Branched-chain amino acids enhance cyst development in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney and liver cysts. The mammalian target of rapamycin (mTOR) cascade is one of the important pathways regulating cyst growth in ADPKD. Branched-chain amino acids (BCAAs), including leucine, play a crucial role to activate mTOR pathway. Therefore, we administered BCAA dissolved in the drinking water to Pkd1flox/flox:Mx1-Cre (cystic) mice from four to 22 weeks of age after polyinosinic-polycytidylic acid-induced conditional Pkd1 knockout at two weeks of age. The BCAA group showed significantly greater kidney/body weight ratio and higher cystic index in both the kidney and liver compared to the placebo-treated mice. We found that the L-type amino acid transporter 1 that facilitates BCAA entry into cells is strongly expressed in cells lining the cysts. We also found increased cyst-lining cell proliferation and upregulation of mTOR and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways in the BCAA group. In vitro, we cultured renal epithelial cell lines from Pkd1 null mice with or without leucine. Leucine was found to stimulate cell proliferation, as well as activate mTOR and MAPK/ERK pathways in these cells. Thus, BCAA accelerated disease progression by mTOR and MAPK/ERK pathways. Hence, BCAA may be harmful to patients with ADPKD.

Genome-Wide Association Study Identifies Risk Variants for Lichen Planus in Patients With Hepatitis C Virus Infection.

BACKGROUND & AIMS: There is a close relationship between hepatitis C virus (HCV) infection and lichen planus, a chronic inflammatory mucocutaneous disease. We performed a genome-wide association study (GWAS) to identify genetic variants associated with HCV-related lichen planus. METHODS: We conducted a GWAS of 261 patients with HCV infection treated at a tertiary medical center in Japan from October 2007 through January 2013; a total of 71 had lichen planus and 190 had normal oral mucosa. We validated our findings in a GWAS of 38 patients with HCV-associated lichen planus and 7 HCV-infected patients with normal oral mucosa treated at a medical center in Italy. RESULTS: Single-nucleotide polymorphisms in NRP2 (rs884000) and IGFBP4 (rs538399) were associated with risk of HCV-associated lichen planus (P < 1 × 10-4). We also found an association between a single-nucleotide polymorphism in the HLA-DR/DQ genes (rs9461799) and susceptibility to HCV-associated lichen planus. The odds ratios for the minor alleles of rs884000, rs538399, and rs9461799 were 3.25 (95% confidence interval, 1.95-5.41), 0.40 (95% confidence interval, 0.25-0.63), and 2.15 (95% confidence interval, 1.41-3.28), respectively. CONCLUSIONS: In a GWAS of Japanese patients with HCV infection, we replicated associations between previously reported polymorphisms in HLA class II genes and risk for lichen planus. We also identified single-nucleotide polymorphisms in NRP2 and IGFBP4 loci that increase and reduce risk of lichen planus, respectively. These genetic variants might be used to identify patients with HCV infection who are at risk for lichen planus.

Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection.

UNLABELLED: All-oral combinations of direct-acting antivirals may improve efficacy and safety outcomes for patients with hepatitis C virus (HCV) infection, particularly those who are poor candidates for current interferon/ribavirin-based regimens. In this open-label, phase 3 study, 135 interferon-ineligible/intolerant and 87 nonresponder patients with chronic HCV genotype 1b infection were enrolled at 24 centers in Japan. Patients received daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily for 24 weeks. The primary endpoint was sustained virologic response 24 weeks after treatment (SVR24 ). This study is registered with ClinicalTrials.gov (NCT01497834). SVR24 was achieved by 87.4% of interferon-ineligible/intolerant patients and 80.5% of nonresponder (null and partial) patients; rates were similar in cirrhosis (90.9%) and noncirrhosis (84.0%) patients, and in patients with IL28B CC (84.5%) or non-CC (84.8%) genotypes. Fourteen patients in each group (12.6%) discontinued dual therapy, mainly due to adverse events or lack of efficacy. Nine nonresponder patients received additional treatment with peginterferon/ribavirin per protocol-defined criteria. The rate of serious adverse events was low (5.9%) and varied among patients. The most common adverse events were nasopharyngitis, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), headache, diarrhea, and pyrexia. CONCLUSION: Interferon-free, ribavirin-free all-oral therapy with daclatasvir and asunaprevir for 24 weeks is well tolerated and can achieve a high rate of SVR in patients with HCV genotype 1b who were ineligible, intolerant, or had not responded to prior interferon-based therapy. (Hepatology 2014;59:2083-2091).

