Necessity for surveillance for hepatocellualr carcinoma in older patients with chronic hepatitis C who achieved sustained virological response.

Background and Aim: Hepatocellular carcinoma (HCC) surveillance in low-risk patients (annual incidence <1.5%) is not recommended per the American Association for the Study of Liver Diseases guidelines. Because patients with chronic hepatitis C with non-advanced fibrosis who have achieved sustained virological response (SVR) have a low risk of HCC, HCC surveillance is not recommended for them. However, aging is a risk factor for HCC; threfore, the necessity for HCC surveillance in older patients with non-advanced fibrosis needs to be verified. Methods: This multicenter, prospective study enrolled 4993 patients with SVR (1998 patients with advanced fibrosis and 2995 patients with non-advanced fibrosis). The HCC incidence was examined with particular attention to age. Results: The 3-year incidence of HCC in patients with advanced and non-advanced fibrosis was 9.2% (95% CI: 7.8-10.9) and 2.9% (95% CI: 2.1-3.7), respectively. HCC incidence was significantly higher in patients with advanced fibrosis (P < 0.001). HCC incidence stratified by age and sex was investigated in patients with non-advanced fibrosis. The HCC incidence in the 18-49, 50s, 60s, 70s, and ≥80 age groups were 0.26, 1.3, 1.8, 1.7, and 2.9 per 100 person-years in men, and 0.00, 0.32, 0.58, 0.49, and 0.57 per 100 person-years in women, respectively. Conclusions: Male patients with non-advanced fibrosis aged ≥60 years have a higher risk of developing HCC and, thus, require HCC surveillance.

Effects on survival of the adverse event of atezolizumab plus bevacizumab for hepatocellular carcinoma: a multicenter study by the Japan Red Cross Liver Study Group.

This study aimed to describe the real-world efficacy and safety of the combination therapy of atezolizumab and bevacizumab (Atezo/Bev) for unresectable hepatocellular carcinoma (HCC). This retrospective analysis of a multicenter registry cohort included 268 patients treated with Atezo/Bev. The incidence of adverse events (AE) and its impact on overall survival (OS) and progression-free survival (PFS) were analyzed. Of the 268 patients, 230 (85.8%) experienced AE. The median OS and PFS in the whole cohort were 462 and 239 days, respectively. The OS and PFS were not different in terms of AE, but they were significantly shorter in patients with increased bilirubin level and those with increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT). Regarding increased bilirubin level, the hazard ratios (HRs) were 2.61 (95% confidence interval [CI]: 1.04-6.58, P = 0.042) and 2.85 (95% CI: 1.37-5.93, P = 0.005) for OS and PFS, respectively. Regarding increased AST or ALT, the HRs were 6.68 (95% CI: 3.22-13.84, P < 0.001) and 3.54 (95% CI: 1.83-6.86, P < 0.001) for OS and PFS, respectively. Contrarily, the OS was significantly longer in patients with proteinuria (HR: 0.46 [95% CI: 0.23-0.92], P = 0.027). Multivariate analysis confirmed that proteinuria (HR: 0.53 [95% CI: 0.25-0.98], P = 0.044) and increased AST or ALT (HR: 6.679 [95% CI: 3.223-13.84], P = 0.003) were independent risk factors for a shorter OS. Furthermore, analysis limited to cases who completed at least 4 cycles confirmed that increased AST or ALT and proteinuria were negative and positive factors for OS, respectively. In the real-world setting, increased AST or ALT and bilirubin level during Atezo/Bev treatment were found to have a negative impact on PFS and OS, whereas proteinuria had a positive impact on OS.

Outcome of untreated low-level viremia versus antiviral therapy-induced or spontaneous undetectable HBV-DNA in compensated cirrhosis.

