岡山医学会Acta Medica Okayama0030-1558128320163 年間の内視鏡所見の変化を観察できた食道異所性皮脂腺の1 例201205ENMasayaIwamuroDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHiroyukiOkadaDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKeitaHaradaDepartment of Endoscopy, Okayama University HospitalHiromitsuKanzakiDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKeisukeHoriDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasahideKitaDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesSeijiKawanoDepartment of Endoscopy, Okayama University HospitalYoshiroKawaharaDepartment of Endoscopy, Okayama University HospitalTakehiroTanakaDepartment of Pathology, Okayama University HospitalKazuhideYamamotoDepartment of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences A 43-year-old Japanese woman was diagnosed with ectopic sebaceous glands in the esophagus by esophagogastroduodenoscopy and biopsy. At the age of 46, typical ectopic sebaceous glands were recognized in the upper esophagus, whereas yellowish white granules were faintly observed in the lower esophagus. Esophagogastroduodenoscopy examinations were repeated when she was 47 and again at 50 years old, and the lesions in the lower esophagus had become more evident over the ensuing 3 years. Esophageal ectopic sebaceous glands are relatively infrequent, and there have been few case reports describing the progression of the endoscopic features. We also report the clinical and endoscopic features of the five similar cases with pathologically proven ectopic sebaceous glands in the esophagus.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6932015Aberrant Expression of Keratin 7 in Hepatocytes as a Predictive Marker of Rapid Progression to Hepatic Failure in Asymptomatic Primary Biliary Cirrhosis137144ENHiroyukiSekiFusaoIkedaShintaroNanbaYukiMoritouYasutoTakeuchiTetsuyaYasunakaHidekiOnishiYasuhiroMiyakeAkinobuTakakiKazuhiroNousoYoshiakiIwasakiMinoruNakamuraKazuhideYamamotoOriginal Article10.18926/AMO/53520A predictive marker of the rapid progression to hepatic failure is desired for patients with asymptomatic primary biliary cirrhosis (aPBC). We performed a systematic cohort analysis of 101 patients diagnosed as having aPBC and the rapid progression to liver failure in some, by focusing on cholestasis. Cholestasis was assessed by aberrant keratin7 (K-7) expressions in the patientsʼ hepatocytes. Intralobular expressions of K-7 were found in 9 of the 101 patients. The grades of K-7 expression were significantly associated with the levels of alanine aminotransferase, alkaline phosphatase, and total bilirubin at the time of diagnosis, but not with bile duct loss or cholestasis. Stepwise logistic regression analysis revealed that high grades of K-7 expression correlated positively with high levels of total bilirubin. During the follow-up period, 8 patients developed jaundice, and the mean period until the development of jaundice was 5.2 years. The proportional hazards models for the risk of developing jaundice identified a high grade of aberrant K-7 expression in hepatocytes as the only significant risk factor. Aberrant K-7 expression in hepatocytes can be used as an additional marker to predict rapid progression to liver failure in patients with aPBC at the time of diagnosis.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0944-117445112010Laparoscopic findings of reddish markings predict hepatocellular carcinoma in patients with hepatitis B virus-related liver disease11721182ENBonShojiFusaoIkedaShin-ichiFujiokaHaruhikoKobashiTetsuyaYasunakaYasuhiroMiyakeHidenoriShirahaAkinobuTakakiKazuhiroNousoYoshiakiIwasakiKazuhideYamamotoFor patients with chronic hepatitis due to hepatitis B virus (HBV), factors predicting hepatocellular carcinoma (HCC) other than high levels of HBV-DNA and alanine aminotransferase (ALT) are needed to prevent HCC development, as many patients with chronic HBV infection fulfill these conditions. The purpose of this study was to clarify factors predictive of HCC development for those patients.
The study was a systematic cohort analysis of 303 consecutive patients with hepatitis B e-antigen, receiving laparoscopic examination for assessment of liver disease. Laparoscopic, histological, and clinical characteristics were investigated as related to HCC development.
HCC occurred in 27 patients during a mean follow-up of 8.0 +/- A 5.0 years, at the age of 37-72 years. Significant associations with HCC development were shown for liver cirrhosis, histological activity grade, reddish markings, and older age. Multivariate analysis revealed that HCC development was strongly associated with older age and male gender (P = 0.002 and P = 0.043, respectively). HCC occurred more frequently in patients of age a parts per thousand yen30 years even with early stage than in patients of age < 30 years (P = 0.031). Severe reddish markings, a laparoscopic finding of widespread parenchymal destruction, were highly associated with HCC development in patients of age a parts per thousand yen30 years at diagnosis (odds ratio = 1.67, P = 0.034), while histological activity grade and ALT level were not (P = 0.075 and P = 0.69, respectively).
HCC development is associated with older age, male gender, and liver cirrhosis. Reddish markings, rather than histological activity or ALT level, can be useful to predict HCC for HBV patients of age a parts per thousand yen30 years.No potential conflict of interest relevant to this article was reported.Public Library ScienceActa Medica Okayama1932-6203972014L-Carnitine Prevents Progression of Non-Alcoholic Steatohepatitis in a Mouse Model with Upregulation of Mitochondrial PathwayENHisashiIshikawaAkinobuTakakiRyuichiroTsuzakiTetsuyaYasunakaKazukoKoikeYasuyukiShimomuraHiroyukiSekiHiroshiMatsushitaYasuhiroMiyakeFusaoIkedaHidenoriShirahaKazuhiroNousoKazuhideYamamotoNon-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease characterized by lobular inflammation, hepatocellular ballooning, and fibrosis with an inherent risk for progression to cirrhosis and hepatocellular carcinoma (HCC). Mitochondrial dysfunction appears to play a role in the progression from simple steatosis to NASH. L-carnitine (L-b-hydroxy-g-N-trimethylaminobutyric acid), an essential nutrient that converts fat into energy in mitochondria, has been shown to ameliorate liver damage. The aim of the present study was to explore the preventive and therapeutic effect of L-carnitine in NASH model mice. Eight-week-old male STAM mice, a NASH-cirrhosis-hepatocarcinogenic model, were divided into 3 experimental groups and fed as follows: 1) high-fat diet (HFD) (control group); 2) HFD mixed with 0.28% L-carnitine (L-carnitine group); and 3) HFD mixed with 0.01% alpha-tocopherol (alpha-tocopherol group). After 4 or 8 weeks, mice were sacrificed. Blood samples and livers were collected, and hepatic tumors were counted and measured. Livers were subjected to histological study, immunohistochemical staining of 4-hydroxynonenal and ferritin, determination of 8-OHdG levels, mRNA and protein expressions for multiple genes, and metabolomic analysis. The intestinal microbiome was also analyzed. L-carnitine increased hepatic expression of genes related to long-chain fatty acid transport, mitochondrial beta-oxidation, and antioxidant enzymes following suppression of hepatic oxidative stress markers and inflammatory cytokines in NASH, and mice treated with L-carnitine developed fewer liver tumors. Although alpha-tocopherol resulted in NASH improvement in the same manner as L-carnitine, it increased periodontitis-related microbiotic changes and hepatic iron transport-related gene expression and led to less effective for anti-hepatocarcinogenesis. Conclusion: L-carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model by upregulating the mitochondrial beta-oxidation and redox system.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama1732012Comprehensive investigation of areae gastricae pattern in gastric corpus using magnifying narrow band imaging endoscopy in patients with chronic atrophic fundic gastritis.224231ENHiromitsuKanzakiNoriyaUedoRyuIshiharaKengoNagaiFumiMatsuiTakashiOhtaMasaoHanafusaNoboruHanaokaYojiTakeuchiKojiHigashinoHiroyasuIishiYasuhikoTomitaMasaharuTatsutaKazuhideYamamotoBackground: Barium radiographic studies have suggested the importance of evaluating areae gastricae pattern for the diagnosis of gastritis. Significance of endoscopic appearance of areae gastricae in the diagnosis of chronic atrophic fundic gastritis (CAFG) was investigated by image-enhanced endoscopy.
Materials and Methods: Endoscopic images of the corpus lesser curvature were studied in 50 patients with CAFG. Extent of CAFG was evaluated with autofluorescence imaging endoscopy. The areae gastricae pattern was evaluated with 0.2% indigo carmine chromoendoscopy. Micro-mucosal structure was examined with magnifying chromoendoscopy and narrow band imaging.
Results: In patients with small extent of CAFG, polygonal areae gastricae separated by a narrow intervening part of areae gastricae was observed, whereas in patients with wide extent of CAFG, the size of the areae gastricae decreased and the width of the intervening part of areae gastricae increased (p < 0.001). Most areae gastricae showed a foveola-type micro-mucosal structure (82.7%), while intervening part of areae gastricae had a groove-type structure (98.0%, p < 0.001). Groove-type mucosa had a higher grade of atrophy (p < 0.001) and intestinal metaplasia (p < 0.001) compared with foveola type.
Conclusions: As extent of CAFG widened, multifocal groove-type mucosa that had high-grade atrophy and intestinal metaplasia developed among areae gastricae and increased along the intervening part of areae gastricae. Our observations facilitate our understanding of the development and progression of CAFG.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6912015Magnified Endoscopic Features of Duodenal Follicular Lymphoma and Other Whitish Lesions3744ENMasayaIwamuroHiroyukiOkadaKatsuyoshiTakataYoshinariKawaiSeijiKawanoJunichiroNasuYoshiroKawaharaTakehiroTanakaTadashiYoshinoKazuhideYamamotoOriginal Article10.18926/AMO/53120The sensitivity and specificity of magnified endoscopic features for differentiating follicular lymphoma from other diseases with duodenal whitish lesions have never been investigated. Here we compared the magnified endoscopic features of duodenal follicular lymphoma with those of other whitish lesions. We retrospectively reviewed the cases of patients with follicular lymphoma (n＝9), lymphangiectasia (n＝7), adenoma (n＝10), duodenitis (n＝4), erosion (n＝1), lymphangioma (n＝1), and hyperplastic polyp (n＝1). The magnified features of the nine follicular lymphomas included enlarged villi (n＝8), dilated microvessels (n＝5), and opaque white spots of various sizes (n＝9). The lymphangiectasias showed enlarged villi, dilated microvessels, and white spots, but the sizes of the white spots were relatively homogeneous and their margin was clear. Observation of the adenoma and duodenitis revealed only whitish villi. Although the lymphangioma was indistinguishable from the follicular lymphomas by magnified features, it was easily diagnosed based on the macroscopic morphology. In conclusion, magnified endoscopic features, in combination with macroscopic features, are useful for differentiating follicular lymphomas from other duodenal diseases presenting whitish lesions.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6862014Ultrastructural Analysis of an Enterolith Composed of Deoxycholic Acid369374ENMasayaIwamuroYuichiMiyashimaTakahiroYoshiokaToshihiroMurataYoshioMiyabeYoshinariKawaiHaruoUrataHidenoriShirahaHiroyukiOkadaKazuhideYamamotoCase Report10.18926/AMO/53026A 67-year-old Japanese man underwent enterotomy because of enterolith ileus. Component analysis by infrared spectroscopy revealed that the enterolith was composed of a high concentration of deoxycholic acid. We further analyzed and compared the ultrastructure of the enterolith and a commercially available powdered form of deoxycholic acid by means of scanning electron microscopy and energy dispersive X-ray spectroscopy. Energy dispersive X-ray spectroscopy analysis revealed that the ratios of carbon and oxygen in the enterolith were equal to those in the deoxycholic acid powder. Scanning electron microscopy analysis showed rectangular prism-shaped particles on the surface of the enterolith. This structure was similar to that of the deoxycholic acid powder. The surgically removed enterolith had a twisted and coiled appearance. Possible mechanisms underlying the formation of this unique form are discussed.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0815-93192952014Potential of adenovirus-mediated REIC/Dkk-3 gene therapy for use in the treatment of pancreatic cancer973983ENDaisukeUchidaHidenoriShirahaHironariKatoTeruyaNagaharaMasayaIwamuroJunroKataokaShigeruHoriguchiMasamiWatanabeAkinobuTakakiKazuhiroNousoYasutomoNasuTakahitoYagiHiromiKumonKazuhideYamamotoBackground and AimThe reduced expression in immortalized cells REIC/the dickkopf 3 (Dkk-3) gene, tumor suppressor gene, is downregulated in various malignant tumors. In a prostate cancer study, an adenovirus vector carrying the REIC/Dkk-3 gene (Ad-REIC) induces apoptosis. In the current study, we examined the effects of REIC/Dkk-3 gene therapy in pancreatic cancer.
MethodsREIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry in the pancreatic cancer cell lines (ASPC1, MIAPaCa2, Panc1, BxPC3, SUIT-2, KLM1, and T3M4) and pancreatic cancer tissues. The Ad-REIC agent was used to investigate the apoptotic effect in vitro and antitumor effects in vivo. We also assessed the therapeutic effects of Ad-REIC therapy with gemcitabine.
ResultsThe REIC/Dkk-3 expression was lost in the pancreatic cancer cell lines and decreased in pancreatic cancer tissues. Ad-REIC induced apoptosis and inhibited cell growth in the ASPC1 and MIAPaCa2 lines in vitro, and Ad-REIC inhibited tumor growth in the mouse xenograft model using ASPC1 cells. The antitumor effect was further enhanced in combination with gemcitabine. This synergistic effect may be caused by the suppression of autophagy via the enhancement of mammalian target of rapamycin signaling.
ConclusionsAd-REIC induces apoptosis and inhibits tumor growth in pancreatic cancer cell lines. REIC/Dkk-3 gene therapy is an attractive therapeutic tool for pancreatic cancer.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0944-11744832013The impact of patatin-like phospholipase domain-containing protein 3 polymorphism on hepatocellular carcinoma prognosis405412ENYasutoTakeuchiFusaoIkedaYukiMoritouHiroakiHagiharaTetsuyaYasunakaKenjiKuwakiYasuhiroMiyakeHidekiOhnishiShinichiroNakamuraHidenoriShirahaAkinobuTakakiYoshiakiIwasakiKazuhiroNousoKazuhideYamamotoThe single nucleotide polymorphism (SNP) rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is associated with hepatic fat accumulation and disease progression in patients with non-alcoholic fatty liver disease and alcoholic liver disease (ALD). This study was conducted to determine whether PNPLA3 rs738409 SNPs affect development and prognosis of hepatocellular carcinoma (HCC) in patients with various liver diseases.
We enrolled 638 consecutive Japanese patients newly diagnosed with HCC between 2001 and 2010: 72 patients with hepatitis B virus (HBV), 462 with hepatitis C virus (HCV), and 104 with non-B non-C (NBNC).
NBNC patients exhibited large tumors of advanced TNM stages at HCC diagnosis, and had significantly poorer prognosis than HBV or HCV patients (P < 0.001 and < 0.001, respectively; log-rank test). The G/G genotype of PNPLA3 rs738409 SNP had significantly higher distribution in NBNC patients (P < 0.001) and was significantly associated with higher body mass index (BMI) and an increased aspartate aminotransferase to platelet ratio index. No significant differences were observed in survival with differences in PNPLA3 SNP genotypes among the patients, although ALD patients with the G/G genotype of PNPLA3 SNP and low BMI had significantly poorer survival than those with high BMI (P = 0.028).
The G/G genotype of PNPLA3 rs738409 SNP was more frequently distributed, and associated with BMI and fibrosis among NBNC-HCC patients but not among HBV or HCV patients. These genotypes might affect HCC prognosis in ALD patients, but not in HBV, HCV, or NAFLD patients.No potential conflict of interest relevant to this article was reported.American Society for MicrobiologyActa Medica Okayama0095-11375222014Necessity for Reassessment of Patients with Serogroup 2 Hepatitis C Virus (HCV) and Undetectable Serum HCV RNA544548ENYukiMoritouFusaoIkedaYasutoTakeuchiHiroyukiSekiShintaroNanbaYoshiakiIwasakiKazuhideYamamotoWe encountered a patient positive for anti-hepatitis C virus (HCV) whose serum HCV RNA was undetectable with the Roche AmpliPrep/Cobas TaqMan HCV assay (CAP/CTM) version 1 but showed a high viral load with the Abbott RealTime HCV assay (ART). Discrepancies in the detectability of serum HCV RNA were investigated among 891 consecutive patients who were positive for anti-HCV. Specific nucleotide variations causing the undetectability of HCV RNA were determined and confirmed by synthesizing RNA coding those variations. Serum samples with the discrepancies were also reassessed by CAP/CTM version 2. Among the 891 anti-HCV-positive patients, 4 patients had serum HCV RNA levels that were undetectable by CAP/CTM version 1 despite having levels of > 5 log IU/ml that were detected by ART. All four patients had HCV genotype 2a and high titers of anti-HCV. Sequencing of the HCV 5' noncoding regions revealed 2 common variations, A at nucleotide (nt) 145 and T at nt 151. Synthesized RNAs of the HCV 5' noncoding region with standard (NCR145G151C) and variant nucleotides at nt 145 and nt 151 were quantified with CAP/CTM. RNAs of NCR145G151C and NCR145G151T were quantifiable with CAP/CTM version 1, while those of NCR145A151T and NCR145A151C went undetected. The substitution from G to A at nt 145 specifically conferred this undetectability, while this undetectability was reverted in synthesized HCV RNA with correction of this variation. Reassessment of these samples by CAP/CTM version 2 resulted in similar levels of HCV RNA being detected by ART. We conclude that HCV patients with undetectable HCV RNA by CAP/CTM version 1 should be reassessed for viral quantification.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6852014Prompt Resolution of Hypoglycemia by Hepatic Transarterial Embolization for Malignant Insulinoma with Multiple Liver Metastases307311ENShinichiroMuroJunichiroNasuRyoHaradaMinoruMatsubaraAsukaNakaraiHiromitsuKanzakiKouichiroTsutsumiHironariKatoTakehiroTanakaHiroyasuFujiwaraMasatoshiUnoHiroyukiOkadaKazuhideYamamotoCase Report10.18926/AMO/52900A 45-year-old female who presented with loss of consciousness and a cold sweat was found to have a pancreatic tumor and multiple liver metastases. Laboratory studies showed marked hypoglycemia and inappropriately elevated serum insulin, C-peptide, and serum tumor markers. Fine needle aspiration revealed Grade 3 small-cell type primary pancreatic neuroendocrine carcinoma. Consequently, the diagnosis of malignant insulinoma was made. Transarterial embolization (TAE) for hepatic metastases resulted in the reduction of tumor volume and prompt resolution of hypoglycemic attacks, whereas diazoxide and systemic chemotherapy had been ineffective for controlling blood glucose levels, and octreotide was unavailable due to the allergic effect. This case report highlights the potential usefulness of TAE for malignant insulinomas in the management of hypoglycemia.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6852014Hepatitis C Virus-specific T-cell Response Correlates with Hepatitis Activity and Donor IL28B Genotype Early after Liver Transplantation291302ENRyuichiroTsuzakiAkinobuTakakiTakahitoYagiFusaoIkedaKazukoKoikeYoshiakiIwasakiHidenoriShirahaYasuhiroMiyakeHiroshiSadamoriSusumuShinouraYuzoUmedaRyuichiYoshidaDaisukeNobuokaMasashiUtsumiEiichiNakayamaToshiyoshiFujiwaraKazuhideYamamotoOriginal Article10.18926/AMO/52898It is not known how the immune system targets hepatitis C virus (HCV)-infected HLA-mismatched hepatocytes under immune-suppressed conditions after orthotopic liver transplantation (OLT). In addition, the relationship between the HCV-specific immune response and IL28B variants as predictors of HCV clearance has not been well-characterized. We determined the IL28B polymorphisms for 57 post-OLT HCV carriers, and we assessed the HCV-specific immune responses by measuring the peripheral blood mononuclear cell-derived HCV-specific interferon-gamma (IFN-γ) response using an enzyme-linked immunospot assay. At 1-3 years after OLT, patients with no active hepatitis showed higher total spots on the immunospot assay. At＞3 years after OLT, patients with resolved HCV showed higher levels of core, NS3, NS5A, and total spots compared to the chronic hepatitis patients. The IL28B major genotype in the donors correlated with higher spot counts for NS5A and NS5B proteins at 1-3 years after OLT. In the post-OLT setting, the HCV-specific immune response could be strongly induced in patients with no active hepatitis with an IL28B major donor or sustained virological response. Strong immune responses in the patients with no active hepatitis could only be maintained for 3 years and diminished later. It may be beneficial to administer IFN treatment starting 3 years after OLT, to induce the maximum immunological effect.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6852014Nursing Support Increases the Efficacy of Interferon Therapy in Patients with Chronic Hepatitis C263268ENShihokoNambaKayokoMiyakeFusaoIkedaTomokoHazamaYuHitobeNorikoYamasakiHidenoriShirahaAkinobuTakakiKazuhiroNousoYoshiakiIwasakiKazuhideYamamotoOriginal Article10.18926/AMO/52894Nursing support might help patients with chronic hepatitis C (CHC) remain in good mental and physical condition during interferon (IFN) therapy. However, the effects of nursing support have not been studied adequately in this context. This case-control study evaluated the effects of nursing support during IFN therapy. Twenty-four CHC patients who received pegylated IFN and ribavirin were enrolled. Nurses advised patients on the maintenance of their mental and physical condition at weekly visits, based on the results of written questionnaires. An additional 24 patients who received IFN therapy without nursing support and who were matched for age, sex, platelet count, viral serogroup and IFN regimen were selected with propensity score matching as controls. The patients with nursing support during IFN therapy achieved higher sustained virological responses (79%) than those without nursing support (58%). Adherence to the IFN and ribavirin regimens at 24 weeks of therapy were slightly higher in the patients with nursing support than those without it, but these differences were not statistically significant. Adherence to ribavirin after 24 weeks of therapy was significantly higher in those with nursing support than those without it (93% and 66%, p＝0.045). These results suggested that nursing support services could contribute to the virological responses of CHC patients by promoting drug-regimen adherence.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0815-93192922014Assessment of health-related quality of life and how it predicts the outcome of pegylated interferon and ribavirin therapy for chronic hepatitis C337343ENHiroshiMatsushitaFusaoIkedaYoshiakiIwasakiHiroyukiSekiShintaroNanbaYasutoTakeuchiYukiMoritouTetsuyaYasunakaHidekiOnishiYasuhiroMiyakeAkinobuTakakiKazuhiroNousoKazuhideYamamotoBackground and Aim: Chronic infection with hepatitis C virus (HCV) decreases health-related quality of life (HRQOL). The present study was planned to investigate the impact of HRQOL of patients with chronic hepatitis C (CHC) on the outcomes of therapy with pegylated interferon and ribavirin (RBV), in addition to IL28B polymorphisms.
