Changes in ALBI Score and PIVKA-II within Three Months after Commencing Atezolizumab Plus Bevacizumab Treatment Affect Overall Survival in Patients with Unresectable Hepatocellular Carcinoma.

In this study, we aimed to evaluate the efficacy and safety of atezolizumab plus bevacizumab (Atez/Bev) treatment for unresectable hepatocellular carcinoma (HCC) and to analyze the factors affecting overall survival (OS). A total of 69 patients who received Atez/Bev at our institutions for unresectable HCC were enrolled in this study. OS and progression-free survival (PFS) were estimated using the Kaplan−Meier method. Changes in clinical indicators within 3 months were defined as delta (∆) values, and the Cox proportional hazards model was used to identify which ∆ values affected OS. The median OS, PFS, objective response rate, and disease control rate were 12.5 months, 5.4 months, 23.8%, and 71.4%, respectively. During the observational period, 62 patients (92.5%) experienced AEs (hypertension (33.3%) and general fatigue), and 27 patients (47.4%) experienced grade ≥ 3 AEs (hypertension (10.1%) and anemia (7.2%)). There was a significant deterioration in the albumin-bilirubin (ALBI) score (−2.22 to −1.97; p < 0.001), and a reduction in PIVKA-II levels (32,458 to 11,584 mAU/mL; p = 0.040) within 3 months after commencing Atez/Bev. Both the worsening ∆ ALBI score (p = 0.005) and increasing ∆ PIVKA-II (p = 0.049) were significantly associated with the OS of patients.

Effects of Rifaximin on Circulating Albumin Structures and Serum Ammonia Levels in Patients with Liver Cirrhosis: A Preliminary Study.

Circulating albumin structures, including their oxidized and reduced forms, are involved in hepatic encephalopathy (HE) development. However, the effects of rifaximin, a key drug in HE treatment, on the circulating albumin structure in patients with liver cirrhosis remain unclear. In this multicenter prospective study, eight patients with hyperammonemia (≥80 µg/dL) were enrolled. The circulating albumin structure was evaluated using the ratio of oxidized albumin (human nonmercaptalbumin, HNA). Patients were administered 400 mg rifaximin 3 times/day for 3 months, and laboratory data were assessed at baseline and during observation. Among the eight patients, three were men; the median age and body mass index were 70 years and 26.4 kg/m2, respectively. The median HNA and serum ammonia levels at baseline were 41% and 143 µg/dL, respectively. After rifaximin therapy, HNA showed a decreasing tendency (median; from 41% to 36%, p = 0.321), but serum albumin levels showed no significant change (from 3.5 g/dL to 3.5 g/dL, p = 1.00); serum ammonia levels significantly reduced (median: 143 µg/dL to 76 µg/dL, p = 0.015). Thus, rifaximin reduces serum ammonia levels and may improve circulating albumin structure in patients with cirrhosis. Further large-scale studies are required to confirm these preliminary results.

A Case of Early-Stage Gallbladder Cancer, Positive for ALDH1A1, Which Arose from Adenomyomatosis of the Gallbladder.

Adenomyomatosis (ADM) of the gallbladder is a condition characterized by the proliferation of Rokitansky-Aschoff sinus (RAS), in which the epithelium of the gallbladder extends into the muscular layer, causing a thickening of the gallbladder wall. Although ADM is generally considered not to be a precancerous lesion of gallbladder cancer, there are some reports of cases of gallbladder cancer from ADM. Therefore, the relationship between ADM and gallbladder cancer remains controversial. We herein report a case of early-stage gallbladder cancer, BilIN3 (high grade), arising from ADM that was positive for ALDH1A1, an important marker of stem cells and cancer stem cells.

No increased risk of hepatocellular carcinoma after eradication of hepatitis C virus by direct-acting antivirals, compared with interferon-based therapy.