BACKGROUND: Comparative outcomes of HBV-infected compensated cirrhosis with low-level viremia (LLV) versus maintained virological response (MVR) are unclear. We conducted a large, multiethnic, multicenter study to examine the natural history of LLV versus MVR in compensated cirrhosis. PATIENTS AND METHODS: We enrolled patients with HBV-infected compensated cirrhosis (n=2316) from 19 hospitals in South Korea, Singapore, and Japan. We defined the LLV group as untreated patients with ≥1 detectable serum HBV-DNA (20-2000 IU/mL), Spontaneous-MVR group as untreated patients with spontaneously achieved MVR, and antiviral therapy (AVT)-MVR group as patients achieving AVT-induced MVR. Study end points were HCC or hepatic decompensation. RESULTS: The annual HCC incidence was 2.7/100 person-years (PYs), 2.6/100 PYs, and 3.3/100 PYs for LLV (n=742), Spontaneous-MVR (n=333), and AVT-MVR (n=1241) groups, respectively ( p = 0.81 between LLV vs. Spontaneous-MVR groups and p = 0.37 between LLV vs. AVT-MVR groups). Similarly, the annual decompensation incidence was 1.6/100 PYs, 1.9/100 PYs, and 1.6/100 PYs for LLV, Spontaneous-MVR, and AVT-MVR groups, respectively ( p = 0.40 between LLV vs. Spontaneous-MVR groups and p = 0.83 between LLV vs. AVT-MVR groups). Multivariable analyses determined that HCC and decompensation risks in the LLV group were comparable to those with Spontaneous-MVR and AVT-MVR groups (all p >0.05). Propensity score matching also reproduced similar results for HCC and decompensation risks (all p >0.05 between LLV vs. Spontaneous-MVR groups and between LLV vs. AVT-MVR groups). CONCLUSIONS: Untreated LLV in HBV-infected compensated cirrhosis is not associated with increased risk of disease progression compared with Spontaneous-MVR and AVT-MVR. These data have important implications for practice and further research.

Risk factors for hepatocellular carcinoma at baseline and 1 year after initiation of nucleos(t)ide analog therapy for chronic hepatitis B.

Nucleos(t)ide analogs (NAs) cannot completely suppress the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study aimed to identify the risk factors for HCC development in naïve CHB patients treated with current NA. Patients receiving NA (n = 905) were recruited retrospectively from the 17 hospitals of the Japanese Red Cross Liver Study Group. All treatment-naïve patients had been receiving current NA continuously for more than 1 year until the end of the follow-up. We analyzed the accuracy of predictive risk score using the area under receiver operating characteristic curve. The albumin-bilirubin (ALBI) score was significantly improved by NA therapy (-0.171 ± 0.396; p < 0.001 at Week 48). A total of 72 (8.0%) patients developed HCC over a median follow-up of 6.2 (1.03-15.7) years. An independent predictive factor of HCC development was older age, cirrhosis, lower platelet counts at baseline and ALBI score, and alpha-fetoprotein (AFP) at 1 year after NA therapy according to multivariate analysis. The accuracy was assessed using the PAGE-B, mPAGE-B, aMAP, APA-B, and REAL-B scores that included these factors. Discrimination was generally acceptable for these models. aMAP and REAL-B demonstrated high discrimination with 0.866/0.862 and 0.833/0.859 for 3- and 5-year prediction from the status of 1 year after NA therapy, respectively. Baseline age and platelet count, as well as ALBI and AFP one year after NA, were useful for stratifying carcinogenesis risk. The aMAP and REAL-B scores were validated with high accuracy in Japanese CHB patients.

Usefulness of neutrophil-to-lymphocyte ratio in predicting progression and survival outcomes after atezolizumab-bevacizumab treatment for hepatocellular carcinoma.

