Early Changes in Alpha-Fetoprotein Are a Useful Predictor of Efficacy of Atezolizumab plus Bevacizumab Treatment in Patients with Advanced Hepatocellular Carcinoma.

INTRODUCTION: The aim of this study was to investigate the early changes in alpha-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) levels in patients with advanced hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab and to evaluate the relationship between changes in these tumor markers and treatment efficacy. METHODS: Of 58 consecutive patients who started atezolizumab plus bevacizumab at our institution, 50 patients with information on antitumor response obtained at 6 weeks after therapy were enrolled in this study and their treatment outcomes were retrospectively evaluated. RESULTS: According to the Response Evaluation Criteria in Solid Tumors at 6 weeks, the objective response (OR) rate was 22.0% and the disease control (DC) rate was 78.0%. In patients who achieved OR at 6 weeks, median AFP and DCP ratios at weeks 1, 2, 3, and 6 were significantly lower than those in patients who did not achieve OR. AFP ratios in patients who did not achieve DC at 6 weeks (Non-6W-DC group) were significantly higher than in those who achieved DC at week 6 (6W-DC group). Median overall survival in the Non-6W-DC group was significantly shorter than in the 6W-DC group (156 days vs. not reached, p = 0.0008). An AFP ratio of 1.4 or higher at 3 weeks had a specificity of 88.0% and a sensitivity of 88.9% for predicting Non-6W-DC. Median progression-free survival was significantly shorter in patients with an AFP ratio of 1.4 or higher at 3 weeks than in those with an AFP ratio of <1.4 (42 days vs. 210 days, p = 0.0003). CONCLUSION: Early changes in AFP might be useful for predicting the antitumor efficacy of atezolizumab plus bevacizumab in patients with advanced HCC. An AFP ratio of 1.4 or higher at 3 weeks might be an early predictor of refractoriness to atezolizumab plus bevacizumab therapy.

Probe-based confocal laser endomicroscopy for the diagnosis of pancreatic ductal structures.

BACKGROUND AND AIM: The image-based diagnosis of pancreatic diseases can be difficult and requires pathological evaluation. Probe-based confocal laser endomicroscopy (pCLE) enables real-time observation of the microscopic tissue pattern of lesion and may be a useful assistance for the diagnosis. This study aimed to evaluate the feasibility and utility of pCLE for the diagnosis of pancreatic diseases. METHODS: Thirty patients who underwent endoscopic retrograde cholangiopancreatography with pCLE for the evaluation of indeterminate pancreatic diseases from June 2015 to October 2018 were included in this study. The pCLE findings were interpreted according to the Miami Classification. RESULTS: Among a total of 30 patients, 12, 10, 4, and 4 patients received the definitive diagnoses of pancreatic ductal adenocarcinoma (PDAC), main duct intrapapillary mucinous neoplasm, autoimmune pancreatitis, and chronic pancreatitis, respectively. The diagnostic accuracy of pCLE for PDAC and pancreatitis (96.7% and 93.3%, respectively) was higher than that of cytology (76.7% and 63.3%, respectively) (P = 0.0227 and 0.0048, respectively). The sensitivity of pCLE for PDAC was significantly higher (91.7%) than that of cytology (41.7%) (P = 0.0094). Moreover, the specificity of pCLE for pancreatitis was significantly higher than that of cytology (90.9% vs 50%; P = 0.0029). However, the diagnostic accuracies of pCLE and cytology for main duct intrapapillary mucinous neoplasm did not differ significantly (96.7% and 86.7%, respectively). CONCLUSIONS: Probe-based confocal laser endomicroscopy may be effective for the diagnosis of pancreatic diseases as adjunct modality. It requires technical learning and further evaluation of its usefulness.

HLA-DQ gene polymorphisms are associated with hepatocellular carcinoma and hepatitis B surface antigen in chronic hepatitis B virus infection.

