Hiroshi Kohno

Serum HBV RNA is a predictor of early emergence of the YMDD mutant in patients treated with lamivudine

Lamivudine (LAM) is a nucleoside analogue widely used for the treatment of chronic hepatitis B virus (HBV) infection. Emergence of resistant strains with amino acid substitutions in the tyrosine‐methionine‐aspartate‐aspartate (YMDD) motif of reverse transcriptase is a serious problem in patients on LAM therapy. The amount of covalently closed circular DNA in the serum is reported to be higher in patients who develop YMDD mutants than in those without mutants. However, there is no useful serum marker that can predict early emergence of mutants during LAM therapy. Analysis of patients who were treated with entecavir (n = 7) and LAM (n = 36) showed some patients had high serum levels of HBV RNA. Median serum levels of HBV RNA were significantly higher in patients in whom the YMDD mutant had emerged within 1 year (n = 6, 1.688 log copies/ml) than in those in whom the YMDD mutant emerged more than 1 year after treatment (n = 12, 0.456 log copies/ml, P = 0.0125) or in whom the YMDD mutant never emerged (n = 18, 0.688 log copies/ml, P = 0.039). Our results suggest that HBV RNA is a valuable predictor of early occurrence of viral mutation during LAM therapy. (HEPATOLOGY 2007;45:1179–1186.)

Dose-finding trial of tolvaptan in liver cirrhosis patients with hepatic edema: A randomized, double-blind, placebo-controlled trial

Liver cirrhosis represents the end stage of any chronic liver disease, and it is associated with hepatic edema such as ascites. Many patients with ascites do not respond to diuretic therapy or require administration of diuretics at high doses that can cause adverse events. This 7‐day, multicenter, double‐blind trial of tolvaptan was designed to determine the optimal dose of tolvaptan for producing the intended pharmacological effect in hepatic edema.

ITPA polymorphism effects on decrease of hemoglobin during sofosbuvir and ribavirin combination treatment for chronic hepatitis C

BackgroundPolymorphisms in the inosine triphosphatase (ITPA) gene is associated with anemia induced by peg-interferon (PEG-IFN) plus ribavirin (RBV) treatment for patients with chronic hepatitis C virus (HCV) infection. However, the effect of ITPA polymorphism on sofosbuvir plus RBV treatment is unknown.MethodsTwo hundred and forty-four patients with chronic HCV genotype 2 infection without decompensated liver cirrhosis were treated with sofosbuvir plus RBV for 12xa0weeks. The effects of ITPA polymorphism on hemoglobin levels and RBV dose reduction and treatment response were analyzed. ITPA (rs1127354) was genotyped using the Invader assay. Multivariate regression analysis was performed to identify factors associated with sustained virological response (SVR).ResultsOverall, SVR12 was achieved in 231 (94.7%) patients, based on intention to treat analysis. During the therapy, reduction of hemoglobin levels was significantly greater in ITPA genotype CC patients than CA/AA patients. Therefore, the cumulative proportion of patients with RBV dose reduction was significantly higher and total dose of RBV was significantly lower in patients with CC genotype compared to CA/AA genotypes. SVR12 rates were similar between ITPA genotypes CC and CA/AA (94.7 and 94.4%, respectively, Pxa0=xa00.933). Multivariate logistic regression analysis identified FIB4 index <3.25 (odds ratio [OR], 9.388 for ≥3.25; Pxa0=xa00.005) and low body weight (OR, 1.059, for high body weight; Pxa0=xa00.017) as independent predictors for SVR12.ConclusionsITPA polymorphism influences hemoglobin levels and incidence of RBV dose reduction during sofosbuvir plus RBV therapy. However, ITPA genotype CC patients can expect a curative effect equivalent to CA/AA patients for chronic HCV genotype 2 infection.

Comparison of hepatic arterial infusion chemotherapy versus sorafenib monotherapy in patients with advanced hepatocellular carcinoma

Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC) with distant metastasis, unresectable HCC, and those refractory to transcatheter arterial chemoembolization (TACE) or with macroscopic vascular invasion (MVI). The application of sorafenib has been approved by the Japanese Government‐sponsored Medicare for unresectable HCC. In this retrospective cohort study we aimed to compare various aspects of HAIC with sorafenib in the treatment of Child–Pugh A patients with advanced HCC who were otherwise free of extrahepatic metastasis.

Efficacy and safety of ledipasvir/sofosbuvir with ribavirin in chronic hepatitis C patients who failed daclatasvir/asunaprevir therapy: pilot study

BackgroundIn Japan, daclatasvir (DCV) and asunaprevir (ASV) therapy was the first IFN-free treatment to be approved, and thousands of patients have since been successfully treated, with an SVR rate of around 90%. The converse, however, is that around 10% of patients fail to achieve viral eradication and must be retreated using a different approach. This study is to evaluate treatment efficacy of ledipasvir/sofosbuvir and ribavirin in patients who failed to respond to DCV and ASV therapy.MethodsThirty patients were treated with 12xa0weeks of ledipasvir/sofosbuvir and ribavirin. We evaluated the rate of sustained virological response 12xa0weeks after the end of treatment (SVR12) and examined the incidence of adverse events during ledipasvir/sofosbuvir and ribavirin treatment. NS5A and NS5B resistance-associated variants (RAVs) in treatment failure cases were examined.ResultsThe overall SVR12 rate was 86.7% (26/30). Large decreases in mean log10 HCV RNA levels were observed in patients without cirrhosis, and the SVR12 rate for these patients was 100% (12/12). In cases of cirrhosis, SVR12 rate was 72.2% (13/18). The common factors in treatment failure cases were the presence of liver cirrhosis and both NS5A L31M/I and Y93H RAVs. The frequency of RAVs did not change before and after treatment among patients who relapsed.ConclusionLedipasvir/sofosbuvir with ribavirin is an effective retreatment option for patients with chronic hepatitis C who failed to respond to prior daclatasvir and asunaprevir therapy.