AIM: We investigated pretreatment neutrophil-to-lymphocyte ratio (NLR) for predicting survival outcomes of atezolizumab plus bevacizumab therapy for hepatocellular carcinoma (HCC) and determined the predictive ability of combined liver reserve-NLR. METHODS: This retrospective, multicenter study enrolled 242 patients receiving atezolizumab plus bevacizumab for unresectable HCC. Pretreatment NLR <2.56 was designated as the "low group" and NLR ≥2.56 as the "high group" (120 and 122 patients, respectively). Propensity score-matched analysis was undertaken between the low and high groups. RESULTS: In this cohort, the objective response and disease control rates were 20% and 72.5%, respectively, in the low group and 19.6% and 72.9%, respectively, in the high group. After matching, median progression-free survival (PFS) time was 283 and 167 days in the low and high groups, respectively (p = 0.022). Neutrophil-to-lymphocyte ratio ≥2.56 (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.05-2.28; p = 0.028), modified albumin-bilirubin index (mALBI) grade 2b or 3 (HR 1.55; 95% CI, 1.05-2.29; p = 0.025), and protein induced by vitamin K absence or antagonist-II ≥ 400 (HR 2.03; 95% CI, 1.36-3.02; p = 0.001) were significantly associated with PFS in univariate analysis using the Cox proportional hazards model. In cases involving mALBI grade 1 or 2a (n = 131), the median PFS time was not reached in the low group, whereas it was 210 days in the high group (p = 0.037). CONCLUSIONS: Pretreatment NLR is a simple tool for routine measurement in clinical practice. It can predict PFS in patients with unresectable HCC treated with atezolizumab plus bevacizumab, especially mALBI grade 1 or 2a.

Optimal threshold of alpha-fetoprotein response in patients with unresectable hepatocellular carcinoma treated with atezolizumab and bevacizumab.

Alpha-fetoprotein (AFP) response (relative decline in AFP) is associated with imaging response evaluated by response evaluation criteria in solid tumors ver1.1 (RECIST) and survival in treatment for hepatocellular carcinoma (HCC). However, the optimal threshold of AFP response is still unknown, especially in atezolizumab and bevacizumab (Atez/Bev) treatment. In this prospective multicenter study, we aimed to investigate an optimal threshold of AFP response in Atez/Bev treatment. Out of 284 patients with unresectable HCC who were treated with Atez/Bev, 91 patients with AFP ≥ 10 ng/ml were enrolled in the multicenter study. We investigated the relationship between various AFP response thresholds (relative decline ≥ 20%, ≥ 50%, and ≥ 75%) and treatment response and progression-free survival (PFS). An AFP relative decrease of ≥ 50% was associated with an overall response rate (ORR) with an odds ratio (95% confidence interval [CI]) of 5.7 (1.9-17). Disease control rate (DCR) was associated with an AFP relative decrease of ≥ 20%, with a 100% positive predictive value and a 52.0% sensitivity. AFP relative decreases of ≥ 50% and ≥ 20% were significantly associated with PFS with a hazard ratio (HR) of 5.60 (95% CI: 1.6-19, p = 0.006) and a HR of 4.44 (95% CI: 1.9-10, p < 0.001), respectively. AFP response of ≥ 50% and ≥ 20% were related to ORR and DCR, respectively, and both of these responses were also associated with PFS. AFP can be used as a real-time monitor during Atez/Bev treatment and is helpful for treatment optimization.

General evaluation score for predicting the development of hepatocellular carcinoma in patients with advanced liver fibrosis associated with hepatitis C virus genotype 1 or 2 after direct-acting antiviral therapy.

