Significance of portal venous blood flow as a factor to determine liver function in patients with decompensated cirrhosis due to hepatitis C virus infection following achievement of sustained viral response by sofosbuvir plus velpatasvir.

AIM: To determine the outcomes concerning portal venous blood flow and portosystemic shunts in patients with decompensated cirrhosis due to hepatitis C virus (HCV) infection who achieved sustained viral response (SVR) following antiviral therapy. METHODS: Portal hypertension-related events and liver function were evaluated in 24 patients achieving SVR following sofosbuvir plus velpatasvir therapy. RESULTS: Serum albumin level (median; g/dL) increased from 2.9 at baseline to 3.5 at 12 weeks after the end of treatment (EOT) (p = 0.005), while liver volumes (cm3 ) decreased from 1260 to 1150 (p = 0.0002). Portal hypertension-related events developed in 10 patients (41.7%), and the cumulative occurrence rates after the EOT were 29.2%, 33.3%, and 46.1% at 24, 48, and 96 weeks, respectively. Multivariate logistic regression analysis revealed that the maximal diameter of the shunts (p = 0.0235) was associated with the development of the events, with a cut-off value of 8.3 mm (p = 0.0105). Meanwhile, multiple linear regression analysis revealed that portal venous blood flow, liver volume, serum albumin, and bilirubin levels at baseline were associated with serum albumin levels at 12 weeks after EOT (p = 0.0019, p = 0.0154, p = 0.0010, and p = 0.0350, respectively). CONCLUSION: In patients with decompensated cirrhosis due to HCV infection, the baseline portal venous blood flow and liver volume and function were predictive of liver function following SVR, while the maximal diameter of portosystemic shunts predicted the occurrence of portal hypertension-related events.

Significance of furosemide in patients with cirrhosis treated with or without zinc acetate hydrate supplementation.

BACKGROUND: The Japanese guidelines for the treatment of cirrhosis suggest zinc supplementation to prevent hepatic encephalopathy in patients with cirrhosis and zinc deficiency, although the factors that are associated with therapeutic efficacy remain unknown. METHOD: A total of 159 patients with chronic liver diseases but without previous zinc supplementation were analyzed. Factors associated with serum zinc levels as well as the therapeutic efficacy of zinc supplementation were evaluated. RESULT: Serum zinc levels decreased with the progression of liver diseases. A multiple linear regression analysis revealed that the serum levels of albumin and cholinesterase and the daily furosemide dose were independently associated with the serum zinc levels. The optimal furosemide cut-off dosage for patients with zinc deficiency (<60 µg/dl) was 5 mg/day. Among 34 patients receiving zinc acetate hydrate, overt hepatic encephalopathy occurred in 12 patients (35.4%). A multivariate analysis identified a minimal serum zinc level of 50 µg/dl after more than 12 weeks of zinc supplementation as a factor associated with overt encephalopathy development, while furosemide use was not associated. The Child-Pugh score at baseline was the only factor associated with the maintenance of sufficient serum zinc levels. CONCLUSION: Although the furosemide dose was negatively correlated with the serum zinc level in patients with chronic liver diseases, furosemide use was not associated with the occurrence of overt encephalopathy in those receiving zinc supplementation. Serum zinc levels of ≥50 µg/dl were required to prevent overt encephalopathy development during zinc supplementation in both patients with and those without furosemide administration.

Superiority of tenofovir alafenamide fumarate over entecavir for serum HBsAg level reduction in patients with chronic HBV infection: A 144-week outcome study after switching of the nucleos(t)ide analog.

