[Show abstract][Hide abstract] ABSTRACT: Sorafenib has been approved in the indication of unresectable hepatocellular carcinoma, but there are many cases in which administration of the drug is discontinued due to severe side effects. In this study, we compared the characteristics of patients who continued and discontinued sorafenib.
Ninety-six patients (75 men and 21 women) were initiated on sorafenib from July 2009 through September 2011. The patient characteristics of interest included gender, age, etiology, Child-Pugh classification, treatment history and frequency, and levels of α-fetoprotein, des- gamma-carboxy prothrombin, aspartate amino acid transferase, and alanine aminotransferase. Duration of administration of sorafenib and reasons for its discontinuation were compared.
Median overall survival was 11.8 months. Discontinuation of sorafenib within 90 days was identified as an independent prognostic factor for overall survival on multivariate analysis (P < 0.0001). Transarterial chemoembolization performed six times or more (P = 0.013) was also identified as an independent factor contributing to discontinuation of sorafenib within 90 days in multivariate analysis. Patients who received sorafenib for ≥90 days had significantly longer overall survival than those who discontinued it (P < 0.0001).
Prolonged treatment with sorafenib is an important factor in achieving extended overall survival. We recommend starting sorafenib before latent liver damage has occurred as a result of too many transarterial chemoembolization procedures.
[Show abstract][Hide abstract] ABSTRACT: The prevalence of Helicobacter pylori (Hp) infection and the development of gastric cancer are both believed to increase with age in Japan. However, no studies have investigated people older than 65 years in detail. In this study, we investigated the prevalence of Hp infection and gastric cancer in the elderly, and analyzed the influence of both factors on longevity.
All patients investigated were 65 years old and over. A total of 1877 autopsy cases were used to investigate the prevalence of gastric cancer and colonic cancer. Serum samples were obtained from 644 patients with dyspepsia and analyzed for Hp-IgG antibodies. Of these 644 patients, 63 underwent upper gastrointestinal endoscopies. Five biopsies were obtained and evaluated for the following morphological variables: neutrophils, mononuclear cell, atrophy, and intestinal metaplasia. Hp infection was evaluated histologically and with the (13)C-urea breath test.
The prevalence of gastric cancer was significantly lower in subjects older than 85 years. The positive rate of serum Hp-IgG, and Hp infection as detected histologically and by the (13)C-urea breath test, also decreased with age. In Hp(+) patients, the neutrophil score significantly decreased with age. In Hp(-) patients, however, the intestinal metaplasia score significantly increased with age.
The non-infection of Hp itself is not related to longevity in Japanese elderly, because even Hp(-) patients appear to have been infected previously with Hp. The lower prevalence of gastric cancer in the elderly may be due to the disappearance of Hp colonization, which may contribute to longevity in Japanese elderly.
Journal of Gastroenterology and Hepatology 10/2005; 20(9):1333-7. · 3.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We recently demonstrated that both lisinopril and candesartan, an angiotensin-converting enzyme inhibitor and angiotensin II type 1 receptor blocker, respectively, attenuate pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori (WBN/Kob) rats. The purpose of the present study was to assess whether combination therapy with low doses of both, ineffective when given alone, might synergistically exert protective effects. Lisinopril, candesartan, or a combination of both in drinking water was administered to 10-week-old male WBN/Kob rats for 10 weeks. Parameters of inflammation and fibrosis, positive immunostaining for alpha-smooth muscle actin, and gene expression of cytokine and growth factors were assessed, as well as circulating renin-angiotensin system components. Dose-dependent effects of combination therapy were also investigated. Only combination therapy attenuated gross alterations in the pancreas, as quantitatively confirmed by increases in pancreatic weights and decreases in myeloperoxidase activity, hydroxyproline content, histologic scores, relative fibrosis area, and relative area of alpha-smooth muscle actin-positive cells. Combination therapy suppressed up-regulation of tumor necrosis factor-alpha, platelet-derived growth factor-receptor beta, and transforming growth factor-beta1 mRNA in the pancreas. Dose dependence of combination therapy was recognized with reference to improvement in these parameters. The conclusions are that combination therapy synergistically alleviated pancreatic inflammation and fibrosis in male WBN/Kob rats. This effect may be related to suppression of tumor necrosis factor-alpha, platelet-derived growth factor-receptor beta, and transforming growth factor-beta1 mRNA. Compared with the either therapy alone, combination therapy with an angiotensin-converting enzyme inhibitor and an angiotensin II type 1 receptor blocker may be more beneficial for treating chronic pancreatitis.
