Junichi Toshimori

Predicting the treatment effect of sorafenib using serum angiogenesis markers in patients with hepatocellular carcinoma.

Background and Aim:  Sorafenib, the first agent demonstrated to have efficacy to improve the survival of patients with advanced hepatocellular carcinoma (HCC), is an active multikinase inhibitor affecting angiogenesis and tumor proliferation. We analyzed cytokines related to angiogenesis or cell proliferation, and tried to determine their utility as biomarkers of sorafenib treatment effect for HCC.

Runt-related transcription factor 3 reverses epithelial–mesenchymal transition in hepatocellular carcinoma

Loss or decreased expression of runt‐related transcription factor 3 (RUNX3), a tumor suppressor gene involved in gastric and other cancers, has been frequently observed in hepatocellular carcinoma (HCC). The objective of this study was to identify the regulatory mechanism of the epithelial–mesenchymal transition (EMT) by RUNX3 in HCC. Human HCC cell lines, Hep3B, Huh7, HLF and SK‐Hep1, were divided into low‐ and high‐EMT lines, based on their expression of TWIST1 and SNAI2, and were used in this in vitro study. Ectopic RUNX3 expression had an anti‐EMT effect in low‐EMT HCC cell lines characterized by increased E‐cadherin expression and decreased N‐cadherin and vimentin expression. RUNX3 expression has previously been reported to reduce jagged‐1 (JAG1) expression; therefore, JAG1 ligand peptide was used to reinduce EMT in RUNX3‐expressing low‐EMT HCC cells. Immunohistochemical analyses were performed for RUNX3, E‐cadherin, N‐cadherin and TWIST1 in 33 human HCC tissues, also divided into low‐ and high‐EMT HCC, based on TWIST1 expression. E‐cadherin expression was correlated positively and N‐cadherin expression was correlated negatively with RUNX3 expression in low‐EMT HCC tissues. Correlations between EMT markers and RUNX3 mRNA expression were analyzed using Oncomine datasets. Similarly, mRNA expression of E‐cadherin was also significantly correlated with that of RUNX3 in low‐EMT HCC, while mRNA expression of JAG1 was negatively correlated with that of RUNX3. These results suggest a novel mechanism by which loss or decreased expression of RUNX3 induces EMT via induction of JAG1 expression in low‐EMT HCC.

Prognostic importance of fucosylated alpha-fetoprotein in hepatocellular carcinoma patients with low alpha-fetoprotein

Background and Aim:  Fucosylated alpha‐fetoprotein (AFP‐L3) is known to be a marker of poor prognosis in patients with hepatocellular carcinoma (HCC). However, it has been difficult to measure AFP‐L3 under low AFP (≤ 20 ng/mL). The aim of this study was to elucidate the role of AFP‐L3 in HCC patients with low AFP conditions.

Loss of runt-related transcription factor 3 expression leads hepatocellular carcinoma cells to escape apoptosis

BackgroundRunt-related transcription factor 3 (RUNX3) is known as a tumor suppressor gene for gastric cancer and other cancers, this gene may be involved in the development of hepatocellular carcinoma (HCC).MethodsRUNX3 expression was analyzed by immunoblot and immunohistochemistry in HCC cells and tissues, respectively. Hep3B cells, lacking endogenous RUNX3, were introduced with RUNX3 constructs. Cell proliferation was measured using the MTT assay and apoptosis was evaluated using DAPI staining. Apoptosis signaling was assessed by immunoblot analysis.ResultsRUNX3 protein expression was frequently inactivated in the HCC cell lines (91%) and tissues (90%). RUNX3 expression inhibited 90 ± 8% of cell growth at 72 h in serum starved Hep3B cells. Forty-eight hour serum starvation-induced apoptosis and the percentage of apoptotic cells reached 31 ± 4% and 4 ± 1% in RUNX3-expressing Hep3B and control cells, respectively. Apoptotic activity was increased by Bim expression and caspase-3 and caspase-9 activation.ConclusionRUNX3 expression enhanced serum starvation-induced apoptosis in HCC cell lines. RUNX3 is deleted or weakly expressed in HCC, which leads to tumorigenesis by escaping apoptosis.