Background and Aim: To validate a composite predictive model for hepatocellular carcinoma (HCC) development in patients with advanced liver fibrosis associated with chronic hepatitis C virus (HCV) who have received direct-acting antiviral (DAA) therapy and achieved sustained virologic response (SVR). Methods: This study included 1258 patients with advanced liver fibrosis associated with HCV genotype 1, 2, or both. General evaluation score (GES), which is based on sex, age, fibrosis stage, albumin, and α-fetoprotein, was used as a composite predictive model. Results: There were 645 (51.3%) patients in the low-risk group, 228 (18.1%) in the intermediate-risk group, and 385 (30.6%) in the high-risk group based on GES categories. The 12-, 36-, and 60-month cumulative incidence of HCC was 0.7%, 5.3%, and 13.0%, respectively. Multivariable analysis with Cox proportional hazards models showed that male sex (hazard ratio [HR], 1.863; 95% confidence interval [CI], 1.204-2.883), F4 fibrosis stage (HR, 3.199; 95% CI, 1.696-6.036), and albumin (HR, 0.489; 95% CI, 0.288-0.828) are independently associated with HCC development. The incidence of HCC differed significantly by GES-based risk category (P < 0.001). Cox proportional hazards models showed that, with the low-risk group as the referent, the HR for HCC development was 1.875 (95% CI, 1.000-3.514) in the intermediate-risk group and 2.819 (95% CI, 1.716-4.630) in the high-risk group. GES had better predictive ability for HCC development than fibrosis-4 index according to time-dependent receiver operating characteristic analysis. Conclusion: GES is useful for predicting HCC development in patients with advanced liver fibrosis after SVR.

Real-World Data on Ramucirumab Therapy including Patients Who Experienced Two or More Systemic Treatments: A Multicenter Study.

BACKGROUND: The present study aimed to clarify the efficacy and safety of ramucirumab in a real-world setting, including patients who experienced two or more systemic treatments or whose hepatic reserve was deteriorated. METHODS: In total, 79 patients with hepatocellular carcinoma (HCC) from 14 institutes throughout Japan were retrospectively analyzed. The response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and AEs were recorded according to the Common Terminology Criteria for AEs (CTCAE) version 5.0. RESULTS: Median overall survival (OS) in the total cohort was 7.5 months (m). Median OS was 8.8 m in patients who were administered ramucirumab as a second-line treatment, while it was 7.3 m in third- or later-line treatment. Progression-free survival rates in the second- and third- or later-line therapies were 3.2 m and 3.2 m, respectively. The disease control rate (DCR) in the study was 43%. There were no statistically significant differences in DCR between the treatment courses. Regarding adverse events (AEs), the development of ascites was observed significantly more frequently in modified albumin-bilirubin (mALBI) 2b/3 patients than in mALBI 1/2a patients (54.5% vs. 25.0%, p = 0.03). CONCLUSIONS: Ramucirumab is useful as a second-line therapy and feasible as a third- or later-line treatment for HCC.

Efficacy of hepatitis C virus eradication after curative treatment for hepatocellular carcinoma in patients with advanced hepatocellular carcinoma and decreased hepatic functional reserve: A nationwide, multicentre study by the Japanese Red Cross Liver Study Group.

Improvements in the hepatocellular carcinoma (HCC) recurrence rate and survival have been frequently reported following virus eradication after hepatitis C virus (HCV)-related HCC cure. However, the efficacy of direct-acting antiviral (DAA) therapy in patients who included those with advanced HCC and decreased hepatic functional reserve is unknown. A comparative examination was retrospectively conducted of 141 patients with hepatitis C who started DAA therapy within 1 year after undergoing curative HCC treatment and showed a sustained viral response (SVR) and 327 patients who underwent curative treatment for HCV-related HCC and did not subsequently receive antiviral therapy. Whether DAA therapy was given was identified as an independent factor related to both HCC recurrence and survival. Both the recurrence and survival rates improved significantly with DAA therapy in Child-Pugh (CP)-A, whereas no difference in the recurrence rate was seen with DAA therapy in CP-B. However, the survival rate was significantly higher in the DAA group in this class. Similarly, dividing the patients by the Milan criteria showed significant improvements in the recurrence rate and survival with DAA therapy in patients within the Milan criteria. Patients with HCC beyond the Milan criteria showed no difference in recurrence rates, but the DAA group tended to have higher survival rates. Thus, DAA after curative therapy for HCC can be expected to improve survival in patients with advanced HCC or decreased hepatic functional reserve. HCV should be aggressively eradicated in all patients eligible for curative treatment of HCC.