Factors associated with sustained virological response in 24-week telaprevir-based triple therapy for chronic hepatitis C genotype 1b patients with the IL28B minor genotype.

AIM: Single nucleotide polymorphisms (SNP) near the interleukin-28B (IL28B) gene affect the outcome of 24-week telaprevir-based triple therapy with telaprevir, pegylated interferon-α and ribavirin for chronic hepatitis C virus (HCV) genotype 1b patients. We aimed to identify factors associated with treatment outcomes in patients with the unfavorable minor IL28B SNP genotype, who have poor response to combination therapy. METHODS: Pretreatment and on-treatment factors associated with sustained virological response (SVR) for 24-week telaprevir-based triple therapy were analyzed using multiple logistic regression analysis in 106 HCV genotype 1b patients with the minor IL28B SNP rs8099917 genotype (non-TT). RESULTS: Of the 106 non-TT patients, 62 (58.5%) achieved SVR. Of the 44 remaining patients, 22 experienced relapse, 13 experienced viral breakthrough and nine were non-responders. Pretreatment factors such as treatment-naïve/prior treatment response (P = 0.0041), high fasting serum low-density lipoprotein cholesterol (LDL-C) concentration (P = 0.0068) and low serum HCV RNA levels (P = 0.0088) were significantly and independently associated with SVR. On-treatment factors such as achievement of rapid virological response (RVR) were significantly and independently associated with SVR (P = 0.0001). For both pre- and on-treatment factors, treatment-naïve/prior treatment response (P = 0.0018), low pretreatment serum fasting LDL-C (P = 0.0062) and achieving RVR (P = 0.0021) were significantly and independently associated with SVR. CONCLUSION: In HCV genotype 1b patients with the minor IL28B SNP rs8099917 genotype, evaluating prior treatment response and achieving RVR and pretreatment serum fasting LDL-C concentrations were useful for predicting SVR achievement after 24-week telaprevir-based triple therapy.

Branched-chain amino acids prevent hepatocarcinogenesis and prolong survival of patients with cirrhosis.

BACKGROUND & AIMS: Although a low plasma level of branched-chain amino acids (BCAAs) is a marker of cirrhosis, it is not clear whether BCAA supplements affect disease progression. We performed a multicenter study to evaluate the effects of BCAA supplementation on hepatocarcinogenesis and survival in patients with cirrhosis. METHODS: We enrolled 299 patients from 14 medical institutions in Japan in a prospective, multicenter study in 2009; 267 patients were followed through 2011. Patients were given BCAA supplements (5.5-12.0 g/day) for more than 2 years (n = 85) or no BCAAs (controls, n = 182). The primary end points were onset of hepatocellular carcinoma (HCC) and death. Factors associated with these events were analyzed by competing risk analysis. RESULTS: During the study period, 41 of 182 controls and 11 of 85 patients given BCAAs developed HCC. On the basis of the Cox and the Fine and Gray models of regression analyses, level of α-fetoprotein, ratio of BCAA:tyrosine, and BCAA supplementation were associated with development of HCC (relative risk for BCAAs, 0.45; 95% confidence interval, 0.24-0.88; P = .019). Sixteen controls and 2 patients given BCAAs died. Factors significantly associated with death were Child-Pugh score, blood level of urea nitrogen, platelet count, male sex, and BCAA supplementation (relative risk of death for BCAAs, 0.009; 95% confidence interval, 0.0002-0.365; P = .015) in both regression models. CONCLUSIONS: On the basis of a prospective study, amino acid imbalance is a significant risk factor for the onset of HCC in patients with cirrhosis. BCAA supplementation reduces the risk for HCC and prolongs survival of patients with cirrhosis.