BACKGROUND: To evaluate the long-term efficacy of switching of the nucleos(t)ide analog used for treatment from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) in patients with chronic HBV infection. METHODS: A total of 103 patients with serum HBsAg levels of ≥100 IU/mL who had received ETV were enrolled. The nucleos(t)ide analog used for the treatment was switched from ETV to TAF, and the changes in serum HBsAg levels during the 144-week period before and after the drug switching were compared in 74 patients who had received ETV at least for 192 weeks. RESULTS: Significant decreases of serum HBsAg levels were observed during both the ETV and the TAF administration period, although the degree of reduction was greater during the latter period than during the former period (P<0.001). Significant decreases of serum HBsAg levels were seen in both patients with genotype B HBV infection and genotype C HBV infection, irrespective of the serum HBsAg and HBcrAg levels at the time of the drug switching. CONCLUSION: Switching of the nucleos(t)ide analog used for treatment from ETV to TAF merits consideration in patients with chronic HBV infection, since the extent of reduction of the serum HBsAg level was greater during the TAF treatment period than during the ETV treatment period.

Furosemide as a factor to deteriorate therapeutic efficacy of tolvaptan in patients with decompensated cirrhosis.

AIM: To optimize the therapeutic strategy for patients with decompensated cirrhosis manifesting hepatic ascites and/or edema, factors affecting the outcome of patients receiving tolvaptan were evaluated. METHODS: The subjects were 165 patients receiving tolvaptan including 116 patients (70%) also treated with furosemide. The therapeutic efficacy of tolvaptan was defined as "effective" when a body weight reduction of 1.5 kg or more was obtained within 1 week. The long-term outcome was defined as "favorable" when the ascites-related events-free duration was prolonged following tolvaptan treatment, compared with that before treatment, or ascites-related events were absent for at least 120 days during treatment based on the hazard function analysis. RESULTS: Tolvaptan was effective in 115 patients (70%). Among them, the long-term outcome was evaluated in 99 patients and was favorable in 70 patients (71%). A multivariate analysis revealed that the serum blood urea nitrogen levels at baseline (odds ratio 0.960 per +1 mg/dL, P = 0.021) and the type of tolvaptan initiation (planned vs. emergent; 3.695, P < 0.001) were associated with therapeutic efficacy, while the furosemide dose (0.280 per +20 mg/day, P = 0.014) and previous ascites-related events (0.074, P < 0.001) were associated with the long-term outcome. Receiver operating curve analyses identified the optimal cut-off values for the furosemide dose as 15 mg/day (P < 0.001). Furthermore, the cumulative survival rates in patients receiving furosemide at 15 mg/day or less were significantly higher than those in the remaining patients (P = 0.048). CONCLUSION: Furosemide given at baseline contributed to an unfavorable outcome in patients receiving tolvaptan; consequently, tolvaptan should be given before increasing the furosemide dose.

Furosemide as a factor to deteriorate therapeutic efficacy of rifaximin in patients with decompensated cirrhosis.

AIM: To optimize the therapeutic strategy for cirrhotic patients manifesting hepatic encephalopathy, factors affecting the outcome of patients receiving rifaximin were evaluated. METHODS: The subjects were 95 patients receiving rifaximin. Serum ammonia levels were measured serially during rifaximin treatment. Factors associated with long-term outcomes and cumulative survival rates were evaluated. RESULTS: Serum ammonia levels were decreased at 4 weeks after rifaximin treatment compared to the levels at baseline even in patients receiving rifaximin as an add-on therapy with lactitol hydrate (P < 0.001) and reduction values were negatively correlated with the maximal diameter of portosystemic shunts (r = -0.275, P = 0.009). Overt encephalopathy occurred in 37 patients (38.9%) during rifaximin treatment, and the hazard function analysis identified 90 days as a high-risk term for developing the first-time overt encephalopathy. Thus, the long-term outcome was judged as favorable in 77 patients (81.1%) in whom overt encephalopathy was absent for at least 90 days during rifaximin initiation. A multivariate analysis revealed that furosemide, especially at daily doses of ≥20 mg both at baseline and during rifaximin treatment, was a significant factor associated with unfavorable outcome (P = 0.009 and P = 0.022, respectively) as well as occurrence and recurrence of overt encephalopathy (P = 0.012). Moreover, furosemide treatment significantly deteriorated the cumulative survival rate of patients receiving rifaximin (P = 0.026). CONCLUSION: Furosemide contributed to the deteriorated outcome of patients receiving rifaximin. Consequently, rifaximin should be given before increasing the furosemide dose, and the furosemide dose should not be increased during rifaximin treatment.