Methods: The present study enrolled 228 CHC patients and assessed their HRQOLs prospectively with the 36-item short-form health survey.
Results: The patients with CHC have lower physical HRQOL status than the general population (P = 0.037, the Z-test). The patients with advanced liver diseases exhibited further decreases in HRQOL (P = 0.036, Spearman's rank correlation coefficient). The score of total HRQOL was significantly lower in the group with sustained virological response (SVR) to the therapy with pegylated interferon and RBV than the non-SVR group (P = 0.031, the Mann-Whitney U-test), with significantly lower scores of mental component and its comprising subscales in the SVR group. Stepwise multivariate logistic regression analysis showed that low HRQOL score <= 400 points was significantly associated with SVR (odds ratio = 2.4, P = 0.013), independently from high platelet counts, low HCV RNA, favorable single-nucleotide polymorphism type of IL28B, and HCV serotype 2. The patients with low HRQOL score will have significantly less decrease in HRQOL score by 4 weeks of the treatment than those with high HRQOL score at baseline (P = 0.0045).
Conclusion: HRQOL is one of the significant predictor of the outcomes of therapy with pegylated interferon and RBV independently from IL28B polymorphism.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0012-28238622012Serum Levels of Soluble Adhesion Molecules as Prognostic Factors for Acute Liver Failure122128ENAtsuyukiOhnishiYasuhiroMiyakeHiroshiMatsushitaKazuyukiMatsumotoAkinobuTakakiTetsuyaYasunakaKazukoKoikeFusaoIkedaHidenoriShirahaKazuhiroNousoKazuhideYamamotoBackground/Aims: In patients with septic shock, the degree of liver dysfunction is correlated with serum levels of soluble intercellular adhesion molecule (sICAM)-1. We aimed to assess the usefulness of serum levels of soluble adhesion molecules as prognostic factors for acute liver failure (ALF). Methods: Serum levels of soluble platelet endothelial cell adhesion molecule (sPECAM)-1, sICAM-3, soluble endothelial (sE) selectin, sICAM-1, soluble platelet selectin, and soluble vascular cell adhesion molecule-1 on admission were measured in 37 ALF patients and 34 healthy controls. Results: Twenty-two ALF patients (59%) reached to fatal outcomes. Serum levels of sPECAM-1, sICAM-3, sE-selectin and sICAM-1 were higher in ALF patients than healthy controls. In 37 ALF patients, by the multivariate logistic regression analysis, ratio of direct to total bilirubin (per 0.1 increase; OR 0.11, 95% CI 0.01-0.99), serum sPECAM-1 level (per 100 ng/ml increase; OR 4.37, 95% CI 1.23-15.5) and serum sICAM-1 level (per 100 ng/ml increase; OR 0.49, 95% CI 0.27-0.89) were associated with fatal outcomes. Using receiver operating characteristics curve, each area under the curve of serum sPECAM-1 and sICMA-1 levels as prognostic factors was 0.71 and 0.74, respectively. Conclusion: Serum sPECAM-1 and sICAM-1 levels may be useful for predicting the prognosis of ALF.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6842014Prevalence and Outcomes of Acute Hepatitis B in Okayama, Japan, 2006-2010243247ENNozomuWadaTetsuyaYasunakaFusaoIkedaSohjiNishinaMasaakiKorenagaKeisukeHinoShin-ichiFujiokaToshiyaOsawaTatsuyaItoshimaMiwaKawanakaGotaroYamadaKazuyaKariyamaHirokiTakayamaJunichiKubotaYoichiMorimotoTakaakiMizushimaHaruhikoYamashitaHiroakiTaniokaYujiNegoroJunichiToshimoriHaruhikoKobashiAtsushiHiranoYasuoItanoAkinobuTakakiKazuhideYamamotoOriginal Article10.18926/AMO/52790Hepatitis B virus (HBV) is one of the major viruses causing acute hepatitis. Recently, the incidence of acute hepatitis with genotype A has been increasing in Japan. The aim of this study was to investigate acute hepatitis B (AHB) in Okayama prefecture, with special attention to HBV genotype A. AHB patients who visited one of 12 general hospitals in Okayama prefecture between 2006 and 2010 were retrospectively analyzed. Over the course of the study period, 128 patients were diagnosed with AHB. Sexual transmission was supposed in the majority of patients (78 patients, 61%), including 59 (76%) having sex with heterosexual partners. The genotypes of HBV were assessed in 90 patients (70%), of whom 27 patients were infected with genotype A, 5 with genotype B, and 58 with genotype C. The prevalence of genotype A was significantly higher among male patients (28.7%), aged 20-29 (35.6%,
p＜0.01), among men who had sex with men (100%, p＜0.005), and among patients having sex with unspecified partners (44.8%, p＜0.005). Genotype A was not a significant factor associated with delayed HBsAg disappearance. Caution should be exercised with regard to sexually transmissible diseases in order to slow the pandemic spread of AHB due to genotype A.No potential conflict of interest relevant to this article was reported.Elsevier Science BV.Acta Medica Okayama0165-24781561-22013IL-7 promotes long-term in vitro survival of unique long-lived memory subset generated from mucosal effector memory CD4(+) T cells in chronic colitis mice8293ENMasahiroTakaharaYasuhiroNemotoShigeruOshimaYuMatsuzawaTakanoriKanaiRyuichiOkamotoKiichiroTsuchiyaTetsuyaNakamuraKazuhideYamamotoMamoruWatanabeColitogenic memory CD4(+) T cells are important in the pathogenesis of inflammatory bowel disease (IBD). Although memory stem cells with high survival and self-renewal capacity were recently identified in both mice and humans, it is unclear whether a similar subset is present in chronic colitis mice. We sought to identify and purify a long-lived subset of colitogenic memory CD4(+) T cells, which may be targets for treatment of IBD. A long-lived subset of colitogenic memory CD4(+) T cells was purified using a long-term culture system. The characteristics of these cells were assessed. Interleukin (IL)-7 promoted the in vitro survival for >8 weeks of lamina propria (LP) CD4(+) T cells from colitic SOD mice previously injected with CD4(+)CD45RB(high) T cells. These cells were in a quiescent state and divided a maximum of 5 times in 4 weeks. LP CD4(+) T cells expressed higher levels of Bcl-2, integrin-alpha 4 beta 7, CXCR3 and CD25 after than before culture, as well as secreting high concentrations of IL-2 and low concentrations of IFN-gamma and IL-17 in response to intestinal bacterial antigens. LP CD4(+) T cells from colitic mice cultured with IL-7 for 8 weeks induced more severe colitis than LP CD4(+) T cells cultured for 4 weeks. We developed a novel culture system to purify a long-lived, highly pathogenic memory subset from activated LP CD4(+) T cells. IL-7 promoted long-term in vitro survival of this subset in a quiescent state. This subset will be a novel, effective target for the treatment of IBD.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0815-93192612011Serum levels of platelet-derived growth factor-BB and vascular endothelial growth factor as prognostic factors for patients with fulminant hepatic failure116121ENHirokiTakayamaYasuhiroMiyakeKazuhiroNousoFusaoIkedaHidenoriShirahaAkinobuTakakiHaruhikoKobashiKazuhideYamamotoBackground and Aims:
In animal models for acute liver injury, the administration of some angiogenic factors such as vascular endothelial growth factor (VEGF) and granulocyte-colony stimulating factor (G-CSF) are shown to reduce liver injury and improve liver proliferative capacity. The aim of the present study was to assess the role of angiogenic factors in fulminant hepatic failure (FHF).
Methods:
Serum levels of nine angiogenic factors (angiopoietin-2, follistatin, G-CSF, hepatocyte growth factor [HGF], interleukin-8, leptin, platelet-derived growth factor [PDGF]-BB, platelet endothelial cell adhesion molecule-1 and VEGF) were measured using the Bio-Plex Protein Array System in 30 patients, 17 of whom were diagnosed with FHF, 13 with acute hepatitis (AH), and 20 controls.
Results:
Serum levels of PDGF-BB and VEGF were lower in FHF patients than AH patients and controls (PDGF-BB; 2050 +/- 1572 pg/mL vs 4521 +/- 2419 pg/mL vs 8506 +/- 5500 pg/mL, VEGF; 39 +/- 38 pg/mL vs 144 +/- 122 pg/mL vs 205 +/- 121 pg/mL). By using univariate logistic regression models, serum levels of PDGF-BB and VEGF were associated with poor outcomes. Serum PDGF-BB levels were strongly correlated with serum VEGF levels (r = 0.70). Furthermore, serum PDGF-BB levels were significantly correlated with platelet counts (r = 0.79), PT activity (r = 0.37) and D.Bil/T.Bil ratio (r = 0.50), while serum VEGF levels were significantly correlated with platelet counts (r = 0.68) and PT activity (r = 0.38).
Conclusions:
We consider that serum levels of PDGF-BB and VEGF are worth investigating as biomarkers for predicting outcomes of FHF patients.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0016-51077212010Diagnostic accuracy of narrow-band imaging and pit pattern analysis significantly improved for less-experienced endoscopists after an expanded training program127135ENReijiHigashiToshioUraokaJunKatoKenjiKuwakiShinIshikawaYutakaSaitoTakahisaMatsudaHiroakiIkematsuYasushiSanoSeiyuuSuzukiYoshitakaMurakamiKazuhideYamamotoBackground: Previous reports assessing diagnostic skill using narrow-band imaging (NBI) and pit pattern analysis for colorectal polyps involved only highly experienced endoscopists.
Objective: To evaluate diagnostic skills of less-experienced endoscopists (LEE group) for. differentiation of diminutive colorectal polyps by using NBI and pit pattern analysis with and without magnification after an expanded training program.
Design: Prospective study.
Patients: This study involved 32 patients with 44 colorectal polyps (27 adenomas and 17 hyperplastic polyps) of 5 mm that were identified and analyzed by using conventional colonoscopy as well as non-magnification and magnification NBI and chromoendoscopy followed by endoscopic removal for histopathological analysis.
Intervention: Before a training course, 220 endoscopic images were distributed in randomized order to residents with no prior endoscopy experience (NEE group) and to the LEE group, who had performed colonoscopies for more than 5 years but had never used NBI. The 220 images were also distributed to highly experienced endoscopists (HEE group) who had routinely used NBI for more than 5 years. The images were distributed to the NEE and LEE groups again after a training class. Magnification NBI and chromoendoscopy images were assessed by using the Sano and Kudo classification systems, respectively.
Main Outcome Measurements: Diagnostic accuracy and interobserver agreement for each endoscopic modality in each group.
Results: Diagnostic accuracy was significantly higher, and kappa (kappa) values improved in the LEE group for NBI with high magnification after expanded training. Diagnostic accuracy and kappa values when using high-magnification NBI were highest among endoscopic techniques for the LEE group after such training and the HEE group (accuracy 90% vs 93%; kappa = 0.79 vs 0.85, respectively).