It is well-known that sustained virological response (SVR) by interferon (IFN)-based therapy against hepatitis C virus (HCV) infection reduced the incidence of hepatocellular carcinoma (HCC). However, whether IFN-free direct-acting antivirals reduce the risk of HCC is controversial. Therefore, this study aims to compare the incidence of HCC after the achievement of SVR between sofosbuvir combined with ledipasvir (SOF/LDV) and simeprevir with pegylated interferon plus ribavirin (Sim+IFN). Japanese patients with HCV infection (genotype 1) who achieved SVR between January 2013 and December 2014 by SOF/LDV (NCT01975675, n = 320) or Sim+IFN (000015933, n = 289) therapy in two nationwide, multicenter, phase III studies were prospectively monitored for the development of HCC by ultrasonography for 5 years after the end of treatment (EOT). No HCC was detected before the treatment. HCC was detected in 9 and 7 patients in the SOF/LDV and the Sim+IFN group in 5 years, respectively. The cumulative incidences of HCC rates 1, 3, and 5 years after EOT were similar between the two groups (1.5%, 2.7%, and 3.2% for the SOF/LDV and 1.8%, 2.8%, and 3.0% for the Sim+IFN group, respectively). No HCC was developed 3.5 years after EOT. Interestingly, a retrospective careful review of imaging taken before therapy revealed hepatic nodules in 50% of HCC patients, suggesting HCC was pre-existed before therapy. In conclusion, we could not find any differences in the incidence of HCC after the HCV eradication between the two therapeutic regimens, suggesting no enhancement of HCC development by DAA.

Combined Use of Calcium-channel Blockers With Ombitasvir/Paritaprevir/Ritonavir Exacerbates Peripheral Edema in Elderly Japanese Patients.

BACKGROUND/AIM: The antiviral agent ritonavir is a substrate for cytochrome P450 3A4 (CYP3A4); therefore, concomitant use of CYP3A4-metabolising drugs might cause adverse reactions to this drug. We investigated the plasma level of calcium channel blockers (CCBs) as CYP3A4 substrates and peripheral edema as a potential adverse drug reaction possibly caused by the anti-hepatitis C virus (HCV) regimen of ombitasvir/paritaprevir/ritonavir (OPR) and CCBs. PATIENTS AND METHODS: We enrolled Japanese patients prescribed OPR for HCV infection. Peripheral edema was graded according to the Common Terminology Criteria for Adverse Events ver. 4. Plasma samples were collected on days 0, 7, 14, 28, and 42 after antiviral treatment, at the trough level. RESULTS: Out of 52 patients, 64% experienced grade 1 or grade 2 peripheral edema, but not grade 3. Concomitant use of CCBs significantly increased the emergence of grade 2 edema (62%), compared with patients treated solely with OPR (48%). The use of OPR significantly increased the plasma concentration of amlodipine. CONCLUSION: Peripheral edema in patients treated with OPR and CCBs, although tolerable, should be closely monitored.

Common Drug Pipelines for the Treatment of Diabetic Nephropathy and Hepatopathy: Can We Kill Two Birds with One Stone?

Type 2 diabetes (T2D) is associated with diabetic nephropathy as well as nonalcoholic steatohepatitis (NASH), which can be called "diabetic hepatopathy or diabetic liver disease". NASH, a severe form of nonalcoholic fatty disease (NAFLD), can sometimes progress to cirrhosis, hepatocellular carcinoma and hepatic failure. T2D patients are at higher risk for liver-related mortality compared with the nondiabetic population. NAFLD is closely associated with chronic kidney disease (CKD) or diabetic nephropathy according to cross-sectional and longitudinal studies. Simultaneous kidney liver transplantation (SKLT) is dramatically increasing in the United States, because NASH-related cirrhosis often complicates end-stage renal disease. Growing evidence suggests that NAFLD and CKD share common pathogenetic mechanisms and potential therapeutic targets. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and diabetic nephropathy/CKD. There are no approved therapies for NASH, but a variety of drug pipelines are now under development. Several agents of them can also ameliorate diabetic nephropathy/CKD, including peroxisome proliferator-activated receptors agonists, apoptosis signaling kinase 1 inhibitor, nuclear factor-erythroid-2-related factor 2 activator, C-C chemokine receptor types 2/5 antagonist and nonsteroidal mineral corticoid receptor antagonist. This review focuses on common drug pipelines in the treatment of diabetic nephropathy and hepatopathy.