Journal of Pharmacology and Experimental Therapeutics 05/2005; 313(1):36-45. · 3.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interleukin-8 (IL-8) has been reported to promote tumor cell growth in colon cancer cells after binding to its receptors, which are members of the G-protein coupled receptor (GPCR) family. Recent studies demonstrated that stimulation of GPCR can induce shedding of epidermal growth factor (EGF) ligands via activation of a disintegrin and metalloprotease (ADAM), with subsequent transactivation of the EGF receptor (EGFR). In this study, we investigated mechanisms of cell proliferation and migration stimulated by IL-8 in a human colon carcinoma cell line (Caco2). IL-8 increased DNA synthesis of Caco2 in a dose dependent manner and this was inhibited by ADAM, EGFR kinase, and MEK inhibitors. IL-8 transiently induced EGFR tyrosine phosphorylation after 5-90 min and this was completely inhibited by ADAM inhibitor. Neutralizing antibody against HB-EGF as a key ligand for EGFR also blocked transactivation of EGFR and cell proliferation by IL-8. Since IL-8-induced cell migration was further suppressed by the ADAM inhibitor and the HB-EGF neutralizing antibody, our data indicate that IL-8 induces cell proliferation and migration by an ADAM-dependent pathway, and that HB-EGF plays an important role as the major ligand for this pathway.
[Show abstract][Hide abstract] ABSTRACT: A prognostic estimation formula of acute liver damage was evaluated by using clinical data and technetium-99m-diethylenetriaminepentaacetic acid-galactosyl-human serum albumin ((99m)Tc-GSA) scintigraphy in order to determine operability for orthotopic liver transplantation (OLT). Forty-six patients hospitalized for acute liver damage were divided into survival (n=35) and non-survival (n=11) groups. Univariate and multivariate analyses were used to identify significant factors that affected prognosis. Logistic regression analysis was performed to predict prognosis with effective factors. Ten independent factors with significant differences were identified and further analyzed for significance by logistic regression analysis. Among the 10 factors, age and LHL15/HH15 were identified as having meaningful differences for predicting convalescence. The following formula was developed: A negative value for R indicates non-survivals, and a positive value indicates survivals. The mortality rate was calculated as=1/(1+e(R)). The sensitivity was 0.909, specificity was 1.000, and accuracy was 0.978. The reliability of this formula was as good as that of another formula presented previously by the Intractable Liver Diseases Study Group of Japan. The use of (99m)Tc-GSA for estimating the prognosis of acute liver damage is useful, especially before the onset of hepatic encephalopathy.
Hepatology Research 04/2005; 31(3):153-159. · 2.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Accumulating evidence suggests that central thyrotropin-releasing hormone (TRH) administration induces gastric erosion 4 h after administration through the vagal nerves. However, early changes in the gastric mucosa during these 4 h have not been described. To assess early changes in the gastric mucosa after intracisternal injection of a stable TRH analog, pGlu-His-(3,3'-dimethyl)-ProNH2 (RX-77368), we measured the blood-to-lumen 51Cr-labeled EDTA clearance and examined the effects of vagotomy, atropine, omeprazole, and hydrochloric acid (HCl) on RX-77368-induced mucosal permeability. A cytoprotective dose of RX-77368 (1.5 ng) did not increase mucosal permeability. However, higher doses significantly increased mucosal permeability. Permeability peaked within 20 min and gradually returned to control levels in response to a 15-ng dose (submaximal dose). Increased mucosal permeability was not recovered after a 150-ng dose (ulcerogenic dose). This increase in permeability was inhibited by vagotomy or atropine. Intragastric perfusion with HCl did not change the RX-77368 (15 ng)-induced increase in permeability, but completely inhibited the recovery of permeability after the peak. Pretreatment with omeprazole did not change the RX-77368 (15 ng)-induced increase in permeability, but quickened the recovery of permeability after the peak. These data indicate that the RX-77368-induced increase in permeability is mediated via the vagal-cholinergic pathway and is not a secondary change in RX-77368-induced acid secretion. Inhibited recovery of permeability on exposure to an ulcerogenic RX-77368 dose or on exposure to HCl plus a submaximal dose of RX-77368 may be crucial for the induction of gastric mucosal lesions by central RX-77368 administration.