Limitations: Study involved only polyps of <= 5 mm.
Conclusion: Using high-magnification NBI increased the differential diagnostic skill of the LEE group after expanded training so that it was equivalent to that of the HEE group.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812622014柿胃石の成分分析における標準物質としての柿渋の有用性127131ENMasayaIwamuroYukoOkamotoToshihiroMurataYoshinariKawaiHidenoriShirahaHiroyukiOkadaKazuhideYamamotoThe definite diagnosis of persimmon phytobezoar (i.e., diospyrobezoar) is often accomplished by a component analysis using infrared spectroscopy. However, no studies have been conducted to investigate which substance is the best as a standard for the component analysis. Here we analyzed tannic acid, Japanese persimmon (kaki), fermented persimmon extract (kaki-shibu), conventional dried persimmon, and dried persimmon smoked in sulfur (ampo-kaki) by infrared spectroscopy to determine which would be optimal as a component analysis standard. The spectrum between 1,600 to 600cm−1 of a persimmon phytobezoar was quite similar to the spectrum of kaki-shibu rather than that of tannic acid. Consequently, we conclude that kaki-shibu should be used as a standard for infrared spectroscopy analyses of persimmon phytobezoars.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama1471-2407112011Hepatitis B virus core promoter mutations G1613A and C1653T are significantly associated with hepatocellular carcinoma in genotype C HBV-infected patientsENMasashiTatsukawaAkinobuTakakiHidenoriShirahaKazukoKoikeYoshiakiIwasakiHaruhikoKobashiShin-IchiFujiokaKohsakuSakaguchiKazuhideYamamotoBackground: Hepatitis B virus (HBV) is a major cause of hepatocarcinogenesis. To identify mutations relevant to hepatocellular carcinoma (HCC) development, we compared the full genome sequences of HBV from the sera of patients with and without HCC.
Methods: We compared the full genome sequences of HBV isolates from 37 HCC patients (HCC group 1) and 38 patients without HCC (non-HCC group 1). We also investigated part of the core promoter region sequences from 40 HCC patients (HCC group 2) and 68 patients without HCC. Of the 68 patients who initially did not have HCC, 52 patients remained HCC-free during the follow-up period (non-HCC group 2), and 16 patients eventually developed HCC (pre-HCC group 2). Serum samples collected from patients were subjected to PCR, and the HBV DNA was directly sequenced.
Results: All patients had genotype C. A comparison of the nucleotide sequences of the HBV genome between HCC group 1 and non-HCC group 1 revealed that the prevalence of G1613A and C1653T mutations in the core promoter region was significantly higher in the HCC group. These mutations tended to occur simultaneously in HCC patients. Multivariate analysis with group 2 revealed that the presence of HCC was associated with aging and the double mutation. Future emergence of HCC was associated with aging and the presence of a single G1613A mutation.
Conclusions: G1613A and C1653T double mutations were frequently found in patients with HCC. A single G1613A mutation was associated with future emergence of HCC. These mutations may serve as useful markers in predicting HCC development.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6812014Impact of Comorbid Hepatic Steatosis on Treatment of Chronic Hepatitis C in Japanese Patients and the Relationship with Genetic Polymorphism of IL28B, PNPLA3 and LDL Receptor1722ENYukiMoritouFusaoIkedaYoshiakiIwasakiNobuyukiBabaKouichiTakaguchiTomonoriSenohTakuyaNaganoYasutoTakeuchiTetsuyaYasunakaHidekiOhnishiYasuhiroMiyakeAkinobuTakakiKazuhiroNousoKazuhideYamamotoOriginal Article10.18926/AMO/52139The impact of hepatic steatosis on interferon therapy for patients with chronic hepatitis C (CHC) has been associated with single-nucleotide polymorphisms (SNP) of IL28B, patatin-like phospholipase domain-containing protein 3 (PNPLA3), and low-density lipoprotein (LDL) receptor. Whether this holds true for Japanese patients, however, remains unresolved. The present study prospectively enrolled 226 Japanese patients with CHC, and investigated the impact of hepatic steatosis and its related SNPs, including rs8099917 of IL28B, rs738409 of PNPLA3, and rs14158 of LDL receptor, on outcomes of peg-interferon and ribavirin therapy. In multivariate logistic regression analysis, significant factors affecting the severity of hepatic steatosis were high body mass index and the minor alleles of IL28B SNP (p＝0.020 and 0.039, respectively). The risk alleles of PNPLA3 SNP also showed weak association
(p＝0.059). Severe steatosis and the minor alleles of IL28B SNP were significantly associated with null or partial virological response in patients with HCV genotype 1, as were female gender, and low LDL cholesterol (p＝0.049, and ＜0.001, respectively). The SNP genotype of PNPLA3 and LDL receptor
did not have a significant impact on therapeutic outcomes. With respect to the SNP sites examined, the SNP of PNPLA3 has a weak association with severe hepatic steatosis, but not with the outcome of interferon therapy.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0944-11744742012Risk factors for recurrence after transarterial chemoembolization for early-stage hepatocellular carcinoma421426ENHideakiKinugasaKazuhiroNousoYasutoTakeuchiTetsuyaYasunakaHidekiOnishiShin-ichiroNakamuraHidenoriShirahaKenjiKuwakiHiroakiHagiharaFusaoIkedaYasuhiroMiyakeAkinobuTakakiKazuhideYamamotoRadiofrequency ablation (RFA) is a standard therapy for the treatment of hepatocellular carcinoma (HCC) with 3 or fewer tumors of up to 3 cm (early-stage HCC); when RFA is unsuccessful or unfeasible, transcatheter arterial chemoembolization (TACE) has often been performed. However, little information about the outcome of TACE for early-stage HCC has been reported and it is hard to decide whether to perform additional treatment following TACE in these difficult conditions. The aim of this study was to determine the risk factors for local or intrahepatic distant recurrence after TACE in early-stage HCC.
Among 1,560 newly diagnosed HCC patients who were admitted to Okayama University Hospital, 43 patients with early-stage HCC who received only TACE in at least one nodule were enrolled in this study. We analyzed the risk factors for local and distant recurrence by the Cox proportional hazard model.
The local recurrence rates and intrahepatic distant recurrence rates at 3 months, 6 months, and 1 year were 18.6, 33.4, and 61.8%, and 2.8, 2.8, and 10.2%, respectively. Among 12 parameters examined as possible risk factors for recurrence, heterogeneous Lipiodol uptake (risk ratio 3.38; 95% confidence interval 1.14-10.60) and high serum des-gamma-carboxy prothrombin (DCP) (2.58; 1.03-7.14) were significantly correlated with local recurrence, and the presence of multiple tumors (10.64; 1.76-93.75) was significantly correlated with intrahepatic distant recurrence.
Heterogeneous Lipiodol uptake, high serum DCP, and multiple tumors are risk factors for recurrence in patients with early-stage HCC who have undergone palliative TACE.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama2041-172342013An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensingENMasahiroOnjiAtsuoKannoShin-IchirohSaitohRyutaroFukuiYujiMotoiTakumaShibataFumiMatsumotoAayamLamichhaneShintaroSatoHiroshiKiyonoKazuhideYamamotoKensukeMiyakeToll-like receptor 9 (TLR9) is an innate immune sensor for microbial DNA that erroneously responds to self DNA in autoimmune disease. To prevent autoimmune responses, Toll-like receptor 9 is excluded from the cell surface and silenced until the N-terminal half of the ectodomain (TLR9N) is cleaved off in the endolysosome. Truncated Toll-like receptor 9 (TLR9C) senses ingested microbial DNA, although the precise role of the truncation remains controversial. Here we show that TLR9 is expressed on the surface of splenic dendritic cells. Following the cleavage of TLR9 in the endolysosome, N-terminal half of the ectodomain remains associated with truncated TLR9, forming the complex TLR9N + C. The TLR9-dependent cytokine production by Tlr9(-/-) dendritic cells is rescued by a combination of TLR9N and TLR9C, but not by TLR9C alone. These results demonstrate that the TLR9N + C complex is a bona fide DNA sensor.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0944-11744492009Mortality rate of patients with asymptomatic primary biliary cirrhosis diagnosed at age 55 years or older is similar to that of the general population10001006ENJunichiKubotaFusaoIkedaRyoTeradaHaruhikoKobashiShin-ichiFujiokaRyoichiOkamotoShinsukeBabaYouichiMorimotoMasaharuAndoYasuhiroMakinoHideakiTaniguchiTetsuyaYasunakaYasuhiroMiyakeYoshiakiIwasakiKazuhideYamamotoRecent routine testing for liver function and anti-mitochondrial antibodies has increased the number of newly diagnosed patients with primary biliary cirrhosis (PBC). This study investigated the prognosis of asymptomatic PBC patients, focusing on age difference, to clarify its effect on the prognosis of PBC patients.
The study was a systematic cohort analysis of 308 consecutive patients diagnosed with asymptomatic PBC. We compared prognosis between the elderly (55 years or older at the time of diagnosis) and the young patients (< 55 years). The mortality rate of the patients was also compared with that of an age- and gender-matched general population.
The elderly patients showed a higher aspartate aminotransferase-to-platelet ratio, and lower alanine aminotransferase level than the young patients (P < 0.01 and P = 0.03, respectively). The two groups showed similar values for alkaline phosphatase and immunoglobulin M. Death in the young patients was more likely to be due to liver failure (71%), while the elderly were likely to die from other causes before the occurrence of liver failure (88%; P < 0.01), especially from malignancies (35%). The mortality rate of the elderly patients was not different from that of the age- and gender-matched general population (standardized mortality ratio, 1.1; 95% confidence interval, 0.6-1.7), although this rate was significantly higher than that of the young patients (P = 0.044).
PBC often presents as more advanced disease in elderly patients than in the young. However, the mortality rate of the elderly patients is not different from that of an age- and gender-matched general population.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama1078-09981792011DNA Methylation of Colon Mucosa in Ulcerative Colitis Patients: Correlation with Inflammatory Status19551965ENShunsukeSaitoJunKatoSakikoHiraokaJoichiroHoriiHideyukiSuzukiReijiHigashiEisukeKajiYoshitakaKondoKazuhideYamamotoBackground: Although DNA methylation of colonic mucosa in ulcerative colitis (UC) has been suggested, the majority of published reports indicate the correlation between methylation of colon mucosa and occurrence of UC-related dysplasia or cancer without considering the mucosal inflammatory status. The aim of this study was to verify whether mucosal inflammation-specific DNA methylation occurs in the colon of UC.
Methods: Of 15 gene loci initially screened, six loci (ABCB1, CDH1. ESR1, GDNF, HPP1, and MYOD1) methylated in colon mucosa of UC were analyzed according to inflammatory status using samples from 28 surgically resected UC patients.
Results: Four of six regions (CDH1, GDNF, HPP1, and MYOD1) were more highly methylated in the active inflamed mucosa than in the quiescent mucosa in each UC patient (P = 0.003, 0.0002, 0.02, and 0.048, respectively). In addition, when the methylation status of all samples taken from examined patients was stratified according to inflammatory status, methylation of CDHI and GDNF loci was significantly higher in active inflamed mucosa than in quiescent mucosa (P = 0.045 and 0.002, respectively). Multiple linear regression analysis revealed that active inflammation was an independent factor of methylation for CDHI and GDNF. DNA methyltransferase 1 and 3b were highly expressed in colon epithelial cells with active mucosa] inflammation, suggesting their involvement in inflammation-dependent methylation.