Hepatitis E virus subtype 3f strains isolated from Japanese hepatitis patients with no history of travel to endemic areas - The origin analyzed by molecular evolution.

Hepatitis E virus subtype 3f (HEV-3f) strains are usually isolated in Europe and Thailand. Recently, HEV-3f strains were detected from six acute hepatitis E patients in Japan, none of whom had a history of travel to endemic areas. We inferred the origin and transmission route of the six HEV-3f strains. A time-scaled phylogenetic tree of the six strains with reference strains was constructed using a Bayesian statistical inference framework. The time-scaled tree indicated that the six strains independently derived from similar European strains between 2008 and 2014. The pattern suggested recent inflow of multiple HEV-3f strains from Europe to Japan. Japan imports a substantial amount of pork from European countries every year. The emergence of acute hepatitis cases caused by HEV-3f strains in Japan, in patients with no history of travel abroad, might be influenced by the increased opportunities to consume pork products imported from European countries.

The advantage of iron-containing fiducial markers placed with a thin needle for radiotherapy of liver cancer in terms of visualization on MRI: an initial experience of Gold Anchor.

Radiotherapy for liver malignancy is increasing due to advances in radiotherapy technique. Visualization of the tumor as well as fiducial markers is essential. To see if improved visibility exists on computed tomography (CT) and magnetic resonance imaging (MRI), we evaluated an iron-containing fiducial marker. A patient with hepatocellular carcinoma and a patient with cholangiocarcinoma were enrolled. Pain caused by placement of marker and the best MRI sequence for visualization of both the fiducial marker as well as the liver tumor on MRI was evaluated. CT was obtained in 2.5-mm thickness, and MRIs were obtained in eight sequences (ie, T2-weighted image). 22G preloaded needles were used for marker placement in both patients; this caused little pain during placement under local anesthesia with xylocaine. No complication occurred in either patient. Both markers and tumors were well visualized by the same MRI sequence. The iron-containing fiducial marker is safe and useful for detecting fiducial markers in the liver and for registration using CT and MRI.

Investigating the origin and global dispersal history of hepatitis E virus genotype 4 using phylogeographical analysis.

BACKGROUND & AIMS: Hepatitis E virus (HEV) genotype 4 has mainly been isolated from sporadic hepatitis cases and swine in Asian countries. We analysed the origin and global dispersal history of genotype 4 using a Bayesian phylogeographical approach. METHODS: The 412-nucleotide sequences of open reading frame 2 of genotype 4 (47 Japanese, 40 Chinese, 1 Indian, 8 Indonesian, 1 Korean, 1 Taiwanese, 2 Danish and 2 Italian), of which sampling date and location were known, were collected. Evolutionary rate, divergence time, demographic growth and phylogeography were co-estimated in the Bayesian statistical inference framework implemented in the BEAST package to model spatial dispersal on a time-scaled genealogy. RESULTS: The most probable origin of genotype 4 was Japan and the time of origin was 1909 (95% highest posterior density, 1871-1940). Seven lineages of genotype 4 migrated from Japan to China. The analysis also showed the migration of genotype 4 from Japan or China to India and Indonesia and from China to Indonesia, Taiwan, Korea and a few European countries. CONCLUSIONS: Swine trade between countries coincided with the migration time and direction of genotype 4 in some cases and was considered the primary cause of dispersal. However, there was no clear cause of dispersal for some cases, for which no records of pig trade were found. Future research should analyse additional nucleotide sequences paired with epidemiological data from various countries to improve our understanding of HEV dispersal.

Usefulness of early vascular phase images from contrast-enhanced ultrasonography using Sonazoid for the diagnosis of hypovascular hepatocellular carcinoma.