AIM: Genome-wide association studies have revealed that single nucleotide polymorphism (SNP) of human leukocyte antigen (HLA)-DQ is associated with the clearance of hepatitis B surface antigen (HBsAg) in acute hepatitis B virus (HBV) infection. We examined the effects of SNPs on the development of hepatocellular carcinoma (HCC) and markers of HBV in chronic HBV infection. METHODS: The SNPs of HLA-DQ (rs2856718 and rs7453920) were determined in 299 patients with chronic HBV infection. RESULTS: In 224 hepatitis B e antigen (HBeAg)-negative patients, those with rs2856718 genotype AG + GG had significantly lower hepatitis B core-related antigen levels (P = 0.0184), less frequent treatment with nucleotide/nucleoside analogs (NAs) (P = 0.0433), and less frequent HCC development (P = 0.0256) than those with genotype AA. Multivariate analysis selected age (P = 0.0460), platelet count (P = 0.0481), γ-glutamyl transpeptidase (P = 0.0030), and nucleotide/nucleoside analog treatment (P = 0.0003) as factors independently associated with HCC development. HBeAg-negative patients with rs7453920 genotype GG had significantly lower HBsAg levels (P < 0.0001), a higher prevalence of HBV genotype C (P = 0.0063), and a lower prevalence of the wild-type basal core promoter region (P = 0.0045) than those with genotype AA + AG. Multivariate analysis selected age (P < 0.0001), platelet count (P = 0.0021), HBV DNA levels (P = 0.0314), wild type of precore region (P = 0.0015), and rs7453920 (P < 0.0001) as factors independently associated with HBsAg levels. CONCLUSION: This study revealed an association between rs2856718 and HCC development and an association between rs7453920 and HBsAg levels.

Contributions of endoscopic ultrasonography-guided tissue acquisition (EUS-TA) to the diagnostics of biliary stricture and gallbladder lesions.

Endoscopic ultrasonography (EUS) provides high spatial resolution and more detailed images than other diagnostic modalities. Furthermore, EUS-guided tissue acquisition (EUS-TA), such as EUS-guided fine needle aspiration or biopsy (EUS-FNA/FNB), is an indispensable tool in pancreaticobiliary disease diagnostics, supporting a conclusive pathological diagnosis. In this review, we evaluate the current status and the usefulness of EUS-TA for the diagnostics of the following biliary tract diseases: (A) biliary stricture diagnostics, (B) biliary tract cancer (BTC) itself, and (C) staging of advanced BTC. Previous reports have shown that EUS-FNA for biliary lesions is a safe procedure that is useful in differentiating biliary cancer from benign lesions and in the staging of BTC. On the other hand, the diagnostic performance of EUS-TA for bile duct lesions is reported to be similar to that of transpapillary biopsy. Overall, EUS-TA for biliary lesions may be a safe and effective method, but it should be performed with an understanding of the risk of serious adverse events such as bile leakage and peritoneal dissemination of cancer. It is recommended for distal biliary stricture lesions for which endoscopic retrograde cholangiopancreatography cannot confirm the diagnosis or gallbladder lesions if they do not require the needle to pass through the biliary lumen.

Use of contrast-enhanced harmonic endoscopic ultrasonography for the diagnosis of pancreatic cystic lesions.

Endoscopic ultrasonography (EUS) provides high spatial and contrast resolution and is a useful tool for evaluating the pancreato-biliary regions. Recently, contrast-enhanced harmonic EUS (CH-EUS) has been used to evaluate lesion vascularity, especially for the diagnosis of pancreatic tumors. CH-EUS adds two major advantages when diagnosing pancreatic cystic lesions (PCL). First, it can differentiate between mural nodules and mucous clots, thereby improving the accurate classification of PCL. Second, it helps with evaluation of the malignant potential of PCL, especially of intraductal papillary mucinous neoplasms by revealing the vascularity in the mural nodules and solid components. This review discusses the use and limitations of CH-EUS for the diagnosis of PCL.

A rare case of inflammatory polyp in the common bile duct with cholangitis.

