Shigeki Mori

The usefulness of simultaneous determinations of glucosaminylation and fucosylation indices of alpha‐fetoprotein in the differential diagnosis of neoplastic diseases of the liver

The degrees of glucosaminylation (glucosaminylation index) and fucosylation (fucosylation index) of alpha‐fetoprotein (AFP) were determined in serum samples of 351 patients with hepatocellular carcinoma (HCC), 47 with carcinoma metastatic to the liver from digestive organs, five with mixed cholangiocellular and HCC, and 176 with benign liver diseases. The glucosaminylation index of AFP in patients with carcinoma metastatic to the liver (42 ± 23%, mean ± SD) was significantly higher than that in patients with HCC (5 ± 7%, P < 0.001) or that in patients with benign liver diseases (2 ± 4%, P < 0.001). The fucosylation indices of AFP in patients with carcinoma metastatic to the liver, with HCC, and with benign liver diseases were 76 ± 25%, 42 ± 30%, and 4 ± 6%, respectively. Thus, the fucosylation indices of AFP were high in two neoplastic liver diseases (carcinoma metastatic to the liver and HCC) and low in benign liver diseases, whereas the glucosaminylation indices were high in carcinoma metastatic to the liver but low in HCC and benign liver diseases. When the values of 30% and 80% were used as the level of the glucosaminylation and fucosylation indices, respectively, to discriminate carcinoma metastatic to the liver from HCC, 40 of 47 patients with carcinoma metastatic to the liver (85%) were able to be discriminated from HCC (sensitivity). The specificity, the positive predictive value, and the overall accuracy were 86% (302/351), 45% (40/40 + 47 + 3 − 2) and 86% (40+302/47 + 351), respectively. These data suggest that the combined information in these two indices provides a potent criterion for the diagnosis of neoplastic diseases of the liver.

Interferon Inhibits Progression of Liver Fibrosis and Reduces the Risk of Hepatocarcinogenesis in Patients with Chronic Hepatitis C: A Retrospective Multicenter Analysis of 652 Patients

A retrospective multicenter analysis of 652 patients with chronic hepatitis C who have been treated with interferon (IFN) was performed to assess the effects of IFN on the clinical course and development of HCC. During a mean follow-up of 54.8 months, hepatocellular carcinoma (HCC) developed in 7.0% of the patients. The rate was significantly higher in the patients who did not respond to IFN treatment than in those with sustained virological response and those who obtained a normalization of alanine aminotransferase levels despite the presence of HCV RNA (incomplete response) (P < 0.01). Using multivariate Coxs proportional hazard model, alcohol abuse (P < 0.05) and a higher level of fibrosis (P < 0.05) before treatment were the significant background factors associated with HCC development in the patients who did not respond to IFN. Interestingly, a significant increase in the rate of HCC development occurred in patients who had a histological finding of progressive fibrosis (F3). In addition, patients with low histological staging scores were likely to have an incomplete response, even if a sustained virological response was not obtained. IFN produced an improvement in histological activity and fibrosis stage in the second biopsy specimens irrespective of the clinical outcome when compared against untreated subjects.

Serum N-acetylglucosaminyltransferase III activities in hepatocellular carcinoma

N‐Acetylglucosaminyltransferase III (GnT III) catalyses the addition of N‐acetylglucosamine through a β 1–4 linkage to the mannose of the trimannosyl core, resulting in conversion of the concanavalin A (Con A)‐reactive glycan into a non‐reactive state. In this study, we measured GnT III activity to evaluate its diagnostic efficacy and its therapeutic effect on hepatocellular carcinoma (HCC). Concanavalin A‐non‐reactive fraction of serum transferrin (Tf) was also determined since the sugar chains of Tf are one of the possible candidates for the product of GnT III. Serum samples (159) were used from patients with HCC (89), liver cirrhosis (30), chronic hepatitis (19), alpha‐fetoprotein (AFP) producing gastric carcinoma metastatic to the liver (five) and healthy controls (16). N‐Acetyl‐glucosaminyltransferase III activity was determined by high performance liquid chromatography. The reactivity of serum Tf to Con A was also analysed in 21 paired HCC samples before and after treatment by crossed immuno‐affinoelectrophoresis. N‐Acetylglucosaminyltransferase III activity from the HCC group (153 ± 72 pmol/mL/h) was significantly higher than that from liver cirrhosis (99 ± 67 pmol/mL per h), chronic hepatitis (84 ± 39pmol/mL per h) and the normal controls (62 ± 16pmol/mL per h). N‐Acetylgiucosaminyltransferase III activity of 21 patients with HCC was significantly reduced after treatment such as transcatheter arterial chemoembolization and/or percutaneous ethanol infection therapy, (123 ± 77 to 100 ± 60pmol/mL per h). Commensurate decreases of AFP and des‐γ‐carboxy prothrombin with GnT III activity were also observed after treatment. The Con A‐non‐reactive fraction (n= 21; 6.4 ± 2.3%) in patients with HCC after treatment was significantly lower than before (8.2 ± 2.4%). The present study suggests that GnT III activity is a possible and in the diagnosis and evaluation of HCC, especially when other tumour markers are negative.