Sepsis-associated liver injury: Incidence, classification and the clinical significance

Aim:  Although it is a common complication of sepsis, sepsis‐associated liver injury has not been substantially recognized, because its diagnostic criteria and clinical implications are unclear. We aimed to elucidate the incidence, manifestation, disease type classification and prognosis of sepsis‐associated liver injury.

Evolution of prognostic factors in hepatocellular carcinoma in Japan

Aliment Pharmacol Ther 31, 407–414

Pneumocystis carinii pneumonia in patients with ulcerative colitis

Pneumocystis carinii pneumonia (PCP) causes pneumonia in immunocompromised patients suffering from diseases such as leukemia, malignant lymphoma, and other cancers, and those treated with corticosteroids and/or immunosuppressive agents. However, it has rarely been reported in patients with ulcerative colitis (UC). We report three patients with UC who developed PCP during corticosteroid and/or azathioprine (AZA) administration. Case 1 was a 26-year-old woman with an 8-month history of ulcerative colitis. She had hematochezia, and colonoscopy showed severe pancolitis. She had a blood transfusion and was treated with prednisolone, at a dose of 60 mg/day. Her disease was unresponsive to therapy with prednisolone. AZA at 100 mg/day was added. Her symptoms improved gradually, but AZA was stopped on the day 34 after the beginning of administration because of leukocytopenia. The following day she had a high-grade fever. Laboratory data were as follows: white blood cell count (WBC), 2500/mm3; lymphocyte count (Ly), 650/mm3; hemoglobin (Hb), 10.3 g/dl; and platelet count (Plt), 24.1 104/mm3. Arterial blood gases in room air were: pH 7.44, PCO2, 36.0 mmHg; and PO2, 56.0 mmHg. The CD4/CD8 ratio in peripheral blood was decreased, at 0.5. X-ray and computed tomography (CT) of the chest revealed bilateral “ground-glass” shadows (Fig. 1). Case 2 was a 68-year-old woman with an 11-year history of left-sided ulcerative colitis. She presented with acute colitis. We started pulse steroid therapy. The response was excellent and she entered the remission stage on clinical tests. She developed a high fever 2 days after the start of maintenance therapy with prednisolone at a dose of 7.5 mg/day. Laboratory data were as follows: WBC, 6200/mm3; Ly, 990/mm3; Hb, 10.5 g/dl; and Plt, 35.9 104/ mm3. Arterial blood gases in room air were: pH 7.47, PCO2, 32.7 mmHg; and PO2, 70.0 mmHg. The CD4/CD8 ratio in peripheral blood was normal (1.1). Chest X-ray and CT showed bilateral “ground-glass” shadows. Case 3 was a 29-year-old man with a 4-month history of ulcerative colitis. He presented with acute colitis exacerbation. Colonoscopy showed total colitis. We changed the corticosteroid from prednisolone, 40 mg/day, to betamethasone, 4 mg/day. AZA, 100 mg/day, was added and the response was satisfactory. Then we began to reduce betamethasone gradually, to 1.5 mg/day. His clinical course was excellent and he was discharged. Four months later, he was readmitted with a high fever. Laboratory data were as follows: WBC, 3400/mm3; Ly, 880/mm3; Hb, 11.0 g/dl; and Plt, 15.6 104/mm3. Arterial blood gases in room air were: pH, 7.39; PCO2, 41.0 mmHg; and PO2, 91.0 mmHg. Chest X-ray was normal, but chest CT revealed faint “ground-glass” shadow in the right lung (Fig. 2). In all three patients, polymerase chain reaction (PCR) for detection of P. carinii in sputa was positive, and we diagnosed PCP. Cytomegalovirus antigen in peripheral blood was negative in all the patients. After the diagnosis of PCP, they were treated

Local recurrence and complications after percutaneous radiofrequency ablation of hepatocellular carcinoma: a retrospective cohort study focused on tumor location.