AIM: This study aimed to evaluate the usefulness of early vascular phase images produced by contrast-enhanced ultrasonography (CE-US) with Sonazoid for the diagnosis of hypovascular hepatocellular carcinoma (HCC). METHODS: Four hundred and seventeen patients with 674 hepatic nodules were evaluated using CE-US with Sonazoid between January 2007 and March 2010. Retrospective analysis was conducted on 49 histologically confirmed nodules showing hypovascularity relative to the surrounding liver tissue in the early vascular phase and no enhancement defect in the Kupffer phase of CE-US with Sonazoid. These nodules were classified according to early vascular phase image enhancement patterns as types I (largest avascular; avascular as a whole), II (second avascular; partially avascular), III (smallest avascular; not avascular, but faintly hypovascular relative to the surrounding liver) and IV (hypovascular as a whole with vessel-like structures passing inside nodules). RESULTS: Among the 49 nodules, types I, II, III and IV were identified in 19 (38.8%), nine (18.4%), 15 (30.6%) and six (12.2%) cases, respectively. The proportion of tumorous nodules (well-differentiated HCC and high-grade dysplastic nodules) significantly decreased with a reduction of the avascular area (68.4% in the type I, 55.6% in the type II and 33.3% in the type III nodules; P < 0.05). All nodules demonstrating the type IV enhancement pattern were non-tumorous. CONCLUSION: Based on the size of avascular area in the early vascular phase of CE-US with Sonazoid, we can predict the malignant potential of the nodules. CE-US with Sonazoid is very useful for evaluation of hypovascular hepatic nodules.

Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial.

BACKGROUND: Compared with other countries, patients with chronic hepatitis C infection in Japan tend to be older, have more advanced liver disease, and are more likely to have been previously treated for hepatitis C. We aimed to assess the efficacy and safety of an all-oral, fixed-dose combination of the hepatitis C virus NS5A inhibitor ledipasvir and the NS5B nucleotide polymerase inhibitor sofosbuvir with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with chronic genotype 1 hepatitis C virus infection. METHODS: In this randomised, open-label study, we enrolled patients from 19 clinical Japanese centres. Patients were randomly assigned (1:1) to receive either ledipasvir (90 mg) and sofosbuvir (400 mg) or ledipasvir, sofosbuvir, and ribavirin (dosed according to the Japanese Copegus product label-ie, patients ≤60 kg received 600 mg daily, patients >60 kg to ≤80 kg received 800 mg daily, and patients >80 kg received 1000 mg daily) orally once daily for 12 weeks. After completion or early discontinuation of treatment, patients were followed up off-treatment for 24 weeks. Eligible patients were at least 20 years of age with chronic genotype 1 hepatitis C virus infection with serum hepatitis C virus RNA concentrations of at least 5 log10 IU/mL, creatinine clearance of at least 1·0 mL/s, and a platelet count of at least 50 × 10(9) per L. An interactive web response system was used to manage patient randomisation and treatment assignment. Randomisation was stratified by the presence or absence of cirrhosis for treatment-naive patients and stratified by presence or absence of cirrhosis and by previous treatment category (relapser or breakthrough, non-responder, or interferon-intolerant) for previously treated patients. Within each strata, patients were sequentially assigned to either treatment with ledipasvir-sofosbuvir or ledipasvir-sofosbuvir plus ribavirin in a 1:1 ratio with block size of 4. The primary endpoint was sustained virological response 12 weeks after completion of treatment (SVR12) assessed in all patients who were randomly assigned and received at least one dose of study drug; safety outcomes were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01975675. FINDINGS: Between Oct 15, 2013 and Dec 13, 2013, 341 patients were randomly assigned to treatment groups and received at least one dose of study treatment. SVR12 was achieved in all 171 (100%) patients (83 of 83 treatment naive and 88 of 88 treatment experienced) receiving ledipasvir-sofosbuvir (95% CI 98-100) and 167 (98%) of 170 patients (80 of 83 treatment naive and 87 of 87 treatment experienced) receiving ledipasvir-sofosbuvir plus ribavirin (95% CI 95-100). Of the 76 patients with baseline NS5A resistant variants, 75 (99%) achieved SVR12. Two (1·2%) of 170 patients in the ledipasvir-sofosbuvir plus ribavirin group discontinued treatment because of adverse events. The most common adverse events were nasopharyngitis (50 [29·2%] of 171), headache (12 [7·0%] of 171), and malaise (nine [5·3%] of 171) in patients receiving ledipasvir-sofosbuvir; and nasopharyngitis (40 [23·5%] of 170), anaemia (23 [13·5%] of 170), and headache in those receiving ledipasvir-sofosbuvir and ribavirin (15 [8·8%] of 170). INTERPRETATION: Although existing regimens for the treatment of hepatitis C virus are effective for many patients, medical needs remain unmet, particularly in Japan where the population with hepatitis C virus genotype 1 is generally older and treatment-experienced, with advanced liver disease. The efficacy, tolerability, and absence of drug-drug interactions of ledipasvir-sofosbuvir suggest that it could be an important option for treatment of genotype 1 hepatitis C virus in Japanese patients. FUNDING: Gilead Sciences.