The diagnosis of bile duct tumors can be difficult at times. A transpapillary bile duct biopsy findings with endoscopic retrograde cholangiopancreatography sometimes contradict diagnostic imaging findings. In bile duct tumors, inflammatory polyps in the extrahepatic bile duct are relatively rare with extrahepatic cholangitis. The disease's clinical relevance, including its natural history and prognosis, is not always clear. We show here a rare case of an inflammatory polyp in the common bile duct. A 69-year-old woman with abdominal pain was diagnosed with cholangitis. The findings of contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography suggested that she had extrahepatic cholangiocarcinoma. The examination and therapy of cholangitis were performed by endoscopic retrograde cholangiopancreatography. The cholangiography revealed a suspected tumor in the hilar bile duct with some common bile duct stones. Then, after endoscopic sphincterotomy to remove tiny common bile duct stones, further detailed examinations were performed at the same time using an oral cholangioscope revealed a papillary raised lesion with a somewhat white surface in the bile duct; a biopsy was conducted on the same spot, and epithelial cells with mild atypia appeared in the shape of a papilla. Since the malignant tumor or the intraductal papillary neoplasm of the bile duct could not be ruled out, extrahepatic bile duct resection was conducted with the patient's informed consent. Bile duct inflammatory polyp was the histopathological diagnosis.

Transcatheter arterial infusion chemotherapy with cisplatin in combination with transcatheter arterial chemoembolization decreases intrahepatic distant recurrence of unresectable hepatocellular carcinoma.

BACKGROUND AND AIM: This study investigated the efficacy of transcatheter arterial infusion (TAI) chemotherapy with cisplatin combined with transcatheter arterial chemoembolization (TACE). The goal was to prevent intrahepatic distant recurrence (IDR) of hepatocellular carcinoma (HCC), compared with TACE alone, in patients with unresectable HCC. METHODS: We conducted a historical cohort study, which involved 68 unresectable HCC patients. The study was performed on 44 and 24 consecutive patients who underwent TAI using cisplatin combined with TACE using epirubicin and TACE using epirubicin alone, respectively. We performed a propensity score analysis to identify the independent risk factors associated with IDR, and constructed propensity score-adjusted survival curves. RESULTS: After propensity score-adjusting, the adjusted cumulative IDR rates at 1 and 3 years were 76.8 and 76.8% in TACE alone group, and 21.3 and 73.1% in TACE with TAI group, respectively. TACE alone group had a significantly higher IDR rate in comparison with TACE with TAI group (P = 0.0073). Combined with TAI was associated with preventing IDR after propensity score-adjusting (hazard ratio [HR] 0.40, 95% confidence intervals [CI] 0.17-0.91, P = 0.028). Combined with TAI (HR 0.26, 95% CI 0.10-0.68, P = 0.0056) and Stage ≥III (HR 2.98, 95% CI 1.25-7.12, P = 0.014) were independent IDR predictors after adjusting for significant risk factors with propensity score. CONCLUSIONS: We demonstrated that cisplatin TAI accompanied with TACE decreased IDR compared with TACE alone. Our findings suggest that cisplatin TAI might contribute to a longer progression-free period in unresectable HCC patients treated with TACE.

Initial Experience of Atezolizumab Plus Bevacizumab for Advanced Hepatocellular Carcinoma in Clinical Practice.

Background/Aim: The aim of this study was to investigate the outcomes of atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma (HCC), including those with disease refractory to lenvatinib, in clinical practice. Patients and Methods: Of 34 patients treated with atezolizumab plus bevacizumab, a total of 23, including 16 with lenvatinib failure, were enrolled in this retrospective study. The adverse events, changes in liver function and antitumor responses at 6 weeks after starting therapy were evaluated. Results: The incidence of grade 3 adverse events was low, at 13.0%. Albumin-bilirubin scores did not worsen at 3 and 6 weeks compared to baseline. The objective response rate and disease control rate at 6 weeks were 17.4% and 78.3% according to Response Evaluation Criteria in Solid Tumors (RECIST), and 30.4% and 78.3% according to modified RECIST, respectively. Conclusion: Our results suggest that atezolizumab plus bevacizumab might have potential therapeutic safety and efficacy in patients with advanced HCC, including those with disease refractory to lenvatinib. Further studies are needed to confirm the outcomes of atezolizumab plus bevacizumab after lenvatinib failure.

