Fumihiko Kusano

Expression of C-C chemokines is associated with portal and periportal inflammation in the liver of patients with chronic hepatitis C.

Inflammation of the portal and periportal areas is a common feature of chronic hepatitis C. Antigen-presenting dendritic cells are located in the portal area, and infiltrating T cells are initially exposed to infected hepatocytes in the periportal area. Thus, these areas could be sites of the initial processes of the immune response in chronic hepatitis C. C-C chemokines (dendritic-cell-derived C-C chemokine [DC-CK1] and regulated upon activation, normal T-cell expressed and secreted [RANTES])-attracting T cells may play a role in the portal inflammatory changes. The relationship between the expression of these C-C chemokines, which attract T cells and the infiltration of T cells into the liver of patients with chronic hepatitis C, was examined by in situ hybridization and reverse transcription-polymerase chain reaction. T-cell activation was examined by immunostaining T-cell subsets. Specific signals were detected for DC-CK1 mRNA in mononuclear cells mainly in the portal area and for RANTES mRNA in the portal area and at sites of piecemeal necrosis in the liver of patients with chronic hepatitis C. Naive T cells were located mainly in the portal area, whereas active T cells were found mainly at sites of piecemeal necrosis in the periportal area. In addition, hepatic DC-CK1– and RANTES-mRNA levels were significantly correlated with serum alanine aminotransferase levels (p < 0.001). These results suggest that the local production of DC-CK1 and RANTES participates in immune responses by attracting naive and active T cells to the portal and periportal areas, respectively.

Diabetes mellitus may be associated with hepatocarcinogenesis in patients with chronic hepatitis C.

It is unknown whether diabetes mellitus is a risk factor of the hepatocarcinogenesis in patients with chronic hepatitis C. Three hundred eleven anti-hepatitis C virus (HCV) -positive patients who had undergone liver biopsies were studied. Patients with histologically proven cirrhosis or withdrawing within 12 months were excluded. Thus, the remaining 279 patients were followed-up for 65.9 ± 29.4 months until the occurrence of hepatocellular carcinoma (HCC). During the observation period, HCC developed in 13 patients. Diabetes, age, sex, habitual alcohol intake, history of blood transfusion, serum α-fetoprotein level, histological findings, HCV genotype, viral load, and interferon therapy were assessed as potential risk factors. The Cox proportional hazard model identified that diabetes mellitus, histological staging, and age were independently associated with the occurrence of HCC. With multivariate analysis, only diabetes mellitus and age were associated with the occurrence of HCC. Diabetes mellitus may be associated with hepatocarcinogenesis in patients with chronic hepatitis C.

Long-term observation after transjugular intrahepatic portosystemic stent-shunt in two patients with hepatocellular carcinoma.

Two patients with hepatocellular carcinoma (HCC) were treated with transjugular intrahepatic portosystemic stent-shunt (TIPS) and followed for 22 and 58 months thereafter. HCC was well controlled by transcatheter arterial chemoembolization. Hepatic failure or metastasis, especially in the lung, was not observed in the long-term observation. TIPS seems to be useful even in patients with HCC, provided HCC is controlled.

Fas-ligand and perforin expression in infiltrating cytotoxic T lymphocytes in the liver of chronic hepatitis C