Involvement of portosystemic shunts in impaired improvement of liver function after direct-acting antiviral therapies in cirrhotic patients with hepatitis C virus.

AIM: Factors responsible for impaired improvement of liver function despite sustained viral response after direct-acting antiviral agents therapies in cirrhotic patients with hepatitis C virus need to be elucidated. METHODS: Liver function and the extent of portosystemic shunting were evaluated for 79 patients with compensated cirrhosis, in whom sustained viral response had been achieved after direct-acting antiviral agents therapies for hepatitis C virus at least 3 years earlier. RESULTS: Portosystemic shunts were observed in 63 patients (80%). Improvement and worsening, as compared with the baseline, of esophageal/gastric varices after direct-acting antiviral agents therapies was seen in three patients (4%) and 10 patients (13%), respectively. Portal hypertension-related events, such as varices and ascites requiring treatment, were observed in six patients (8%), in whom three patients showing worsening of Child-Pugh scores were included. Multivariate analysis showed that maximal diameter of the shunts (P = 0.012) and serum Mac-2 binding protein glycosylation isomer levels at the end of treatment (P = 0.005) were associated with the development of portal hypertension-related events, with cut-off values of 5.25 mm (P = 0.001) and 6.84 cut-off index (P < 0.001), respectively. The increase of serum albumin levels at 3 years, as compared with the baseline, was smaller in 22 patients having shunts with maximal diameters of ≥5 mm than in the remaining 57 patients (P = 0.034), whereas no such difference was seen between the patients with and without elevation of serum Mac-2 binding protein glycosylation isomer level of ≥6.8 cut-off index. CONCLUSIONS: A large size of portosystemic shunts was found to be a crucial determinant of impaired improvement of liver function, as well as of the development of portal hypertension-related events, even after sustained viral response in patients with compensated cirrhosis.

Significance of switching of the nucleos(t)ide analog used to treat Japanese patients with chronic hepatitis B virus infection from entecavir to tenofovir alafenamide fumarate.

The significance of switching of the nucleos(t)ide analog used to treat patients with hepatitis B virus (HBV) from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) is uncertain. The subjects of this study were 159 patients with HBV who received treatment with ETV followed by TAF. Among these patients, serial changes in the HBV marker levels were monitored in 92 patients in whom the serum HBsAg levels were ≥100 IU/mL during the 48-week period immediately before and after the switching. A questionnaire survey for medication compliance was performed in 127 patients. The serum HBsAg levels (log IU/mL) decreased by 0.041 during the ETV treatment period and by 0.068 during the TAF administration period. The degree of reduction was higher during the TAF administration period than during the ETV administration period in patients without cirrhosis (P = .030), patients with genotype B HBV (P = .014), and patients with undetectable serum HBcrAg (P = .038). Multivariate analysis revealed the HBV genotype (B vs C; odds ratio, 3.400; P = .025) and serum aspartate aminotransferase level (every 1+; 1.111; P = .015) at the time of switching as factors influencing the treatment efficacy. Thirty-six patients (28%) responded that the number of days that they forgot to take the drug decreased after the drug switching, and 77 patients (61%) reported feeling satisfied with the drug switching. Switching of the nucleos(t)ide analog used from ETV to TAF may be useful in the treatment of patients with HBV infection, as it is associated with both a decrease in the serum HBsAg level and improvement of the medication compliance.

Deteriorated outcome of recent patients with acute liver failure and late-onset hepatic failure caused by infection with hepatitis A virus: A subanalysis of patients seen between 1998 and 2015 and enrolled in nationwide surveys in Japan.