The loss of HBeAg without precore mutation results in lower HBV DNA levels and ALT levels in chronic hepatitis B virus infection.

BACKGROUND: The aim of this study was to investigate the correlation between precore (PC)/basal core promoter (BCP) mutations and the viral loads or activity of hepatitis in patients with chronic hepatitis B virus (HBV) infection. METHODS: HBV genotypes, PC mutations, BCP mutations, HBV DNA levels, and serological markers of HBV were analyzed in all the patients with chronic HBV infection seen in Fujita Health University Hospital from June 2004 to November 2008 (n=215). RESULTS: HBV genotype was C in 169 patients, B in 16, A in 3, F in 1, and unclassifiable in 5. Among the patients with genotype C, the prevalence of PC wild type was significantly lower in hepatitis B envelope antigen (HBeAg)(-) patients than in HBeAg(+) patients (9.5% versus 49.0%, P<0.0001). Among HBeAg(-) patients, the patients with PC wild type had significantly lower serum viral loads and alanine aminotransferase (ALT) levels compared with those with PC mutant (P<0.001). Among HBeAg(-) patients, the patients with genotype B had lower serum viral loads compared with those with genotype C (3.6+/-0.9 versus 4.6+/-1.6, P<0.05), and the prevalence of BCP wild type was significantly higher in those with genotype B than in those with genotype C (58.3% versus 10.8%, P<0.05). CONCLUSIONS: Among HBeAg(-) patients with genotype C, the patients with PC wild type had significantly lower viral loads and ALT levels than those with PC mutant. This suggests that the patients with PC wild type may have better prognosis than those with PC mutant among HBeAg(-) patients with genotype C.

Liver stiffness measured by transient elastography correlates with fibrosis area in liver biopsy in patients with chronic hepatitis C.

AIM: Liver stiffness (LS) measured by transient elastography (TE) has been reported to correlate with liver fibrosis, which is usually semiquantitatively assessed. In the present study, the fibrosis area was measured by image analysis software in liver biopsy specimens and its correlation with LS was assessed. METHODS: LS was measured by TE in all 165 patients with chronic hepatitis C virus (HCV) infection who underwent liver biopsy consecutively in Fujita Health University Hospital from July 2004 to September 2007. RESULTS: Fibrosis area was significantly correlated with fibrosis stage as assessed by the Metavir score (rho = 0.733, P < 0.0001). The optimal cut-off value of fibrosis area was 1.6% for F > or = 2, 3.1% for F > or = 3, and 3.8-6.4% for F4. LS was significantly correlated with fibrosis stage (rho = 0.734, P < 0.0001). The optimal cut-off value of LS was 7.1 kPa for F > or = 2, 9.6 kPa for F > or = 3 and 11.6-16.9 kPa for F4. Multiple linear regression analysis selected fibrosis area (P = 0.0002), alanine aminotransferase (ALT) (P = 0.0237), gamma-glutamyltransferase (gamma-GTP) (P = 0.0114), prothrombin time (P = 0.0114) and hyaluronic acid (P < 0.0001) as factors correlating with LS. CONCLUSION: The correlation between LS and liver fibrosis was confirmed by the objective measurement of fibrosis area. ALT was significantly correlated with LS, suggesting that inflammatory activity also affects LS values. Despite some limitation, LS measurement is a useful method for the diagnosis of liver fibrosis.

Assessment of nutritional status of patients with hepatitis C virus-related liver cirrhosis.