Cytotoxic T cells (CTLs) are believed to play an important role in the pathogenesis of chronic hepatitis C based on histological findings of the liver and in vivo experiments. Fas-ligand-Fas and perforin dependent pathways are two major killing systems when CTLs induce their target-cell death. Thus, the present study attempts to determine whether these pathways are activated, and if they are, how they are related in chronic hepatitis C. To investigate the expression of Fas-ligand and perforin, we performed double immunofluorescent staining of liver biopsy specimens from patients with chronic hepatitis C. Fas-ligand and perforin expression was observed in mononuclear cells, and the partial coexistence of the two proteins was observed. Cells expressing both proteins were positive for CD45RO(+) T cells (active T cells), whereas cells expressing perforin were negative for CD68 (macrophages). In the cases which had sustained negative HCV-RNA over 6 months after interferon treatment, Fas-ligand was not expressed, although perforin was slightly detectable. To quantitatively assess the balance of these pathways, hepatic mRNAs of Fas-ligand and perforin were measured by quantitative RT-PCR. The ratio of Fas-ligand-mRNA/perforin-mRNA was significantly correlated with serum alanine aminotransferase (ALT) levels (r=0.913). These results suggest that both pathways are activated in chronic hepatitis C and that Fas-ligand-Fas pathway may be predominant in active inflammation.

Collaboration between Hepatologists and Primary Care Physicians in Treating Patients with Chronic Hepatitis C

Objective: The purpose of this study was to assess the treatment outcome in patients with chronic hepatitis C (CHC) using the current standard antiviral therapy when patient were treated in collaboration between hepatologists and primary care physicians (PCPs). Patients and Methods: One hundred and ten patients with CHC were treated with a combination therapy of peginterferon-alpha 2b and ribavirin. Among them, 25 patients were treated by a collaboration between hepatologists and PCPs (collaboration group), whereas 85 patients were treated with exclusively by hepatologists (noncollaboration group). The duration of the therapy was 48 weeks for 58 ‘difficult- to-treat’ patients (genotype 1 with a high load of HCV-RNA; 1H patients) and 24 weeks for the remaining 52 patients (non-1H patients). In the collaboration group, antiviral therapy was initiated and adjusted, if needed, by hepatologists (visits every four weeks), whereas the weekly administration of peginterferon-alpha 2b was performed by PCPs. Clinical characteristics and the treatment outcome were compared between these two groups. Results: The two groups had similar baseline characteristics. By intention to treat, the two groups showed similar rates of treatment-related serious adverse effects (0% vs. 1%, respectively) and dropout rates for adverse effects (8% vs. 13%, respectively). Sustained virologic response rates were also similar between the two groups, being 42% vs. 39% in the 58 1H patients (NS) and 62% vs. 64% in the 52 non-1H patients (NS), respectively. Conclusions: Collaboration between hepatologists and PCPs may be a valid treatment alternative to treat patients with CHC using the current standard antiviral therapy.

Effects of esomeprazole on the healing process of post-endoscopic submucosal dissection gastric ulcers: a single arm, prospective trial

Objectives: Gastric endoscopic submucosal dissection (ESD) is currently a standard procedure. ESD enables en-bloc resection of large lesions, while inducing larger artificial ulcers to a greater extent than conventional procedures. Several studies have reported that proton pump inhibitors (PPIs) prevent delayed bleeding and expedite the artificial ulcer healing process. Esomeprazole, an S-isomer of omeprazole, is reportedly one of strongest inhibitors of gastric acid secretion. Previous studies have examined the effectiveness of esomeprazole. Our goal was to verify the effects of esomeprazole on artificial ulcers in a prospective study. Methods: A total of 185 patients underwent ESD for gastric neoplasms at our hospital between January 2013 and June 2015. Among these 185 patients, 49 post-ESD scar lesions were included in this prospective trial. First, 20 mg esomeprazole was orally administered to all subjects before and after the procedure. We then evaluated the delayed bleeding rate and ulcer scarring rates at 4 weeks and 8 weeks after the procedure by using a gastric ulcer stage system. Results: There was one case of delayed bleeding (2.0%). Regardless of Helicobacter pylori infection status, ulcer scarring rates at weeks 4 and 8 were respectively 28.6% (14/49) and 98% (48/49). Conclusions: Our results suggest that oral administration of esomeprazole alone may be sufficient for prompt healing of artificial gastric ulcers induced by ESD (UMIN000009367).