Highly enhanced fucosylation of α-fetoprotein in patients with germ cell tumor

Background. We have recently reported that simultaneous determination of the fucosylation and glucosaminylation of α‐fetoprotein (AFP) was useful in the differential diagnosis of various liver diseases. Here, we measured these indices in germ cell tumor and compared them with those in various diseases to reveal the characteristic feature of the carbohydrate moiety of AFP in this tumor.

Sustained biochemical remission after interferon treatment may closely be related to the end of treatment biochemical response and associated with a lower incidence of hepatocarcinogenesis

Abstract: Clinical background and incidence of hepatocellular carcinoma (HCC) of patients with chronic hepatitis C who obtained biochemical remission without eradication of virus (biochemical response) after interferon (IFN) treatment was retrospectively analyzed for 755 patients. Annual incidence of HCC was significantly lower in the patients with biochemical response and sustained response than that of the patients that did not show these responses. Logistic regression analysis showed that only the normalization of alanine aminotransferase (ALT) value at the end of IFN treatment was a significant factor for biochemical response. Annual incidence of HCC was significantly lower in the patients who obtained normalization of ALT values at the end of treatment than those who did not. Patients who were younger, who had a lower level of activity and fibrosis indices in histology, higher platelet count, and who were given more higher total dose of IFN were more likely to attain normalization of ALT levels at the end of treatment, and this was related to biochemical response. Low incidence of HCC in patients who obtained normalization of ALT values at the end of treatment was likely because they were in the earlier stage of chronic hepatitis. Active treatment of chronic hepatitis C with interferon in the early phase of the disease may bring about a biochemical response in some patients, even if sustained virological response is not obtained.

Microheterogeneity of serum transferrin in the diagnosis of hepatocellular carcinoma

Heterogeneous reactivity of human serum transferrin (Tf) with lectins was analysed using patient sera to determine whether it can be used to distinguish patients with hepatocellular carcinoma (HCC) from those with liver cirrhosis (LC). Microheterogeneity of Tf was analysed by crossed immunoaffinity electrophoresis (CIAE) with concanavalin A (Con A) and Lens culinaris agglutinin (LCA). Sample sera from 58 patients with HCC, 43 patients with LC and 10 normal controls were used in this study and the results were evaluated statistically. The increments of Con A‐non‐reactive (C1) and ‐weakly reactive (C2) species of Tf were observed in HCC compared with those of LC and Norm. Significant increase in the combined percentage of Con A‐ C1 + C2 species was also revealed in HCC (35.5 ± 8.5%, mean ± s.d.) compared with those of LC (29.1 ± 6.8%; P < 0.001) and normal controls (17.1 ± 2.3%; P < 0.001). The elevation of LCA‐reactive (L2) species of Tf was recognized in HCC (8.2 ± 3.8%) in comparison with those of LC (4.8 ± 3.1%; P<0.001) and normal controls (1.3 ± 1.7%; P < 0.001). The increment of C1+C2 species and/or L2 species of Tf was observed in 78% (sensitivity) of patients with HCC. The specificity, the positive predictive value and the overall accuracy were 81, 88 and 72%, respectively. Positive ratio of C1+C2 and/or L2 species was 77 and 70% in alpha‐fetoprotein low and ‐high producing HCC patients, respectively. These results indicate that the microheterogeneity analysis of human serum Tf is useful for distinguishing patients with HCC from those with LC and normal controls.

Therapeutic effect of a CDDP-epirubicin-lipiodol emulsion on advanced hepatocellular carcinoma

Prior injection of an anticancer agent and Lipiodol mixture is a key point for the treatment of hepatocellular carcinoma (HCC). We therefore prepared a new, improved emulsion of Lipiodol containing a high dose ofcis-diamminedichloroplatinum (CDDP) and epirubicin by replacing the ionic contrast medium (Urografin 67) with a nonionic contrast medium (Iopamidol; Iopamiron 300) and adding phosphatidyl choline. This CDDP-epirubicin-Lipiodol emulsion (CELE) was examined pharmacologically and chemically with the following results. The size of these particles is less than 10 μm (diameter) for up to 24 h; the release of 28%–34% of the CDDP and 80%–90% of the epirubicin was estimated in the dissolution test, and 85% of the CDDP and 35% of the epirubicin was retained in the organs in the moment calculation. CELE was injected into 58 HCC patients via a celiac angiographic catheter. In 36 of these patients, the CELE injection was followed by transcatheter arterial embolization (TAE) therapy. Following the administration of CELE as one-shot injection therapy for stage IV HCC, the 1-year survival rate was 59% and the 2-year survival rate was 27%. Moreover, in patients (stage II, 12; stage III, 8; stage IV, 16) who received CELE and subsequently underwent TAE therapy, the 1-year survival rate was 90% and the 2-year survival rate was 67%. The nonionic contrast medium with Lipiodol forms finer emulsified particles, and these particles are more capable of penetrating into the tumor. In addition, the greater pharmacological stability of these particles provides a slow-release effect and prolonged stability of their shape. Finally, theoretically, the use of two major anticancer agents such as CDDP and epirubicin showed a greater clinical effect in the treatment of HCC than either our earlier suspension or a single anticancer agent.