We conducted a retrospective cohort study to investigate the predisposing factors for local recurrence and complications after percutaneous radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). HCC patients (n＝397) consecutively treated with RFA (256 males, 141 females, median age 69 years) were enrolled. In these patients, 1,455 nodules (median size 17mm) were ablated. Predisposing factors for overall recurrence and local recurrence in the context of tumor location and complications were examined. Local recurrence was observed for 113 of the 1,455 nodules. The 1-, 3- and 5-year local recurrence rates were 2.2%, 7.4% and 9.5%, respectively. A multivariate Cox proportional hazard analysis revealed that large tumor size (＞2cm), tumor location (adjacent to the major portal branch or hepatic vein), and small ablated margin (＜3mm) were independent predisposing factors for local recurrence after RFA (HR＝1.70-2.81). Tumor location (adjacent to the major portal branch, hepatic vein, or diaphragm) was also revealed as a risk factor for liver damage due to RFA. HCC adjacent to the major portal vein or hepatic vein was associated with a higher risk for local recurrence and for complications;therefore, special precautions are necessary when applying RFA to HCC near vessels even when the tumors are located at an easy-to-puncture site.

Hepatocellular carcinoma occurring in hepatobiliary fibropolycystic disease

Congenital hepatic fibrosis (CHF) and bile duct hamartomas (von Meyenburg complexes) are hepatobiliary fibropolycystic diseases. There have been several reports of liver neoplasias arising in hepatobiliary fibropolycystic diseases. However, most of them were cholangiocarcinomas and cases involving hepatocellular carcinoma (HCC) are rare. A 51‐year‐old woman was found to have multiple hepatic tumors by ultrasonography and enhanced computed tomography (CT) during a regular work‐up for the recurrence of lung cancer and thyroid cancer, which had been surgically removed 4 and 3 years ago, respectively. Nodules were observed at S3, S5, and S6 (2 cm in diameter). All of the nodules were hyperattenuated at the early arterial phase, and the main tumor at S5 showed hypoattenuation at the delayed phase on dynamic CT and magnetic resonance imaging (MRI). HCC was suspected from these findings. She also suffered from multiple small cystic lesions in the liver. The surgically removed liver showed HCC arising in CHF, which is a rare histological finding.

Sa1871 Local Recurrences and Complications After Percutaneous Radiofrequency Ablation of Hepatocellular Carcinoma: Analysis Focused on Tumor Locations

Background: Palliation for inoperable malignant distal biliary strictures can be achieved with metallic and plastic biliary stents. There have been recent retrospective studies and randomized controlled trials that evaluated the mortality and morbidity in patients with metal versus plastic stents. This is a meta-analysis to pool the evidence for survival benefit and morbidity in metallic versus plastic stents in patients with malignant distal biliary strictures. Aim: Compare survival benefit and morbidity in patients with distal biliary strictures managed with metallic stents versus plastic stents. Method: Study Selection Criteria: Studies using metallic and plastic stents for palliation in patients with malignant distal biliary stricture / obstruction. Data collection & extraction: Articles were searched in Medline, Pubmed, Ovid journals, CINAH, International pharmaceutical abstracts, old Medline, Medline nonindexed citations, and Cochrane Central Register of Controlled Trials & Database of Systematic Reviews. Two reviewers independently searched and extracted data. Any differences were resolved by mutual agreement. Statistical Method: Pooled proportions were calculated using both Mantel-Haenszel method (fixed effects model) and DerSimonian Laird method (random effects model). The heterogeneity among studies was tested using Cochrans Q test based upon inverse variance weights. Results: Initial search identified 1376 reference articles, of which 91 were selected and reviewed. 10 studies (N=892) for metallic and plastic stents which met the inclusion criteria were included in this analysis. Pooled analysis by fixed effects showed an overall survival/ time to death in metallic stent group to be 157.3 days (95% CI = 148.9 to 165.6) compared to 120.6 days (95% CI = 114.3 to 126.9) in plastic stent group. Metal stents had a pooled complication rate of 3.83 % (95% CI = 3.52 to 4.14) compared to 2.17 % (95% CI = 1.91 to 2.42) for plastic stents. The pooled effects estimated by fixed and random effect models were similar. The p for chisquared heterogeneity for all the pooled accuracy estimates was > 0.10. Conclusions: In our meta-analysis of patients with malignant distal biliary strictures managed with palliative stenting, metallic stents might be associated with longer overall survival period compared to plastic stents.Metallic stenting seems to havemarginally higher percentage of complications when compared to plastic stenting.