Yohei Fukumoto

A comparison of DNA copy number changes detected by comparative genomic hybridization in malignancies of the liver, biliary tract and pancreas.

Tumors arising from the liver, biliary tract and pancreas, which originate in the foregut and are in close anatomical proximity to each other, sometimes show similar histological features. No studies have focused on genetic similarities and differences between tumors of these organs. To elucidate the similarities and differences in DNA copy number alterations between tumors of these organs, we applied comparative genomic hybridization (CGH) to cancers of the liver (31 cases), biliary tract (42 cases) and pancreas (27 cases). Some alterations were common to tumors of all three organs, and some were preferential in certain types of tumor. Gains of 1q and 8q and losses of 8p and 17p were common to all tumors. In contrast, 13q14 and 16q losses were detected exclusively in hepatocellular carcinomas (HCCs; p < 0.01). The incidence of 17q21 gain and 5q loss was higher in biliary tract cancers than in the other two types (p < 0.05). Pancreatic cancers exhibited higher incidence of 5q14-q23 gain and 19p loss than tumors of other organs (p < 0.01). Gains of 7p, 7q, 12p and 20q and losses of 3p, 6q, 9p and 18q were frequent in both biliary tract and pancreatic cancers but rare in HCCs (p < 0.05). The present results suggest that although genes located at 1q, 8p, 8q and 17p are frequently involved in HCC, biliary tract and pancreatic cancer, at least some of the genes implicated in carcinogenesis are different between these three types. It is also suggested that CGH analysis is useful as a potential adjunct for the diagnosis and management of these tumors of organs that are anatomically close to one another.

Cytochrome c is a possible new marker for fulminant hepatitis in humans

BackgroundCytochrome c is known as a substance related to apoptosis. We investigated serum cytochrome c levels in patients with fulminant hepatitis (FH) compared with these levels in patients with acute or chronic liver diseases.MethodsSerum cytochrome c was measured by an electrochemiluminescence immunoassay (ECLIA) method. The numbers of patients were as follows: fulminant hepatitis (FH; n = 15), acute hepatitis (AH; n = 12), chronic hepatitis (CH; n = 30), chronic hepatitis with acute aggravation (CHA; n = 6), liver cirrhosis (LC; n = 30), hepatocellular carcinoma (HCC; n = 30), and healthy volunteers (controls; n = 9).ResultsThe serum cytochrome c level in FH was 10 686 ± 7787 pg/ml, with a significant difference (P < 0.01) compared to levels in the other groups. In the FH patients, the serum cytochrome c level was significantly correlated to serum mitochondria (m)-GOT, hepatocyte growth factor (HGF), aspartate aminotransferase (AST), lactic dehydrogenase (LDH), and alkaline phosphatase (ALP), and it was negatively correlated to serum alpha-fetoprotein (AFP), and total bilirubin (T.Bil.) The serum cytochrome c level seemed to parallel the severity of hepatic coma. Immunohistochemical study indicated TdT mediated dUTP nick end labeling (TUNEL)-positive cells in the livers of patients with FH.ConclusionsThese results suggest that serum cytochrome c may be a possible new marker for acute liver failure.

Clinical use of glucagon and insulin in therapy of fulminant hepatic failure

SummaryWe have reported 5 cases of fulminant hepatic failure who were treated with a combination of glucagon and insulin. Marked improvement of hepatic coma was characteristically noted in all cases.

Early lesions and development of primary hepatocellular carcinoma in man--association with hepatitis B viral infection.

SummaryIt is well known that primary hepatocellular carcinoma could be derived from chronic hepatitis and liver cirrhosis in epidemiologic studies. However, it is still not clear what kinds of hepatocyte are premalignant cells. Recently we have focused on liver cell dysplasia as a possible premalignant cell, and showed localization of α-fetoprotein in the cytoplasma of these cells. Although the dysplastic cells were often seen in the liver of chronic active hepatitis, hepatitis B virus associated DNA polymerase activity was also significantly high in the sera from the patients with chronic active hepatitis. In this paper, we discuss the possible role of hepatitis B virus through hepatocarcinogenesis in human.

A new therapeutic trial of secretin in the treatment of intrahepatic cholestasis

SummaryMany animal experiments have been studied on the choleretic effects of secretin. We intended to estimate secretin choleresis in human (15 patients) who had received PTCD or T-tube insertion into the common bile duct. Based upon these data of secretin and choleresis, secretin was administered to 11 patients with prolonged jaundice due to intrahepatic cholestasis in order to evaluate this as a new therapy for intrahepatic jaundice. As controls, eleven patients with intrahepatic cholestasis treated with steroid hormones and/or phenobarbital were used. In all cases with biliary drainage, secretin produced a remarkable choleretic effect with a high concentration of bicarbonate. In 9 out of 11 patients with intrahepatic cholestasis who were treated with secretin, levels of serum bilirubin decreased linearly and other liver function tests returned to the normal range. The mean values of T1/2 (number of days required for reduction by half) of serum bilirubin in 9 effective cases to secretin was 10.8 days. On the other hand, that in 11 effective cases treated with steroid hormones and/or phenobarbital was 23.2 days. These results suggest that secretin therapy may be an effective treatment for intrahepatic cholestasis.