The significance of classifying microvascular invasion in patients with hepatocellular carcinoma.

BACKGROUND: Microvascular invasion (MVI) has been recognized as a risk factor for outcome following curative resection in hepatocellular carcinoma (HCC). Because MVI can range from few to many invaded vessels, we evaluated the significance of MVI classification in this study. METHODS: Between January 1995 and December 2010, 207 consecutive patients who underwent curative resection for HCC within Milan criteria were included in this retrospective study. Patients were classified into mild and severe MVI groups based on the number of vessels invaded. This study evaluated whether MVI classification can help to predict recurrence and survival after curative resection. RESULTS: Of the total 207 patients, 103 (50 %) patients had no detectable MVI, whereas 59 (28 %) had mild MVI, and 45 (22 %) had severe MVI. Recurrence-free survival rates at 2 years for patients without MVI, with mild MVI, and severe MVI were 75.9, 47.2, and 32.7 %, respectively. Patients with severe MVI experienced a high frequency of fatal recurrence, such as multiple tumors, macroscopic vascular invasion, and extrahepatic metastasis after curative resection. Multivariate analysis revealed age, number of tumors, mild MVI, and severe MVI as independent predictors of recurrence-free survival. Disease-specific survival rates at 5 years for patients without MVI, with mild MVI, and severe MVI were 91.5, 70.4, and 51.4, respectively. Multivariate analysis also revealed cirrhosis, tumor size, mild MVI, and severe MVI as independent predictors of disease-specific survival. CONCLUSIONS: We demonstrated that MVI classification can stratify HCC patients by different patterns of recurrence and risk of survival after curative resection.

Methylated-(3'')-epigallocatechin gallate analog suppresses tumor growth in Huh7 hepatoma cells via inhibition of angiogenesis.

It is agreed that many of the antitumor effects of (-)-epigallocatechin gallate (EGCG) are mediated by various other effects. We report a new finding, namely, the antiproliferation potential and mechanism of methylated-(3'')-epigallocatechin gallate analog (MethylEGCG) having a stronger anti-oxidation effect than EGCG. MethylEGCG inhibited activity of vascular endothelial growth factor (VEGF)-depended VEGF receptor 2 and p42/44 MAPK, cell proliferation, and tube formation in human umbilical vascular endothelial cells (HUVECs) at 1 µ M. Even low- dose (1.1 mg/kg i.p. 8.3 mg/kg p.o.) administration suppressed tumor growth in xenografted Huh7 hepatoma mice by 50%. CD31 positive cells, visualized in blood vessels, were reduced in tumors by 18%, suggesting high antitumor activity via inhibition of angiogenesis. This study indicated that the modification of the 3'' position methylation of EGCG (MethylEGCG) could reduce cell growth effects at a low concentration in vivo.

Characteristics and outcomes of HCV genotype-1-infected patients treated with peginterferon and ribavirin combination therapy with discordant HCV responses 4 and 12 weeks after starting therapy.

OBJECTIVE: Some patients with chronic hepatitis C virus (HCV) infection fail to achieve complete early virologic response (EVR) despite a marked decrease in HCV RNA at 4 weeks. We investigated the characteristics and final treatment outcomes of this patient subpopulation. METHODS: A total of 516 patients with HCV genotype 1 were enrolled. Background characteristics and final outcomes were compared between patients who achieved complete EVR and those who did not among patients whose HCV RNA levels decreased 3.0 log10 or more at 4 weeks. RESULTS: 78 of 334 patients (23.4%) with a ≥3.0 log10 reduction in HCV RNA levels at 4 weeks failed to achieve complete EVR. Female sex, higher pretreatment HCV RNA levels and lower baseline alanine aminotransferase (ALT) activity were independently associated with failure of complete EVR. The rate of sustained virologic response (SVR) in patients without complete EVR was 47.4%, significantly lower than that in patients with complete EVR (89.7%, p < 0.0001). CONCLUSIONS: Female patients, patients with higher pretreatment HCV RNA levels and patients with lower baseline ALT have a high likelihood of failure of complete EVR even when they had a ≥3 log10 reduction of HCV RNA at 4 weeks, resulting in a significantly lower SVR rate.