AIM: Nutrition support for patients with liver cirrhosis, such as late evening snacks and branched-chain amino acids, has been demonstrated to be effective. However, the assessment of the malnutrition of liver cirrhosis is still a problem. The aim of this study was to assess the nutritional status of patients with liver cirrhosis due to hepatitis C virus by six methods and to test the sensitivity and specificity of these methods. METHODS: In total, 86 patients with liver cirrhosis due to hepatitis C virus were assessed for nutritional status by triceps skinfold thickness (TSF), arm muscle circumference (AMC), subjective global assessment (SGA), nutritional risk index (NRI), Maastricht index (MI), and instant nutritional assessment (INA). RESULTS: Malnutrition was found in 11 (12.8%) patients by TSF, 15 (17.4%) by AMC, 22 (25.6%) by SGA, 52 (60.5%) by the NRI, 66 (76.7%) by the MI, and in 54 (62.8%) by INA. The MI detected malnutrition at a significantly higher rate compared with the other five methods. Sixty-two patients were diagnosed as malnourished by the combined index, which defines the patients as malnourished when any two of the NRI, MI, and INA also define them as malnourished. The misclassification rate compared with the combined indexes was significantly lower in the MI (4.7%) than in any of the TSF (59.3%), AMC (59.3%), SGA (46.5%), NRI (16.3%), and INA (14.0%). CONCLUSION: The MI was the best single score to identify the patients who had malnutrition, including early stage, and may benefit from nutrition support.

Evaluation of a 12-mm diameter covered self-expandable end bare metal stent for malignant biliary obstruction.

Background and study aims Biliary metallic stents are used to drain unresectable malignant distal biliary obstructions. This study aimed to evaluate the efficacy of a novel 12-mm-diameter covered, self-expandable end bare metal stent (12-mm CSEEMS). Patients and methods We evaluated 99 patients with unresectable malignant distal biliary obstructions treated with covered biliary metallic stents. Of the 99 patients, 33 underwent 12-mm CSEEMS placement between June 2015 and April 2017 (12-mm-CSEEMS group) and 66 underwent 10-mm fully-covered self-expandable metal stent (FCSEMS) placement between January 2010 and July 2015 (10-mm-FCSEMS group). The overall survival (OS), the recurrent biliary obstruction (RBO), cause of RBO, time to RBO (TRBO) and adverse events in 12-mm-CSEEMS group and 10-mm-FCSEMS group were evaluated retrospectively. Results The OS tended to be longer in the 12-mm-CSEEMS group (log rank, P  = 0.081) and TRBO was significantly longer in the 12-mm-CSEEMS group (log rank, P  = 0.001) than in the 10-mm-FCSEMS group. Both univariate (HR, 0.449; 95 % CI, 0.27967 - 0.72215; P  = 0.001) and multivariate (HR, 0.458; 95 % CI, 0.28395 - 0.73744; P  = 0.001) Cox hazard analysis found that risk of RBO was significantly lower in 12-mm CSEEMS than in 10-mm FCSEMS. There were no significant differences between the 12-mm-CSEEMS group and 10-mm-FCSEMS group regarding the cause of RBO and adverse events. Conclusions The 12-mm CSEEMS showed a low risk of RBO compared with 10-mm FCSEMS and was considered to be effective and safe for draining unresectable malignant distal biliary obstruction.

Increase in Albumin by Daclatasvir/asunaprevir Therapy is Correlated with Decrease in Aspartate Transaminase.