Endoscopic submucosal dissection of early colorectal neoplasms with a monopolar scissor-type knife: short- to long-term outcomes

Background and study aimsu2002Endoscopic submucosal dissection (ESD) for colorectal neoplasms remains challenging because of technical issues imposed by the complex anatomical features of the large intestine. We evaluated the feasibility, and the short- and long-term clinical outcomes of ESD for early colorectal neoplasms performed using the Stag-beetle Knife Jr. (SB Knife Jr.) Patients and methodsu2002We retrospectively assessed 228 patients who underwent ESD for 247 colorectal lesions with the SB Knife Jr. Clinicopathological characteristics of the neoplasms, complications, and various short- and long-term outcomes were evaluated. Resultsu2002Mean tumor size was 34.3u200amm and median procedure time was 76 minutes. The SB Knife Jr. achieved 98.4u200a% en bloc resection, 93.9u200a% complete resection, and 85.4u200a% curative resection. No perforations occurred during the procedure, and a delayed bleeding rate of 2.4u200a% was observed. Long-term outcomes were favorable with no distant recurrence, 1.1u200a% local recurrence, a 5-year overall survival rate of 94.1u200a% and 5-year tumor-specific survival rate of 98.6u200a% in patients with cancer. Conclusionsu2002ESD using the SB Knife Jr. is technically efficient and safe in treating early colorectal neoplasms and is associated with favorable short- and long-term outcomes.

Long‐term follow up of peginterferon‐α‐2a treatment of hepatitis B e‐antigen (HBeAg) positive and HBeAg negative chronic hepatitis B patients in phase II and III studies

We analyzed the 5‐year post‐treatment response to peginterferon α‐2a (PEG IFN‐α‐2a) in hepatitis B e‐antigen (HBeAg) positive and negative chronic hepatitis B patients.

Endoscopic submucosal dissection with a scissors-type knife for post-EMR recurrence tumor involving the colon diverticulum

The advantages of endoscopic submucosal dissection (ESD) include the ability to control resection size and shape and permit en bloc resection of large and ulcerated lesions. However, even with ESD, endoscopic treatment is challenging for post-EMR recurrence of colorectal tumors because of severe fibrosis. Moreover, lesions involving the colon diverticulum are considered contraindicated for endoscopic treatment because of the risk of perforation in the absence of a muscle layer.

Endoscopic full-thickness resection for inverted Meckel’s diverticulum using double-balloon enteroscopy

Meckel’s diverticulum contains all layers of the small bowel wall and is usually treated by surgery [1, 2]. Inverted Meckel’s diverticulum is rare, with only two reports of endoscopic resection [3, 4]. As preoperative diagnosis of an inverted Meckel’s diverticulum is difficult [5], it was not diagnosed prior to resection in either case, and consequently perforation due to endoscopic resection was reported in one case [3]. In the current case, we diagnosed the condition preoperatively, and subsequently used two detachable snares prior to resection to prevent hemorrhage or perforation. We then safely treated the inverted Meckel’s diverticulum using endoscopic full-thickness resection with double-balloon enteroscopy (DBE). A 78-year-old man was admitted to our institution because of anemia and a positive fecal occult blood test. Abdominal ultrasound identified a hypoechoic polypoid lesion, with a hyperechoic head (▶Video1). A contrasted abdominal computed tomography scan also identified an elongated pedunculated polypoid lesion, with fat tissue in its center, in the distal ileum (▶Video1). Capsule endoscopy demonstrated a submucosal tumor-like lesion (▶Video1), and selective contrast-enhanced radiography indicated an elongated intraluminal polypoid lesion that was approximately 8 cm in size (▶Video1). Retrograde DBE indicated that the polypoid lesion exhibited intestinal villous mucosa on the surface at the head and typical mucosal features at the stalk of the antimesenteric attachment (▶Fig. 1). This indicated that the lesion was an inverted Meckel’s diverticulum, and endoscopic full-thickness resection with DBE was attempted. First, the stem of the polyp was closed with two detachable snares before resection to prevent hemorrhage or perforation. Then, conventional polypectomy with DBE was performed. The resection surface was closed with four clips after the polypectomy (▶Fig. 2, ▶Video1). Histopathological analysis revealed an 80×10mm inverted Meckel’s diverticulum without ectopic tissue (▶Video1). The patient was discharged 2 days later without adverse events. Endoscopy_UCTN_Code_TTT_1AP_2AD

Endoscopic submucosal dissection using a stag beetle knife for early esophageal cancer in lower esophageal diverticula

re 1. Esophageal ESD using the stag beetle (SB) knife. A single-channel endoscope (H260Z) and a high-frequency electric surgical unit (VIO 300D; Tübingen, Germany) were used. A, Visualization of the esophageal cancer (white arrows) in the lower esophageal diverticula. B, Circumferential sal cutting done with the SB knife. C, D, ESD performed directly grasping the submucosal layer with the SB knife. E,Mucosal defect after the ESD. F, cted lesion in a single piece. Histopathology confirmed a squamous cell carcinoma tumor confined to the lamina propria, with a negative lateral and margin.