Takeshi Hori

Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma

BACKGROUND In Japan and South Korea, transarterial chemoembolisation (TACE) is an important locoregional treatment for patients with unresectable hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, has been shown effective and safe in patients with advanced HCC. This phase III trial assessed the efficacy and safety of sorafenib in Japanese and Korean patients with unresectable HCC who responded to TACE. METHODS Patients (n=458) with unresectable HCC, Child-Pugh class A cirrhosis and ≥25% tumour necrosis/shrinkage 1-3 months after 1 or 2 TACE sessions were randomised 1:1 to sorafenib 400mg bid or placebo and treated until progression/recurrence or unacceptable toxicity. Primary end-point was time to progression/recurrence (TTP). Secondary end-point was overall survival (OS). FINDINGS Baseline characteristics in the two groups were similar; >50% of patients started sorafenib>9 weeks after TACE. Median TTP in the sorafenib and placebo groups was 5.4 and 3.7 months, respectively (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.70-1.09; P=0.252). HR (sorafenib/placebo) for OS was 1.06 (95% CI, 0.69-1.64; P=0.790). Median daily dose of sorafenib was 386 mg, with 73% of patients having dose reductions and 91% having dose interruptions. Median administration of sorafenib and placebo was 17.1 and 20.1 weeks, respectively. No unexpected adverse events were observed. INTERPRETATION This trial, conducted prior to the reporting of registrational phase III trials, found that sorafenib did not significantly prolong TTP in patients who responded to TACE. This may have been due to delays in starting sorafenib after TACE and/or low daily sorafenib doses.

Risk factors for the local recurrence of hepatocellular carcinoma after a single session of percutaneous radiofrequency ablation.

BackgroundRadiofrequency ablation (RFA) is a new, minimally invasive treatment for hepatocellular carcinoma (HCC). However, there is little available information regarding local recurrence after a single session of RFA with a single electrode insertion.MethodsFrom February 1999 to September 2001, we treated 104 HCC tumors with an expandable needle with four hooks. Ninety-nine of the 104 tumors were successfully treated by single-session RFA with a single electrode insertion. We investigated the relationships between pretreatment factors (tumor size, tumor staining, tumor capsule, and tumor location) and local recurrence in these 99 tumors.ResultsThe mean size of the 99 tumors was 21.5 mm in diameter (range, 10 to 33 mm). The overall local recurrence rates were 9.7%, 15.4%, and 20.4%, at 1, 2, and 3 years, respectively. For small tumors (smaller than 25 mm), the local recurrence rates at 1, 2, and 3 years were 4.0%, 8.0%, and 14.6%, respectively. The local recurrence rates were 21.1% and 32.3% at 1 and 2 years, respectively, for large tumors (25 mm or larger), and at 3 years the rate was over 50% for tumors located close to the liver surface. Tumor size and tumor location relative to the liver surface were significantly associated with a higher local recurrence rate. However, other variables tested showed no significant relationship to the local recurrence rate.ConclusionsThis study demonstrated that both tumor size and location relative to the liver surface influence the local efficacy of single-session RFA with a single electrode insertion.

Osteoactivin expressed during cirrhosis development in rats fed a choline-deficient, l-amino acid-defined diet, accelerates motility of hepatoma cells

BACKGROUND/AIMS Hepatocellular carcinoma (HCC) is closely associated with chronic liver diseases, particularly cirrhosis. However, the genes involved in hepatocarcinogenesis in the context of developing cirrhosis remain unknown. This study aims to identify genes associated with early cirrhosis-associated hepatocarcinogenesis. METHODS We examined genes differentially expressed between the livers of normal rats and rats fed a choline-deficient, L-amino acid-defined (CDAA) diet using suppression subtractive hybridization. We examined both the expression in the liver and HCC tissues of osteoactivin (OA), isolated in this screen, and its effect on invasiveness and metastasis. RESULTS OA mRNA was strongly expressed in the livers of rats fed the CDAA diet for 1-3 months. Moderate expression was sustained for 18 months. OA overexpression increased the invasiveness and metastasis of rat hepatoma cells in vitro and in vivo. In humans, OA expression was not detectable in normal liver tissues. While OA transcripts were detectable in cirrhotic nontumorous liver tissues surrounding HCCs, the majority of HCC tissue samples exhibited higher levels of OA expression than the surrounding normal tissue. CONCLUSIONS These results indicate that OA is a novel factor involved in the progression of HCC via stimulation of tumor invasiveness and metastatic potential.