OBJECTIVE: To elucidate the mechanism of an increase in the albumin levels by daclatasvir (DCV)/asunaprevir (ASV) therapy, we assessed the factors associated with an increase in the albumin levels. METHODS: We retrospectively analyzed 125 patients with chronic hepatitis C virus (HCV) infection, treated with DCV/ASV from November 2014 to January 2016. RESULTS: Albumin levels significantly increased from 4.0 ± 0.4 g/dL at baseline to 4.2 ± 0.4 g/dL at 24 weeks after the end of treatment (EOT) (P < 0.0001) in 108 patients with SVR. Patients with SVR were divided into three groups according to their baseline albumin levels: group A, ≥ 4 g/dL; group B, 3.6-3.9 g/dL; and group C, ≤ 3.5 g/dL. The increase in albumin levels from baseline to at 24 weeks after EOT was significantly larger in group C (0.5 ± 0.5 g/dL, P < 0.0001) and group B (0.2 ± 0.4 g/dL, P = 0.0059) than in group A (0.0 ± 0.3 g/dL). Multivariate analysis showed that aspartate transaminase (AST) levels was the only factor associated with ≥ 0.3 g/dL increase in albumin levels in groups B and C (P = 0.0305). An increase in albumin levels was significantly correlated with a decrease in AST levels (r = 0.4729, P = 0.0119). CONCLUSION: DCV/ASV therapy resulted in an increase in albumin levels in SVR patients, which was significantly correlated with a decrease in AST levels. It is probable that the reduction of inflammation, but not by reduction of fibrosis, mainly caused an increase in albumin levels.

The clinical features of patients with a Y93H variant of hepatitis C virus detected by a PCR invader assay.

BACKGROUND: Resistance-associated variants (RAVs) reduce the efficacy of interferon (IFN)-free therapy with asunaprevir and daclatasvir for patients infected with hepatitis C virus (HCV) genotype 1b. The characteristics of patients with an L31 or a Y93 variant in the nonstructural 5A region detected by a polymerase chain reaction invader assay were investigated. METHODS: In total, 201 patients with HCV genotype 1b were examined for L31F/M/V variants or a Y93H variant by the polymerase chain reaction invader assay. RESULTS: L31M and Y93H variants were detected in 4.6 and 21.4 % of patients, respectively. Patients with an L31M variant had no significant characteristics. Patients with a Y93H variant had significantly higher HCV RNA levels (6.5 ± 0.5 log copies per milliliter vs 6.1 ± 0.7 log copies per milliliter, p = 0.0002), higher frequency of mutant type of the IFN-sensitivity-determining region (88.4 % vs 71.7 %, p = 0.0251), and higher frequency of TT genotype at rs8099917 of IL28B (91.7 % vs 54.3 %, p < 0.0001) than those with Y93 wild-type strains. Multivariate analysis identified HCV RNA levels [odds ratio (OR) 3.72, 95 % confidence interval (CI) 1.71-8.06, p = 0.0009] and TT genotype at rs8099917 (OR 7.45, 95 % CI 2.11-26.4, p = 0.0018) as factors associated with the presence of a Y93H variant. CONCLUSION: The presence of a Y93H variant was associated with higher HCV RNA levels and TT genotype at rs8099917 of IL28B. Thus, patients with a Y93H variant may be ideal candidates for IFN-based therapy rather than IFN-free therapy, although the high viral load of these patients may reduce the response rate of IFN-based therapy.

Vitamin E reduces liver stiffness in nonalcoholic fatty liver disease.

AIM: To evaluate the efficacy of vitamin E treatment on liver stiffness in nonalcoholic fatty liver disease (NAFLD). METHODS: Thirty-eight NAFLD patients were administered vitamin E for > 1 year. The doses of vitamin E were 150, 300, or 600 mg; three times per day after each meal. Responses were assessed by liver enzyme levels [aspartate aminotransferase (AST), alanine aminotranferease (ALT), and γ-glutamyl transpeptidase (γ-GTP)], noninvasive scoring systems of hepatic fibrosis-4 [FIB-4 index and aspartate aminotransferase-to-platelet index (APRI)], and liver stiffness [velocity of shear wave (Vs)] measured by acoustic radiation force impulse elastography. Vs measurements were performed at baseline and 12 mo after baseline. The patients were genotyped for the patatin-like phospholipase domain containing 3 (PNPLA3) polymorphisms and then divided into either the CC/CG or GG group to examine each group's responses to vitamin E treatment. RESULTS: We found marked differences in the platelet count, serum albumin levels, alkaline phosphatase levels, FIB-4 index, APRI, and Vs at baseline depending on the PNPLA3 polymorphism. AST, ALT, and γ-GTP levels (all P < 0.001); FIB-4 index (P = 0.035); APRI (P < 0.001); and Vs (P < 0.001) significantly decreased from baseline to 12 mo in the analysis of all patients. In the subset analyses of PNPLA3 genotypes, AST levels (P = 0.011), ALT levels (P < 0.001), γ-GTP levels (P = 0.005), APRI (P = 0.036), and Vs (P = 0.029) in genotype GG patients significantly improved, and AST and ALT levels (both P < 0.001), γ-GTP levels (P = 0.003), FIB-4 index (P = 0.017), and APRI (P < 0.001) in genotype CC/CG patients. CONCLUSION: One year of vitamin E treatment improved noninvasive fibrosis scores and liver stiffness in NAFLD patients. The responses were similar between different PNPLA3 genotypes.

