Kaori Kuramitsu

A Nationwide Survey of Hepatitis E Virus Infection and Chronic Hepatitis E in Liver Transplant Recipients in Japan

Background Recently, chronic hepatitis E has been increasingly reported in organ transplant recipients in European countries. In Japan, the prevalence of hepatitis E virus (HEV) infection after transplantation remains unclear, so we conducted a nationwide cross-sectional study to clarify the prevalence of chronic HEV infection in Japanese liver transplant recipients. Methods A total of 1893 liver transplant recipients in 17 university hospitals in Japan were examined for the presence of immunoglobulin G (IgG), IgM and IgA classes of anti-HEV antibodies, and HEV RNA in serum. Findings The prevalence of anti-HEV IgG, IgM and IgA class antibodies was 2.9% (54/1893), 0.05% (1/1893) and 0% (0/1893), respectively. Of 1651 patients tested for HEV RNA, two patients (0.12%) were found to be positive and developed chronic infection after liver transplantation. In both cases, HEV RNA was also detected in one of the blood products transfused at the perioperative period. Analysis of the HEV genomes revealed that the HEV isolates obtained from the recipients and the transfused blood products were identical in both cases, indicating transfusion-transmitted HEV infection. Interpretation The prevalence of HEV antibodies in liver transplant recipients was 2.9%, which is low compared with the healthy population in Japan and with organ transplant recipients in European countries; however, the present study found, for the first time, two Japanese patients with chronic HEV infection that was acquired via blood transfusion during or after liver transplantation.

Specific Activin Receptor-Like Kinase 3 Inhibitors Enhance Liver Regeneration

Pharmacologic agents to enhance liver regeneration after injury would have wide therapeutic application. Based on previous work suggesting inhibition of bone morphogenetic protein (BMP) signaling stimulates liver regeneration, we tested known and novel BMP inhibitors for their ability to accelerate regeneration in a partial hepatectomy (PH) model. Compounds were produced based on the 3,6-disubstituted pyrazolo[1,5-a] pyrimidine core of the BMP antagonist dorsomorphin and evaluated for their ability to inhibit BMP signaling and enhance liver regeneration. Antagonists of the BMP receptor activin receptor–like kinase 3 (ALK3), including LDN-193189 (LDN; 4-[6-[4-(1-piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-quinoline), DMH2 (4-(2-(4-(3-(quinolin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)phenoxy)ethyl)morpholine; VU0364849), and the novel compound VU0465350 (7-(4-isopropoxyphenyl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine; VU5350), blocked SMAD phosphorylation in vitro and in vivo, and enhanced liver regeneration after PH. In contrast, an antagonist of the BMP receptor ALK2, VU0469381 (5-(6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinolone; 1LWY), did not affect liver regeneration. LDN did not affect liver synthetic or metabolic function. Mechanistically, LDN increased serum interleukin-6 levels and signal transducer and activator of transcription 3 phosphorylation in the liver, and modulated other factors known to be important for liver regeneration, including suppressor of cytokine signaling 3 and p53. These findings suggest that inhibition of ALK3 may be part of a therapeutic strategy for treating human liver disease.

Quantification of Pregenomic RNA and Covalently Closed Circular DNA in Hepatitis B Virus-Related Hepatocellular Carcinoma

Pregenomic RNA (pgRNA) is generated from covalently closed circular DNA (cccDNA) and plays important roles in viral genome amplification and replication. Hepatic pgRNA and cccDNA expression levels indicate viral persistence and replication activity. This study was aimed to measure hepatic pgRNA and cccDNA expression levels in various states of hepatitis B virus (HBV) infection. Thirty-eight hepatocellular carcinoma (HCC) patients, including 14 positive for hepatitis B surface antigen (HBsAg) and 24 negative for HBsAg but positive for anti-hepatitis B core (anti-HBc) antibody, were enrolled in this study. In HBsAg-negative but anti-HBc-positive group, HBV-DNA was detected in 20 of 24 (83%) noncancerous liver tissues for at least two genomic regions based on polymerase chain reaction (PCR) analysis. pgRNA and cccDNA expression levels in occult HBV-infected patients were significantly lower than those in HBsAg-positive patients (P < 0.001). pgRNA and cccDNA in cancerous tissues were also detected without significant difference from those in noncancerous tissues. In conclusion, cccDNA and pgRNA are detected and represented HBV replication not only in noncancerous but also in cancerous liver tissues. In addition, the replication is shown in not only patients with HBsAg-positive but also occult HBV-infected patients, suggesting the contribution to HCC development.