Clinical efficacy of combination therapy with ME3738 and pegylated interferon-alpha-2a in patients with hepatitis C virus genotype 1.

AIM: ME3738, a derivative of soyasapogenol B, enhances the anti-hepatitis C virus (HCV) effect of interferon in an in vitro replication system and an in vivo mouse model of HCV infection. ME3738 plus pegylated interferon (PEG IFN)-α-2a treatment for 12 weeks decreased HCV RNA levels in enrolled late virus responder (LVR) patients with relapsed HCV. Half of the patients reached undetectable HCV RNA level. The present clinical study of ME3738 was conducted in naïve chronic hepatitis C patients to investigate the sustained virological response (SVR) and safety of 48-week treatment with ME3738 plus PEG IFN-α-2a. METHODS: Subjects (n = 135) with genotype 1b chronic hepatitis C with high viral loads were divided into three groups (ME3738 50 mg b.i.d., 200 mg b.i.d. or 800 mg b.i.d.). ME3738 was administrated p.o. and PEG IFN-α-2a (180 µg/week) s.c. for 48 weeks, and SVR was assessed at 24 weeks of treatment-free follow up. RESULTS: The viral disappearance rates at 12 and 48 weeks were 23.0% and 48.9%, respectively. SVR was seen in 5.9% of subjects. ME3738 did not worsen the adverse reactions generally seen with PEG IFN-α-2a treatment, and any adverse reactions specific to ME3738 were not observed. CONCLUSION: ME3738 plus PEG IFN-α-2a treatment to naïve chronic hepatitis C patients showed an antiviral effect and a good safety profile up to 48 weeks. However, HCV RNA was again detected in many subjects after treatment termination. Even though ME3738 is not enough to suppress HCV reproduction in this treatment. ME3738 was concurrently used with PEG IFN-α-2a treatment; however, a clear additional effect on SVR was not confirmed.

Open-labeled randomized controlled trial to compare diuretic therapy with recombinant human serum albumin and diuretic therapy for therapeutic treatment of ascites in patients with advanced liver cirrhosis: An exploratory trial.

AIM: There have been only a few trials demonstrating additional effects of human serum albumin (HSA) on diuretic therapy in patients with cirrhotic ascites. We aimed to evaluate the safety and efficacy of recombinant HSA, KD-294, treatment in patients with cirrhotic ascites. METHODS: The inclusion criteria were patients 20-75 years of age, with cirrhotic ascites and a serum albumin concentration of less than 3.0 g/dL. Eighty-five patients were registered and 71 patients underwent randomization. Enrolled patients received oral spironolactone at 50 mg/day and i.v. furosemide at 20 mg/day in addition to low-sodium diet. They were divided randomly into a KD-294 treatment group (n = 35) or non-treatment control group (n = 36). Patients in the KD-294 group received KD-294 at 25 g/day for up to 5 days and those in the control group continued the diuretic therapy. They were followed up for 5 weeks. RESULTS: KD-294 was well tolerated. A correlation between the increases in serum albumin and decreases in bodyweight was not shown. However, changes of plasma renin concentration (PRC) showed a significant decrease in the KD-294 group compared with the control group. As a result of this exploratory analysis, patients with high PRC showed a significant correlation between increases in serum albumin and decreases in bodyweight. CONCLUSION: The present data do not show efficacy in all patients with cirrhotic ascites, however, they suggest that additional effects of HSA on diuretic therapy are expected in high PRC patients.