Conclusions: Methylation in colonic mucosa of UC was correlated with mucosal inflammatory status, suggesting the involvement of methylation due to chronic active inflammation in UC carcinogenesis.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0815-931927102012Des-gamma-carboxyl prothrombin is associated with tumor angiogenesis in hepatocellular carcinoma16021608ENMinoruMatsubaraHidenoriShirahaJyunroKataokaMasayaIwamuroShigeruHoriguchiShin-ichiNishinaNobuyukiTakaokaMasayukiUemuraAkinobuTakakiShinichiroNakamuraYoshiyukiKobayashiKazuhiroNousoKazuhideYamamotoBackground and Aim: Hepatocellular carcinoma (HCC) is a hypervascular tumor, and angiogenesis plays an important role in its development. Previously, we demonstrated that des-gamma-carboxyl prothrombin (DCP) promotes both cell proliferation and migration of human umbilical vein endothelial cells (HUVECs) by inducing the autophosphorylation of kinase insert domain receptor (KDR). In the present study, DCP-associated tumor angiogenesis was assessed by comparing hypovascular and common hypervascular HCC. Methods: The solitary HCCs of 827 patients were classified into two groups according to the tumor density at the arterial phase of a dynamic computed tomography scan; the initial clinical data of patients with the hyper- and hypovascular types were compared. The HCC tissues from 95 tumors were analyzed by immunohistochemical staining for DCP and phosphorylated KDR, and intratumoral microvessel density (MVD) was analyzed to evaluate microvessel angiogenesis. Results: The serum DCP levels (320 +/- 3532 mAU/mL) and tumor size (18.4 +/- 9.0 mm) of patients with hypervascular HCC were significantly greater than those with hypovascular HCC (38.7 +/- 80 mAU/mL and 14.6 +/- 5.2 mm, P < 0.001). Immunohistochemical analysis revealed that the expressions of DCP and phospho-KDR were significantly greater in hypervascular HCC (71.4% and 31.0%, respectively) than in hypovascular HCC (7.6% and 5.7%, respectively). Intratumoral MVD was significantly correlated with DCP (r = 0.48, P < 0.0001). Conclusions: des-gamma-carboxyl prothrombin production is associated with tumor angiogenesis in HCC.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0172-6390601232013Management of Occluded Metallic Stents in Malignant Hilar Biliary Stricture447451ENMasakuniFujiiHirofumiKawamotoKoichiroTsutsumiHironariKatoKenHiraoNaokoKuriharaOsamuMizunoEtsujiIshidaTsuneyoshiOgawaHirotoshiFukatsuKazuhideYamamotoBackground/Aims: Little is known about the management of occluded multiple metallic stent (MS) deployed in malignant hilar biliary strictures (HBS). The purpose of this study was to evaluate the endoscopic management of occluded multiple MSs deployed in HBS. Methodology: Fifty-five patients with unresectable biliary tract carcinoma had multiple MSs inserted due to HBS. The endoscopic intervention through the duodenal papilla was performed on 30 cases that had MS occlusion. The procedure success rate, the survival time after the procedure and the number of endoscopic interventions before death were analyzed, retrospectively. Results: The causes of MS obstruction were tissue ingrowth (n=20), sludge (n=7), tumor overgrowth (n=2), and hemobilia (n=1). Endoscopic cleaning or deployment of plastic stents or metallic stents was performed on these patients and was successfully accomplished only via the transpapillary approach. The survival time after MS obstruction was 219 days. The median number of endoscopic interventions before death was 3. The median interval of endoscopic intervention after the first plastic stent occlusion was 84 days. Conclusions: Our long-term data regarding the endoscopic management of occluded MSs deployed in malignant hilar biliary strictures are acceptable although the patency time of plastic stents deployed after MS occlusion was relatively short.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812532013免疫学的便潜血定量法による潰瘍性大腸炎の粘膜治癒評価221223ENAsukaNakaraiJunKatoSakikoHiraokaMotoakiKuriyamaToshihiroInokuchiDaisukeTakeiYukiMoritouMitsuhiroAkitaSakumaTakahashiKeitaHaradaHiroyukiOkadaKazuhideYamamotoNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812532013NASHに対する水素分子の有用性201204ENDaisukeKawaiAkinobuTakakiKazuhideYamamotoNo potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6752013Is Presence or History of Extracolonic Primary Malignancy a Risk for Colorectal Neoplasia? An Analysis of Patients Who Underwent Colonoscopy285292ENMitsuhiroAkitaSakikoHiraokaEisukeKajiKojiTakemotoYasuhiroNagaharaHiroshiYamamotoKazuhideYamamotoJunKatoOriginal Article10.18926/AMO/51864Whether presence or history of extracolonic primary malignancy is a risk for colorectal neoplasia is not fully known. In this study, 26,452 first-time colonoscopy cases were examined using a colonoscopy database. Among the analyzed subjects, 3,026 (11%) subjects had history or concomitance of extracolonic primary malignancy, while the remaining 23,426 subjects did not. Colorectal neoplasia was observed in 39% of all the subjects. A crude comparison showed that the prevalence of any type of colorectal neoplasia was higher in subjects with extracolonic malignancy than in those without (42% vs. 39%, p＝0.0012). However, after adjusting for confounding factors, the odds ratios (ORs) of subjects with extracolonic malignancy for having colorectal neoplasia, advanced neoplasia, and cancer were all less than 1.0, and all significantly different from those of subjects without extracolonic malignancy. Analysis according to the type of extracolonic malignancy revealed that gastric cancer cases had a significantly lower risk for colorectal advanced neoplasia (OR:0.81;95% CI:0.67-0.99). Among major malignancies, only esophageal squamous cell cancer cases had increased risk for colorectal neoplasia (OR:1.66;95% CI:1.20-2.29). Patients with presence or history of extracolonic malignancy did not carry a higher risk of occurrence of colorectal neoplasia.No potential conflict of interest relevant to this article was reported.Wiley-BlackwellActa Medica Okayama1386-634643102013Serum oxidative-anti-oxidative stress balance is dysregulated in patients with hepatitis C virus-related hepatocellular carcinoma10781092ENMamoruNishimuraAkinobuTakakiNaofumiTamakiTakayukiMaruyamaHidekiOnishiSayoKobayashiKazuhiroNousoTetsuyaYasunakaKazukoKoikeHiroakiHagiharaKenjiKuwakiShinichiroNakamuraFusaoIkedaYoshiakiIwasakiTakaakiTomofujiManabuMoritaKazuhideYamamotoAim
Oxidative stress is associated with progression of chronic liver disease (CLD). This association is best established in chronic hepatitis C. However, the anti-oxidative state is not well characterized. The objective of the present study was to investigate the balance of oxidative and anti-oxidative stress in CLD patients.
Methods
We recruited a study population of 208 patients, including healthy volunteers (HV; n = 15), patients with hepatitis B virus (HBV)-related CLD without or with hepatocellular carcinoma (HBV-non-HCC, n = 25, and HBV-HCC, n = 50, respectively), and patients with hepatitis C virus (HCV)-related CLD without or with HCC (HCV-non-HCC, n = 49, and HCV-HCC, n = 69, respectively). Serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY-adsorbent test; OXY) were determined, and the balance of these values was used as the oxidative index. Correlations among ROM, OXY, oxidative index and clinical characteristics were investigated.
Results
Patients with CLD exhibited elevated ROM and oxidative index compared to HV. Among patients with CLD, HCV positive status correlated with increased ROM. In CLD, HCV-HCC patients exhibited the highest ROM levels. Among HCV-related CLD patients, lower OXY correlated with HCC positive status, but was recovered by eradication of HCC. In HCV-HCC, lower OXY correlated with high PT-INR.
Conclusion
HCV positive CLD patients displayed higher oxidative stress and HCV-HCC patients displayed lower anti-oxidative state. Anti-oxidative state depression was associated with liver reservoir-related data in HCV-HCC and could be reversed with HCC eradication.No potential conflict of interest relevant to this article was reported.KargerActa Medica Okayama1424-39031252012Monitoring of CA19-9 and SPan-1 can facilitate the earlier confirmation of progressing pancreatic cancer during chemotherapy409416ENKoichiroTsutsumiHirofumiKawamotoKenHiraoIchiroSakakiharaNaokiYamamotoYasuhiroNomaMasakuniFujiiHironariKatoTsuneyoshiOgawaEtsujiIshidaKenjiKuwakiKazuhiroNousoHiroyukiOkadaKazuhideYamamotoBackground: Measurement of objective response to chemotherapy using imaging modalities is sometimes difficult in pancreatic cancer (PC). We aimed to verify whether monitoring of serum tumor markers (TMs), namely carcinoembryonic antigen, CA19-9, DUPAN-2, SPan-1, can facilitate earlier confirmation of treatment failure.
Methods: Monitoring of serum TMs and computed tomography were performed every 4 weeks until progression of disease in 90 patients with PC undergoing gemcitabine therapy. In Group A (January 2006 October 2007), we analyzed the fluctuation rates of TMs with high pretreatment positive rates, and defined the criteria of progressive disease under TM monitoring (TM-PD). In Group B (November 2007 October 2008), we calculated the time to progression (TTP) under this TM-PD criteria, which was compared with the UP under the RECIST criteria.
Results: CA19-9 and SPan-1 had the highest pretreatment positive rates: 83% and 90%, respectively. In Group A (CA19-9, n = 38; SPan-1, n = 36), TM-PD criteria were defined as follows: fluctuation rates were >25% for a month or >= 10% for 2 consecutive months in CA19-9, and >= 10% for a month in SPan-1. In Group B (CA19-9, n = 18; SPan-1, n = 17), under these criteria, one-month earlier confirmation of treatment failure was feasible in 61% by CA19-9 and 59% by SPan-1. Furthermore, the combination could facilitate this determination in 72% (35/49), significantly better than CA19-9 alone (P = 0.004).
Conclusion: Monitoring of serum CA19-9 and Span-1 is helpful for earlier confirmation of treatment failure during gemcitabine therapy in PC.No potential conflict of interest relevant to this article was reported.Lippincott Williams & WilkinsActa Medica Okayama0885-31774212013Utility of Contrast-Enhanced FDG-PET/CT in the Clinical Management of Pancreatic Cancer Impact on Diagnosis, Staging, Evaluation of Treatment Response, and Detection of Recurrence1119ENAkinoriAsagiKojiOhtaJunichirouNasuMinoruTanadaSeijinNadanoRiekoNishimuraNorihiroTeramotoKazuhideYamamotoTakeshiInoueHaruoIguchiObjectives: Fluorodeoxyglucose (FDG)-positron emission tomography/contrast-enhanced computed tomography (PET/CE-CT) involving whole-body scanning first by non-CE-CT and FDG-PET followed by CE-CT has been used for detailed examination of pancreatic lesions. We evaluated PET/CE-CT images with regard to differential diagnosis, staging, treatment response, and postoperative recurrence in pancreatic cancer.
Methods: Positron emission tomography/CE-CT was conducted in 108 patients with pancreatic cancer and in 41 patients with other pancreatic tumor diseases.
