A genome-wide association study identified PTPN2 as a population-specific susceptibility gene locus for primary biliary cholangitis.

BACKGROUND AIMS: Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-non-specific) and non-shared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC. APPROACH RESULTS: Protein tyrosine phosphatase non-receptor type 2 (PTPN2) was identified as a novel PBC susceptibility gene locus through a GWAS and subsequent genome-wide meta-analysis involving 2,181 cases and 2,699 controls from the Japanese population (GWAS-lead variant: rs8098858, p=2.6×10-8). In-silico and in-vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells (Tfh) and plasmacytoid dendritic cells (pDCs). Infiltration of PTPN2-positive T-cells and pDCs were confirmed in the portal area of the PBC-liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in-vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758. CONCLUSIONS: PTPN2, a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC via an insufficient negative feedback loop caused by the PTPN2 risk allele of rs2292758 in IFN signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.

The Impact of Nutritional Support on Survival Outcomes in Patients with Advanced Gastric Adenocarcinoma Treated with Chemotherapy.

Malnutrition and cachexia occur commonly in patients with advanced gastric cancer (AGC). This study elucidated the effect of nutritional support (NS) on survival outcomes among patients with AGC undergoing chemotherapy. We retrospectively evaluated new AGC cases at our institute between January 2015 and January 2021. Inclusion criteria were unresectable or recurrent chemotherapy-treated gastric adenocarcinoma, ECOG performance status (PS) 0-2, and adequate organ function. Time to treatment failure (TTF) and overall survival (OS) were evaluated, and univariate and multivariate analyses identified prognostic factors. A total of 103 eligible patients were separated into groups: 69 patients (67%) into NS and 34 (33%) into routine care (RC). The median follow-up time was 11.0 mo, (0.5-92). NS was offered to patients with poorer PS (p = 0.03), Glasgow prognostic score (GPS) positivity (p = 0.001), and high neutrophil-to-lymphocyte ratios (cut-off ≤ 3, p = 0.02). Median OS and TTF in the RC and NS groups were 11.6 and 10.4 mo, (p = 0.99) and 4.2 and 5.5 mo, (p = 0.07), respectively. Multivariate analyses identified NS (hazard ratio [HR] = 0.53, p = 0.01) and GPS positivity for TTF, and low body mass index (HR = 2.03, p = 0.007) and GPS positivity (HR = 2.25, p = 0.001) for OS as significant prognostic factors. Thus, NS with chemotherapy is a potentially effective intervention for AGC.

Subclinical hepatitis E virus (HEV) infection detected by nucleic acid amplification test on blood donation: short-term positivity for immunoglobulin G class of antibody against HEV.

A case of subclinical hepatitis E virus (HEV) infection was detected by nucleic acid amplification test on blood donation. The patient was followed-up until day 220 after the blood donation but showed no symptoms throughout the observation period. Aspartate aminotransferase and alanine aminotransferase levels reached the maximum values on day 37 with a slight increase but remained in normal ranges from day 67 to 220. The quantity of HEV RNA at the initial examination on day 13 was 1.1 × 102 copies/mL, which increased to 2.8 × 103 copies/mL by day 37. It was not detected from day 67 to 220. Immunoglobulin G class antibody to HEV (anti-HEV IgG) was below the cut-off value until day 37 and exceeded the cut-off value to positive on day 67, accompanied by normalization of liver function and negative conversion of HEV RNA. Thereafter, the titer decreased gradually, falling below the cut-off value on day 163, and continuing negative until day 220. Although the persistent duration of anti-HEV IgG positive is believed to be generally long, it was within only 126 days for this subclinical case. Further investigation is needed to determine whether short-term positivity for anti-HEV IgG is typical in subclinical HEV infection.

Evaluating patient acceptability and bowel preparation efficacy of sodium picosulfate-magnesium citrate for colonoscopy.