Additional BCAA-enriched nutrient mixture improves the nutritional condition in cirrhotic patients with hypoalbuminemia despite treatment with regular BCAA granules: A pilot study.

BACKGROUND/AIMS: To elucidate the effect of adding branched-chain amino acid (BCAA)-enriched nutrient mixtures in cirrhotic patients with hypoalbuminemia despite the use of BCAA granules. MATERIALS AND METHODS: A BCAA-enriched nutrient mixture containing 5.6 g of BCAA and 210 kcal was additionally administered in 40 cirrhotic patients with hypoalbuminemia despite their treatment with BCAA granules containing 12 g of BCAA. Laboratory data were assessed at 6 months before beginning additional therapy, at baseline, and at 6 months after baseline. RESULTS: Serum albumin levels significantly decreased from 6 months before baseline (3.14±0.47 g/dL) to baseline (2.83±0.46 g/dL), despite the treatment with BCAA granules (p<0.001), and tended to increase from baseline to 6 months after baseline (2.95±0.42 g/dL) (p=0.084). In the subset of 23 patients without hepatocellular carcinoma treatments, upper gastrointestinal tract bleeding, or albumin infusion, serum albumin levels significantly increased from baseline (2.93±0.38 g/dL) to 6 months after baseline (3.15±0.34 g/dL) (p=0.014). CONCLUSION: Additional therapy with BCAA-enriched nutrient mixtures increased serum albumin levels of the cirrhotic patients with hypoalbuminemia despite the treatment with BCAA granules and without hepatocellular carcinoma treatment, upper gastrointestinal tract bleeding, or albumin infusion.

PNPLA3 I148M associations with liver carcinogenesis in Japanese chronic hepatitis C patients.

AIM: To investigate associations between patatin-like phospholipase domain-containing 3 (PNPLA3) genotypes and fibrosis and hepatocarcinogenesis in Japanese chronic hepatitis C (CHC) patients. METHODS: Two hundred and thirty-one patients with CHC were examined for PNPLA3 genotypes, liver stiffness measurements (LSM), and hepatocellular carcinoma (HCC) from May 2010 to October 2012 at Fujita Health University Hospital. The rs738409 single nucleotide polymorphism (SNP) encoding for a functional PNPLA3 I148M protein variant was genotyped using a TaqMan predesigned SNP genotyping assay. LSM was determined as the velocity of a shear wave (Vs) with an acoustic radiation force impulse. Vs cut-off values for cirrhosis were set at 1.55 m/s. We excluded CHC patients with a sustained virological response or relapse after interferon treatment. RESULTS: PNPLA3 genotypes were CC, CG, and GG for 118, 72, and 41 patients, respectively. Multivariable logistic regression analysis selected older age (OR = 1.06; 95% CI: 1.03-1.09; p < 0.0001), higher body mass index (BMI) (OR= 1.12; 95% CI: 1.03-1.22; p = 0.0082), and PNPLA3 genotype GG (OR = 2.07; 95% CI: 0.97-4.42; p = 0.0599) as the factors independently associated with cirrhosis. When 137 patients without past history of interferon treatment were separately assessed, multivariable logistic regression analysis selected older age (OR = 1.05; 95% CI: 1.02-1.09; p = 0.0034), and PNPLA3 genotype GG (OR = 3.35; 95% CI: 1.13-9.91; p = 0.0291) as the factors independently associated with cirrhosis. Multivariable logistic regression analysis selected older age (OR = 1.12; 95% CI: 1.07-1.17; p < 0.0001), PNPLA3 genotype GG (OR = 2.62; 95% CI: 1.15-5.96; p = 0.0218), and male gender (OR = 1.83; 95% CI: 0.90-3.71); p = 0.0936) as the factors independently associated with HCC. CONCLUSION: PNPLA3 genotype I148M is one of risk factors for developing HCC in Japanese CHC patients, and is one of risk factors for progress to cirrhosis in the patients without past history of interferon treatment.