Pathological characteristics of patients who develop hepatocellular carcinoma with negative results of both serous hepatitis B surface antigen and hepatitis C virus antibody.

AIM: We tried to characterize the pathological features of patients who developed hepatocellular carcinoma (HCC) with the negative results of both serous hepatitis B surface antigen and hepatitis C virus antibody (non-B, non-C). METHODS: In a multicenter study in Kyushu, Japan, we studied the histopathological characteristics of non-cancerous liver tissues in 129 patients (103 men and 26 women) with non-B, non-C HCC. The histological liver damage was evaluated for fibrosis (stage) and inflammation (grade) according to the Ludwig classification of chronic hepatitis. In addition, we examined the hepatitis B virus (HBV) genome in serum samples and liver tissues of 20 patients with non-B, non-C HCC. RESULTS: Positivity of serum hepatitis B core (HBc) antibody, alcohol abuse, diabetes and non-alcoholic steatohepatitis were present in 61 (47%), 76 (59%), 57 (44%) and eight (6%) patients, respectively. The degree of fibrosis was mild (stage 1.6 ± 1.2). The stage of patients with neither serum HBc antibody nor alcohol abuse was significantly lower than the stage of patients with HBc antibody and no alcohol abuse (P < 0.05). HBV genome was detected in 15 cancerous tissues (75%) and 16 non-cancerous liver tissues (80%) in 20 patients with non-B, non-C HCC. Only three of the 20 patients were positive for serum HBc antibody. CONCLUSION: Non-B, non-C patients appear to develop HCC at a low stage of fibrosis. Occult hepatitis B virus infection is the major risk factor for HCC of non-B, non-C patients in Kyushu, Japan.

Decreased serum levels of immunoglobulin A, immunoglobulin M and immunoglobulin G in a patient with primary biliary cirrhosis: A case report.

Primary biliary cirrhosis (PBC) is a cholestatic liver disease with an elevated serum immunoglobulin (Ig)M level. Patients with PBC may develop extrahepatic manifestations, including hypogammaglobulinemia. However, hypogammaglobulinemia seldom occurs, and the associated changes of lymphocytes remain unknown. Furthermore, the impact of Ig on the progression of PBC is still unclear. Here, we describe a case of hypogammaglobulinemia developed in a female patient with PBC. The patient was diagnosed with PBC at the age of 46 years and treated with ursodeoxycholic acid and bezafibrate. At the age of 50 years, the patient developed bronchitis, and laboratory test results indicated a marked decrease in serum levels of IgA, IgM and IgG. Then, the patient was diagnosed as having idiopathic hypogammaglobulinemia and treated with Ig replacement therapy; however, respiratory infections recurred frequently, leading to the patient's death at the age of 53 years. An autopsy revealed hyperplastic bone marrow with CD3, CD20 and IgG positive lymphocytes. However, no CD79a, CD138, IgA and IgM positive lymphocytes were observed. Moreover, the severity of PBC progressed even after the onset of hypogammaglobulinemia. In addition, CD3 positive cells were seen around chronic non-suppurative destructive cholangitis in the autopsy specimen of the liver. Thus, the present case demonstrated changes of lymphocytes in hypogammaglobulinemia developed in patients with PBC. Furthermore, the clinical course of the present case of PBC may indicate that the Ig-mediated mechanisms may be non-essential for the progression of PBC.

Radiofrequency ablation combined with transarterial chemoembolization for intermediate hepatocellular carcinoma.