A validation study of after direct-acting antivirals recommendation for surveillance score for the development of hepatocellular carcinoma in patients with hepatitis C virus infection who had received direct-acting antiviral therapy and achieved sustained virological response.

BACKGROUND AND AIM: The pathogenic process underlying the development of hepatocellular carcinoma (HCC) is not yet clear in patients with hepatitis C virus (HCV) who have received direct-acting antiviral (DAA) therapy and achieved sustained virological response (SVR). This study validated a composite predictive model for HCC in these patients. METHODS: This study included 3058 patients in whom HCV was eradicated with DAA therapy. After DAAs recommendation for surveillance (ADRES) score, which is based on sex, FIB-4 index, and α-fetoprotein, was used as a composite predictive model for HCC development. RESULTS: The 1-, 3-, and 5-year cumulative incidence rates of HCC were 0.9, 4.5, and 15.2%, respectively. Multivariate analysis with Cox proportional hazards models showed that male sex (hazard ratio [HR], 2.646; 95% confidence interval [CI], 1.790-3.911), FIB-4 index >3.25 (HR, 2.891; 95% CI, 1.947-4.293), and α-fetoprotein >5 ng/mL (HR, 2.835; 95% CI, 1.914-4.200) are independently associated with HCC development. The incidence of HCC differed significantly by ADRES score (P < 0.001). Cox proportional hazards models showed that compared to the ADRES score 0 group, the HR for HCC development was 2.947 (95% CI, 1.367-6.354) in the ADRES score 1 group, 9.171 (95% CI, 4.339-19.380) in the ADRES score 2 group, and 20.630 (95% CI, 8.641-49.230) in the ADRES score 3 group. ADRES score had superior predictive power for HCC development compared with the FIB-4 index and α-fetoprotein according to time-dependent receiver operating characteristic analysis. CONCLUSION: The ADRES score is useful for predicting HCC development after SVR.

Hepatocellular Carcinoma Risk Assessment for Patients With Advanced Fibrosis After Eradication of Hepatitis C Virus.

The identification of patients with advanced fibrosis who do not need any further hepatocellular carcinoma (HCC) surveillance after the eradication of hepatitis C is pivotal. In this study, we developed a simple serum-based risk model that could identify patients with low-risk HCC. This was a nationwide multicenter study involving 16 Hospitals in Japan. Patients with advanced fibrosis (1,325 in a derivation cohort and 508 in a validation cohort) who achieved sustained virological responses at 24 weeks after treatment (SVR24) were enrolled. The HCC risk model at any point after SVR24 and its change were evaluated, and subsequent HCC development was analyzed. Based on the multivariable analysis, patients fulfilling all of the factors (GAF4 criteria: gamma-glutamyl transferase < 28 IU/L, alpha-fetoprotein < 4.0 ng/mL, and Fibrosis-4 Index < 4.28) were classified as low-risk and others were classified as high-risk. When patients were stratified at the SVR24, and 1 year, and 2 years after SVR24, subsequent HCC development was significantly lower in low-risk patients (0.5-1.1 per 100 person-years in the derivation cohort and 0.9-1.1 per 100 person-years in the validation cohort) than in high-risk patients at each point. HCC risk from 1 year after SVR24 decreased in patients whose risk improved from high-risk to low-risk (HCC incidence: 0.6 per 100 person-years [hazard ratio (HR) = 0.163 in the derivation cohort] and 1.3 per 100 person-years [HR = 0.239 in the validation cohort]) than in those with sustained high risk. Conclusion: The HCC risk model based on simple serum markers at any point after SVR and its change can identify patients with advanced fibrosis who are at low HCC risk, and these patients may be able to reduce HCC surveillance.

The Real-World Data in Japanese Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib from a Nationwide Multicenter Study.