Results: The maximum standardized uptake value (SUVmax) overlapped in benign and malignant cases, suggesting that differential diagnosis of pancreatic tumors based on the SUVmax is difficult. In the evaluation of staging in 31 resectable pancreatic cancer by PET/CE-CT, the diagnostic accuracy rate was more than 80% for most factors concerning local invasion and 94% for distant metastasis but only 42% for lymph node metastasis. Significant positive correlations were found between the SUVmax and tumor size/markers, suggesting that SUVmax may be a useful indicator for the treatment response. Regarding the diagnosis of the postoperative recurrence, PET/CE-CT correctly detected local recurrence in all the 11 cases of recurrence, whereas abdominal CE-CT detected only 7 of 11 cases, suggesting that PET/CE-CT is superior in this context.
Conclusions: Positron emission tomography/CE-CT is useful for the clinical management of pancreatic cancer.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0020-7136131112012Runt-related transcription factor 3 reverses epithelial-mesenchymal transition in hepatocellular carcinoma25372546ENShigetomiTanakaHidenoriShirahaYutakaNakanishiShin-IchiNishinaMinoruMatsubaraShigeruHoriguchiNobuyukiTakaokaMasayaIwamuroJunroKataokaKenjiKuwakiHiroakiHagiharaJunichiToshimoriHidekiOhnishiAkinobuTakakiShinichiroNakamuraKazuhiroNousoTakahitoYagiKazuhideYamamotoLoss 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 epithelialmesenchymal 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.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6722013The Genetic Diversity of Helicobacter pylori Virulence Genes Is Not Associated with Gastric Atrophy Progression9398ENMasahideKitaKenjiYokotaHiroyukiOkadaSusumuTakeRyutaTakenakaYoshiroKawaharaKeijiOgumaOsamuMatsushitaKazuhideYamamotoOriginal Article10.18926/AMO/49667Atrophy of the gastric mucosa is a precursor of intestinal-type gastric cancer, and Helicobacter pylori infection causes atrophic gastritis. The aim of this study was to determine whether the genetic diversity of H. pylori virulence genes is associated with the development and progression of gastric atrophy in humans. We isolated and cultured H. pylori strains from patients with gastric ulcer and duodenal ulcer accompanied by atrophic gastritis in background mucosa. H. pylori strains were stored at −80℃ prior to the experiments being carried out. We analyzed iceA, babA, vacA, cagA, and cagE genes by PCR. The cagA gene was analyzed through sequencing of the C-terminal region containing the EPIYA motif, which is related to tyrosine phosphorylation. Severe atrophy was observed in patients with gastric ulcer. The major phenotype of the vacA gene was s1c/m1 (93ｵ). The cagA gene was detected in all strains. The cagE gene was not detected in 2 and 5 strains from the mild cases and severe cases, respectively. The major cagA EPIYA motif, which is amino acids repeat in the C terminus, was the A-B-D type (44 of 58 strains). The virulence genes were not statistically associated with the severity of atrophy in the background gastric mucosa in humans. Not only identification of bacterial virulence factors but also studies of the host response will be necessary to investigate the progression of gastric atrophy and subsequent cancer development in humans.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0944-11744722012Detectability of colorectal neoplasia with fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (FDG-PET/CT)127135ENTomokoHirakawaJunKatoYoshihiroOkumuraKeisukeHoriSakumaTakahashiHideyukiSuzukiMitsuhiroAkitaReijiHigashiShunsukeSaitoEisukeKajiToshioUraokaSakikoHiraokaKazuhideYamamotoThe purpose of this study was to analyze the detectability of colorectal neoplasia with fluorine-18-2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG-PET/CT).
Data for a total of 492 patients who had undergone both PET/CT and colonoscopy were analyzed. After the findings of PET/CT and colonoscopy were determined independently, the results were compared in each of the six colonic sites examined in all patients. The efficacy of PET/CT was determined using colonoscopic examination as the gold standard.
In all, 270 colorectal lesions 5 mm or more in size, including 70 pathologically confirmed malignant lesions, were found in 172 patients by colonoscopy. The sensitivity and specificity of PET/CT for detecting any of the colorectal lesions were 36 and 98%, respectively. For detecting lesions 11 mm or larger, the sensitivity was increased to 85%, with the specificity remaining consistent (97%). Moreover, the sensitivity for tumors 21 mm or larger was 96% (48/50). Tumors with malignant or high-grade pathology were likely to be positive with PET/CT. A size of 10 mm or smaller [odds ratio (OR) 44.14, 95% confidence interval (95% CI) 11.44-221.67] and flat morphology (OR 7.78, 95% CI 1.79-36.25) were significant factors that were associated with false-negative cases on PET/CT.
The sensitivity of PET/CT for detecting colorectal lesions is acceptable, showing size- and pathology-dependence, suggesting, for the most part, that clinically relevant lesions are detectable with PET/CT. However, when considering PET/CT for screening purposes caution must be exercised because there are cases of false-negative results.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6662012Eradication of Hepatitis C Virus Subgenomic Replicon by Interferon Results in Aberrant Retinol-Related Protein Expression461468ENKazukoKoikeAkinobuTakakiNobuyukiKatoMamoruOuchidaHirotakaKanzakiTetsuyaYasunakaHidenoriShirahaYasuhiroMiyakeKazuhideYamamotoOriginal Article10.18926/AMO/49042Hepatitis C virus (HCV) infection induces several changes in hepatocytes, such as oxidative stress, steatosis, and hepatocarcinogenesis. Although considerable progress has been made during recent years, the mechanisms underlying these functions remain unclear. We employed proteomic techniques in HCV replicon-harboring cells to determine the effects of HCV replication on host-cell protein expression. We examined two-dimensional electrophoresis (2-DE) and mass spectrometry to compare and identify differentially expressed proteins between HCV subgenomic replicon-harboring cells and their “cured” cells. One of the identified proteins was confirmed using enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Full-length HCV genome RNA replicating and cured cells were also assessed using ELISA. Replicon-harboring cells showed higher expression of retinal dehydrogenase 1 (RALDH-1), which converts retinol to retinoic acid, and the cured cells showed higher expression of retinol-binding protein (RBP), which transports retinol from the liver to target tissues. The alteration in RBP expression was also confirmed by ELISA and Western blot analysis. We conclude that protein expression profiling demonstrated that HCV replicon eradication affected retinol-related protein expression.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama1471-2407112011Loss of runt-related transcription factor 3 expression leads hepatocellular carcinoma cells to escape apoptosisENYutakaNakanishiHidenoriShirahaShin-ichiNishinaShigetomiTanakaMinoruMatsubaraShigeruHoriguchiMasayaIwamuroNobuyukiTakaokaMasayukiUemuraKenjiKuwakiHiroakiHagiharaJunichiToshimoriHidekiOhnishiAkinobuTakakiShinichiroNakamuraYoshiyukiKobayashiKazuhiroNousoTakahitoYagiKazuhideYamamotoBackground: Runt-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).
Methods: RUNX3 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.
Results: RUNX3 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.
Conclusion: RUNX3 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.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama1471-240792009Twist expression promotes migration and invasion in hepatocellular carcinomaENNoriyukiMatsuoHidenoriShirahaTatsuyaFujikawaNobuyukiTakaokaNaokiUedaShigetomiTanakaShinichiNishinaYutakaNakanishiMasayukiUemuraAkinobuTakakiShinichiroNakamuraYoshiyukiKobayashiKazuhiroNousoTakahitoYagiKazuhideYamamotoBackground: Twist, a transcription factor of the basic helix-loop-helix class, is reported to regulate cancer metastasis. It is known to induce epithelial-mesenchymal transition (EMT). In this study, we evaluated the expression of twist and its effect on cell migration in hepatocellular carcinoma (HCC).
Methods: We examined twist expression using immunohistochemistry in 20 tissue samples of hepatocellular carcinoma, and assessed twist expression in HCC cell lines by RT-PCR and Western blot analysis. Ectopic twist expression was created by introducing a twist construct in the twist-negative HCC cell lines. Endogenous twist expression was blocked by twist siRNA in the twist-positive HCC cell lines. We studied EMT related markers, E-cadherin, Vimentin, and N-cadherin by Western blot analysis. Cell proliferation was measured by MTT assay, and cell migration was measured by in vitro wound healing assay. We used immunofluorescent vinculin staining to visualize focal adhesion.
Results: We detected strong and intermediate twist expression in 7 of 20 tumor samples, and no significant twist expression was found in the tumor-free resection margins. In addition, we detected twist expression in HLE, HLF, and SK-Hep1 cells, but not in PLC/RPF/5, HepG2, and Huh7 cells. Ectopic twist-expressing cells demonstrated enhanced cell motility, but twist expression did not affect cell proliferation. Twist expression induced epithelial-mesenchymal transition together with related morphologic changes. Focal adhesion contact was reduced significantly in ectopic twist-expressing cells. Twist-siRNA-treated HLE, HLF, and SK-Hep1 cells demonstrated a reduction in cell migration by 50, 40 and 18%, respectively.
