Twelve patients with primary biliary cirrhosis (PBC), stages I to III, received long-term therapy with a combination of 600 mg ursodeoxycholic acid (UDCA) and 1 mg colchicine given daily for more than 2 years. Drug toxicity was mild; one patient experienced diarrhoea that was probably due to colchicine. Serum levels of bilirubin, alkaline phosphatase (ALPase), gamma-glutamyl transpeptidase and alanine aminotransferase decreased by more than 50% of the initial values. Serum albumin and cholesterol levels also improved, but immunoglobulins and anti-mitochondrial antibody titre did not change. Histologic features in the eight patients who received serial liver biopsies before and 2 years after the beginning of treatment were evaluated. Piecemeal necrosis and portal inflammation were improved, but there was no change in portal fibrosis. Patients were divided into two groups; the first received both drugs from the outset, and the second group were started on UDCA for 3 months followed by the addition of colchicine. After 3 months, the improvement in serum bilirubin and ALPase in the first group was greater than in the second. However, in the second group, the ALPase levels had decreased significantly when measured at 6 and 9 months after the treatment compared with the levels at 3 months. These findings suggest that UDCA and colchicine may have a synergistic effect. This combination therapy appears to be safe and effective, both clinically and histologically, for treating PBC.

Colchicine↗

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Clinical evaluation of titration of hepatitis C virus core antibody and its subclasses.

Titrations of anti-hepatitis C core (anti-HCc) immunoglobulin G (IgG) antibodies and its subclasses were studied in 90 patients with acute and chronic hepatitis C virus (HCV) infection, including 27 patients who underwent interferon (IFN) therapy. The positivity rates for each anti-HCc subclass were as follows: 95.2% for IgG1, 12.0% for IgG2, 69.9% for IgG3 and 19.3% for IgG4. The total anti-HCc IgG titre correlated well with the IgG1, titre, indicating that IgG1 was the main virus-specific IgG. Changes of IgG1 production mainly contributed to fluctuations of the anti-HCc IgG titre and corresponded well to positivity for HCV-RNA during and after IFN therapy. IgG3 was detected prior to IgG1 during the early phase of acute hepatitis in some cases and also appeared with relapse after IFN therapy. The serial assay of anti-HCc subclasses showed the patients' humoral immune response to HCV infection, and might be useful for evaluation of anti-viral immunity influenced by IFN therapy.

Acute Disease↗

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Hepatic arterial infusion chemotherapy with continuous low dose administration of cisplatin and 5-fluorouracil for multiple recurrence of hepatocellular carcinoma after surgical treatment.

To date, conventional treatments for multiple intrahepatic recurrence of hepatocellular carcinoma (HCC) after surgery are unsuccessful. The aim of this retrospective study was to evaluate the prognostic effectiveness of a new infusion chemotherapy of cisplatin (CDDP) and 5-fluorouracil (5-FU) via hepatic artery for HCC with multiple intrahepatic recurrence. Fifty-two patients, who had postoperative multiple recurrence of HCC (more than 3 tumors), were enrolled in this study. Thirty-one patients were treated by hepatic arterial infusion chemotherapy via a subcutaneously implanted injection port. A one-week course of this treatment consisted of daily administration of cisplatin (10 mg for 1 h on days 1-5) and subsequent daily administration of 5-fluorouracil (250 mg for 5 h on days 1-5). Three to six sequential one-week courses were performed (the CDDP,5-FU group). Twenty-one patients underwent conventional interventional therapies including transcatheter arterial chemoembolization, lipiodolization (the conventional group). The complete response rate and the effective response rate in the CDDP,5-FU group were 29.0% and 71.0%, respectively. The 5-year survival rate in this group was 45.7%, which was significantly better than that in the conventional group. Based on multivariate analysis, CDDP,5-FU hepatic arterial infusion chemotherapy was found to be significant in prolonging survival, and this treatment achieved favorable therapeutic results for multiple recurrence of HCC. As part of a multidisciplinary approach this treatment is expected to improve the prognosis of patients with advanced HCC.

Adult↗

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Prognosis of patients with resection of stage IV gastric cancer.

We retrospectively analyzed 116 patients who underwent resection of stage IV gastric cancer to investigate the prognostic factors responsible for long-term survival. Statistically significant clinicopathological differences between patients surviving 3 years or more (n = 9) and those surviving less than 3 years (n = 107) were observed in regard to macroscopic type, curability of surgery, lymph node metastasis and blood vessel invasion. These four variables also had a statistically significant influence on survival by univariate analysis. Multivariate analysis revealed that no residual tumor (R0) surgery was a significantly beneficial factor for long-term survival. However, no patients with the diffusely infiltrative type of tumor survived for more than 2 years even if they underwent R0 surgery. Patients without the diffusely infiltrative type who underwent R0 surgery had better survival rates: a 27.3% and 13.6%, 3 and 5 year survival rate, respectively. In conclusion, R0 surgery contributes to long-term survival even in stage IV gastric cancer, and some patients with the not diffusely infiltrative type, in particular, may receive a survival benefit by R0 surgery.

Adolescent↗

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Anticancer effect of 4-[3,5-bis(trimethylsilyl)benzamido] benzoic acid (TAC-101) against A549 non-small cell lung cancer cell line is related to its anti-invasive activity.