AIM: Radiofrequency ablation therapy (RFA) combined with transarterial chemoembolization (TACE) (combination therapy) is effective for early-stage hepatocellular carcinoma (HCC). The aim of this study was to compare the long-term effects of combination therapy with supportive care alone for intermediate HCC. METHODS: The study included 58 patients with intermediate HCC who received combination therapy (n = 34) or supportive care alone (n = 24). The inclusion criteria were a single nodule of more than 50 mm in diameter or two to three nodules, each measuring more than 30 mm in diameter, or more than three nodules, no vascular invasion and no extrahepatic metastasis. RESULTS: The overall survival rates at 1, 2, 3 and 5 years of the combination therapy group (91%, 65%, 53% and 27%, respectively) were significantly better (P < 0.0001) than those of the supportive care group (42%, 8%, 8% and 0%, respectively). Multivariate analysis identified treatment modality (combination therapy vs supportive care alone: P < 0.0001, risk ratio [RR] = 4.290 [95% confidence interval [CI] = 2.157-8.529]) and serum α-fetoprotein (P = 0.017, RR = 2.318 [95% CI = 1.166-4.610]) as independent and significant factors of overall survival. CONCLUSION: The combination of TACE and RFA is a safe and effective therapy in patients with intermediate HCC.

Long-term outcome of elderly patients (75 years or older) with hepatocellular carcinoma.

AIM: The aim of this study was to evaluate the long-term outcome of elderly patients with hepatocellular carcinoma (HCC) aged 75 years or older. METHODS: The study included 422 patients with HCC, who were divided into two age groups: 75 years or older (n = 140) and younger than 75 (n = 282). Outcomes were compared between the two groups. RESULTS: The number of elderly patients treated with supportive care alone (33 patients; 24%) was significantly higher than younger patients (30 patients; 11%, P < 0.01). The 1-, 3-, 5- and 7-year overall survival rates of the elderly patients (81%, 55%, 39% and 23%, respectively) were worse than those of younger patients (85%, 64%, 49% and 36%, respectively, P = 0.042). However, the overall survival rate of the elderly group after excluding 63 patients treated with supportive care alone, was similar to that of the younger group (P = 0.615). Multivariate analysis identified age, total bilirubin levels, albumin levels, serum des-γ-carboxy prothrombin levels, tumor size, number of HCC nodules, vascular invasion, extrahepatic metastasis and treatment modality as independent and significant factors of overall survival. CONCLUSION: Advanced age is a negative prognostic factor in patients with HCC due to the tendency for frequent use of conservative treatment rather than locoregional or surgical treatment.

Serum albumin level is a notable profiling factor for non-B, non-C hepatitis virus-related hepatocellular carcinoma: A data-mining analysis.

AIM: Various factors are underlying for the onset of non-B, non-C hepatitis virus-related hepatocellular carcinoma (NBNC-HCC). We aimed to investigate the independent risk factors and profiles associated with NBNC-HCC using a data-mining technique. METHODS: We conducted a case-control study and enrolled 223 NBNC-HCC patients and 669 controls from a health checkup database (n = 176 886). Multivariate analysis, random forest analysis and a decision-tree algorithm were employed to examine the independent risk factors, factors distinguishing between the case and control groups, and to identify profiles for the incidence of NBNC-HCC, respectively. RESULTS: In multivariate analysis, besides γ-glutamyltransferase (GGT) levels and the Brinkman index, albumin level was an independent negative risk factor for the incidence of NBNC-HCC (odds ratio = 0.67; 95% confidence interval = 0.60-0.70; P < 0.0001). In random forest analysis, serum albumin level was the highest-ranked variable for distinguishing between the case and control groups (98 variable importance). A decision-tree algorithm was created for albumin and GGT levels, the aspartate aminotransferase-to-platelet ratio index (APRI) and the Brinkman index. The serum albumin level was selected as the initial split variable, and 82.5% of the subjects with albumin levels of less than 4.01 g/dL were found to have NBNC-HCC. CONCLUSION: Data-mining analysis revealed that serum albumin level is an independent risk factor and the most distinguishable factor associated with the incidence of NBNC-HCC. Furthermore, we created an NBNC-HCC profile consisting of albumin and GGT levels, the APRI and the Brinkman index. This profile could be used in the screening strategy for NBNC-HCC.