Changes of shear-wave velocity by interferon-based therapy in chronic hepatitis C.

AIM: To evaluate the changes of shear-wave velocity (Vs) by acoustic radiation force impulse after treatment in chronic hepatitis C. METHODS: Eighty-seven patients with chronic hepatitis C were consecutively treated with combinations of interferon (IFN) plus ribavirin (RBV). Vs value (m/s) was measured with acoustic radiation force impulse before treatment, at end of treatment (EOT), 1 year after EOT, and 2 years after EOT. RESULTS: In patients with a sustained virological response (SVR) (n = 41), Vs significantly decreased at EOT [1.19 (1.07-1.37), P = 0.0004], 1 year after EOT [1.10 (1.00-1.22), P = 0.0001], and 2 years after EOT [1.05 (0.95-1.16), P < 0.0001] compared with baseline [1.27 (1.11-1.49)]. In patients with a relapse (n = 26), Vs did not significantly decrease at EOT [1.23 (1.12-1.55)], 1 year after EOT [1.20 (1.12-1.80)], and 2 years after EOT [1.41 (1.08-2.01)] compared with baseline [1.39 (1.15-1.57)]. In patients with a nonvirological response (n = 20), Vs did not significantly decrease at EOT [1.64 (1.43-2.06)], 1 year after EOT [1.66 (1.30-1.95)], and 2 years after EOT [1.61 (1.36-2.37)] compared with baseline [1.80 (1.54-2.01)]. Among genotype 1 patients, baseline Vs was significantly lower in SVR patients [1.28 (1.04-1.40)] than in non-SVR patients [1.56 (1.20-1.83)] (P = 0.0142). CONCLUSION: Reduction of Vs values was shown in SVR patients after IFN-plus-RBV therapy by acoustic radiation force impulse.

Factors correlating with acoustic radiation force impulse elastography in chronic hepatitis C.

AIM: To investigate the factors other than fibrosis stage correlating with acoustic radiation force impulse (ARFI) elastograpy in chronic hepatitis C. METHODS: ARFI elastograpy was performed in 108 consecutive patients with chronic hepatitis C who underwent a liver biopsy. The proportion of fibrosis area in the biopsy specimens was measured by computer-assisted morphometric image analysis. RESULTS: ARFI correlated significantly with fibrosis stage (ß = 0.1865, P < 0.0001) and hyaluronic acid levels (ß = 0.0008, P = 0.0039) in all patients by multiple regression analysis. Fibrosis area correlated significantly with ARFI by Spearman's rank correlation test but not by multiple regression analysis. ARFI correlated significantly with body mass index (BMI) (ß = -0.0334, P = 0.0001) in F 0 or F 1, with γ-glutamyltranspeptidase levels (ß = 0.0048, P = 0.0012) in F 2, and with fibrosis stage (ß = 0.2921, P = 0.0044) and hyaluronic acid levels (ß = 0.0012, P = 0.0025) in F 3 or F 4. The ARFI cutoff value was 1.28 m/s for F ≥ 2, 1.44 m/s for F ≥ 3, and 1.73 m/s for F 4. CONCLUSION: ARFI correlated with fibrosis stage and hyaluronic acid but not with inflammation. ARFI was affected by BMI, γ-glutamyltranspeptidase, and hyaluronic acid in each fibrosis stage.