BACKGROUND: Lenvatinib (LEN) has been approved for patients with unresectable hepatocellular carcinoma (u-HCC) since March 2018 in Japan. We performed a retrospective nationwide multicenter study to clarify the clinical characteristics of LEN in real-world practice. METHODS: A total of 343 u-HCC patients who received LEN from March 2018 to May 2020 at 23 sites in Japan were registered. RESULTS: During the median observation period of 10.5 months, 143 patients died. In Child-Pugh A (n = 276) and Child-Pugh B (n = 67) patients, the median overall survival (OS) was 21.0 and 9.0 months. The median progression-free survival (PFS) was 8.8 months in Child-Pugh A patients. The objective response rate (ORR) and disease control rate (DCR) according to modified response evaluation criteria in solid tumors (RECIST criteria) were 42.1% and 82.1%. The independent pretreatment factors associated with mortality in all patients were AFP ≥ 400 ng/mL (hazard ratio (HR) 2.00, 95% confidential interval (95% CI) 1.08-2.09, p < 0.0001), modified albumin-bilirubin (ALBI) grade 2b or 3 (HR 1.56, 95% CI 1.09-2.17, p = 0.012), major vascular invasion (HR 1.91, 95% CI 1.26-2.89, p = 0.0022), PS > 0 (HR 1.50, 95% CI 1.09-2.08, p = 0.014), and MTT (molecular targeted therapy) experience (HR 2.22, 95% CI 1.56-3.13, p = 0.00038). In the MTT naïve patients with ALBI grade 1 or modified ALBI 2a and BCLC stage B (n = 68), median OS and PFS were 25.3 and 12.3 months. Liver-related adverse events during LEN were the only significant adverse event associated with OS (HR 2.74, 95% CI 1.93-3.88, p < 0.0001). Among the Child-Pugh A patients with extrahepatic metastasis and no major vascular invasion, median PFS in the patients with bone metastasis was significantly shorter than those with lung or adrenal grand metastasis (6.3 vs. 12.5 months, p = 0.0025). CONCLUSION: LEN showed a high response rate in real-world practice. Pretreatment factors, including ALBI score, AFP, and major vascular invasion are important in making a treatment strategy for patients with u-HCC. The patients with bone metastasis would be candidates for new therapeutic approaches.

Real-world clinical outcomes of sofosbuvir and velpatasvir treatment in HCV genotype 1- and 2-infected patients with decompensated cirrhosis: A nationwide multicenter study by the Japanese Red Cross Liver Study Group.

The real-world virological efficacy and safety of interferon-free direct-acting antiviral (DAA) therapy with sofosbuvir (SOF) and velpatasvir (VEL) were assessed in hepatitis C virus (HCV) genotype 1- and 2-infected patients with decompensated cirrhosis. A total of 65 patients with HCV-related decompensated cirrhosis (Child-Pugh score of 7 points or more) who were treated with the SOF/VEL regimen were enrolled. The sustained virological response (SVR) rate and safety profile were analyzed. SVR was defined as undetectable serum HCV RNA at 12 weeks after the end of treatment (SVR12). The percentages of patients with undetectable HCV RNA at 4, 8, and 12 weeks after the start of therapy were 81.2% (95% confidence interval [CI], 69.5-89.9) (52/64), 98.4% (95% CI, 91.2-100.0) (60/61), and 98.5% (95% CI, 91.7-100.0) (64/65), respectively. The overall SVR rate was 92.3% (95% CI, 83.0-97.5) (60/65). Albumin-bilirubin (ALBI) scores decreased during and after treatment (p < 0.001), and there were significant differences between baseline and end of treatment and between baseline and SVR12. Subgroup analyses showed no significant differences in SVR rates according to patient age, sex, HCV genotype (subtype), Child-Pugh classification, modified ALBI grade, presence of ascites, presence of hepatic coma, or history of hepatocellular carcinoma. In all subpopulations, the SVR rates were higher than 80%. There were no severe adverse events associated with the treatment. The SOF/VEL regimen showed good virological efficacy and acceptable safety even in patients with HCV-related decompensated cirrhosis.