Hepatocyte growth factor accelerates the proliferation of hepatic oval cells and possibly promotes the differentiation in a 2-acetylaminofluorene/partial hepatectomy model in rats

Background:  Hepatocyte growth factor (HGF) is the primary agent promoting the proliferation of mature hepatocytes. The purpose of the present paper was to clarify the effects of HGF on the proliferation and  differentiation  of  hepatic  oval  cells  using  a  2‐acetylaminofluorene/partial  hepatectomy  (2‐AAF/PH) model in rats.

A case of chronic hepatitis C developing insulin-dependent diabetes mellitus associated with various autoantibodies during interferon therapy.

We report a case of chronic hepatitis C presenting insulin-dependent diabetes mellitus (IDDM) associated with various autoantibodies including possible anti-insulin receptor antibody (AIRA) during interferon (IFN) therapy. A 57-year-old man having chronic hepatitis C virus (HCV) infection with chronic thyroiditis received IFN therapy. The thyroid function was well-controlled by administration of thyroid hormone, although thyroid autoantibodies were positive. At 15 weeks after starting IFN (reaching 530 million units of total dose), marked thirst happened, with increased fasting plasma glucose level (488 mg/dl) and decreased daily urinary C peptide immunoreactivity level (less than 4.2 microg/day). IDDM occurred with anti-nuclear antibody (ANA), anti-DNA antibody and possible AIRA, and thyroid autoantibodies titers increased, but without pancreatic islet cell antibody and anti-glutamic acid decarboxylase antibody. Administration of IFN was stopped and insulin treatment was started, but plasma glucose level was not controlled well. AIRA became negative 2 months later, however, insulin antibody (IA) was positive when tested after 18 months. Serum HCV RNA has been negative, and a normal level of serum transaminase has been observed since IFN therapy. It is likely that IFN therapy induced the immunological disturbance and resulted in occurrence of various autoantibodies and IDDM in the patient.

Endoscopic characterization of the small bowel in patients with portal hypertension evaluated by double balloon endoscopy

BackgroundThe endoscopic abnormalities present in the small bowel (SB) of patients with portal hypertension (PH) are not well understood. This study sought to evaluate endoscopic findings of the SB in patients with PH by double balloon endoscopy (DBE).MethodsWe evaluated the endoscopic findings of SB in 15 patients with PH and 49 controls without liver disease or PH. A total of 24 and 90 procedures were performed for PH patients and control patients, respectively, through oral and/or anal approaches.ResultsFourteen of the 15 patients exhibited villous abnormalities, including edema (73%), atrophy (40%), and reddening (47%) of villi. Vascular lesions, such as angiodysplasia-like abnormalities (67%), dilated/proliferated vessels (93%), and varices (7%), were observed in all patients with PH. Although they were associated with ascites, these abnormalities did not correlate with any laboratory findings. None of these abnormalities was observed in controls. Definitive or suspected bleeding sources were identified in 9 of 13 patients with both PH and obscure gastrointestinal bleeding (OGIB), which was similar to the incidence in controls with OGIB. Although the frequency of postprocedure fever (>37.5°C) was higher in patients with PH in comparison to controls (29% vs. 2%, P < 0.01), endoscopic treatment under DBE was performed on 3 PH patients without serious complications.ConclusionsEndoscopic abnormalities of the SB may be prevalent in patients with PH. Although postprocedure fever of DBE may occur more commonly in patients with PH, DBE is useful as both a diagnostic and therapeutic tool to evaluate the SB.

Inflammatory pseudotumor of the liver diagnosed by needle liver biopsy under ultrasonographic tomography guidance

Abstract: Inflammatory pseudotumor of the liver is a rare benign lesion, but exploratory laparotomy and a hepatectomy are often performed unnecessarily after various misdiagnoses, including liver abscess, hepatocellular carcinoma, metastatic liver tumor, and cholangiocarcinoma. We present a case of hepatic inflammatory pseudotumor in a 17-year-old man in whom diagnosis was confirmed by liver needle biopsy under ultrasonographic tomography (UST) guidance. He had complained of fever and right hypochondralgia 2 months after being operated for appendicitis. He was admitted to our hospital because of the persistence of these symptoms and the presence of a hepatic mass lesion detected by UST. He had hepatomegaly, with tenderness; leukocytosis and elevated erythrocyte sedimentation rate and C-reactive protein level were noted. UST showed a hypoechoic mass in the liver and pre-contrast computerized tomography (CT) revealed a low-density area with an ill defined margin, which was barely enhanced by the contrast medium. On the basis of the patients clinical symptoms and the laboratory data and imaging studies, the presence of a liver abscess was suspected and antibiotics were administered. One month after the initiation of the antibiotic therapy, UST demonstrated that the portal vein had dilated serpiginously and penetrated into the mass. As the heterogeneous appearance displayed by post-enhanced CT indicated the need for a differential diagnosis of the hepatic mass lesion to rule out hepatocellular carcinoma, percutaneous needle biopsy was performed, under UST guidance. Histopathological examination demonstrated marked infiltration of plasma cells and fibrosis, findings which were consistent with those of hepatic inflammatory pseudotumor. There was a spontaneous reduction of the hepatic pseudotumor without continuous antibiotics and this reduction was documented on follow-up UST and CT.