Quality of care associated with number of cases seen and self-reports of clinical competence for Japanese physicians-in-training in internal medicine

BackgroundThe extent of clinical exposure needed to ensure quality care has not been well determined during internal medicine training. We aimed to determine the association between clinical exposure (number of cases seen), self- reports of clinical competence, and type of institution (predictor variables) and quality of care (outcome variable) as measured by clinical vignettes.MethodsCross-sectional study using univariate and multivariate linear analyses in 11 teaching hospitals in Japan. Participants were physicians-in-training in internal medicine departments. Main outcome measure was standardized t-scores (quality of care) derived from responses to five clinical vignettes.ResultsOf the 375 eligible participants, 263 (70.1%) completed the vignettes. Most were in their first (57.8%) and second year (28.5%) of training; on average, the participants were 1.8 years (range = 1–8) after graduation. Two thirds of the participants (68.8%) worked in university-affiliated teaching hospitals. The median number of cases seen was 210 (range = 10–11400). Greater exposure to cases (p = 0.0005), higher self-reports of clinical competence (p = 0.0095), and type of institution (p < 0.0001) were significantly associated with higher quality of care, using a multivariate linear model and adjusting for the remaining factors. Quality of care rapidly increased for the first 100 to 200 cases seen and tapered thereafter.ConclusionThe amount of clinical exposure and levels of self-reports of clinical competence, not years after graduation, were positively associated with quality of care, adjusting for the remaining factors. The learning curve tapered after about 200 cases.

Prolyl 4-hydroxylase inhibitor is more effective for the inhibition of proliferation than for inhibition of collagen synthesis of rat hepatic stellate cells

The aim of this study was to investigate whether a prolyl 4-hydroxylase inhibitor (HOE 077) prevents the proliferation and collagen synthesis of rat hepatic stellate cells (HSCs). Rat HSCs were isolated and cultured with 100, 500, 1000 or 2000 &mgr;g/ml of HOE 077 with or without hepatocytes. After 4 day culture, the cell cycle of HSCs was examined by flow cytometry along with messenger RNA expression of procollagen type I. After 4 days of culture, HSCs had DNA synthesis and a high concentration (2000 &mgr;g/ml) of HOE 077 significantly reduced this DNA synthesis. However, HOE 077 incubated with hepatocytes could significantly reduce mitosis at a lower concentration of HOE077 (500 &mgr;g/ml) without significant reduction of alpha(2)(I) procollagen mRNA expression. These results indicate that the prolyl 4-hydroxylase inhibitor is more effective for the inhibition of proliferation than for inhibition of collagen synthesis of HSCs.

Complication of laparoscopy in Japan.

SummaryTrends of examinees and complications of laparoscopy were examined by a questionaire sent to all representative institutions in Japan. As a conclusion, the rate of complication by this examination was 10 times higher, while its mortality was 25 times higher, as compared with gastroenterological endoscopie examination.This article may indicate the present status of laparoscopy in Japan.

Effects of secretin on TCDCA- or TDCA-induced cholestatic liver injury in the rat.

Secretin, a gastrointestinal hormone, is known to act on bile duct epithelial cells and has been thought to have no effects on the bile acid transport in the liver. However, secretin was proved recently to stimulate biliary secretion of taurocholic acid (TCA) and elevate the maximum hepatic transport capacity of TCA. In this study, to evaluate the effect of secretin on the biliary secretion of taurochenodeoxycholic acid (TCDCA) or taurodeoxycholic acid (TDCA), which are known as cytotoxic bile acids, changes in bile flow, biliary excretions of bile acids and serum levels of TCDCA or TDCA were studied in a TCDCA- or TDCA-induced cholestatic rat model with and without secretin administration. Secretin prevented the decrease in bile flow and enhanced biliary excretions of bile acids and bicarbonate, but serum levels of TCDCA or TDCA at the end of the study showed no significant changes in the secretin group as compared with controls. Serum levels of alanine and asparate aminotransferases were highly elevated in all rats given TCDCA or TDCA. These data indicate secretin is a possible treatment for patients with prolonged intrahepatic cholestasis.

HBV-related fulminant hepatic failure: successful intensive medical therapy in a candidate for liver transplantation

Fulminant hepatic failure (FHF) usually has a fatal prognosis without liver transplantation. We describe the case of a woman who developed FHF, and was evaluated as a candidate for liver transplantation, but who was cured without transplantation through intensive medical care that included glucagon-insulin therapy, methylprednisolone pulse therapy, interferon beta and lamivudine administration, cyclosporine administration, and high-volume hemodiafiltration and plasma exchange. In a patient with FHF who is a candidate for liver transplantation but for whom the transplantation cannot be performed for some reason, intensive medical therapy, including regeneration-promoting therapy, immunosuppressive therapy, antiviral therapy, and vigorous hepatic support, should be carried out.