Objective: To evaluate patient acceptability and bowel preparation efficacy of sodium picosulfate-magnesium citrate (PICOPREP) for colonoscopy. Methods: A questionnaire survey regarding the patient acceptability of bowel preparation agent PICOPREP was administered to 54 patients, and its efficacy was evaluated using the Ottawa Bowel Preparation Scale (OBPS). Results: Eighteen (33.3%) participants reported that PICOPREP is very easy to drink, 30 (55.5%) easy, four (7.4%) acceptable, one (1.9%) difficult, and one (1.9%) very difficult. The flavor was very good as reported by eight (14.8%) participants, good by 25 (46.3%), neutral by 20 (37.0%), bad by one (1.9%), and very bad by none. The number of patients who requested PICOPREP was 42 (77.7%), indicating its high acceptability. Evaluation of the OBPS score showed that the rectosigmoid colon had significantly better polyethylene glycol (PEG) scores than PICOPREP, but the entire colon did not show a significant difference between PICOPREP and PEG scores (1.09 ± 0.65 vs. 1.17 ± 0.76, p = 0.632 in the right colon; 0.48 ± 0.52 vs. 0.72 ± 0.66, p = 0.079 in the mid colon, 0.93 ± 0.49 vs. 0.63 ± 0.52, p = 0.012 in the rectosigmoid colon, and 3.28 ± 1.70 vs. 3.20 ± 1.90, p = 0.836 in the entire colon). Conclusion: PICOPREP is considered as one of the important options due to its good patient acceptability and high efficacy similar to PEG.

A genome-wide association study identifying SVEP1 variant as a predictor of response to tolvaptan for cirrhotic ascites.

BACKGROUND & AIMS: Tolvaptan, vasopressin V2-receptor antagonist, has been used for patients with difficult-to-treat ascites in Japan. In this study, we conducted a genome-wide association study (GWAS) in the Japanese population to identify genetic variants associated with tolvaptan's efficacy for patients with hepatic ascites. METHODS: From 2014 through 2018, genomic DNA samples were obtained from 550 patients who were treated with tolvaptan. Of those, 80 cases (non-responder; increase of body weight [BW]) and 333 controls (responder; >1.5 kg decrease of BW) were included in the GWAS and replication study. RESULTS: Genome-wide association study showed 5 candidate SNPs around the miR818, KIAA1109, and SVEP1 genes. After validation and performing a replication study, an SNP (rs2991364) located in the SVEP1 gene was found to have a significant genome-wide association (OR = 3.55, P = 2.01 × 10-8 ). Multivariate analyses showed that serum sodium (Na), blood urea nitrogen (BUN) and SVEP1 SNP were significantly associated with the response (OR = 0.92, P = .003; OR = 1.02, P = .02 and OR = 3.98, P = .000008, respectively). Based on a prediction model of logistic regression analysis in a population with the rs2991364 risk allele, the failure probability (=exp (score: 22.234 + BUN*0.077 + Na*-0.179) (1 + exp (score)) was determined for the detection of non-responders. Assuming a cutoff of failure probability at 38.6%, sensitivity was 84.4%, specificity was 70% and AUC was 0.774. CONCLUSION: SVEP1 rs2991364 was identified as the specific SNP for the tolvaptan response. The prediction score (>38.6%) can identify tolvaptan non-responders and help to avoid a lengthy period of futile treatment.

Cytokines and Chemokines Involved in Hepatitis B Surface Antigen Loss in Human Immunodeficiency Virus/Hepatitis B Virus Coinfected Patients.

It has been reported that hepatic flare (HF), attributable to the development of immune reconstitution inflammatory syndrome (IRIS) in human immunodeficiency virus (HIV)/hepatitis B virus (HBV) coinfected patients, occurs frequently after the start of anti-retroviral therapy (ART). We have observed several cases of hepatitis B surface antigen (HBsAg) loss after IRIS. However, the factors leading to HBsAg clearance remain unknown. We measured CD4+ and CD8+ T cells, cytokines and chemokines in 16 patients coinfected HIV-1 and HBV with IRIS, and analyzed the factors leading to HBsAg clearance after IRIS. There was no significant difference in the CD4+ and CD8+ T cell counts between the HBsAg clearance and non-clearance groups, while the serum concentrations of almost all cytokines and chemokines in the HBsAg clearance group were higher than in the HBsAg non-clearance group at any time of observation. In particular, IP-10 at the ALT peak, GM-CSF and IL-12 one month after the ALT peak and TNF-α and GM-CSF after the ALT concentrations fell to within normal limits, were significantly higher in the HBsAg clearance group. It seems that HBsAg loss after IRIS requires continued immune responses against HBV, involving Th1 cytokines.

