[A case of foveolar-type gastric adenocarcinoma with a raspberry-like appearance followed up by endoscopy].

A 47-year-old man was referred to our hospital for detailed examination of a gastric polypoid lesion. Esophagogastroduodenoscopy revealed a raspberry-like polyp at the gastric body. Pathological examination of the biopsy specimen revealed this polypoid lesion to be a gastric adenocarcinoma. Endoscopic submucosal dissection was performed, and histopathological examination revealed that lesion to be a well-differentiated adenocarcinoma. Immunohistochemical staining showed that the neoplasm was positive for MUC5AC and negative for MUC6, CD10, and pepsinogen I, indicating that this lesion was a foveolar-type gastric adenocarcinoma. From about 10 years now, this patient has been undergoing esophagogastroduodenoscopy almost every year. This lesion was absent until six years ago. Five years ago, a small polypoid lesion appeared at the gastric body, and this lesion gradually enlarged. The present case showed the growing process of the foveolar-type gastric adenocarcinoma with a raspberry-like appearance.

A novel biomarker TERTmRNA is applicable for early detection of hepatoma.

BACKGROUNDS: We previously reported a highly sensitive method for serum human telomerase reverse transcriptase (hTERT) mRNA for hepatocellular carcinoma (HCC). alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) are good markers for HCC. In this study, we verified the significance of hTERTmRNA in a large scale multi-centered trial, collating quantified values with clinical course. METHODS: In 638 subjects including 303 patients with HCC, 89 with chronic hepatitis (CH), 45 with liver cirrhosis (LC) and 201 healthy individuals, we quantified serum hTERTmRNA using the real-time RT-PCR. We examined its sensitivity and specificity in HCC diagnosis, clinical significance, ROC curve analysis in comparison with other tumor markers, and its correlations with the clinical parameters using Pearson relative test and multivariate analyses. Furthermore, we performed a prospective and comparative study to observe the change of biomarkers, including hTERTmRNA in HCC patients receiving anti-cancer therapies. RESULTS: hTERTmRNA was demonstrated to be independently correlated with clinical parameters; tumor size and tumor differentiation (P < 0.001, each). The sensitivity/specificity of hTERTmRNA in HCC diagnosis showed 90.2%/85.4% for hTERT. hTERTmRNA proved to be superior to AFP, AFP-L3, and DCP in the diagnosis and underwent an indisputable change in response to therapy. The detection rate of small HCC by hTERTmRNA was superior to the other markers. CONCLUSIONS: hTERTmRNA is superior to conventional tumor markers in the diagnosis and recurrence of HCC at an early stage.

[Effectiveness of S-1 therapy for unresectable/advanced pancreas cancer].

PURPOSE: Although the susceptibility to chemotherapy of unresectable/advanced pancreatic cancer is very poor, the usefulness of new anticancer drugs, such as S-1, has been reported in recent years. We clinically investigated whether or not S-1 would prolong survival in this study. OBJECTIVE: 17 unresectable pancreatic cancer patients who came for consultation between November 2001 and August 2008 (ten men, seven women). The average age was 72.5 years and performance statuses before medical treatment were 0-2. METHOD: A group of 8 patients did not use S-1 (non-S-1 group) and a group of a patients (S-1 group)did. The average survival period, one-year survival rate, and hospitalization rate were examined. RESULT: The average survival period of the non-S-1 group was 173.1 days, and its one-year survival rate was 12.5%, compared to 435.1 days and 55.6% in the S-1 group. The hospitalization rate was 25.6% in the S-1 group, against 53.1% in the non-S-1 group. DISCUSSION: S-1 treatment for unresectable/advanced pancreatic cancer served to prolong the survival period, suggesting it enabled extension of the recuperation-at-home period.

Nucleotide analogs for patients with HBV-related hepatocellular carcinoma increase the survival rate through improved liver function.

BACKGROUND AND AIM: This study evaluated the outcomes of antiviral therapy with nucleotide analogs for hepatitis B virus infection-related hepatocellular carcinoma. METHODS: Thirty patients orally received nucleotide analogs and, as a matched control group, 20 patients who were not treated with nucleotide analogs were selected. We compared changes in liver function, HCC recurrence and survival rate between both groups. RESULTS: In the nucleotide analog group, serum albumin, AST and ALT were significantly improved compared with baseline values. The Child-Pugh score was significantly decreased in the nucleotide analog group. Furthermore, of the 36 patients curatively treated with the initial treatment, more patients in the nucleotide analog group improved or maintained their Child-Pugh score at the time of recurrent HCC than in the control group (p=0.023). The cumulative recurrent-free survival rate of HCC did not significantly differ between the two groups; however, the cumulative survival rates of not only curative-treated patients but also all patients in the nucleotide analog group were significantly higher than those of patients in the control group (p=0.047 and p=0.02, respectively). CONCLUSION: The results suggest that nucleotide analog treatment increases the survival rate in patients with HCC by contributing to the improvement of remnant liver function.