A 48-week telaprevir-based triple combination therapy improves sustained virological response rate in previous non-responders to peginterferon and ribavirin with genotype 1b chronic hepatitis C: A multicenter study.

AIM: The sustained virological response (SVR) rate of non-responders to peginterferon and ribavirin therapy (PR) is low for 24-week telaprevir-based triple combination therapy (T12PR24), compared to that of treatment-naïve patients or previous-treatment relapsers. This study investigated which characteristics of non-responders were associated with a better SVR rate to 48-week therapy (T12PR48). METHODS: A total of 103 Japanese non-responders with genotype 1b chronic hepatitis C received telaprevir-based therapy. Among them, 81 patients (50 partial and 31 null responders) received T12PR24 and 22 (seven partial and 15 null responders) who agreed to the extended therapy received T12PR48. RESULTS: Multivariate logistic regression analysis for SVR identified the interleukin-28B (IL28B) rs8099917 TT genotype (P = 0.0005, odds ratio [OR] = 10.38), extended rapid virological response (P = 0.0008, OR = 7.02), T12PR48 regimen (P = 0.0016, OR = 9.31) and previous partial responders (P = 0.0022, OR = 5.89). Among partial responders, the SVR rate did not differ significantly between T12PR48 (85.7%) and T12PR24 (70.0%). Among null responders, the SVR rate was significantly higher with T12PR48 than T12PR24 (66.7% vs 22.6%, P = 0.0037). Among patients with the IL28B non-TT genotype, the SVR rate was significantly higher with T12PR48 than T12PR24 (68.8% vs 37.7%, P = 0.0288). Moreover, among null responders with the non-TT genotype, the SVR rate was significantly higher with T12PR48 than T12PR24 (66.7% vs 9.1%, P = 0.0009). CONCLUSION: T12PR48 improves the SVR rate in null responders, patients with the non-TT genotype, and null responders with a non-TT genotype.

CD34(+) cell therapy is safe and effective in slowing the decline of hepatic reserve function in patients with decompensated liver cirrhosis.

BACKGROUND AND AIM: Preclinical studies in rodent models of chronic liver fibrosis have shown that transplantation of peripheral blood (PB) CD34(+) cells leads to hepatic regeneration and a reduction of liver fibrosis by suppressing hepatic stellate cell activity and increasing matrix metalloproteinase activity. The aim of this study was to examine the safety and clinical efficacy of intrahepatic transplantation of autologous granulocyte colony-stimulating factor (G-CSF)-mobilized PB-CD34(+) cells in patients with decompensated liver cirrhosis. METHODS: PB-CD34(+) cells were isolated from G-CSF-mobilized apheresis products. Ten patients were treated with G-CSF-mobilized PB-CD34(+) cells (treatment group) and seven patients were treated with standard medical therapy. For mobilization, patients in the treatment group received subcutaneous injections of 10 µg G-CSF/kg/day for 5 days. The cells were then injected at three different doses (5 × 10(5) , 1 × 10(6) and 2 × 10(6) cells/kg) through the hepatic artery. Thereafter, all patients were followed up for 24 months. RESULTS: G-CSF treatment and leukapheresis were well tolerated, and no serious adverse events were observed. Patients in the treatment group had a significant but transient splenomegaly. After 24 weeks, serum albumin was significantly increased in patients who had received middle or high doses of CD34(+) cells compared with baseline. Doppler ultrasound showed a significant increase in hepatic blood flow velocity and blood flow volume after CD34(+) cell therapy. The hepatic vein pressure gradient decreased in two patients who received high-dose CD34(+) cells at week 16. CONCLUSIONS: CD34(+) cell therapy is feasible, safe and effective in slowing the decline of hepatic reserve function.

Evaluation of endoscopic transpapillary brushing cytology for the diagnosis of bile duct cancer based on the histopathologic findings.