Contrast-Enhanced Intraoperative Ultrasonic Cholangiography for Real-Time Biliary Navigation in Hepatobiliary Surgery

Recent progress in medical technology, perioperative management, and surgical technique has contributed greatly to the safety of hepatobiliary surgery. In particular, imaging techniques, including intraoperative imaging, have played a major role in advancing the success of these operations. Precise assessment of biliary anatomy before and during surgery reduces biliary complications. More than 42% of the population is reported to have anatomical variations of the biliary tree. If a biliary anatomical variation is suspected before surgery, confirmatory intraoperative cholangiography (IOC) is recommended. Using radiography and iodinated contrast medium, IOC was first reported by Mirizzi in 1937 and has been widely used to define the biliary tree in surgery for benign and malignant diseases. However, radiographic IOC has several drawbacks; it exposes patients and medical staff to radiation, it requires a large C-arm machine for fluoroscopy and an attendant to operate it, and it requires special techniques to generate 3-dimensional (3D) images. Intraoperative ultrasonography, specifically, contrast-enhanced intraoperative ultrasonic cholangiography (CE-IOUSC), can address these issues. Intraoperative ultrasonography has become an essential tool for the identification of intrahepatic vessels, tumor location, and definition of surgical margins for safe and effective hepatic surgery. Its diagnostic accuracy has been enhanced by the introduction of intravascular ultrasound contrast agents. However, it is still limited in visualization of nondilated bile ducts.

Morphometric analysis of conformational changes in hepatic venous system after right lobe living donor liver transplantation

Aim:  After living donor liver transplantation (LDLT), the graft liver regenerates to the standard liver volume. However, little is known about the influence of this phenomenon on the hepatic venous system.

A case of intravascular lymphoma diagnosed in an explanted liver after liver transplantation.

Intravascular lymphoma (IVL) is a rare form of B‐cell lymphoma. We encountered a rare case of IVL diagnosed in an explanted liver. A 49‐year‐old man visited a clinic with high fever. Because of elevated liver function, he was diagnosed with acute liver failure. Deceased donor liver transplantation (LT) was performed 16 days after admission. The post‐transplantation course was uneventful until IVL was reported in the explanted liver on postoperative day (POD) 21. Rituximab was administered on POD 27, and rituximab–cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone (R‐CHOP) treatment administered on POD 38. The R‐CHOP treatment was repeated for eight cycles, and the patient remains free of recurrence 1 year post‐transplantation. Although systemic lymphoma is a contraindication to transplantation, our experience indicates that IVL can be successfully treated by the administration of prompt chemotherapy after LT for fulminant hepatitis.

Asunaprevir and daclatasvir for recurrent hepatitis C after liver transplantation; a Japanese multicenter experience

The safety and efficacy of an IFN‐free regimen using asunaprevir (ASV) and daclatasvir (DCV) for recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) have not been evaluated in Japan. A multicenter study of LT recipients (n = 74) with recurrent HCV genotype 1b infection treated with ASV‐DCV for 24 weeks was performed. Medical history was positive for pegylated interferon and ribavirin (Peg‐IFN/RBV) in 40 (54.1%) patients, and for simeprevir (SMV) with Peg‐IFN/RBV in 12 (16.2%) patients. Resistance‐associated variants (RAVs) were positive at D168 (n = 1) in the NS3, and at L31 (n = 4), Y93 (n = 4), and L31/Y93 (n = 1) in the NS5A region of the HCV genome. Sixty‐one (82.4%) patients completed the 24‐week treatment protocol. Although sustained viral response (SVR) was achieved in 49 (80.3%) patients, it was achieved in only two (16.7%) patients among those with histories of receiving SMV (n = 12). Univariate analysis showed that a history of SMV (P < .01) and the presence of mutations in NS5A (P = .02) were the significant factors for no‐SVR. By excluding the patients with either a history of SMV‐based treatment or RAVs in NS3/NS5A, the SVR rate was 96.4%. By excluding the patients with a history of SMV and those with RAVs in NS3/NS5A, viral clearance of ASV‐DCV was favorable, with a high SVR rate.