Survey of survival among patients with hepatitis C virus-related hepatocellular carcinoma treated with peretinoin, an acyclic retinoid, after the completion of a randomized, placebo-controlled trial.

BACKGROUND: This study examined the effects of peretinoin, an acyclic retinoid, on the survival of patients with hepatitis C virus-related hepatocellular carcinoma (HCC) who had completed curative therapy and participated in a randomized, placebo-controlled trial. METHODS: This study was an investigator-initiated retrospective cohort study. Subjects were all patients who were administered the investigational drug (peretinoin 600 mg/day, peretinoin 300 mg/day, or placebo) in the randomized trial. Survivals between the groups were compared using the log-rank test, and hazard ratios were estimated by Cox regression. RESULTS: Survey data were collected from all patients (n = 392) who participated in the randomized trial, all of whom were then divided into the peretinoin 600 mg/day (n = 132), peretinoin 300 mg/day (n = 131), and placebo (n = 129) groups. At the median follow-up of 4.9 years, 5-year cumulative survival rates for patients in the 600 mg/day, 300 mg/day, and placebo groups were 73.9, 56.8, and 64.3 %, respectively. Comparison of overall survival among patients classified as Child-Pugh A revealed that survival of the 600 mg/day group (n = 105) was significantly longer than that of the placebo group (n = 108) (hazard ratio 0.575, 95 % CI 0.341-0.967; P = 0.0347). CONCLUSIONS: Administration of 600 mg/day peretinoin to patients with hepatitis C virus-related HCC who have completed curative therapy may improve survival for those classified as Child-Pugh A, for whom liver function is relatively stable.

Peretinoin after curative therapy of hepatitis C-related hepatocellular carcinoma: a randomized double-blind placebo-controlled study.

BACKGROUND: Effective prophylactic therapies have not been established for hepatocellular carcinoma recurrence. Peretinoin represents one novel option for patients with hepatitis C virus-related hepatocellular carcinoma (HCV-HCC), and it was tested in a multicenter, randomized, double-blind, placebo-controlled study. METHODS: Patients with curative therapy were assigned to one of the following regimens: peretinoin 600, 300 mg/day, or placebo for up to 96 weeks. The primary outcome was recurrence-free survival (RFS). RESULTS: Of the 401 patients initially enrolled, 377 patients were analyzed for efficacy. The RFS rates in the 600-mg group, the 300-mg group, and the placebo group were 71.9, 63.6, and 66.0 % at 1 year, and 43.7, 24.9, and 29.3 % at 3 years, respectively. The primary comparison of peretinoin (300 and 600-mg) with placebo was not significant (P = 0.434). The dose-response relationship based on the hypothesis that "efficacy begins to increase at 600 mg/day" was significant (P = 0.023, multiplicity-adjusted P = 0.048). The hazard ratios for RFS in the 600-mg group vs. the placebo group were 0.73 [95 % confidence interval (CI) 0.51-1.03] for the entire study period and 0.27 (95 % CI 0.07-0.96) after 2 years of the randomization. Common adverse events included ascites, increased blood pressure, headache, presence of urine albumin, and increased transaminases. CONCLUSIONS: Although the superiority of peretinoin to placebo could not be validated, 600 mg/day was shown to be the optimal dose, and treatment may possibly reduce the recurrence of HCV-HCC, particularly after 2 years. The efficacy and safety of peretinoin 600 mg/day should continue to be evaluated in further studies.