Evaluation of Muscle Cramp Associated with Liver Cirrhosis with a Focus on the Liver Function and Nutritional Status.

Objective We investigated the muscle cramp status of patients with liver cirrhosis by focusing on the degree of liver damage, skeletal muscle mass, and nutritional status. Methods All enrolled patients completed a questionnaire about muscle cramps. The degree of liver damage was examined using the Child-Pugh classification and the albumin-bilirubin (ALBI) grade. The nutritional status and skeletal muscle mass were examined using the Controlling Nutritional Status (CONUT) method and the psoas muscle index (PMI). Results Among the respondents, 55.7% of the patients reported experiencing muscle cramps. An analysis of the two patient groups-those who experienced muscle cramps and those who did not-revealed significant differences in Child-Pugh classification (muscle cramp-positive vs. muscle cramp-negative: A/B/C, 54.1%/32.4%/13.5% vs. 90.0%/10.0%/0.0%; p=0.004), ALBI grade (1/2/3, 20.5%/71.8%/7.7% vs. 54.8%/38.7%/6.5%; p=0.011), modified ALBI grade (1/2a/2b/3, 20.5%/20.5%/51.3%/7.7% vs. 54.8%/22.6%/16.1%/6.5%; p=0.008), CONUT score (normal/mild/moderate/severe, 25.6%/28.2%/41.0%/5.1% vs. 22.6%/61.3%/12.9%/3.2%; p=0.024), and PMI (3.85±1.13 cm2/m2 vs. 4.94±1.86 cm2/m2; p=0.012). Conclusion Our findings suggest that muscle cramps occur more frequently in patients with liver cirrhosis due to their decreased liver function and poorer nutritional status.

Successful treatment of adult-onset type II citrullinemia with a low-carbohydrate diet and L-arginine after DNA analysis produced a definitive diagnosis.

A 60-year-old male, who exhibited finger tremors, obnubilation, and hyperammonemia (409 µg/dL), was admitted to our hospital. Initially, we suspected that a portosystemic shunt had caused his hyperammonemia. However, his symptoms did not improve after balloon-occluded retrograde transvenous obliteration. He was subsequently found to have some peculiar eating habits, including a fondness for bean curd and peanuts, and an aversion to alcohol and sweets. Furthermore, marked citrullinemia (454.2 nmol/mL) was revealed, which led us to suspect adult-onset type II citrullinemia (CTLN2). DNA analysis of the patient and his mother, son, and daughter confirmed that he was homozygous for the c.852_855del mutation in the SLC25A13 gene, and his relatives were heterozygous for the c.852_855del mutation, which led to a definitive diagnosis. A low-carbohydrate diet and the administration of L-arginine ameliorated his symptoms. It is important to be aware that CTLN2 can occur in elderly patients. Thus, patients who exhibit symptoms of CTLN2 should be interviewed about their dietary habits and subjected to plasma amino acid analysis.In this report, we consider the metabolic disorders seen in citrin deficiency and the associated compensatory mechanisms in relation to the clinical features and treatment of CTLN2.

POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33.

Primary biliary cholangitis (PBC) is a chronic and cholestatic autoimmune liver disease caused by the destruction of intrahepatic small bile ducts. Our previous genome-wide association study (GWAS) identified six susceptibility loci for PBC. Here, in order to further elucidate the genetic architecture of PBC, a GWAS was performed on an additional independent sample set, then a genome-wide meta-analysis with our previous GWAS was performed based on a whole-genome single nucleotide polymorphism (SNP) imputation analysis of a total of 4,045 Japanese individuals (2,060 cases and 1,985 healthy controls). A susceptibility locus on chromosome 3q13.33 (including ARHGAP31, TMEM39A, POGLUT1, TIMMDC1, and CD80) was previously identified both in the European and Chinese populations and was replicated in the Japanese population (OR = 0.7241, P = 3.5 × 10-9). Subsequent in silico and in vitro functional analyses identified rs2293370, previously reported as the top-hit SNP in this locus in the European population, as the primary functional SNP. Moreover, e-QTL analysis indicated that the effector gene of rs2293370 was Protein O-Glucosyltransferase 1 (POGLUT1) (P = 3.4 × 10-8). This is the first study to demonstrate that POGLUT1 and not CD80 is the effector gene regulated by the primary functional SNP rs2293370, and that increased expression of POGLUT1 might be involved in the pathogenesis of PBC.

TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus by interferon-free therapy.

BACKGROUND: The aim of this study is to ascertain whether the TLL1 variant at rs17047200 is associated with the development of HCC after achieving sustained virological response (SVR) by interferon (IFN)-free therapy for chronic hepatitis C (CHC). METHODS: A total of 1029 Japanese CHC patients with the following inclusion criteria were enrolled: (i) achieved SVR by IFN-free therapy, (ii) followed up at least 1 year from the end of treatment (EOT) (median 104 weeks), (iii) no history of hepatocellular carcinoma (HCC) by 1 year from the EOT. RESULTS: Nineteen patients developed HCC (HCC group) and 1010 did not (non-HCC group). The proportion of rs17047200 AT/TT was significantly higher in the HCC group than the non-HCC group (47.4% vs. 20.1%, P = 0.008). Multivariate analysis showed that higher levels of α-fetoprotein, FIB-4 and rs17047200 AT/TT were independent risk factors for developing HCC (HR = 3.22, P = 0.021 for α-fetoprotein > 4.6 ng/ml; HR = 3.89, P = 0.036 for FIB-4 > 2.67; HR = 2.80, P = 0.026 for rs17047200 AT/TT). Cumulative incidence of HCC was significantly higher in patients with rs17047200 AT/TT than in those with AA (P = 0.006). Comparing clinical characteristics according to the TLL1 genotypes, patients with rs17047200 AT/TT had significantly lower platelet counts and higher levels of FIB-4 than those with AA (P = 0.011 and 0.032, respectively). CONCLUSIONS: The TLL1 variant was independently associated with HCC development after HCV eradication by IFN-free regimen. It might be involved in hepatic fibrogenesis and thereby carcinogenesis.

Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population.

A previous genome-wide association study (GWAS) performed in 963 Japanese individuals (487 primary biliary cholangitis [PBC] cases and 476 healthy controls) identified TNFSF15 (rs4979462) and POU2AF1 (rs4938534) as strong susceptibility loci for PBC. In this study, we performed GWAS in additional 1,923 Japanese individuals (894 PBC cases and 1,029 healthy controls), and combined the results with the previous data. This GWAS, together with a subsequent replication study in an independent set of 7,024 Japanese individuals (512 PBC cases and 6,512 healthy controls), identified PRKCB (rs7404928) as a novel susceptibility locus for PBC (odds ratio [OR] = 1.26, P = 4.13 × 10-9). Furthermore, a primary functional variant of PRKCB (rs35015313) was identified by genotype imputation using a phased panel of 1,070 Japanese individuals from a prospective, general population cohort study and subsequent in vitro functional analyses. These results may lead to improved understanding of the disease pathways involved in PBC, forming a basis for prevention of PBC and development of novel therapeutics.

Efficacy of daclatasvir/asunaprevir according to resistance-associated variants in chronic hepatitis C with genotype 1.