Change in Fibrosis 4 Index as Predictor of High Risk of Incident Hepatocellular Carcinoma After Eradication of Hepatitis C Virus.

BACKGROUND: It is unclear whether the fibrosis 4 index (FIB-4), a marker of liver fibrosis, at baseline and change in FIB-4 after sustained virological response (SVR) is associated with incident hepatocellular carcinoma (HCC) risk. In this study, we examined the association of incident HCC risk with baseline FIB-4 and sustained high FIB-4 (>3.25) at any time point after SVR. METHODS: A total of 3823 patients who received direct-acting antiviral treatment and achieved SVR were enrolled. The FIB-4 was measured 24 weeks after the end of direct-acting antiviral treatment and achievement of SVR (SVR24), and 1, 2, and 3 years after SVR24, after which subsequent HCC development was investigated. RESULTS: In patients with an FIB-4 >3.25 at SVR24 and 1, 2, and 3 years after SVR24, subsequent HCC development was significantly higher than in those with an FIB-4 ≤3.25 at each point. The rates of HCC development 1, 2, 3, and 4 years after SVR24 were significantly higher in patients with sustained FIB-4 >3.25 than in those whose FIB-4 decreased to ≤3.25 (5.4%, 9.2%, 11.7%, and 16.0%, respectively, vs 2.2%, 3.1%, 3.7%, and 4.4%; P < .001). The adjusted hazard ratios (95% confidence intervals) for an FIB-4 >3.25 at SVR24 and 1, 2, and 3 years later were 3.38 (2.4-4.8), 2.95 (1.9-4.7), 2.62 (1.3-5.1), and 3.37 (1.4-9.8), respectively. CONCLUSIONS: The FIB-4 could be used to assess HCC development risk at any time after SVR, and changes in FIB-4 were associated with changes in the HCC development risk. Repeated assessments of FIB-4 could serve as a prognostic indicator of a high-risk HCC cohort that may require more intensive HCC surveillance strategy.

Prevalence of organic colonic lesions in patients meeting Rome III criteria for diagnosis of IBS: a prospective multi-center study utilizing colonoscopy.

BACKGROUND: It remains unknown whether the Rome III criteria can exclude organic colonic lesions prior to the diagnosis of irritable bowel syndrome (IBS). We evaluated the colonoscopy results of patients meeting the Rome III criteria for the diagnosis of IBS to determine the presence of organic colonic lesions. METHODS: This study was prospectively conducted at 17 centers in Japan. We enrolled 4528 patients who underwent diagnostic colonoscopy examinations. The diagnosis of IBS was evaluated by questionnaire results according to the Rome III criteria. RESULTS: We evaluated 4178 patients (350 were excluded because of incomplete data or previous colonic surgery), of whom 203 met the Rome III criteria (mean age 57.9 years; range 14-87 years) prior to the diagnostic colonoscopy examination. We identified organic colonic diseases in 21 of these 203 patients (10.3 %) , and these disease were also identified in 338 (8.5 %) of 3975 patients who did not fulfill the Rome III criteria. There were no differences in regard to the prevalence of organic colonic diseases between patients who did and did not fulfill the Rome III criteria. CONCLUSIONS: The prevalence of organic colonic diseases in patients who met the Rome III criteria was at an acceptably low level, indicating that the Rome III criteria are adequately specific for the diagnosis of IBS without performing a colonoscopy examination.

Anti-tumor effects of cimetidine on hepatocellular carcinomas in diethylnitrosamine-treated rats.