Conclusion: Twist induces migratory effect on hepatocellular carcinoma by causing epithelial-mesenchymal transition.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6632012Safety and Efficacy of Radiofrequency Ablation with Artificial Ascites for Hepatocellular Carcinoma279284ENMamoruNishimuraKazuhiroNousoKazuyaKariyamaAkikoWakutaMasayukiKishidaNozomuWadaToshihiroHigashiKazuhideYamamotoOriginal Article10.18926/AMO/48568The artificial ascites technique is often used during radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) treatment because it prevents visceral damage and improves visualization by minimizing
interference of the lungs and mesentery. This study determined the efficacy and safety of RFA using the artificial ascites technique in HCC patients. We examined 188 HCC patients who were treated by RFA and fulfilled the Milan criteria. Treatment outcomes (complete ablation rate, local recurrence rate, complication rate, liver function including total bilirubin level, alanine aminotransferase level, albumin level, and prothrombin time) were compared among patients divided into 3 groups based on the volume of artificial ascites injected:GroupT (n＝86), no artificial ascites injected;GroupU (n＝35), ＜1,000ml artificial ascites injected;and Group V (n＝67), ＞1,000ml artificial ascites injected. No significant difference was observed in complete ablation or local recurrence rates among the 3 groups, or in the extent of liver function damage after RFA. Artificial ascites disappeared within 7 days;
additional diuretics were needed only in 5 (all from Group V) of 102 patients. No serious complications
such as intestinal perforation or intraperitoneal bleeding were observed. Thus, we found that artificial ascites injection during RFA is effective and safe, and can be used to prevent major procedural
complications.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812322011Large serrated polypの存在は大腸癌の危険因子である97101ENSakikoHiraokaJunKatoShigeatsuFujikiEisukeKajiTamiyaMorikawaTakatoshiMurakamiToruNawaMotoakiKuriyamaToshioUraokaNobuyaOharaKazuhideYamamotoNo potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6522011Usefulness and Problems of Endoscopic Ultrasonography in Prediction of the Depth of Tumor Invasion in Early Gastric Cancer105112ENTakaoTsuzukiHiroyukiOkadaJunichiroNasuRyutaTakenakaMasafumiInoueSeijiKawanoMasahideKitaKeisukeHoriKazuhideYamamotoOriginal Article10.18926/AMO/45269The objectives of this study were to evaluate the accuracy of endoscopic ultrasonography (EUS) in local and regional staging of early gastric cancer, to analyze the factors influencing the accuracy of EUS, and to reveal the usefulness and problems of EUS in pre-treatment staging of gastric cancer. We examined 105 lesions in 104 patients with histologically confirmed gastric cancer and retrospectively evaluated them with EUS. The diagnostic accuracy, sensitivity, and specificity of EUS were determined by comparing the pre-treatment EUS with the postoperative histopathological findings. The overall diagnostic accuracy of EUS for the depth of cancer invasion was 86%. The overall sensitivity and specificity were 60% and 96%, respectively. The accuracy significantly declined in lesions located in the upper-third of the stomach (70%). Type 0-I lesions tended to be over-staged (12&), and the upper-third lesions tended to be under-staged (23%). The accuracy significantly declined in differentiated adenocarcinoma with massive submucosal invasion (56.5%). EUS is useful for evaluating the depth of gastric cancer invasion which determines the feasibility of endoscopic treatment. However, it is noteworthy that the diagnostic accuracy of the invasion depth diminished for lesions in the upper third of the stomach.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6512011Prognostic Model for Hepatocellular Carcinoma with Time-Dependent Factors1119ENKenjiKuwakiKazuhiroNousoYoshiyukiKobayashiShinichiroNakamuraYoichi M.ItoShoutaIwadouHiroakiHagiharaTetsuyaYasunakaJunichiToshimoriHirokazuMiyatakeKenjiMiyoshiHidekiOnishiYasuhiroMiyakeBonShojiAkinobuTakakiHidenoriShirahaYoshiakiIwasakiHaruhikoKobashiKazuhideYamamotoOriginal Article10.18926/AMO/43825The purpose of this study was to build a prognostic model of hepatocellular carcinoma (HCC) using time-dependent covariates to re-evaluate the prognosis at any stage of the disease. The subjects were consecutive HCC patients who were treated at our institute between 1995 and 2007. We constructed time-fixed and time-dependent prognostic models with a training group (n＝336) and compared the prognostic abilities between conventional Cancer of the Liver Italian Program (CLIP) scores, Japan Integrated Staging (JIS) scores, an Okuda classification, and our prognostic models in the testing group (n＝227) with the c-index. The time-dependent prognostic model consisted of main tumor size, tumor number, portal vein invasion, distant metastasis, alpha-fetoprotein, des-gamma-carboxy prothrombin (DCP), bilirubin, and albumin and the weighted scores were set for each factor depending on the hazard ratio for the prognosis. The prognostic index was determined by summing the scores. The c-index values for the CLIP scores, JIS scores, Okuda classification, and our time-dependent model were 0.741, 0.727, 0.609, and 0.870, respectively. These results indicate that our time-dependent model can estimate the prognosis of HCC more precisely than traditional time-fixed models and can be used to re-predict the prognosis of HCC.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812232010胆道癌診療ガイドライン249251ENMasakuniFujiiHirofumiKawamotoKazuhideYamamotoNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812232010急性胆管炎・胆嚢炎の診療ガイドラインについて243247ENKoichiroTsutsumiHirofumiKawamotoKazuhideYamamotoNo potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6362009Significance of Des-gamma-carboxy Prothrombin Production in Hepatocellular Carcinoma299304ENTatsuyaFujikawaHidenoriShirahaKazuhideYamamotoReview10.18926/AMO/31826<p>Serum des-gamma-carboxy prothrombin (DCP) is commonly used to detect hepatocellular carcinoma (HCC). This review focuses on the clinical features of DCP-positive HCC and the molecular function of DCP in HCC. DCP-positive HCC demonstrates more aggressive clinicopathological features than DCP-negative HCC. Analysis of the biological effects of DCP revealed that DCP acts as a growth factor in both an autocrine and paracrine manner. DCP stimulates HCC cell proliferation through the Met-Janus kinase 1-signal transducer and activator of transcription 3 signaling pathway, whereas for vascular endothelial cells, it stimulates cell proliferation and migration through the kinase insert domain receptor-phospholipase C-gamma-mitogen-activated protein kinase signaling pathway.</p>No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X5632002Development of syngeneic monoclonal anti-idiotype antibodies to mouse monoclonal anti-asialoglycoprotein receptor antibody.135139ENMichioHiraiMotowoMizunoYoshikoMorisueMasaoYoshiokaMorizouShimadaJunichirouNasuHiroyukiOkadaHiroyukiShimomuraKazuhideYamamotoTakaoTsujiArticle10.18926/AMO/31715<p>Anti-idiotype antibodies (Ab2) play an important role in the homeostasis of immune responses and are related to the development and the disease activity of certain autoimmune diseases. The asialoglycoprotein receptor (ASGPR) is considered one of the target antigens in the pathogenesis of autoimmune chronic active hepatitis (AIH). We previously developed a mouse monoclonal antibody (clone 8D7) which recognizes rat and human ASGPR. In this study, to help investigate the anti-ASGPR antibody-anti-idiotype antibody network in patients with AIH, we developed a syngeneic mouse monoclonal Ab2 to the 8D7 anti-ASGPR antibody (Ab1). One clone, designated as 3C8, tested positive for specific reactivity to 8D7-Ab1 and did not bind to other irrelevant immunoglobulins. By competitive inhibition assays, the binding of 8D7-Ab1 to liver membrane extracts, i.e., the crude antigen preparation, was inhibited by 3C8-Ab2 in a dose-dependent manner, and the binding of 8D7-Ab1 to 3C8-Ab2 was inhibited by the liver membrane extracts. In the immunohistochemical analysis, 3C8-Ab2 blocked the specific staining of sinusoidal margins of rat hepatocytes by 8D7-Ab1. These results suggest that 3C8 anti-idiotype antibody recognizes the specific idiotypic determinants within the antigen-binding site of 8D7-Ab1.</p>
No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X5622002Anti-asialoglycoprotein receptor autoantibodies, detected by a capture-immunoassay, are associated with autoimmune liver diseases.99105ENMasaoYoshiokaMotowoMizunoYoshikoMorisueMorizouShimadaMichioHiraiJunichirouNasuHiroyukiOkadaKousakuSakaguchiKazuhideYamamotoTakaoTsujiArticle10.18926/AMO/31695<p>In autoimmune chronic active hepatitis (AIH) and primary biliary cirrhosis (PBC), various autoantibodies including anti-asialoglycoprotein receptor (ASGPR) antibodies have been found in patients' sera. We have previously developed a mouse monoclonal antibody against rat and human ASGPR. In this study, we developed a capture enzyme-linked immunosorbent assay (ELISA) for detection of anti-ASGPR antibodies using this monoclonal antibody and investigated the occurrence of anti-ASGPR antibodies in the sera of patients with various liver diseases. Serum samples were obtained from 123 patients with various liver diseases, including 21 patients with AIH and 40 patients with PBC. In this capture ELISA, the target antigen in the crude rat liver membrane extracts was captured on the ELISA wells by the ASGPR-specific mouse monoclonal antibody. Thus, the cumbersome process of antigen purification was rendered unnecessary. Using this capture ELISA, we detected the anti-ASGPR antibody in 67% of the patients with AIH, in 100% of the patients with PBC, and in 57% of the patients with acute hepatitis type A. However, the anti-ASGPR antibody was rarely detected in patients with other liver diseases such as primary sclerosing cholangitis and obstructive jaundice. Our findings suggest that this capture ELISA would be useful for the detection of anti-ASGPR antibodies in autoimmune liver diseases.</p>
No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X5642002Improvements in the measurement of stool decay-accelerating factor in the detection of colorectal cancer.171176ENShogenOhyaMotowoMizunoMikihiroKawadaJunichirouNasuHiroyukiOkadaHiroyukiShimomuraKazuhideYamamotoTeizouFujitaTakaoTsujiArticle10.18926/AMO/31686<p>We have previously developed an enzyme-linked immunosorbent assay (ELISA) to measure stool decay-accelerating factor (DAF) and found that stool DAF concentrations were significantly elevated in patients with colorectal cancer, suggesting that the measurement of stool DAF may be valuable for the detection of colorectal cancer. In order to refine the assay for the measurement of stool DAF, we investigated 1) effects of centrifugation of stool samples, 2) effects of detergents, and 3) adequate combination of various anti-DAF monoclonal antibodies for the ELISA system using only monoclonal antibodies. We found that high-speed centrifugation could be omitted and that only the removal of large undigested food residues by centrifugation of short duration in a low-speed benchtop microcentrifuge sufficed to adequately prepare the stool samples. Addition of 2 detergents, octyl beta-glucoside and sodium deoxycholate, known to solubilize glycosyl-phosphatidylinositol-anchored proteins such as DAF, did not influence stool DAF values. By using 2 mouse anti-DAF monoclonal antibodies (clone 4F11 and 1C6), we were able to achieve a stable ELISA for the measurement of stool DAF using a uniform source of antibodies. The results should allow us to consistently apply the DAF assay for routine use in the detection of colorectal cancer.</p>
No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X5642002Mutations in the hepatitis B virus preS2 region and abrogated receptor activity for polymerized human albumin.193198ENJunichiKondoHiroyukiShimomuraShin-ichiFujiokaYoshiakiIwasakiShinjiroTakagiYasuhiroOhnishiHideyukiTsujiKosakuSakaguchiKazuhideYamamotoTakaoTsujiArticle10.18926/AMO/31685<p>The preS2 region of the hepatitis B virus (HBV) has been reported to have human polymerized albumin receptor (PAR) activity, which correlates with viral replication. Here, we studied the genomic sequence of the preS region from rare patients lacking PAR activity, despite active viral replication. PAR and DNA polymerase activity was identified in 178 HBe antigen-positive HBV carriers, and a significant correlation between 2 markers was shown, except in 2 hepatitis patients lacking PAR activity. Nucleotide sequences of the preS region of HBV from both patients were examined by direct sequencing of PCR products. In one patient, a 45-base deletion was found to overlap half of the putative polymerized human albumin binding site in the preS2 region. In the other patient, a point mutation at the first nucleotide of the start codon of the preS2 region of HBV was found. There was no such genomic change in the 3 control HBV sequences. These results indicate that the preS2 region is necessary for binding of polymerized human albumin, and this is the first report of naturally existing mutant virus with no or low PAR activity.</p>