Efficacy and safety of cisplatin versus miriplatin in transcatheter arterial chemoembolization and transarterial infusion chemotherapy for hepatocellular carcinoma: A randomized controlled trial.

AIM: Transcatheter arterial chemoembolization (TACE) and transarterial infusion chemotherapy (TAI) are the main therapeutic strategies for treatment of advanced hepatocellular carcinoma (HCC). We conducted a randomized controlled trial to compare the efficacy and safety of cisplatin and miriplatin in TACE and TAI. METHODS: Patients with HCC of indication for TACE or TAI were randomly assigned to receive either cisplatin or miriplatin (49 patients per group) between April 2010 and May 2013. The primary end-point was the therapeutic effect (TE) 3 months after initial treatment, and the secondary end-point was overall survival. RESULTS: TE could be evaluated in 26 patients of the cisplatin group and 20 patients of the miriplatin group. In the cisplatin group, 11 (42.3%) and 15 (57.7%) patients were classified as showing TE3 + 4 and TE1 + 2, respectively, while in the miriplatin group, each number was nine (45.0%) and 11 (55.0%) (P = 0.8551). Furthermore, no significant difference in overall survival was found between two groups for all patients (P = 0.905) or those treated only with TAI (10 in the cisplatin group and eight in the miriplatin group; P = 0.695). TE3 + 4 group showed better overall survival than TE1 + 2 group (P = 0.0263). Grade 4 or higher adverse event did not occur in either group. Creatinine levels in the cisplatin group rose 3 days after TACE or TAI (P = 0.0397). CONCLUSION: Cisplatin and miriplatin had equal efficacy for TACE and TAI, but cisplatin should be avoided for patients with renal dysfunction or inadequate hydration. Good TE improved overall survival.

Usefulness of contrast-enhanced ultrasonography using Sonazoid for the assessment of therapeutic response to percutaneous radiofrequency ablation for hepatocellular carcinoma.

AIM: Accurate assessment of the coagulated area is imperative to achieve an excellent outcome from percutaneous radiofrequency ablation (PRFA) for the treatment of hepatocellular carcinoma (HCC). We evaluated the efficacy of contrast-enhanced ultrasonography (CEUS) with the contrast-enhancing agent Sonazoid for precisely assessing the therapeutic effect of PRFA for HCC. METHODS: We enrolled 87 consecutive patients with solitary naïve HCC of less than 3 cm in diameter. PRFA treatment was performed with a 17-G cool-tip needle, and CEUS was performed to assess the ablative margin 3 h after the procedure, when the coagulated tumor outline was easiest to discern. The treatment was repeated until an ablative margin greater than 5 mm was confirmed. After CEUS assessment of the therapeutic response, the patients were followed to investigate local tumor recurrence. RESULTS: In 78 patients (89.7%), the outline of the coagulated tumors could be recognized by ultrasonography, and CEUS assessment of the ablative margin was successful. The remaining nine patients were assessed by computed tomography. The 5-year cumulative survival rate after the assessment of the treatment response with CEUS was 58.4%, and the 4-year cumulative total recurrence rate was 72.3%. The 5-year cumulative local tumor recurrence rate was very low (2.3%). CONCLUSION: The assessment with CEUS at 3 h after the PRFA procedure was successful in the majority of the patients, and it yielded a very low rate of local recurrence.