Development of a novel assay to quantify serum human telomerase reverse transcriptase messenger RNA and its significance as a tumor marker for hepatocellular carcinoma.

Currently available tumor markers for hepatocellular carcinoma (HCC) are alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive AFP (AFP-L3), and Des-gamma-carboxy prothrombin (DCP). However, their positive rate can not surpass abdominal ultrasonography (US) as modalities to detect small HCC at early stage, resulting in a possible delay of its diagnosis. There is a need to develop an additional sensitive marker to improve the early detection of HCC. We here introduced a newly developed quantitative detection method for serum hTERT mRNA, which has a clinical significance in HCC diagnosis. Briefly, we examined its sensitivity and specificity in HCC diagnosis, clinical significance in comparison with other tumor markers, and its correlations with the clinical parameters. Serum hTERT mRNA showed higher values in patients with HCC than those with chronic liver diseases. hTERT mRNA expression independently correlated with clinical parameters such as differentiation degree (p < 0.001). The sensitivity/specificity of hTERT mRNA in HCC diagnosis showed 88.2/70.0%. hTERT mRNA proved to be expectedly superior to AFP mRNA , AFP and DCP in HCC diagnosis. Importantly, hTERT mRNA in serum correlated with that in HCC tissue. Thus, we report that serum hTERT mRNA is a novel and available marker for HCC diagnosis.

Significance of urinary excretion of 8-hydroxy-2'-deoxyguanosine in healthy subjects and liver disease patients.

BACKGROUND/AIMS: Although the importance of reactive oxygen species (ROS) in the pathogenesis of various diseases is stressed, clinical significance of the markers reflecting DNA oxidation such as 8-hydroxy-2'-deoxyguanosine (8-OHdG) remains to be clarified. METHODOLOGY: To examine clinical usefulness of 8-OHdG in healthy individuals in comparison with liver disease patients, urinary excretion of 8-OHdG was measured in 336 healthy individuals and 110 patients with liver disease. RESULTS: In healthy persons, the 8-OHdG excretion was increased in an age-dependent manner. It was positively correlated with cigarettes smoked a day and negatively correlated with body mass index (BMI) (P < 0.05, each). Age, smoking and BMI were independent predictors of urinary 8-OHdG excretion (P < 0.01, P < 0.01 and P < 0.05, respectively). In liver disease, the excretion of 8-OHdG was not changed, as compared with healthy individuals. However, the liver disease patients under the age of 40 had higher values of 8-OHdG than healthy persons. In addition, the urinary excretion of 8-OHdG was higher in patients with hepatitis C virus (HCV) infection than those with hepatitis B virus (HBV) infection. CONCLUSIONS: The results of the present study suggest that measurement of urinary 8-OHdG excretion is useful in assessing DNA oxidation caused by aging, smoking, body composition and liver disease.

FibroIndex, a practical index for predicting significant fibrosis in patients with chronic hepatitis C.

UNLABELLED: Diagnosis of the stage of liver fibrosis in chronic hepatitis C is essential for making a prognosis and deciding on antiviral therapy. In the present study a simple model consisting of routine laboratory tests was constructed and then validated in cross-sectional and longitudinal investigations. Consecutive treatment-naive patients with chronic hepatitis C who had undergone liver biopsy were divided into 2 cohorts: an estimation set (n = 240) and a validation set (n = 120). A longitudinal set consisted of 30 patients who had undergone a liver biopsy twice, before and after IFN treatment. The FibroIndex was derived from the platelet count, AST, and gamma globulin measurements in the estimation set. The areas under the ROC curves of the FibroIndex for predicting significant fibrosis were 0.83 and 0.82 for the validation set, better than those of the Forns index and the aminotransferase-to-platelet ratio index (APRI). Using the best cutoff values, whether significant fibrosis was present was diagnosed with high positive predictive values, and 35% of patients could avoid liver biopsy. In the longitudinal set, there was a significant decrease in the FibroIndex of 14 patients whose fibrosis stage improved, and a significant increase in that of 5 patients whose fibrosis stage deteriorated. Change in the FibroIndex correlated significantly with variation in fibrosis stage. There was no such correlation with the Forns index or the APRI. CONCLUSION: The FibroIndex is a simple and reliable index for predicting significant fibrosis in chronic hepatitis C and could also be used as a surrogate marker during antifibrotic treatment for chronic hepatitis C.