No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X5642002Identification of a target antigen recognized by a mouse monoclonal antibody to the bile canalicular surface of rat hepatocytes with a random phage display library.187191ENMasanoriAriyoshiMotowoMIzunoYoshikoMorisueMorizouShimadaShirouFujitaJunichirouNasuHiroyukiOkadaHiroyukiShimomuraKazuhideYamamotoTakaoTsujiArticle10.18926/AMO/31684<p>We developed a monoclonal antibody (MoAb) (clone 5E8) against an antigen on the bile canalicular membrane of rat hepatocyte. By immunoblotting, MoAb 5E8 detected a band of 110 kD. In this study, we used the phage display technique to identify the target antigen recognized by MoAb 5E8. We screened a random phage display library expressing 12-mer peptide sequences and identified a peptide sequence, FHFNPYTGHPLT, as an epitope. We compared this peptide sequence with those of dipeptidyl peptidase IV (DPP IV, E.C.3.4.14.5) and Cell-CAM105, which proteins were located by a database search based on the information of tissue localization and approximate molecular weight of the MoAb 5E8 antigen, and sequence similarity with a region in DPP IV (amino acids 225-233) but not with Cell-CAM105 was found. In addition, we immunohistochemically stained various tissues (liver, small intestine, and kidney) of Japanese Fischer 344 rats, known to be deficient for DPP IV, with MoAb 5E8 and showed that the expression of MoAb 5E8 antigen was negligible or weak. In contrast, tissues sampled from the same organs of Sprague-Dawley rats, known to express DPP IV, were positively stained. These findings suggest that the antigen recognized by MoAb 5E8 is DDPIV and its major epitope is located in amino acids at positions 225-233.</p>
No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X4231988Three-dimensional arrangement of ductular structures formed by oval cells during hepatocarcinogenesis.143150ENYasuhiroMakinoKazuhideYamamotoTakaoTsujiArticle10.18926/AMO/31029<p>The three-dimensional arrangement of ductular structures formed by oval cells in rats fed 2-acetylaminofluorene (2-AAF) was studied by scanning electron microscopy (SEM) of biliary tract casts and light microscopy of sections of liver injected with india ink via the biliary tract. Both resin and india ink were well injected up to bile ductules, and the findings of each method correlated with each other. By the second week after 2-AAF administration, a few oval cells appeared in the periportal areas forming ductular structures which connected with the portal bile ducts. At the 4th week, increased ductular structures occupied two thirds of the lobule and formed networks communicating with each other, and with the portal bile ducts. At the 8th week, such ductular structures were compressed around hyperplastic nodules and appeared like a basket in biliary casts examined by SEM. Although a histochemical study of gamma-glutamyl transpeptidase revealed activity both on the luminal side of the ductular structures and hepatocytes in hyperplastic nodules, no transition was observed between these two cell populations. These results suggest that oval cells have characteristics more similar to those of biliary epithelia than of hepatocytes, and have no relation to the development of hyperplastic nodules.</p>
No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X4241988Phalloidin-induced alterations of bile canaliculi.207213ENKazuhideYamamotoYasuhiroMakinoTatsuyaItoshimaToshinariKobayashiTakaoTsujiArticle10.18926/AMO/30997<p>Phalloidin, a toxin from the plant Amanita phalloides, irreversibly polymerizes actin filaments and causes cholestasis. Three-dimensional structural changes induced by phalloidin in the bile canaliculi and the intra-acinar localization of these changes were studied in the rat liver by scanning and transmission electron microscopy. After 3 days of treatment, canalicular changes appeared mainly in zones 2 and 3 of Rappaport's acinus, but after 7 days of treatment changes occurred in bile canaliculi of the whole acinus. The changes in the bile canaliculi included tortuosity, saccular dilatation, loss of microvilli, bleb formation and elongation of canalicular side branches. Some side branches extended near to Disse's space, leaving only a thin cytoplasmic rim between the canalicular lumen and Disse's space. Kupffer cells were occasionally situated near such extended bile canaliculi and protruded their processes into the hepatic cord. These results suggest that bile canaliculi in zone 3 are more susceptible to phalloidin toxicity than those in zone 1 and that biliary constituents may leak from such altered bile canaliculi.</p>
No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6242008Current Status of Autoimmune Hepatitis in Japan217226ENYasuhiroMiyakeKazuhideYamamotoReview10.18926/AMO/30943<p>Autoimmune hepatitis (AIH) is a chronic and progressive disease characterized by histological interface hepatitis, hypergammaglobulinemia, and circulating autoantibodies. Multiple factors, including molecular mimicry, a genetic background including major histocompatibility complex class II, and defective function of regulatory T-cells, are involved in the pathogenesis. The diagnosis is made based on the scoring system of the International Autoimmune Hepatitis Group, the sensitivity and specificity of which are90%, respectively. AIH is classified into 3 sub-types based on the profiles of circulating autoantibodies: anti-nuclear antibody and/or smooth muscle antibody-positive (type 1), anti-liver-kidney microsomal antibody-positive (type 2), and anti-soluble liver antigen/liver-pancreas antigen antibody- positive (type 3). Recently, however, the number of atypical cases lacking the usual features has increased-for example, patients with acute-onset or fulminant-type AIH, autoantibody-negative patients, male patients, and patients with bile duct injury-and thus the clinical features of AIH have been diversified. AIH is responsive to immunosuppressive treatment in most cases; however, relapse occurs in more than 80% of patients within 1 year after immunosuppressive treatment withdrawal. The 10-year survival rate and the 10-year hepatocellular carcinoma-free rate are90%, respectively, indicating that some patients reach liver failure or develop hepatocellular carcinoma. To improve the prognosis of these patients, persistent normalization of transaminase is required.</p>No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X5051996Primary Sclerosing Cholangitis in Japanese Patients: Association with Inflammatory Bowel Disease227235ENHiroyukiOkadaMotowoMizunoKazuhideYamamotoTakaoTsujiArticle10.18926/AMO/30499<p>To characterize primary sclerosing cholangitis (PSC) in Japanese patients and its association with inflammatory bowel disease (IBD), 155 reported cases of PSC, including 6 cases of our own, were reviewed. The prevalence of IBD was less in Japanese PSC patients than in Western patients (23% versus 62-100%). Japanese PSC patients with IBD were younger (mean age, 33.1 versus 51.8 years) and were more often women (51% versus 36%) than those without IBD. Seventy-four percent of PSC patients with IBD had extensive colonic lesions, and 89% of those developed IBD simultaneously, with or prior to PSC. There were 3 cases of neutrophilic cholangitis among the PSC patients with IBD but none in those without IBD. Based on these observations, we speculate that there may be subtypes of PSC which differ pathophysiologically.</p>
No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812132009急性膵炎の診断と初期治療199203ENTsuneyoshiOgawaHirofumiKawamotoKazuhideYamamotoNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812132009膵癌診療ガイドライン―内科治療の総論について―195198ENKenHiraoHirofumiKawamotoKazuhideYamamotoNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-1558963-41984散発性A型肝炎の臨床像 ―その臨床症状,経過と予後について―305312ENTetsuyaFukudaGotaroYamadaHiromichiOgawaHiroakiOkushinIchinosukeHyodoTakashiNishiharaMotowoMizunoYujiSakamotoHideoNagashimaKazuhideYamamotoToshinariKobayashiTomoroYoshidaClinical and laboratory features of 66 patients with sporadic hepatitis A were evaluated from October 1978 to July 1981. Jaundice was reported in 88.6% of the patients, and the frequency of skin rash was 15.7%. Less than 5% atypical lymphocytes were noted in 29.5% of the patients. Proteinuria and hematuria were present in 23.4% and 6.3% of the patients. However, immune complexes were not detected in their sera. One of the patients who had hematuria developed acute renal failure. About 10% of the patients transiently showed both low levels of cholinesterase and cholesterol and prolongation of the prothrombin time. There was no patient with fulminant hepatic failure. Liver function tests returned to normal except for 3 patients within 3 months. For 10 months after the onset, slight elevation of SGPT peristed in the patient with acute renal failure and also in a patients with a previous history of liver disease. One of two patients with acute intrahepatic cholestasis showed protraction of mild hyperbilirubinemia more than 6 months after the onset of acute illness.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812122009早期胃癌内視鏡治療のガイドライン113115ENSeijiKawanoHiroyukiOkadaYoshiroKawaharaMasafumiInoueKazuhideYamamotoNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812122009胃潰瘍診療のガイドライン109112ENMasafumiInoueHiroyukiOkadaYoshiroKawaharaSeijiKawanoKazuhideYamamotoNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812112009肝癌診療ガイドライン4145ENYoshiyukiKobayashiShinichiroNakamuraHidekiOhnishiJunichiToshimoriKenjiKuwakiHiroakiHagiharaYasuhiroMiyakeHidenoriShirahaKazuhiroNousoTakahitoYagiNoriakiTanakaKazuhideYamamotoNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812112009Des-γ-carboxy prothrombinは血管内皮細胞の増殖能と移動能を亢進させる18ENTatsuyaFujikawaHidenoriShirahaKazuhideYamamotoNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-15581065-61994腹腔動脈完全閉塞をきたした肝細胞癌合併高齢者糖尿病の興味ある一例663668ENTakahikoOkaJunTomodaHaruhikoKobashiNobuyukiSakaiKohsakuSakaguchiKazuhideYamamotoToshihiroHigashiToshioItoGotaroYamadaTakaoTsujiWe report a 75-year-old female with diabetes mellitus complicated with celiac arterial obliteration and hepatocellular cercinoma (HCC). She had been treated with diet therapy by her family doctor for essential hypertension and diabetes mellitus and was referred to our hospital because a space occupying lesion (SOL) was detected in the liver by abdominal CT examination. The SOL was confirmed as hepatocellular carcinoma by ultrasonography and magnetic resoance imaging. Celiac angiography revealed complete obliteration of the celiac artery probably due to diabetic macroangiopathy. Sine the deterioration of the liver function was not conspicuous, it was suggested that the development of HCC was affected by diabetes mellitus.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812032008肝細胞癌の治療アルゴリズムと内科的治療279284ENKazuhideYamamotoNo potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155811722005Schönlein-Henoch 紫斑病による腹痛症を呈し，内視鏡所見を観察しえた成人男性の２例127133ENMasayaIwamuroShogenOhyaMasaoYoshiokaTatsuyoNasuTsuneyoshiOgawaMamoruItoShuheiIshiyamaAkikoFujiwaraJunjiShiodeKazuhideYamamotoTatsuyaItoshimaWe describe two cases of adult-onset Schonlein-Henoch purpura with gastrointestinal manifestations. Case 1: A 73-year-old man was admitted to our hospital because of abdominal pain, diarrhea and fever. On physical examination, the abdomen was normal, and there were many palpable petechial hemorrhages on the lower extremities.Skin biopsy revealed infiltrations of lymphocytes, neutrophils and eosinophils into the dermis. A computed tomographic (CT) scan of the abdomen disclosed thickening of the intestinal wall in the duodenum and jejunum.Upper gastrointestinal fiberscopy revealed petechiation on the stomach and erosions on the duodenum. Case 2: A 54-year-old man was admitted to our hospital because of hematochezia.The patient had pharyngitis 4 days before admission, and his serum anti-streptolysion O level was increased.On physical examination, there were faint purpuras on the lower extremities.Skin biopsy revealed a histological image of leukocytoclastic vasculitis. A CT scan of the abdomen disclosed thickening of the intestinal wall in the duodenum, jejunum and ileum.Gastrointestinal fiberscopy revealed petechiation on the stomach and ulceration on the cecum.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030155811932008IV 消化器癌の内科的標準治療301309ENToruYagiYoshiroKawaharaHiroyukiOkadaKojiTakemotoJunKatoYoshiyukiKobayashiHirofumiKawamotoKazuhideYamamotoNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama1978第1編 Morphological studies of the spleen in idiopathic portal hypertension (so-called Banti's syndrome without liver cirrhosis) using light microscopy, scanning electron microscopy and histometry 第2編 Morphological studies of the spleen in splenomegalic liver cirrhosis compariing with the spleen in idiopathic portal hypertension (so-called Banti's syndrome without liver cirrhosis)ENNo potential conflict of interest relevant to this article was reported.