Sofosbuvir plus ribavirin in Japanese patients with chronic genotype 2 HCV infection: an open-label, phase 3 trial.

Genotype 2 hepatitis C virus (HCV) accounts for up to 30% of chronic HCV infections in Japan. The standard of care for patients with genotype 2 HCV - peginterferon and ribavirin for 24 weeks - is poorly tolerated, especially among older patients and those with advanced liver disease. We conducted a phase 3, open-label study to assess the efficacy and safety of an all-oral combination of the NS5B polymerase inhibitor sofosbuvir and ribavirin in patients with chronic genotype 2 HCV infection in Japan. We enrolled 90 treatment-naïve and 63 previously treated patients at 20 sites in Japan. All patients received sofosbuvir 400 mg plus ribavirin (weight-based dosing) for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after therapy (SVR12). Of the 153 patients enrolled and treated, 60% had HCV genotype 2a, 11% had cirrhosis, and 22% were over the aged 65 or older. Overall, 148 patients (97%) achieved SVR12. Of the 90 treatment-naïve patients, 88 (98%) achieved SVR12, and of the 63 previously treated patients, 60 (95%) achieved SVR12. The rate of SVR12 was 94% in patients with cirrhosis and in those aged 65 and older. No patients discontinued study treatment due to adverse events. The most common adverse events were nasopharyngitis, anaemia and headache. Twelve weeks of sofosbuvir and ribavirin resulted in high rates of SVR12 in treatment-naïve and previously treated patients with chronic genotype 2 HCV infection. The treatment was safe and well tolerated by patients, including the elderly and those with cirrhosis.

Effects of pioglitazone on nonalcoholic steatohepatitis in a patient with anorexia nervosa: A case report.

Diseases associated with metabolic syndromes are of major concern in developed countries. Nonalcoholic steatohepatitis (NASH) is one of the manifestations of metabolic syndrome in the liver. Previous studies have shown that NASH is also caused by malnutrition. In the present study, a case of malnutrition-associated NASH in a 66-year-old female with anorexia nervosa is reported. The patient had a body mass index (BMI) of only 11.1 kg/m2 and serum alanine aminotransferase levels of 1,495 IU/l. Steatohepatitis with fibrosis was confirmed by percutaneous liver needle biopsy. Total parenteral nutrition was conducted at first, followed by the administration of Stronger Neo-Minophagen C (a glycyrrhizin-containing preparation), ursodeoxycholic acid and prednisolone. The abnormal elevation of aminotransferase levels of the patient was prolonged and total bilirubin levels increased. Pioglitazone (15 mg/day), which has been identified to be effective for nonalcoholic steatohepatitis, was then administered. This resulted in marked reductions in aminotransferase and bilirubin levels within three months. Histological improvement of the liver was also confirmed by percutaneous liver needle biopsy after one year. The observations in the present case suggest that pioglitazone may be useful for the treatment of malnutrition-associated NASH.

Hepatocellular carcinoma patients with increased oxidative stress levels are prone to recurrence after curative treatment: a prospective case series study using the d-ROM test.