[Show abstract][Hide abstract] ABSTRACT: A 37-year-old man presented complaining of epigastralgia. Abdominal ultrasonography revealed the presence of a papillary tumor (9 mm in diameter) in the cystic lesion (18 mm in diameter) in hepatic segment 4, which was accompanied by mild intrahepatic bile duct dilatation. Although abdominal computed tomography also showed the cystic lesion, it did not show papillary tumors inside the lesion. Endoscopic retrograde cholangiography showed the communication between the cystic lesion and the left hepatic duct. In addition, mucus was observed in the common bile duct. When transpapillary intraductal ultrasonography was performed through the left hepatic duct using a fine ultrasonic probe, a hyperechoic papillary and lobulated tumor was clearly shown in the cystic lesion. The wall of the cyst was smooth and there was no sign of tumor infiltration. Based on these findings, biliary cystadenoma was diagnosed and an extended left lobectomy was carried out. However, pathological findings postoperatively revealed that the lesion was a localized biliary papilloma, developing and extending to the intrahepatic duct. This case is rare and there have been no published reports describing a biliary papilloma morphologically similar to biliary cystadenoma.
Journal of Gastroenterology and Hepatology 03/2005; 20(2):321-4. · 3.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sclerosing cholangitis (SC) with autoimmune pancreatitis (AIP) is similar to primary sclerosing cholangitis (PSC) with regard to cholangiographic findings, but only the former responds well to steroid therapy. This report concentrates on the clinical differences between these diseases.
The presenting complaint or abnormality, associated disease, cholangiographic findings, pancreatic changes, treatment, and clinical course were studied for several cases of PSC (n = 27) and SC with AIP (n = 20).
SC with AIP as a diagnosis occurs abruptly with obstructive jaundice compared with PSC where diagnosis is often based on findings of asymptomatic liver test abnormalities. In addition, inflammatory bowel disease is only associated with PSC. The most prominent features of cholangiograms for the SC with AIP cases were stenosis of the lower common bile duct. However, sclerosing changes in the intra- and extrahepatic bile ducts or hilar hepatic region were observed for half of the cases. Only PSC showed stage III or IV liver biopsy findings. IgG4 was significantly higher in SC with AIP.
SC with AIP and PSC are different clinical entities.
[Show abstract][Hide abstract] ABSTRACT: Sclerosing cholangitis with autoimmune pancreatitis has a cholangiographic appearance that is similar to that of primary sclerosing cholangitis, but only the former responds well to corticosteroid therapy. It, therefore, is necessary to distinguish between these two diseases. Cholangiography is the reference standard for the diagnosis of primary sclerosing cholangitis. The present study compared the characteristic findings for these two types of sclerosing cholangitis.
Cholangiograms from patients with primary sclerosing cholangitis (n = 29) and sclerosing cholangitis with autoimmune pancreatitis (n = 26) were studied with regard to length and region of stricture formation, and other characteristic findings.
Band-like stricture, beaded or pruned-tree appearance, and diverticulum-like formation were significantly more frequent in primary sclerosing cholangitis. In contrast, segmental stricture, long stricture with prestenotic dilatation and stricture of the distal common bile duct were significantly more common in sclerosing cholangitis with autoimmune pancreatitis. Discriminant analysis based on these findings correctly identified 27 of 28 patients with primary sclerosing cholangitis and 25 of 26 patients with sclerosing cholangitis with autoimmune pancreatitis. It also identified a patient with an incorrect diagnosis of primary sclerosing cholangitis who proved, on review of a surgical specimen, to have findings consistent with lymphoplasmacytic sclerosing cholangitis.