AIM: A nationwide survey of acute liver failure (ALF) and late-onset hepatic failure (LOHF) has revealed that the outcomes of recent patients whose diseases were caused by infection with hepatitis A virus (HAV) have worsened, compared with those of previously reported patients. The factors associated with this deterioration were evaluated. METHODS: A total of 83 patients with HAV infection seen between 1998 and 2015 were enrolled. All the patients had a prothrombin time-international normalized ratio of 1.5 or more and hepatic encephalopathy of grade 2 or more severe. The demographic and clinical features of 45 patients seen prior to 2003 (cohort 1) and 38 patients seen during 2004 and thereafter (cohort 2) were compared. RESULTS: Three and four patients in cohort 1 and cohort 2, respectively, received liver transplantations; the survival rates among the remaining patients were 56% for cohort 2 and 79% for cohort 1 (P < 0.05). The mean age (±standard deviation) of the patients was higher in cohort 2 than in cohort 1 (58 ± 11 vs. 48 ± 13 years; P < 0.01). The percentages of patients with underlying metabolic diseases were 22% in cohort 1 and 61% in cohort 2 (P < 0.01). Diabetic mellitus was more common among deceased patients than among rescued patients (29% vs. 8%; P < 0.05) among patients who did not receive liver transplantations, and a multivariate analysis revealed that patient age and disease type were significantly and independently associated with the outcome. CONCLUSION: The outcomes of recent patients with ALF or LOHF caused by HAV infection have recently worsened mainly because of an increase in underlying metabolic diseases as a consequence of aging.

A case of genotype-3b hepatitis C virus in which the whole genome was successfully analyzed using third-generation nanopore sequencing.

A 42-year-old Chinese man with chronic hepatitis C virus (HCV) infection visited our hospital for antiviral therapy. The subgenotype could not be determined using the HCV GENOTYPE Primer Kit (Institute of Immunology, Tokyo, Japan), which can identify genotype 3a HCV exclusively among genotype 3 HCV. Thus, the whole-genome sequence of HCV was analyzed using the MinION nanopore sequencer (Oxford Nanopore Technologies, Oxford, UK), a third-generation single-molecule sequencing platform. Consequently, a total of 9442 bases with a 73.6 mean depth, corresponding to the sequences between nt25 and PolyU/UC were determined (LC414155.2). The similarity analysis revealed that the obtained sequence was classified into genotype 3b HCV and showed nucleotide identities from 87.6% to 93.9% with those of 12 previously reported strains. Furthermore, possible resistance-associated substitutions in non-structural protein (NS)3, NS5A, and NS5B based on consensus sequences of 12 genotype 3b HCV strains, including NS5A-Y93H and NS5B-S282 T substitutions, were absent. In conclusion, the MinION nanopore sequencer is useful for analyzing the HCV genome, especially the genomes of genotype 3 HCV strains for which standardized real- time PCR methods for all subgenotypes have not been established.

NS5A-P32 deletion as a factor involved in virologic failure in patients receiving glecaprevir and pibrentasvir.