We examined the effects of TAC-101 on the invasion and metastasis of human non-small cell lung cancer (NSCLC) cell lines. TAC-101 showed an ability to inhibit in vitro invasiveness of NSCLC at a non-cytotoxic concentration range of 3-10 microM; such concentration levels were easily achievable following oral administration of therapeutically effective doses. The inhibition of cell invasion at 10 microM of TAC-101 accounted for 58-69% when compared with control cells. Oral administration of TAC-101 (4 mg/kg/day) to mice bearing lung implanted A549 lung cancer resulted in significant life-prolonging effect (T/C: 143%). More pronounced life-prolonging effect was observed in the experimental liver metastasis model of A549, where T/C of 215% was observed following administration at 4 mg/kg/day of TAC-101. However, TAC-101 did not show the direct anti-tumor effect against the established A549 tumor xenografts after subcutaneous implantation. These findings suggest that TAC-101 interferes with cell-to-cell interaction processes leading, for instance, to the inhibition of the invasion of NSCLC cells. Taking into account the pharmacological properties of TAC-101, it is expected that TAC-101 may be a suitable candidate drug for the treatment of lung cancer patients, especially those with a predictable metastasizing potential.

Animals↗

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The induction of apoptosis and inhibition of AP-1 activity by TAC-101 (4-[3,5-bis(trimethylsilyl) benzamido] benzoic acid) may result in life prolonging effect in animals bearing metastasizing cancer.

BACKGROUND: The incidence of cancers of the digestive tract has been high among all of the cancers in Japan and the western hemisphere. The poor prognosis of patients, especially those with liver metastases, has become a great challenge for the development of a new drug to cope with this problem. MATERIALS AND METHODS: Mice implanted by intrasplenic injection of TMK-1, human gastric carcinoma cells, were used to examine the life-prolonging effect of TAC-101. To elucidate a mechanism of action of TAC-101, the drug-induced apoptosis was assessed by DNA ladder formation whilst the prevention of transcription factor AP-1 binding to its DNA recognition sequence was assessed by gel shift assay. RESULTS: TAC-101 showed the life prolonging effect in a model of experimental liver metastasis of TMK-1. The antitumor effect, expressed as T/C (%), was 201, 141 and 112%, for TAC-101 (2 mg/kg), ATRA (8 mg/kg) and 5-FU (19 mg/kg), respectively. The in vitro experiments revealed that the anticancer activity of TAC-101 is related to its ability to induce apoptosis within a short period of time in TMK-1 cells and human leukemic cells, HL-60. TAC-101-induced apoptosis was suppressed by the inhibitors of proteases, specifically by Z-Val-Ala-DL-Asp-fluoromethylketone, indicating the involvement of caspase activation. TAC-101 also inhibited, in a concentration-dependent manner, the binding of AP-1 to its DNA binding sites present in the promoter region of the genes involved in the control of cell migration, invasion, and angiogenesis. CONCLUSION: TAC-101 may suppress liver metastasis by the induction of an apoptotic mechanism(s) in cancer cells and possibly by controlling transcriptional activity of AP-1.

Animals↗

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Evaluation of surgical risk in preoperative biliary drainage patients by blood chemistry laboratory data--with special reference to rate of reduction of serum bilirubin levels.

BACKGROUND/AIM: In Japan, it is generally accepted that biliary decompression should be performed before surgical operations on patients with obstructive jaundice. However, even when adequate decompression and effective reduction of serum bilirubin levels are achieved before surgical operations, it is not uncommon for unforeseen postoperative complications to occur. In this study, we analyzed the effectiveness of biliary drainage prior to pancreatoduodenectomy in patients with malignant obstruction of the papilla of Vater clinically manifested by obstructive jaundice. PATIENTS AND METHODS: We retrospectively examined the serial blood chemistry laboratory data of 44 patients with periampullary carcinoma who had preoperative obstructive jaundice and underwent pancreatoduodenectomy during the last 10 years. We divided the cases into three groups according to the rate of decrease in serum bilirubin levels, "b": group I, b <-0.09; group II, -0.09<b<-0.05; and group III, -0.05<b. There were no significant differences between the three groups in regard to sex, location of tumor and method of biliary decompression, however, there was significantly higher morbidity rate in group III. RESULTS: The level of biliary enzymes (gamma-GTP, ALP) tended to be higher in group I and lower in group III. Although TB and DB decreased to below 5 mg/dl before pancreatoduodenectomy in all three groups, transaminase levels instead rose in group III just before pancreatoduodenectomy. CONCLUSION: This suggested that liver damage continued to progress after biliary decompression when the reduction rate was low, and thus we should carefully monitor such patients for postoperative complications.

Aged↗

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Zinc absorption and its correlation with results of oral zinc tolerance testing in nonalcoholic liver cirrhosis; kinetic study.

BACKGROUND/AIMS: Liver cirrhosis is often complicated by symptoms of zinc deficiency, i.e., disturbances of taste and smell, skin eruptions, and other symptoms. We evaluated zinc absorption in patients with nonalcoholic liver cirrhosis to clarify the cause of zinc deficiency. METHODS AND MATERIALS: The absorption of zinc was calculated from the results of both the oral and intravenous zinc loading tests. RESULTS: Absorption was significantly reduced the cirrhotic patients, 20.4 +/- 10.7% as compared with the controls, 38.3 +/- 11.0%. In the cirrhotic patients with hepatocellular carcinoma, it was 17.8 +/- 9.3%, not significantly different from that of cirrhotics without hepatocellular carcinoma, 24.1 +/- 10.7%. CONCLUSIONS: Therefore, the development of hepatocellular carcinoma in patients with nonalcoholic liver cirrhosis had no influence on zinc absorption. Because a lower correlation between zinc absorption and the results of oral zinc tolerance testing was observed, the oral zinc tolerance test alone cannot be used as an accurate procedure for evaluating zinc absorption in liver cirrhosis. One should thus use both the intravenous as well as the oral zinc loading test when evaluating zinc absorption.

Absorption↗