Characteristic cholangiographic features allow discrimination of sclerosing cholangitis with autoimmune pancreatitis and lymphoplasmacytic sclerosing cholangitis without pancreatitis from primary sclerosing cholangitis.
[Show abstract][Hide abstract] ABSTRACT: Objectives: Sclerosing cholangitis (SC) with autoimmune pancreatitis (AIP) is similar to primary sclerosing cholangitis (PSC) with regard to cholangiographic findings, but only the former responds well to steroid therapy. This report concentrates on the clinical differences between these diseases.
Methods: The presenting complaint or abnormality, associated disease, cholangiographic findings, pancreatic changes, treatment, and clinical course were studied for several cases of PSC (n = 27) and SC with AIP (n = 20).
Results: SC with AIP as a diagnosis occurs abruptly with obstructive jaundice compared with PSC where diagnosis is often based on findings of asymptomatic liver test abnormalities. In addition, inflammatory bowel disease is only associated with PSC. The most prominent features of cholangiograms for the SC with AIP cases were stenosis of the lower common bile duct. However, sclerosing changes in the intra- and extrahepatic bile ducts or hilar hepatic region were observed for half of the cases. Only PSC showed stage III or IV liver biopsy findings. IgG4 was significantly higher in SC with AIP.
Conclusions: SC with AIP and PSC are different clinical entities.
[Show abstract][Hide abstract] ABSTRACT: Multiseptate gallbladder is a rare congenital malformation. We present a case that emphasizes the importance of ultrasonography and magnetic resonance imaging. Ultrasound examination of the abdomen showed multiple linear internal echoes consistent with multiple septa crossing the entire gallbladder lumen, creating a honeycomb appearance. Magnetic resonance cholangiopancreatography showed a grapelike cluster of the whole gallbladder.
[Show abstract][Hide abstract] ABSTRACT: There have been few reports concerning the occurrence of hepatocellular carcinoma (HCC) in heavy drinkers not sensitized by hepatitis B virus (HBV) or hepatitis C virus. With current advances in diagnostic methods, hypervascular tumors are often discovered on imaging findings in alcoholics, and it is important to differentiate them from HCCs.
The subjects were 16 alcoholics who had hepatic nodules and were hepatitis B surface antigen negative and hepatitis C virus antibody negative and were classified into two groups: (1) the HBV group with hepatitis B surface antibody and/or hepatitis B core antibody and (2) the alcoholic group without these antibodies. Computed tomography (CT), magnetic resonance imaging, and tumor biopsy were conducted for all subjects, and digital subtraction angiography or CT during arterial portography and CT during arteriography were performed for all but one case.
In the alcoholic group, there were no significant differences in the clinical features between the presence and absence of HCC. All nodules in the HBV group were HCCs, whereas in the alcoholic group, 6 of 16 lesions were HCCs and the others were hyperplastic nodules. Limited to the hypervascular tumors in the alcoholic group, on magnetic resonance imaging T1-weighted images, hyperplastic nodules showed hyperintensity, whereas HCCs were iso- or hypointense.
HCCs can occur at a high rate in alcoholics, especially in those with HBV-associated antibodies. The patients with alcoholic liver cirrhosis sometimes have hypervascular tumors that are not cancer but hyperplastic nodules, and care must be taken in their treatment.
Alcoholism Clinical and Experimental Research 09/2004; 28(8 Suppl Proceedings):186S-190S. · 3.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The epidermal growth factor (EGF) receptor (EGFR) can be transactivated by many factors including G-protein-coupled receptor agonists and cytokines. Although this EGFR transactivation reportedly requires a disintegrin and metalloproteinase (ADAM) that sheds the ectodomain of EGFR ligands, the detailed mechanisms are still unknown. This study evaluated the mechanism of interleukin (IL)-8- and IL-1beta-dependent shedding of the EGFR ligand in KATO III cells.