BACKGROUND: This study sought to clarify the factors involved in virologic failure in patients with HCV receiving retreatment with glecaprevir/pibrentasvir (GLE/PIB) in real-world practice. METHODS: Forty-two patients who had previously received direct-acting antivirals (DAAs) therapies consisting of 35, 3, 3, and 1 patient(s) with genotype (GT)-1b, GT-2a, GT-2b, and GT-3b HCV, respectively, received GLE/PIB for 12 weeks. Resistance-associated substitutions (RASs) at baseline were evaluated, and the dynamics of NS5A-RASs were assessed by deep sequencing in patients showing virologic failure. RESULTS: Baseline NS5A-RASs were found in all the patients with GT-1b HCV including 16 patients with NS3-RASs. In contrast, both NS5A-RASs and NS3-RASs were absent in 3 and 2 patients with GT-2a and GT-2b HCV, respectively. Virologic failure occurred in 3 patients with GT-1b HCV with NS5A-P32del, while a sustained virologic response (SVR) was achieved in the remaining 39 patients including those with GT-1b HCV carrying NS5A-L31V + Y93H and NS5A-A92K. Virologic failure even occurred in a patient in whom the NS5A-P32del HCV strains had become undetectable by direct sequencing, and the percentage of such strains relative to the total HCV strains was 10%, as determined by deep sequencing. In the other patient with GT-1b HCV with NS5A-P32del, NS3-A156A/V/S were found at 4 weeks after GLE/PIB therapy, but had disappeared at 11 weeks, as determined by direct sequencing. CONCLUSIONS: GLE/PIB was effective for patients with HCV who failed to achieve an SVR after prior DAA therapies except in those with GT-1b HCV carrying NS5A-P32del even when such strains became undetectable by direct sequencing.

Serum asunaprevir concentrations showing correlation with the extent of liver fibrosis as a factor inducing liver injuries in patients with genotype-1b hepatitis C virus receiving daclatasvir plus asunaprevir therapy.

AIMS: Liver injury can occur during antiviral therapies with direct-acting antivirals (DAAs), potentially necessitating discontinuation of the therapies, with consequent worsening of the sustained viral response (SVR) rates, in patients with hepatitis C virus (HCV). To clarify the mechanisms involved in serum transaminase level elevation, we performed a retrospective evaluation of the serum concentrations of daclatasvir and asunaprevir, both classified as DAAs, in patients receiving treatment with a combination of the two drugs. METHODS: Subjects were 278 Japanese patients with genotype-1b HCV who received daclatasvir plus asunaprevir therapy for more than 4 weeks. Serum concentrations of both the DAAs were measured at 4 weeks after the initiation of therapy. RESULT: Liver injuries including serum AST and/or ALT level elevation to 150 U/L or over were found in 34 patients (12.2%). Multivariate logistic regression analysis identified serum asunaprevir concentrations as being significantly associated with developing liver injury, with an odds ratio of 1.046 (95% confidence interval 1.011-1.082, p<0.05). Serum asunaprevir concentrations showed correlation with the extent of liver fibrosis, estimated by peripheral platelets counts and serum albumin levels and baseline and FIB4 index and serum Mac-2 binding protein glycosylation isomer (M2BPGi) levels at 4 weeks of the therapy; the concentrations were significantly higher among patients showing 3.0 or more of M2BPGi levels than among those with the levels less than 3.0; on the other hand, no such correlation/difference was found in serum daclatasvir concentrations. CONCLUSION: High serum concentrations of serum asunaprevir, which were associated with the extent of liver fibrosis, appear to provoke the occurrence of liver injury in patients with genotype-1b HCV receiving combined daclatasvir plus asunaprevir therapy.

Retreatment with sofosbuvir/ledipasvir with or without lead-in interferon-ß injections in patients infected with genotype 1b hepatitis C virus after unsuccessful daclatasvir/asunaprevir therapy.