BACKGROUND: The present study explored the treatment outcome of daclatasvir (DCV) and asunaprevir (ASV) therapy combining oral direct-acting antiviral agents (DAAs) for chronic hepatitis C (HCV) including liver cirrhosis according to resistance-associated variants (RAVs) in NS3/NS5A region. METHODS: Overall, 641 patients enrolled in Japan with HCV-1b received DCV and ASV for 24 weeks. Baseline drug-resistant mutations L31F/I/M/V, Q54H, P58S, A92K, and Y93H in the HCV NS5A region and V36A, T54A/S, Q80K/L/R, R155K/T/Q, A156S/V/T, and D168A/E/H/T/V in the HCV NS3/4A region were assessed by direct sequencing. RESULTS: Overall, 86.9 % (543/625) of patients had SVR12, which was significantly higher in NS5A 93Y (wild) (88.3 %) compared with NS5A 93H at baseline (48.0 %), indicating the SVR12 rate was significantly lower in patients with 93H mutations. Additionally, 66.7 % (18/27) of patients with prior triple therapy including simeprevir (SMV) failure had virological failure. The virological failure rate of DCV/ASV therapy after SMV failure was significantly higher in those with preexisting NS3/4A 168 substitutions compared with without substitutions at baseline [84.2 % (16/19) vs. 28.6 % (2/7), p = 0.014]. The number of patients with multiple RAVs or deletions in NS5A increased from 0 to 85 % in failed patients. Alanine aminotransferase elevation was a frequent adverse event causing discontinuation of DCV/ASV therapy, although 87.5 % (14/16) patients achieved SVR12, subsequently. CONCLUSIONS: History of SMV therapy and pre-existing NS5A Y93H were associated with virological failure of DCV/ASV therapy, resulting in the emergence of multiple RAVs. Patients with RAVs at baseline should be assessed to optimize future DAA therapies.

Successful treatment of three patients with human immunodeficiency virus and hepatitis C virus genotype 1b co-infection by daclatasvir plus asunaprevir.

Co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) often accelerates the course of HCV-associated liver disease. Daclatasvir (DCV) plus asunaprevir (ASV) have been shown to be highly effective for HCV-infected patients with genotype 1b. Three patients co-infected with HIV/HCV genotype 1b were enrolled in this study. Prior to initiation of HCV treatment, the variants associated with L31 and Y93 in the non-structural protein 5A (NS5A) region of the HCV genome were confirmed to be absent using a direct sequencing method. Taking into consideration the lower risk of drug-drug interaction and the need for immediate treatment, the patients received 60 mg DCV once daily plus 100 mg ASV twice daily for 24 weeks. In one patient, the alanine aminotransferase level was elevated to 228 IU/L at 24 weeks after the start of treatment, but he completed the 24-week treatment course. All three patients achieved sustained viral response, without severe complications (including HIV virological rebound). Thus, in cases where NS5A variants are confirmed to be absent and patients are antiretroviral therapy-naïve, with CD4+ over 500/µL or HIV well controlled by RAL-based cART, DCV plus ASV may represent a good treatment option for HIV and HCV genotype 1b co-infected patients.

An Hepatitis C Virus (HCV)/HIV Co-Infected Patient who Developed Severe Hepatitis during Chronic HCV Infection: Sustained Viral Response with Simeprevir Plus Peginterferon-Alpha and Ribavirin.

We herein describe the case of a 42-year-old man who developed severe hepatitis caused by hepatitis C virus (HCV) infection at 14 years after the start of human immunodeficiency virus (HIV) treatment. Surprisingly, the levels of alanine aminotransferase (ALT) fluctuated, reaching a peak higher than 1,000 IU/L during chronic HCV infection, and the hepatic histology showed advanced liver fibrosis at 3 years after the primary HCV infection. He was treated with simeprevir, peginterferon-alpha, and ribavirin with a sustained viral response. We conclude that HCV/HIV co-infected patients need to commence anti-HCV therapy when the levels of ALT fluctuate severely under successful HIV control.

Association of STAT4 polymorphisms with susceptibility to type-1 autoimmune hepatitis in the Japanese population.

