (stage F1: 231, F2: 638, F3: 336, F4: 41) who received interferon therapy and were followed for more than 2 years (mean, 7.7 years). Approximately 90% of HCV carriers with PNAL had normal to mild liver histology, and 30% developed symptomatic chronic hepatitis C within 5 years. The frequency of steatosis and iron loading was significantly lower in these patients than in symptomatic chronic hepatitis C patients. The progression rate of fibrosis was slower than in chronic hepatitis C patients with elevated serum ALT levels. HCC was noted in 157 chronic hepatitis C patients after interferon therapy, and the development of HCC was significantly reduced in both sustained responders and transient biochemical responders compared with nonresponders. HCC in sustained responders mainly developed in male patients older than 55 years with advanced stage liver histology at entry. Approximately 30% of HCV-infected patients with PNAL become candidates for antiviral therapy within 5 years. Interferon therapy lowers the rate of the development of HCC in both sustained responders and transient biochemical responders.

Aims: In a previous pilot study, we reported the usefulness of the modified the Cancer of the Liver Italian Program (CLIP) score for patients with hepatocellular carcinoma (HCC). To determine the best staging system for predicting the survival of HCC patients, we conducted a comparative analysis of prognosis using multivariate analysis in 210 Japanese HCC patients who underwent hepatic resection., Methods: We compared the survival as predicted by various staging systems, including tumour node metastasis (TNM) stage of the American Joint Commission on Cancer (AJCC) and the Liver Cancer Study Group of Japan, the Japan Integrated Staging (JIS) score (Japanese TNM and Child-Pugh classification), CLIP score and our modified CLIP score using protein induced by vitamin K absence or antagonist II (PIVKA-II)., Results: Univariate analysis showed that discrimination of disease-free survival in the early and advanced stages by the JIS score and modified CLIP score was clearer than by the Japanese or AJCC TNM or the original CLIP score. Discrimination between stages of overall survival by all staging systems was significant. Multivariate analysis showed that the JIS, CLIP and modified CLIP scores were better staging systems for predicting survival than the Japanese and AJCC TNM. The modified CLIP score showed the lowest Akaike information criteria statistical value for disease-free and overall survival, which means the best discrimination ability for patient survival compared with the JIS score and CLIP score., Conclusions: A staging system that combines tumour factors, sensitive tumour marker(s) and hepatic function is the best predictor of prognosis of HCC patients.

Background/aims: The aim of our retrospective study was to compare the factors contributing to postoperative complications according to the extent of hepatectomy., Methodology: We examined 166 patients with hepatobiliary carcinoma who underwent hepatectomy. Patients were divided into three groups according to the type and extent of hepatectomy: 1) left lobectomy (n=27), 2) right lobectomy or posterior segmentectomy (n=55) and 3) other hepatectomies (n=84). Patient demographics, major complications (infection, ascites, pleural effusion, atelectasis, static symptoms of the stomach, biliary leakage and hepatic failure) after hepatectomy were analyzed., Results: In patients with obstructive jaundice, lobectomy was the most commonly performed operation due to the extent of tumor along the main hepatic duct. Prolonged ascites or massive pleural effusion was frequently observed after right lobectomy (p=0.001) and posterior segmentectomy (p=0.002). However, the incidences of these complications were similar in patients with chronic viral hepatitis. Symptoms related to gastric stasis and biliary leakage were significantly more common after left lobectomy than other surgeries. The incidence of hepatic failure was higher (p<0.05) after major hepatectomy, particularly right lobectomy, than other surgeries., Conclusions: Our results emphasize the need to understand characteristics of specific complications occurring after different types of hepatic resection surgery to prevent post-hepatectomy complications.

Aims: The new Japanese staging system for hepatocellular carcinoma (HCC), the Japan integrated staging (JIS) score, accounts for both Child-Pugh classification and Japan tumour node metastasis (TNM) staging. However, in HCC patients who undergo hepatectomy, liver function is relatively good and a better prognostic classification of hepatic function is necessary., Methods: The present study was designed to analyse the modified JIS score using liver damage grade by the Liver Cancer Study Group of Japan instead of the Child-Pugh classification (using the category indocyanine green retention rate at 15 min [ICG(R15)] instead of encephalopathy), and to compare the Japan TNM stage in 101 patients who underwent resection of HCC., Results: The liver damage grade showed significantly better discrimination of disease-free and overall survival than did the Child-Pugh classification. The modified JIS score system showed significant differences of disease-free and overall survivals in each score and this system was superior for discriminating survivals compared with the TNM staging., Conclusions: The combined staging system of hepatic function, particularly ICG(R15), and tumour stage provides a better prediction of prognosis. The JIS score using the liver damage grade was a useful predictor of prognosis of HCC patients who underwent hepatic resection.

Background: The relationship between patient prognosis and various tumor biological factors has been reported previously, and prognostic factors of tumor biology may improve predictions of prognosis after hepatectomy for hepatocellular carcinoma (HCC) and may contribute to a new staging classification. This study was designed to provide an immunohistochemical analysis of tumor biological factors in patients who underwent hepatectomy for HCC., Methods: Factors analyzed included p53 overexpression, microvessel counts, proliferating cell nuclear antigen, and expression of nm23. We examined 81 HCCs from patients with chronic liver diseases., Results: In patients who underwent chemoembolization before surgery, or those a who had confluent multinodular tumor, p53 expression tended to be higher than in patients without chemoembolization (33% vs 11%) or those with a simple nodular tumor (28% vs 10%), but the difference was not statistically significant ( P = 0.051 and P = 0.092, respectively). A lower tumor microvessel count and negative nm23 expression were significantly associated with poor disease-free survival by univariate analysis ( P < 0.01 and P < 0.05, respectively). A lower tumor microvessel count was found to be a significant prognostic factor for disease-free and overall survivals (risk ratios, 2.44 and 3.13, respectively; P << 0.05), in addition to tumor size, vascular invasion, and longterm ascites, by Cox's multivariate analysis., Conclusions: Tumor microvessel count appears to be a useful prognostic marker for predicting HCC recurrence and patient survival.

To clarify the relationship between multidrug resistance protein (MRP) and clinicopathologic features, the influence of adjuvant chemotherapy, and prognosis of patients who underwent resection of metastatic liver carcinomas originating from colorectal carcinomas, we examined the expression of MRP in tumor tissues by immunostaining. Specimens of 38 primary colorectal tumors and 44 metastatic liver tumors of colorectal origin were examined (metastatic group). We also examined 28 nonmetastatic colorectal carcinomas. The percentages of nonmetastatic tumors and of primary and metastatic tumors of the metastasis group that expressed MRP were similar. MRP expression in primary and metastatic tumors did not correlate with any clinicopathologic features. The use of adjuvant chemotherapy after operation for primary colorectal carcinomas was associated with increased MRP expression among metastatic liver tumors. Expression of MRP in the tumor did not influence the prognosis or survival rate after resection of primary or metastatic tumors. Our data suggest that MRP expression in metachronous liver metastases from colorectal carcinomas may be induced by administration of anticancer drugs but is not associated with clinicopathologic features of the tumor, liver metastasis, or prognosis.