AIM: To improve the therapeutic efficacy of sofosbuvir/ledipasvir (SOF/LDV) for the retreatment of patients after daclatasvir/asunaprevir (DCV/ASV), a customized therapy with or without lead-in interferon (IFN)-ß injections was formulated according to the types of resistance-associated substitutions (RAS) in the non-structural protein (NS)5A region of genotype 1b hepatitis C virus (HCV). METHODS: Thirty-three patients failing prior DCV/ASV received SOF/LDV for 12 weeks. Patients with HCV carrying unfavorable NS5A-RAS and/or those previously treated with simeprevir were given lead-in IFN-ß injections twice a day for 2 weeks; sequential changes in the NS5A-RAS during the injection period were evaluated using deep sequencing. RESULTS: Lead-in injections were not undertaken in 27 patients; a sustained viral response (SVR) was achieved in 26 patients, while viral relapse occurred in 1 patient with HCV carrying NS5A-L28M/R30H/Y93H mutations. Among the 6 patients receiving lead-in injections, viral relapse occurred in 2 patients who had an unfavorable IFN-λ3-related gene single nucleotide polymorphism allele; both patients had been previously treated with simeprevir, and HCV carrying NS5A-L31V/Y93H mutations had emerged after DCV/ASV. Deep sequencing revealed no changes in the NS5A-RAS profiles during the lead-in injection period in either patient. In contrast, in a patient with a favorable allele who was infected with similar unfavorable HCV strains, NS5A-L31/Y93 wild-type strains appeared during the injection period, enabling an SVR. CONCLUSION: Using customized therapies based on the NS5A-RAS profiles, a high SVR rate was obtained after SOF/LDV in patients failing prior DCV/ASV. Lead-in IFN-ß injections did not improve the efficacy in patients with HCV carrying unfavorable NS5A-RAS except in those with a favorable IFN-λ3-related gene allele.

Chronic hepatitis caused by hepatitis C virus showing a discrepancy between serogroup and genotype because of intergenotypic 2b/1b recombination: A pitfall in antiviral therapy with direct-acting antivirals.

A 40-year-old male patient with virologic relapse after daclatasvir plus asunaprevir therapy for a serogroup 1 hepatitis C virus (HCV) infection visited our hospital for retreatment. Virologic examinations revealed that a genotype 2b HCV strain carrying both NS3-S122N / D168A and NA5A-R30Q / L31M / Q54H / Y93H mutations had relapsed. The patient received sofosbuvir plus ribavirin therapy, but virologic relapse occurred once again. Sequencing of the HCV genome clarified an intergenotypic recombination of 2b and 1b with an estimated crossover point between nucleotides 3114 and 3115, corresponding to the N-terminal end of the NS3 region (DDBJ/EMBL/GenBank databases accession no. LC273304). The NS5B-S282T mutation was not detected in the HCV strain, and resistance-association substitutions in the NS3 and NS5A regions were similar to those at baseline. Direct sequencing of the core and NS4A regions corresponding to the targeting sites of genotyping and serogrouping, respectively, is useful to determine the combination of direct-acting antivirals when a discrepancy is observed between the serogroup and genotype of HCV strains.

Nationwide survey for acute liver failure and late-onset hepatic failure in Japan.

BACKGROUND: A nationwide survey was performed to clarify the recent status of acute liver failure (ALF) and late-onset hepatic failure (LOHF) in Japan. METHODS: Two-step surveys for patients with ALF and LOHF meeting the Japanese diagnostic criteria were performed annually in 782 hospitals. The clinical features of the patients were then compared to those reported in previous surveys. RESULTS: In total, 1554 and 49 patients with ALF and LOHF, respectively, who were seen between 2010 and 2015 were enrolled. The subjects were classified into 1280 patients with hepatitis (642 non-comatose and 638 comatose) and 323 patients without hepatitis (190 non-comatose and 133 comatose). Compared with patients seen between 1998 and 2009, an older patient age and a higher percentage of underlying extrahepatic disease were observed. Although hepatitis virus infection was the most frequent etiology, the percentage of patients with this etiology had decreased, compared with previous cohorts, while the percentages of patients with drug-induced liver injuries, autoimmune hepatitis, and an indeterminate etiology had increased. Liver transplantation was performed in 170 patients (10.6%), whereas artificial liver support with plasmapheresis and/or hemodiafiltration were performed for most of the comatose patients. The outcomes of comatose patients were unfavorable, similar to previous surveys, especially the outcomes of hepatitis B virus carriers, including those with de novo hepatitis B (survival rate of 5.4% without liver transplantation). CONCLUSION: Although the clinical features, including the etiologies, of patients with ALF and LOHF have changed, the outcomes of patients have not improved in recent years.