PURPOSE: Oxidative stress plays an important role in liver carcinogenesis. To determine the impact of oxidative stress on the recurrence of stage I/II hepatocellular carcinoma (HCC) after curative treatment, we conducted a prospective case series analysis. METHODS: This study included 45 consecutive patients with stage I/II HCC, who underwent curative treatment by surgical resection or radiofrequency ablation at Gifu Municipal Hospital from 2006 to 2007. In these 45 cases, recurrence-free survival was estimated using the Kaplan-Meier method. The factors contributing to HCC recurrence, including the serum levels of derivatives of reactive oxygen metabolites (d-ROM) as an index of oxidative stress, were subjected to univariate and multivariate analyses using the Cox proportional hazards model. RESULTS: The serum levels of d-ROM (P = 0.0231), α-fetoprotein (AFP, P = 0.0274), and fasting plasma glucose (P = 0.0400) were significantly associated with HCC recurrence in the univariate analysis. Multivariate analysis showed that the serum levels of d-ROM (hazard ratio [HR] 1.0038, 95 % confidence interval [CI] 1.0002-1.0071, P = 0.0392) and AFP (HR 1.0002, 95 % CI 1.0000-1.0003, P = 0.0316) were independent predictors of HCC recurrence. Kaplan-Meier analysis showed that recurrence-free survival was low in patients with high serum d-ROM (≥570 Carr U, P = 0.0036) and serum AFP (≥40 ng/dL, P = 0.0185) levels. CONCLUSIONS: The serum levels of d-ROM and AFP can be used for screening patients with a high risk for HCC recurrence. Patients who show increased levels of these factors require careful surveillance.

Insulin resistance raises the risk for recurrence of stage I hepatocellular carcinoma after curative radiofrequency ablation in hepatitis C virus-positive patients: A prospective, case series study.

AIM: Several studies have reported that insulin resistance raises the risk of primary hepatocellular carcinoma (HCC). We conducted a prospective, case series study to test the impact of insulin resistance on the recurrence after curative radiofrequency ablation (RFA) of stage I HCC in HCV-positive patients. METHODS: From January 2006 to December 2007, 226 consecutive patients underwent treatment for primary HCC at our institutions, including 37 stage I cases. Among them, 33 were HCV-positive, and three, six and 24 received curative surgery, transarterial chemoembolization or RFA, respectively. In the 24 patients treated with RFA, recurrence-free survival was analyzed using the Kaplan-Meier method. The factors contributing to recurrence of HCC were subjected to univariate and multivariate analyses using the Cox proportional hazards model. Insulin resistance was estimated by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). RESULTS: Kaplan-Meier analysis showed that the recurrence-free survival was lower in patients with higher HOMA-IR (>2.3, P = 0.0252) or with lower serum albumin level (<3.3 g/dL, P = 0.0004). In the univariate analysis, HOMA-IR (P = 0.0420) and albumin (P = 0.0036) were significantly associated with recurrence of HCC. Multivariate analysis revealed albumin (odds ratio = 0.01, 95% confidence interval = 0.0002-0.015, P = 0.0001) and HOMA-IR (odds ratio = 3.85, 95% confidence interval = 1.57-14.2, P = 0.0015) to be independent predictors for recurrence of HCC. CONCLUSION: Serum albumin level and HOMA-IR were independent risk factors for recurrence of stage I HCC after curative RFA in HCV-positive patients. Patients with these factors require closer surveillance.

A patient with small-cell carcinoma of the stomach with long survival after percutaneous microwave coagulating therapy (PMCT) for liver metastasis.

A 66-year-old man was admitted to our hospital with epigastralgia. Preoperative examinations revealed an 8.0 x 8.0-cm, Borrmann type 2 tumor in the posterior wall of the cardia, without distant metastases. Total gastrectomy with pancreato-splenectomy and regional lymph node dissection was performed curatively. Histologically, the tumor was composed mainly of small cells with hyperchromatic nuclei and scant cytoplasm, which showed positive staining for Grimelius, gamma-neuron-specific enolase (gamma-NSE), chromogranin A, and serotonin. About 10 months after the operation, a solitary tumor was revealed in S8 of the liver by abdominal computed tomography (CT), and it was histologically confirmed by needle biopsy to be a metastasis of the small-cell carcinoma from the stomach. Instead of hepatectomy, percutaneous microwave coagulating therapy (PMCT) was indicated, because of the patients' liver dysfunction (ICG R15, 39.9%); CT showed complete necrosis of the metastatic focus in the liver after the PMCT. Now, 33 months after the first detection of the liver metastasis (43 months after the gastrectomy), the patient is still alive without any growth of the liver metastasis. The 67 previously reported cases of small-cell carcinoma of the stomach in Japan, including ours, are also reviewed.