BACKGROUND AND AIM: Diagnosis of the bile duct cancer still needs more accuracy. Studies on endoscopic retrograde cholangiopancreatography (ERCP)-guided brushing cytology were carried to evaluate the role of the endoscopic transpapillary brushing cytology for the diagnosis of bile duct cancer. PATIENTS AND METHOD: The study involved 76 consecutive patients who underwent ERCP-guided bile duct cytology for the diagnosis of bile duct cancer from 2008 to August 2012. Three types of cytological specimens were obtained using different sampling methods, i.e., bile aspiration cytology (BAC), brush tip cytology (BTC), and post brushing bile cytology (PBC), to investigate their diagnostic abilities, and comparatively studied with each macroscopic type of the surgically resected specimens. RESULTS: The cancer-positive rate was 67.1 % (BAC alone: 41.9 %), and the use of BTC and PBC in addition to BAC yielded a statistically significant increase of the cancer-positive rate (p = 0.0031). In 34 resected cases, the cancer-positive rate in relation to the macroscopic type was improved by the addition of BTC and PBC to BAC alone for the papillary (87.5 vs. 40.0 %, p = 0.071) and nodular (100 vs. 70.0 %, p = 0.0603) types, but not for the flat type (62.5 vs. 57.1 %; p = 0.7651). CONCLUSION: The diagnostic ability of ERCP-guided brushing cytology could be improved by the addition of PBC. However, the cancer-positive rate was the lowest for the flat type of bile duct cancer.

Successful treatment of rectal ulcers in a patient with systemic lupus erythematosus using corticosteroids and tacrolimus.

Systemic lupus erythematosus (SLE) is frequently accompanied by gastrointestinal symptoms. Although all parts of the gastrointestinal tract may be affected, colonic involvement is quite rare. Colonic ulceration, particularly in the rectum, is associated with a high mortality rate in patients with SLE, despite immunosuppressive therapy. While a standard regimen for treating rectal ulcers as a complication of SLE has not been established, combination therapy with steroids and immunosuppressive agents is necessary because of the associated high mortality rate. In this report, we describe a patient with SLE whose condition was complicated with ulcerative lesions in the rectum and sigmoid colon; the lesions were successfully treated with a combination of corticosteroids and tacrolimus therapy. Tacrolimus could be a useful additional or alternative modality for treating rectal involvement in SLE.

Pigment epithelium-derived factor (PEDF) inhibits survival and proliferation of VEGF-exposed multiple myeloma cells through its anti-oxidative properties.

Vascular endothelial growth factor (VEGF) has been reported not only to induce angiogenesis within the bone marrow, but also directly stimulate the proliferation and survival of multiple myeloma cells, thus being involved in the development and progression of this second most common hematological malignancy. We, along with others, have found that pigment epithelium-derived factor (PEDF) has anti-angiogenic and anti-vasopermeability properties both in cell culture and animal models by counteracting the biological actions of VEGF. However, effects of PEDF on VEGF-exposed myeloma cells remain unknown. In this study, we examined whether and how PEDF could inhibit the VEGF-induced proliferation and survival of myeloma cells. PEDF, a glutathione peroxidase mimetic, ebselen, or an inhibitor of NADPH oxidase, diphenylene iodonium significantly inhibited the VEGF-induced reactive oxygen species (ROS) generation, increase in anti-apoptotic and growth-promoting factor, myeloid cell leukemia 1 (Mcl-1) expression, and proliferation in U266 myeloma cells. VEGF blocked apoptosis of multiple myeloma cells isolated from patients, which was prevented by PEDF. PEDF also reduced p22phox levels in VEGF-exposed U266 cells. Furthermore, overexpression of dominant-negative human Rac-1 mutant mimicked the effects of PEDF on ROS generation and Mcl-1 expression in U266 cells. Our present study suggests that PEDF could block the VEGF-induced proliferation and survival of multiple myeloma U266 cells through its anti-oxidative properties via suppression of p22phox, one of the membrane components of NADPH oxidase. Suppression of VEGF signaling by PEDF may be a novel therapeutic target for multiple myeloma.