Naked gene therapy of hepatocyte growth factor for dextran sulfate sodium-induced colitis in mice.

Ulcerative colitis (UC) is progressive and relapsing disease. To explore the therapeutic effects of naked gene therapy of hepatocyte growth factor (HGF) on UC, the SRalpha promoter driving HGF gene was intrarectally administered to the mice in which colitis was induced by dextran sulfate sodium (DSS). Expression of the transgene was seen in surface epithelium, lamina propria, and muscularis mucosae. The HGF-treated mice showed reduced colonic mucosal damage and increased body weights, compared with control mice (P < 0.01 and P < 0.05, respectively). The HGF-treated mice displayed increased number of PCNA-positive cells and decreased number of apoptotic cells than in control mice (P < 0.01, each). Phosphorylated AKT was dramatically increased after HGF gene administration, however, phosphorylated ERK1/2 was not altered. Microarray analysis revealed that HGF induced expression of proliferation- and apoptosis-associated genes. These data suggest that naked HGF gene delivery causes therapeutic effects through regulation of many downstream genes.

Expression of oxidative stress-related molecules in circulating leukocytes and urine in patients with chronic viral hepatitis.

AIMS: Oxidative stress plays a role in pathogenesis of chronic viral hepatitis. Expression of oxidative stress-related molecules remains to be clarified. METHODS: 4-hydroxy-2-nonenal (4-HNE), 4-hydroxy-2-hexenal (4-HHE), catalase, superoxide dismutase-1 (SOD-1), glutathione peroxidase-1, thioredoxin (TRX) in leukocytes and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) were examined in 164 persons, including 130 chronic viral hepatitis patients and 34 normal individuals, by Western blot analysis and enzyme-linked immunosorbent assay, respectively. Hepatic expression of these proteins was immunohistochemically examined in 12 patients with chronic viral hepatitis, compared with three persons without liver damage. RESULTS: The 4-HNE/beta-actin ratios in chronic viral hepatitis were significantly higher than those in normal individuals (P<0.01), and were significantly correlated with asparate aminotransferase (AST) and alanine aminotransferase (ALT) (P<0.01, each). The catalase/beta-actin and SOD-1/beta-actin ratios in chronic viral hepatitis were higher than those in normal individuals, and were significantly correlated with 4-HNE/beta-actin ratios (P<0.01, each). Hepatic expression of 4-HNE, 4-HHE, catalase, SOD-1 and TRX in chronic viral hepatitis was higher than that without liver damage. Urinary excretion of 8-OHdG was not changed in chronic viral hepatitis. CONCLUSIONS: The results of the present study suggest that expression of oxidative stress-related molecules in leukocytes is upregulated in relation to serum aminotransferase levels.

Increase in serum 7S domain of type IV collagen and N-terminal propeptide of type III procollagen levels with normal serum transaminase levels after long-term oral administration of Tegaful-Uracil.

To evaluate whether oral administration of Tegaful-Uracil (UFT(R)), a biochemical modulator of 5-fluorouracil that contains tegafur and uracil, can induce hepatic fibrosis, serum 7S domain of type IV collagen and N-terminal propeptide of type III procollagen levels were measured in 63 UFT(R)-treated, 38 tegafur-treated and 40 untreated patients. Serum transaminase and bilirubin levels were normal in almost all patients. Serum levels of 7S collagen and type III propeptide increased in 25 and 17% of the UFT(R)-treated patients, respectively, although a majority of tegafur-treated and untreated patients showed no increase in these markers. The patients with the elevated levels demonstrated mild or moderate hepatic fibrosis without necroinflammation in the liver. Both serum levels decreased markedly after the discontinuation of UFT(R). These findings suggest that long-term oral administration of UFT(R) can induce hepatic fibrosis without the elevation of serum transaminase levels and necroinflammation in the liver, and serum 7S collagen and type III procollagen are of diagnostic value for UFT(R)-induced hepatotoxicity.