Novel Non-Trocar Technique for Laparoscopic Radiofrequency Ablation

We have developed a novel insertion method, a non-trocar technique (NTT), for laparoscopic radiofrequency ablation, whereby an ablation needle, guided by a 14.8-mm echo probe (PVM-787LA; Toshiba, Tokyo, Japan), accurately and easily punctures the target tumor in the liver. By existing methods, an ablation needle is inserted into the abdominal cavity through a puncture hole away from the echo probe because of the presence of a 15-mm trocar. Under such circumstances, fitting and sliding an ablation needle along the groove of the probe into the abdominal cavity is difficult because of the longitudinal dissociation between the needle and the probe. To avoid this dissociation, an echo probe is inserted directly through the small incision from which the 12-mm trocar is withdrawn and an ablation needle is introduced directly into the abdominal cavity through a puncture hole adjacent to and slid along the groove of the probe.

Analysis of Portal Vein Reconstruction Technique with High-Grade Portal Vein Thrombus in Living Donor Liver Transplantation

BACKGROUND Portal vein thrombus (PVT) has been an absolute contraindication for liver transplantation because of technical difficulties and inadequate vessel graft supply. With recent surgical innovations many difficulties have been overcome and PVT is no longer a contraindication to liver transplantation. MATERIAL AND METHODS From June 2000 to December 2014, 72 patients underwent living donor liver transplantation at Kobe University Hospital, with a focus on the high-grade PVT cases and analysis of modified PV reconstruction technique and clinical course. RESULTS Four recipients (5.6%) developed Yerdel classification grade III PVT and 2 recipients (2.8%) developed grade IV PVT. There were no statistically significant differences between the severity of PVT grades by sex (p=0.77), recipient age (p=0.49), model for end-stage liver disease (MELD) score (p=0.68), graft-recipient weight ratio (GWRW) (p=0.15), graft type of right or left lobe (p=0.55), original liver disease (p=0.09), or intra-operative bleeding (p=0.21). Four grade III recipients were anastomosed with SMV, and 2 grade IV recipients were anastomosed with coronary vein, both of which were interpositioned with vein grafts. Only 1 recipient had died of hepatocellular carcinoma recurrence by 1.5 years after liver transplantation, and all 5 remaining severe PVT recipients survived. Overall 1- and 5-year survival rates for grade 0, I, and II recipients were 78.8% and 62.4%, respectively; 75.0% and 75.0%, respectively, for grade III recipients; and 100% and 100%, respectively, for grade IV recipients (p=0.54). CONCLUSIONS High-grade PVT had comparable survival without the recurrence of PVT after living donor liver transplantation.

Surgical resection for liver metastases developing 10 and 21 years after primary surgery for mucinous colon adenocarcinoma: A Case Report

Abstract Introduction Optimal management for liver metastases from colorectal mucinous adenocarcinoma is still controversial. Here, we report such a case of liver metastases which developed twice with 10 year intervals after curative resection. Case presentation An 84-year-old man had undergone a radical left hemicolectomy for descending colon cancer at 63 years of age. The histopathological diagnosis was mucinous adenocarcinoma. Ten years later, he was found to have a cystic tumor in liver and underwent partial hepatectomy of segment 5. Moreover, eleven years later of hepatic resection, CT showed low density tumor with calcification in remnant liver and partial hepatectomy of segment 8 was performed. Histopathological and immunohistochemical findings of each liver tumor indicated metastasis from primary colon mucinous adenocarcinoma. It is rare that colorectal mucinous adenocarcinoma recurs twice after long intervals of 10 years. However, also in a patient with a history of colorectal mucinous adenocarci...