We established transfectants stably expressing alkaline phosphatase-tagged heparin-binding EGF-like growth factor (HB-EGF), transforming growth factor alpha, or amphiregulin precursors, and depleted ADAM proteins, using short interfering RNA against ADAM10, 12, or 17. We assessed shedding of EGFR ligands by measuring AP activities in the conditioned media after IL-1beta or IL-8 stimulation. EGFR activation was examined by immunoprecipitation and Western blotting using antiphosphotyrosine antibody. KB-R7785 and anti-IL-8 neutralizing antibody were used to inhibit activities of ADAMs and IL-8 action, respectively.
IL-8 dose dependently released the EGFR ligands and transiently phosphorylated EGFR, with a peak at 15 minutes. KB-R7785 completely blocked IL-8-induced shedding and EGFR transactivation. Depletion of ADAM10 also dramatically reduced IL-8-induced shedding and EGFR transactivation, but depletion of ADAM12 and 17 did not. IL-1beta dose dependently enhanced shedding of HB-EGF, which was not blocked by KB-R7785 in the early phase. In the late phase, however, the EGFR transactivation was blocked by KB-R7785 and abrogated by anti-IL-8 neutralizing antibody.
IL-8 induces shedding of EGFR ligands because of an ADAM10-dependent pathway in gastric cancer cells, whereas IL-1beta acts principally by an ADAM-independent pathway. IL-1beta-dependent prolonged EGFR transactivation involves multiple pathways, including an IL-8-dependent pathway.
[Show abstract][Hide abstract] ABSTRACT: The effect of Helicobacter pylori infection on systemic disorders is not well understood.
The purpose of this study was to elucidate the systemic effects of H. pylori infection by comparing differential counts of leukocytes and platelets in peripheral blood before and after eradication of H. pylori.
A total of 164 H. pylori-positive patients underwent eradication therapy, and populations of peripheral blood leukocytes and platelets before and 0 (just after therapy), 1, 3 and 12 months after eradication were retrospectively analysed.
In the eradicated group (n = 138), blood leukocytes, neutrophils and monocytes decreased significantly after eradication, but there was no significant change in eosinophils, basophils, lymphocytes or platelets. In the non-eradicated group (n = 26), there was no significant change in any studied parameter. With regard to smoking status, although leukocytes and neutrophils did not decrease after eradication in the smoking group, they significantly decreased after eradication in the nonsmoking group.
These findings suggest that: (1) H. pylori infection increases neutrophil and monocyte counts in the peripheral blood, which indicates a significant role of H. pylori infection in systemic disorders; and (2) Smoking may mask the effect of H. pylori eradication on peripheral leukocytes, which would explain the controversy in previous reports concerning H. pylori infection and peripheral leukocytes.
[Show abstract][Hide abstract] ABSTRACT: We report an autoimmune pancreatitis case with diverse manifestation of biliary stricture, lung ﬁbrosis and immune thrombocytopenic purpura. The patient was a 70-year-old man who presented with jaundice. Abdominal ultrasonography and computed tomography revealed enlargement of the entire pancreas and endoscopic retrograde pancreatography showed diffuse irregular narrowing of the main pancreatic duct. Endoscopic retrograde cholangiography revealed a band-like stricture of the bile duct in the hilar hepatic region with intrahepatic duct dilation. Chest X-rays and computed tomography revealed interstitial ﬁbrosis of the bilateral lower lungs. Thrombocytopenia and purpura appeared. Antinuclear antibody, anti-Ro (SS-A) and anti-La (SS-B) antibodies and rheumatoid factor were positive. All manifestations responded well to steroid therapy. From the present case it would appear that a multitude of manifestations are linked within one syndrome. If we encounter patients with autoimmune pancreatitis, we should not focus on a disease but rather on the possibility of a syndrome complex.
[Show abstract][Hide abstract] ABSTRACT: ATBF1 was first discovered as a suppressor of AFP expression in hepatocytes. It is present in brain, adult liver, lung, and gastro-intestinal tract. Recently, it has been reported that ATBF1 regulates myoblastic differentiation and interacts with v-Myb in regulation of its transactivation. Using the yeast two-hybrid system, we searched for protein-protein interactions to uncover new functions for ATBF1. We present here experimental evidence that ATBF1 is a new regulatory factor for STAT3-mediated signal transduction through its interaction with PIAS3. PIAS3 was thus identified as an ATBF1-binding protein. In co-transfection experiments, the full-length ATBF1 was found to form complexes with PIAS3 in Hep G2 cells. In the luciferase assay, ATBF1 was found to have no influence on STAT3 signaling induced by IL-6 stimulation, but it did synergistically enhance PIAS3 inhibition of activated STAT3. In conclusion, ATBF1 can suppress the IL-6-mediated cellular response by acting together with PIAS3.