Randomized Controlled Trial Comparing the Effects of Vonoprazan Plus Rebamipide and Esomeprazole Plus Rebamipide on Gastric Ulcer Healing Induced by Endoscopic Submucosal Dissection

Objective Gastric endoscopic submucosal dissection (ESD) is currently a standard procedure, and proton pump inhibitors (PPIs) are most commonly used to treat post-ESD ulcers. Vonoprazan, a potassium-competitive acid blocker (P-CAB), reportedly inhibits gastric acid secretions more effectively than PPIs. Combination therapy of a PPI plus rebamipide is effective for treating larger ulcers. Our goal was to evaluate the effects of vonoprazan plus rebamipide compared to esomeprazole plus rebamipide for the treatment of post-ESD ulcers. Methods First, vonoprazan plus rebamipide (V group) or esomeprazole plus rebamipide (E group) was orally administered to subjects for eight weeks. We then evaluated the ulcer healing process at four and eight weeks after the procedure using a gastric ulcer stage system and by measuring the ulcer size. Patients A total of 84 patients who underwent ESD for gastric neoplasms between September 2015 and December 2017 in Tsuchiura Kyodo General Hospital were included in this randomized controlled trial. Results The ulcer scar rates at week 4 in the V group (n=43) and E groups (n=39) were 20.9% and 15.4%, while those at week 8 were 90.7% and 92.3%, respectively. The ulcer reduction rates at week 4 in the V and E groups were 94.6% and 93.8%, and those at week 8 were 99.7% and 99.3%, respectively. The ulcer scar rates and reduction rates were not significantly different between the two groups. Conclusion Combination therapy consisting of vonoprazan plus rebamipide was not superior to that of esomeprazole plus rebamipide for post-ESD ulcer healing (UMIN000019516).

A phase II study of bevacizumab in combination with irinotecan plus S-1 as first-line treatment in patients with KRAS mutant-type metastatic colorectal cancer.

676 Background: FOLFIRI+bevacizumab (BV) is considered as a first-line treatment in patients (pts) with metastatic colorectal cancer (mCRC). The FIRIS study showed the non-inferiority of irinotecan plus S-1 (IRIS) to FOLFIRI. Therefore, we conducted a phase II study to evaluate the efficacy and safety of BV in combination with IRIS as first-line chemotherapy for KRAS mutant-type (mt) mCRC (clinical trial information: UMIN000004630). Methods: Eligibility criteria included histologically confirmed mCRC, KRAS mt, no previous chemotherapy, ECOG performance status (PS) of 0/1, and adequate organ function. S-1 was administered at 80 mg/m2 on days 1–14 and irinotecan at 100 mg/m2 on days 1 and 15 every 28 days. BV was administered at 5 mg/kg on days 1 and 15 every 28 days. The primary endpoint was response rate (RR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. The sample size was calculated to reject a RR of 25% in favor of a target RR of 50% with a signif...

Ofloxacin prevents spontaneous bacterial peritonitis recurrence in HCV-antibody positive cirrhosis. A case report.

症例は66歳,男性.1982年に食道静脈瘤破裂で当科に入院し,内視鏡的硬化術を施行.その後もC型肝硬変に伴う肝性脳症や腹水のため入退院を繰り返していた.1992年3月と5月に特発性細菌性腹膜炎(SBP)にて入院.1回紹は腹水細菌培養陰性でCZXとDKBにて軽快した.2回目は黄色ブドウ球菌陽性でcefotaximeで軽快せずIMP/CSにて軽快した.同年6月にSBPが再発し入院.腹水中の好中球12,000/μlで細菌培養は陰性だった.IMP/CS長期投与にて7月末には軽快したが,8月初めに再発した.PIPCとCAZの投与で同年9月中旬には軽快した.以後再発を防ぐ目的でofloxacinの長期投与を開始したところ,1年9カ月後の今日までSBPの再発はみられていない.C型肝硬変に伴う再発性のSBPに対するofloxacinの有用性が示唆された.