Nationwide prospective and retrospective surveys for hepatitis B virus reactivation during immunosuppressive therapies.

BACKGROUND: The significance of HBV reactivation during immunosuppressive therapy was evaluated in three nationwide cohorts including patients with previously resolved HBV (prHBV) infection. METHODS: The clinical features of 1061 patients with acute liver failure (ALF) or late-onset hepatic failure (LOHF) were retrospectively examined, focusing on those who experienced HBV reactivation. Additionally, 420 patients with prHBV infection were prospectively enrolled: 203 received immunosuppressive therapies immediately after enrollment, while the remaining 217 were enrolled after having received immunosuppressive therapies without the occurrence of HBV reactivation. The serum HBV-DNA levels were prospectively monitored every month, and the incidences of HBV reactivation, defined as a serum HBV-DNA level of 1.3 log IU/ml or more, were evaluated. RESULTS: In the retrospective study, persistent HBV infection was found in 90 patients, and HBV reactivation was responsible for liver injuries in 50 patients including 23 receiving immunosuppressive therapies (26 with HBs-antigen positivity, 7 with prHBV infection). None of seven patients with prHBV infection were rescued. In the prospective studies, HBV reactivation occurred in ten patients, but preemptive entecavir administration prevented liver injury. The cumulative reactivation rate was 3.2 % at 6 months, and the increase of the rate compared to that at 6 months was +1.5 % at 48 months. CONCLUSIONS: HBV reactivation during immunosuppression was responsible for liver injuries in a quarter of the ALF/LOHF patients with persistent HBV infection. Early serum HBV-DNA monitoring may improve patient prognosis, since HBV reactivation typically occurs within 6 months of the start of immunosuppressive therapies in patients with prHBV infection.

Significance of variants associated with resistance to NS5A inhibitors in Japanese patients with genotype 1b hepatitis C virus infection as evaluated using cycling-probe real-time PCR combined with direct sequencing.

BACKGROUND: Dual oral therapy with daclatasvir plus asunaprevir yielded an SVR rate of 85% among patients with genotype 1b HCV. Treatment failure mainly occurred in patients with pre-existing HCV with NS5A-Y93H mutation. The significance of the mutation was evaluated. METHODS: The percent of serum NS5A-Y93H strains relative to the total strains was quantified using cycling-probe real-time PCR combined with direct sequencing in 444 patients with genotype 1b HCV, and the factors associated with mutation were analyzed. The mutation rates during interferon therapy were measured sequentially. RESULTS: NS5A-Y93H strains (1-100% of the total strains) were detected in 87 patients (19.6%). Mutant strains were detected more frequently among women than among men, in patients with a favorable allele in the IL28B-related gene SNP than among those with unfavorable alleles, and among patients without HCC and/or with serum AFP levels less than 6.0 ng/ml than among those with HCC and/or levels of 6.0 ng/ml or more. A multivariate analysis revealed that IL28B-related gene polymorphisms were significant factors associated with mutant strains. Although the frequency of patients with mutant strains was equivalent among patients depending on their previous interferon therapies, a sequential analysis during the interferon administrations revealed that the mutant strains disappeared earlier than the wild-type strains. CONCLUSIONS: NS5A-Y93H mutation was associated with sex, serum AFP levels, and IL28B-related gene polymorphisms in patients infected with genotype 1b HCV. The indications for NS5A inhibitor use should be determined based on these factors, since mutant strains seem to be sensitive to interferon.

Usefulness of the DL in ME with NBI for determining the expanded area of early-stage differentiated gastric carcinoma.