BACKGROUND/AIMS: Recent studies demonstrated an association of STAT4 polymorphisms with autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis, indicating multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 polymorphisms on the susceptibility and phenotype of type-1 autoimmune hepatitis in a Japanese National Hospital Organization (NHO) AIH multicenter cohort study. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA from 460 individuals of Japanese origin including 230 patients with type-1 autoimmune hepatitis and 230 healthy controls was analyzed for two single nucleotide polymorphisms in the STAT4 gene (rs7574865, rs7582694). The STAT4 rs7574865T allele conferred risk for type-1 autoimmune hepatitis (OR = 1.61, 95% CI = 1.23-2.11; P = 0.001), and patients without accompanying autoimmune diseases exhibited an association with the rs7574865T allele (OR = 1.50, 95%CI = 1.13-1.99; P = 0.005). Detailed genotype-phenotype analysis of type-1 autoimmune hepatitis patients with (n = 44) or without liver cirrhosis (n = 186) demonstrated that rs7574865 was not associated with the development of liver cirrhosis and phenotype (biochemical data and the presence of auto-antibodies). CONCLUSIONS/SIGNIFICANCE: This is the first study to show a positive association between a STAT4 polymorphism and type-1 autoimmune hepatitis, suggesting that autoimmune hepatitis shares a gene commonly associated with risk for other autoimmune diseases.

Concurrent chemoradiotherapy with a novel fluoropyrimidine, S-1, and cisplatin for locally advanced esophageal cancer: long-term results of a phase II trial.

OBJECTIVES: A phase II study was performed to investigate the safety and efficacy of concurrent chemoradiotherapy (CCRT) combined with an orally active fluoropyrimidine, S-1, plus cisplatin for locally advanced esophageal cancer (LAEC). METHODS: CCRT comprised 2 courses, a 30-Gy radiotherapy over 3 weeks plus daily oral S-1 (80 mg/m(2)/day) for 2 weeks and a 24-hour cisplatin infusion (70 mg/m(2)) on day 8, and an identical course administered after a 2-week break. RESULTS: One hundred and sixteen patients, 12 with stage II, 71 with stage III, and 33 with stage IVa LAEC participated, and 106 of them (91.4%) completed the CCRT course. The most serious toxicity was myelosuppression: grade 3 and 4 neutropenia occurred in 28.4 and 9.5% of patients, respectively. Nonhematologic toxicity was moderate. Complete response rates in patients with stage II, III, and IVa LAEC were 91.7, 67.6, and 36.4%, respectively. The overall median survival time was 2.3 years and that of patients with stage II, III, and IVa cancer was 7.0, 2.6, and 1.3 years, respectively. CONCLUSIONS: CCRT combined with S-1 plus cisplatin showed promising safety and efficacy. Potentially, this combination therapy could become a baseline medication for patients with LAEC.

[Clinical evaluation of peginterferon α plus ribavirin for patients co-infected with HIV and HCV at Nagoya Medical Center].

At Nagoya Medical Center, 10 patients co-infected with HIV and HCV received peginterferon α (PEG-IFNα) plus ribavirin therapy. Three of the cases were HCV genotype 1b, 2 cases were HCV 3b, and 1 case each were 2b, 2c, 3a, 4a and 6n. Nine patients received anti HIV therapy from the beginning. In 5 of these patients, anti HIV therapy was modified when PEG-IFNα plus ribavirin treatment was started. Of the above, 7 patients completed the protocol. No patients had severe adverse effects. Sustained virological response was achieved in 1 of 4 (25%) of the patients with genotypes 1 or 4, and in 5 of 6 (83%) of the patients with other genotypes. PEG-IFNα plus ribavirin therapy is considered a safe and efficacious treatment for patients co-infected with HIV and HCV.

Efficacy and safety of double filtration plasmapheresis in combination with interferon therapy for chronic hepatitis C.