Cimetidine is known to have an anti-tumor effect on certain types of malignancies, though on hepatocellular carcinomas (HCCs), its effect remains unclear. We studied the anti-tumor effects of cimetidine on chemically-induced HCCs in rats. Four-week-old male Wistar rats (n=105) were divided into 4 groups. Those in groups A and B were administered diethylnitrosamine (DEN) intraperitoneally at 100 mg/kg body weight every week for 6 weeks, during which rats in group A were given tap water and those in group B received cimetidine (100 mg/kg/day) in their drinking water. Rats in groups C and D were administered saline instead of DEN and given tap water with 100 mg/kg/day of cimetidine, respectively. The animals were sacrificed at 7, 12, 22 and 32 weeks after the first administration of drugs and examined. Liver nodules were observed only in groups A and B, with the number of nodules, maximum diameter of the largest nodule, and liver weight significantly lower in group B. Immunohistochemistry findings showed that glutathione S-transferase placental-positive preneoplastic foci were significantly decreased in group B. Cimetidine treatment decreased the number of proliferating cell nuclear antigen-positive hepatocytes and tended to enhance natural killer (NK) cell activity in splenic lymphocytes. In addition, flow cytometry revealed that the proportion of NK cells among total splenic lymphocytes was not affected by cimetidine treatment. Our results showed that cimetidine has an inhibiting effect on hepatocarcinogenesis.

A Japanese case of eosinophilic esophagitis.

Eosinophilic esophagitis (EE) is a rarely diagnosed condition involving eosinophilic infiltration of the esophageal mucosa. Here we present a case of EE in a 69-year-old Japanese man, who presented with abdominal pain, appetite loss, and a history of bronchial asthma. Laboratory findings included peripheral eosinophilia and an increased serum immunoglobulin E level. Computed tomography showed diffuse severe thickening of the esophageal wall, and a barium esophagogram revealed a small caliber of the middle and lower portion of the esophagus, without normal peristaltic contractions. Endoscopy of the esophagus showed a pale mucosa, with adherent whitish exudates resembling fungal infection, and prominent ring-like contractions. Histologic examination of a biopsy specimen revealed marked eosinophil infiltration into the esophageal mucosa. Endoscopic ultrasonography (EUS) demonstrated marked circumferential thickening of the esophageal submucosal layer, and an esophageal manometry study showed a high percentage of ineffective esophageal peristalsis and high-amplitude esophageal body contractions. EUS findings showed no change even after oral corticosteroid therapy, although the histological findings were improved. This is thought to be the first documented Japanese case of EE. EE should be considered in the differential diagnosis in cases of esophageal motility disturbance, even if the patients do not complain of dysphagia.

Quantitative measurement of hepatitis B virus DNA in different areas of hepatic lobules in patients with chronic hepatitis B.

Liver histology in chronic hepatitis B is marked by inflammatory infiltration involving the peripheral zones. The cause of such cellular infiltration remains unknown. The aim of the present study was to investigate the amounts of intrahepatic hepatitis B virus (HBV) DNA separately in the peripheral and central zones, using laser capture microdissection coupled with real-time quantitative polymerase chain reaction. Fourteen patients with chronic hepatitis B were included in the study. Liver biopsy samples were taken and hepatocytes were microdissected separately from peripheral and central zones. DNA was extracted from hepatocytes in each zone and evaluated the amounts of HBV-DNA. Immunohistochemical study for hepatitis B core antigen (HBcAg) was also performed. The amounts of total intrahepatic HBV-DNA in patients positive for hepatitis Be antigen (HBeAg) were greater than those in HBeAg-negative patients. There was no difference in HBV-DNA between the peripheral and central zones. Immunohistochemistry also showed that HBcAg-positive cells were distributed homogeneously in the hepatic lobules. In patients with peripherally predominant HBV-DNA, the serum alanine aminotransferase (ALT) level was lower than in patients with centrally predominant HBV-DNA. HBV-DNA was distributed homogeneously in the hepatic lobules. In patients with lower amounts of HBV-DNA in the peripheral zone, the serum ALT level tended to be higher than in other patients.