AIM: To investigate whether magnifying endoscopy with narrow band imaging (ME-NBI) is useful for evaluating the area of superficial, depressed- or flat-type differentiated adenocarcinoma of the stomach. METHODS: This procedure was performed in Saitama Medical University International Medical Center, Japanese Red Cross Kumamoto Hospital and Kitakyushu Municipal Medical Center. The subjects were 31 patients in whom biopsy findings, from superficial, depressed- or flat-type gastric lesion, suggested differentiated adenocarcinoma in the above 3 hospitals between January and December 2009. Biopsy was performed on the lesion and non-lesion sides of a boundary (imaginary boundary) visualized on ME-NBI. The results were pathologically investigated. We evaluated the accuracy of estimating a demarcation line (DL) on ME-NBI in comparison with biopsy findings as a gold standard. RESULTS: The DL that could be recognized at 2 points on the orifice and anal sides of each lesion during ME-NBI was consistent with the pathological findings in 22 patients with 0-IIc lesions, 7 with 0-IIb lesions, and 2 with 0-IIb + IIc lesions, showing an accuracy of 100%. CONCLUSION: The results suggest the usefulness of ME-NBI for evaluating the area of superficial, depressed- and flat-type differentiated adenocarcinoma of the stomach.

Possibilities of interventional endoscopic ultrasound.

Since endoscopic ultrasound (EUS) was developed in the 1990s, EUS has become widely accepted as an imaging tool. EUS is categorized into radial and linear in design. Radial endoscopes provide cross-sectional imaging of the mediastinum, gastrointestinal tract, liver, spleen, kidney, adrenal gland, and pancreas, which has highly accuracy in the T and N staging of esophageal, lung, gastric, rectal, and pancreatic cancer. Tumor staging is common indication of radial-EUS, and EUS-staging is predictive of surgical resectability. In contrast, linear array endoscope uses a side-viewing probe and has advantages in the ability to perform EUS-guides fine needle aspiration (EUS-FNA), which has been established for cytologic diagnosis. For example, EUS-FNA arrows accurate nodal staging of esophageal cancer before surgery, which provides more accurate assessment of nodes than radial-EUS imaging alone. EUS-FNA has been also commonly used for diagnose of pancreatic diseases because of the highly accuracy than US or computed tomography. EUS and EUS-FNA has been used not only for TNM staging and cytologic diagnosis of pancreatic cancer, but also for evaluation of chronic pancreatitis, pancreatic cystic lesions, and other pancreatic masses. More recently, EUS-FNA has developed into EUS-guided fine needle injection including EUS-guided celiac plexus neurolysis, celiac plexus block, and other "interventional EUS" procedures. In this review, we have summarized the new possibilities offered by "interventional EUS".

A case of gastric mucosa-associated lymphoid tissue lymphoma in which magnified endoscopy with narrow band imaging was useful in the diagnosis.

Recently, we reported a case of gastric mucosa-associated lymphoid tissue (MALT) lymphoma presenting with unique vascular features. In the report, we defined the tree-like appearance (TLA) on the images of abnormal blood vessels which resembled branches from the trunk of a tree in the shiny mucosa, in which the glandular structure was lost. The 67-year-old female was diagnosed with gastric MALT lymphoma. The patient received eradication therapy for H. pylori. Conventional endoscopy revealed multiple ill-delineated brownish depressions in the stomach and cobblestone-like mucosa was observed at the greater curvature to the posterior wall of the upper gastric body 7 mo after successful eradication. Unsuccessful treatment of gastric MALT lymphoma was suspected on conventional endoscopy. Conventional endoscopic observations found focal depressions and cobblestone-like appearance, and these lesions were subsequently observed using magnified endoscopy combined with narrow band imaging to identify abnormal vessels presenting with a TLA within the lesions. Ten biopsies were taken from the area where abnormal vessels were present within these lesions. Ten biopsies were also taken from the lesions without abnormal vessels as a control. A total of 20 biopsy samples were evaluated to determine whether the diagnosis of MALT lymphoma could be obtained histologically from each sample. A positive diagnosis was obtained in 8/10 TLA (+) sites and in 2/10 TLA(-) sites. Target biopsies of the site with abnormal blood vessels can potentially improve diagnostic accuracy of gastric MALT lymphoma.