Biochemical and Biophysical Research Communications 02/2004; 314(1):97-103. · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Intramural injection of peptidoglycan-polysaccharide polymers into the distal colon in rats induces granulomatous colitis associated with extracolonic manifestations. We sought to clarify the effects of Kupffer-cell depletion induced by the intravenous administration of gadolinium on colonic and extracolonic inflammation in this model. The effects of Kupffer-cell depletion on acute and chronic inflammation were evaluated 3 days and 3 weeks after injection of peptidoglycan-polysaccharide, respectively. We assessed the effects of gadolinium on colonic cytokine levels in vivo and the viability of elicited peritoneal macrophages and peptidoglycan-polysaccharide-induced production of nitrite, an indirect index of nitric oxide production, by these cells in vitro. A single injection of gadolinium caused a marked decrease in the number of Kupffer cells stained with antibodies within 3 days. Gadolinium treatment did not alter acute inflammation at 3 days. Repeated treatment with gadolinium dramatically attenuated grossly observed chronic inflammation, including thickening of colon wall, hepatic and splenic nodules, and swelling of foot joints; and significantly reduced the proportional areas occupied by granulomas in the colon, liver, and spleen at 3 weeks. These protective effects were reflected in significant reduction in colon and liver weights; gross scores; colonic myeloperoxidase activity, an indirect quantitative index of granulocyte infiltration; colonic interleukin-1beta levels; plasma nitrite and nitrate levels; and decreased tendency toward arthritis. Although gadolinium did not cause injury in elicited peritoneal macrophages in vitro, the compound dose-dependently attenuated peptidoglycan-polysaccharide-induced production of nitrite by these cells. Chronic Kupffer-cell depletion attenuates peptidoglycan-polysaccharide-induced granulomatous inflammation in the colon, liver, and spleen and reduces the incidence of arthritis, possibly by suppressing the production of interleukin-1beta and nitric oxide.
Journal of Laboratory and Clinical Medicine 11/2003; 142(4):268-77. · 2.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists attenuate fibrosis in the kidney, heart, and liver by suppressing transforming growth factor-beta1 mRNA and decreasing production of extracellular matrix proteins. We recently demonstrated that lisinopril, an angiotensin-converting enzyme inhibitor, alleviates pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori rats. The involvement of angiotensin II receptor and its receptor interaction in the pathogenesis of spontaneous chronic pancreatitis was assessed in this model. Candesartan, an angiotensin II receptor antagonist, was administered in drinking water (10.5, 42, or 125 mg/l) to 10-week-old male WBN/Kob rats for 10 weeks and inflammatory parameters, fibrosis, and gene expression of renin-angiotensin system components and transforming growth factor-beta1 were assessed in the pancreas. Immunostaining for alpha-smooth muscle actin was also performed. Candesartan significantly suppressed decrease in pancreatic weight and increases in pancreatic myeloperoxidase activity, hydroxyproline content, ratio of fibrous tissue, histologic scores, and ratio of alpha-smooth muscle actin-positive cells (activated pancreatic stellate cells) at 20 weeks. The high dose enhanced the expression of angiotensinogen and angiotensin II receptor type 2 mRNA and suppressed the overexpression of transforming growth factor-beta1 mRNA. The conclusion is that candesartan alleviates chronic pancreatitis and fibrosis by suppressing the overexpression of transforming growth factor-beta1, resulting in prevention of activation of pancreatic stellate cells in male WBN/Kob rats. We propose that angiotensin II receptor type 1 antagonists may be useful for the treatment of chronic pancreatitis involving angiotensin II interaction with its receptor.
Journal of Pharmacology and Experimental Therapeutics 11/2003; 307(1):17-23. · 3.86 Impact Factor