AIM: Efficacy and safety of double filtration plasmapheresis (DFPP) for chronic hepatitis C were prospectively analyzed in Japanese clinical settings. METHODS: All patients who received DFPP in combination with interferon (IFN) therapy for chronic hepatitis C were serially recruited at 36 institutions between April 2008 and July 2009 in Japan. RESULTS: A total of 239 patients were analyzed for the safety of DFPP and 206 patients for the efficacy. Of the 206 patients, 181 patients were treated with DFPP in combination with pegylated interferon plus ribavirin (PEG-IFN/RBV + DFPP). Among the 181 patients, 60 patients (33.1%) were treatment-naïves, 35 (19.3%) relapsers and 62 (34.3%) non-responders. Complete early virological response (cEVR) in patients treated with PEG-IFN/RBV + DFPP was achieved in 57.5% overall, 70.0% in treatment-naïves, 57.1% in relapsers and 41.9% in non-responders. In patients with previous PEG-IFN/RBV therapy, cEVR were found in 63.0% of relapsers and 18.9 % of non-responders, and cEVR in patients with other than PEG-IFN/RBV therapy as previous IFN therapy, relapsers and non-responders was 37.5% and 76.0%, respectively. Adverse events were found in 55 patients (23.0%). Serious adverse events were found in four patients (1.7%) who showed puncture-site injury. Adverse events were related to female sex, but not related to age, and DFPP could be performed safely. CONCLUSION: The cEVR results in this study suggest that high rates of sustained virological response can be achieved in retreated and treatment-naïve patients using DFPP in combination with PEG-IFN/RBV therapy. Results indicate that this therapy could be safely conducted, even in elderly patients.

A pilot study of leukocytapheresis efficacy with 1.5 liter blood processing volume in patients with ulcerative colitis.

Standard leukocytapheresis (LCAP) protocols recommend the processing of a 3 L blood volume. In this study, we evaluated the clinical effects of LCAP with 1.5 L of blood processing (1.5L-LCAP) in patients with active ulcerative colitis (UC). Ten patients with moderate to severe UC were enrolled. Their clinical and endoscopic responses, the kinetics of the peripheral blood counts and cytokine responses were evaluated. Clinical and endoscopic effects were assessed using the clinical activity index described by Rachmilewitz, and by Matts' endoscopic classification, respectively. The 1.5L-LCAP induced clinical remission in 8 out of 10 patients (80%). Endoscopic improvement was noted in 6 out of 7 patients (85.7%). Prednisolone (PSL) was used in 8 patients; the PSL dose could be reduced in 6 patients, and weaning was possible in one patient. Adverse effects were not observed during 1.5L-LCAP therapy. During the 1.5L-LCAP session, the leukocyte count reached the minimum at 1.0 L of blood processing, but promptly increased after completion of the session, and reached a maximum after 30 min. Interleukin (IL)-1beta-induced IL-8 and IL-6 secretion by peripheral blood mononuclear cells were both significantly reduced by 1.5L-LCAP therapy. 1.5L-LCAP was clinically effective for active UC patients. Cellular responses induced by 1.5L-LCAP were similar to those induced by a standard LCAP session.

Evaluation of anti-hepatitis E virus (HEV) immunoglobulin A in a serological screening for HEV infection.

BACKGROUND: Several formulations of serological diagnostic kits were developed recently in Japan for detecting hepatitis E virus (HEV) infection. The present study was conducted to evaluate a novel anti-HEV serological kit based on detection of class A immunoglobulin antibody (anti-HEV IgA). METHODS: Serum samples from 81 acute hepatitis (AH) and 112 chronic hepatitis (CH) patients were tested for anti-HEV IgG, anti-HEV IgM, and anti-HEV IgA by enzyme immunoassay, and HEV RNA was detected by reverse transcription-polymerase chain reaction. RESULTS: Eight of 81 (9.9%) AH patients were positive for anti-HEV IgG; 6/81 (7.4%) were positive for anti-HEV IgM; and 3/81 (3.7%) were positive for anti-HEV IgA. HEV RNA was detected only in two patients, and both were positive for anti-HEV IgA and negative for hepatitis A, B, and C virus markers. Of 112 CH patients, reactivity to anti-HEV IgM and anti-HEV IgG was found in two and four patients, respectively. None of these six patients was positive for anti-HEV IgA or HEV RNA. For these six CH patients, serial serum samples stored during the clinical follow-up (1994-2003) were further subjected to anti-HEV IgG, IgM, IgA, and HEV RNA examinations. None of the examined stored samples was reactive for anti-HEV IgA or HEV RNA despite reactivity to anti-HEV IgM and IgG. CONCLUSIONS: Serological examination for anti-HEV IgA together with IgM and IgG allows sensitive and specific determination of acute or past infection with HEV. Although its prevalence is low, HEV infection must be investigated in acute hepatitis patients even in nonendemic HEV countries.