Malignant potential of hepatic angiomyolipoma : case report and literature review

Hepatic angiomyolipoma (AML) is known as a rare benign tumor with invasive growth. In the past, some of these tumors were misdiagnosed as hepatocellular carcinomas, because of the similar pattern on imaging studies. Recently, correct diagnoses have been increasing, with the development of HMB-45 immunohistochemical staining, and it appears that the majority of these tumors behave as benign tumors. However, there are not a few cases which have resulted in fatal courses because of recurrence and metastasis of the tumor. The clinical features and signs of the malignant potential of this tumor are unknown; thus, the management and treatment of the tumor are still controversial. Here in this article, we report a case of hepatic AML which showed a size increase of 175% in 1xa0year, and portal vein thrombosis detected by angiography. During a follow up of 3xa0years after a curative hepatic lobectomy, no metastasis or recurrence was seen. Review of the literature suggests that portal vein thrombosis could be one of the markers of the malignant potential and transformation of this tumor. Therefore, in this paper, we recommend surgical treatment of hepatic AML in which there is a strong suspicion of portal vein thrombosis.

Alpha-fetoprotein-producing renal cell carcinoma with increased activity of N-acetylglucosaminyl-transferase III.

N-acetylglucosaminyltransferase (GnT) III catalyzes the addition of N-acetylglucosamine through a beta 1-4 linkage to the mannose of the trimannosyl core, resulting in conversion of the concanavalin-A-(ConA)-reactive glycan into the ConA-nonreactive one. In this study, we measured GnT III levels in serum, tumor, and surrounding normal tissues together with a glucosaminylation index of alpha-fetoprotein (AFP), which is defined as the percentage of the ConA-nonreactive species in total AFP, in a case of AFP-producing renal cell carcinoma. The glucosaminylation index was determined by affinoelectrophoresis in the presence of ConA. GnT III was measured by using a pyridylaminated asialoagalactobiantennary sugar chain as a substrate by high-performance liquid chromatography. The glucosaminylation index of serum AFP, the concentration of which was 68 ng/ml, was 60%. This value is much higher than observed in hepatocellular carcinomas. The tumor tissue level of GnT III was 55.34 pmol/mg/h which was about six fold higher (9.50 pmol/mg/h) than in normal surrounding tissues. The serum level of this enzyme before surgery was 27.65 pmol/ml/h and decreased to 5.38 pmol/ml/h thereafter in association with a depression of serum AFP from 68 to 5.4 ng/ml. Thus, an increased level of GnT III in tumor tissues could account for the elevated conversion of a biantennary complex type sugar chain of AFP into a bisecting glucosaminylated biantennary one resulting from the addition of an N-acetylglucosamine residue at the trimannosyl core. This is, to our knowledge, the first report explaining the change in the carbohydrate structure of AFP with different affinity to ConA on the enzymatic basis in a renal cell carcinoma.

Granulocytapheresis for the Treatment of Severe Alcoholic Hepatitis: A Case Series and Literature Review

Severe alcoholic hepatitis has a high mortality rate due to limited therapeutic methods. Although corticosteroids have been used to control the inflammatory response, the outcomes vary and no standardized therapy has been established. Novel therapeutic approaches, such as anti-TNF-α, pentoxifilline, and others have been tested clinically on the basis of their cytokinemic pathophysiology with limited success. However, treatment of leukocytosis that causes cytokinemia and hepatic inflammation in patients via granulocytapheresis and leukocytapheresis showed promising results in a number of reports. Here, we report two cases of severe alcoholic hepatitis treated with granulocytapheresis. The liver function and inflammation recovered after the therapy. A review of 35 cases treated with granulocytapheresis and leukocytapheresis demonstrated their efficacy in treating alcoholic hepatitis by controlling leukocytosis as well as cytokines such as IL-8. Multidisciplinary treatment for severe alcoholic hepatitis should be considered case by case on the basis of the complexity and severity of the condition.