A CRE and the region occupied by a protein induced by growth factors contribute to up-regulation of cyclin D1 expression in hepatocytes

Induction of cyclin D1 expression is a critical feature of growth factor-induced cell proliferation in hepatocytes. To clarify the mechanisms regulating cyclin D1 gene expression, we isolated the rat cyclin D1 gene and analyzed the transcriptional regulatory elements in rat hepatoma cells and primary cultured rat hepatocytes. Two transcriptional regulatory regions were analyzed. One was mapped to a cAMP-responsive element (CRE) at position -41bp and was occupied by a CRE-binding protein (CREB), resulting in cyclin D1 expression. Another (CD1E0.7), located at -753bp, revealed high homology with binding sites for the Ets family, the hepatocyte nuclear factor-3beta, or the nuclear factor of activated T cells. However, CD1E0.7 did not interact with these nuclear factors and specific interaction with a protein extracted from growth factor-treated rat hepatocytes in primary cultures. These results indicate that CREB binds to the CRE and mediates activation of the cyclin D1 promoter, and suggest that CD1E0.7 may be possibly occupied by a protein induced by growth factors in hepatocytes.

Salvage surgery after chemotherapy with S-1 plus cisplatin for α-fetoprotein-producing gastric cancer with a portal vein tumor thrombus: a case report

BackgroundPatient with α-Fetoprotein (AFP)-producing gastric cancer usually has a short survival time due to frequent hepatic and lymph node metastases. Gastric cancer with portal vein tumor thrombus (PVTT) is rare and has an extremely poor prognosis.Case presentationA 63-year-old man was found to have a huge Type 3 gastric cancer with a PVTT and a highly elevated serum AFP level. Chemotherapy with S-1 plus cisplatin was given to this patient with unresectable gastric cancer for 4 months. The serum AFP level decreased from 6,160 ng/mL to 60.7 ng/mL with chemotherapy. Since the PVTT disappeared after the chemotherapy, the patient underwent total gastrectomy. Histological findings of the primary tumor after chemotherapy showed poorly differentiated adenocarcinoma without hepatoid cells and viable tumor cells remaining in less than 1/3 of the neoplastic area of mucosa and one lymph node. The cancerous cells were immunohistochemically stained by anti-AFP antibody. The patient has survived for 48 month without recurrence.ConclusionsAFP-producing gastric cancer with a PVTT has an extremely poor prognosis, but long-term survival was achieved for this dismal condition by salvage surgery after chemotherapy.

Activation of hepatocyte growth factor in monkey stomach following gastric mucosal injury

BackgroundHepatocyte growth factor (HGF) is involved in the proliferation and migration of various types of epithelial cells. HGF is produced as a single-chain precursor (pro-HGF) and functions after activation by HGF activator (HGFA). In this study, we aimed to examine the activation of pro-HGF to mature HGF and the expressions of HGF-related molecules, such as HGFA and HGFA inhibitor type 1 (HAI-1), in a monkey model of gastric mucosal injury.MethodsGastric mucosal injury was induced in Japanese monkeys by administration of HCl using nasal-gastric tubes. HGF activation was evaluated by Western blotting and enzyme-linked immunosorbent assay (ELISA), and the expression of HGF, HGFA, HAI-1, and c-Met were examined by Northern blotting and immunohistochemistry.ResultsPro-HGF, but not mature HGF, was detected in normal gastric mucosa. When gastric mucosal injuries were induced, the expression of HGF significantly increased, and immunostaining of HGF was detected in fibroblasts in the gastric mucosa. In addition, conversion to mature HGF was observed in the injured gastric tissues, and mature HGF continued to increase for 48 h. HGFA was stably expressed in monkey livers, regardless of HCl administration. HAI-1 expression was detected in normal gastric mucosa, and its levels decreased after the induction of gastric mucosal injury.ConclusionsThese results indicate that pro-HGF is stored in normal gastric tissues, and suggest that its conversion to mature HGF, associated with HGFA and HAI-1, is important for the repair of gastric mucosal injury.