Toshimasa Osada

The efficacy of continuous local arterial infusion of 5-fluorouracil and cisplatin through an implanted reservoir for severe advanced hepatocellular carcinoma.

There is not yet an effective standard therapy for severe advanced hepatocellular carcinoma (HCC). We attempted continuous local arterial infusion chemotherapy using 5-fluorouracil (5-FU) and cisplatin (CDDP) with an implanted reservoir for these patients, and evaluated its efficacy. Twenty-one HCC patients received continuous arterial infusion of 5-FU and CDDP for 1 week, followed by a 1-week no-infusion period; this regimen was repeated 1-32 times, and patients were observed for 36-549 days. The 1-year survival rate was 61.1%, and alpha fetoprotein levels decreased in 13 patients. All could continue as outpatients for 94.0% of the entire course of therapy. Because CDDP amplifies the effect of 5-FU as a biochemical modulator, and because continuous infusion strengthens the effect of 5-FU and reduces the side effects of CDDP, we consider this therapy to be effective for patients with severe advanced HCC, prolonging survival and improving the quality of life.

Quasispecies nature of hepatitis C virus and response to alpha interferon: significance as a predictor of direct response to interferon

BACKGROUND/AIMS We evaluated the significance of the quasispecies nature of HCV as a predictor of the response to alpha interferon therapy in patients with chronic hepatitis C. METHODS Natural alpha interferon was administered in 62 patients for 24 weeks (daily for 2 weeks, then three times weekly for 22 weeks) and factors were analyzed that could affect the response. HCV subtype, HCV RNA concentrations and the number of HCV quasispecies were evaluated before treatment. HCV RNA concentrations were measured by branched DNA probe assay. The number of HCV quasispecies was measured by fluorescence single-strand conformation polymorphism analysis. RESULTS The HCV RNA concentration (p < 0.0001), HCV subtype (p = 0.0076), and the number of HCV quasispecies (p = 0.0024) were significantly associated with a complete response. Multivariate analyses showed that the number of HCV quasispecies was an independent predictor of the disappearance of HCV RNA during the administration of alpha interferon, but did not predict a relapse after its completion. Pretreatment concentration of HCV RNA was the only factor that was related to a long-term disappearance of HCV RNA. CONCLUSIONS The number of HCV quasispecies was significantly related to the response to alpha interferon early in its administration. The pretreatment concentration of HCV RNA was mainly related to a relapse following completion of treatment.

Estimation of usefulness of N-butyl-2-cyanoacrylate-lipiodol mixture in transcatheter arterial embolization for urgent control of life-threatening massive bleeding from gastric or duodenal ulcer

We estimated the usefulness of a mixture of N‐butyl‐2‐cyanoacrylate (NBCA) with lipiodol for transcatheter arterial embolization (TAE) used to control massive bleeding from gastric or duodenal ulcer. Thirty patients who had gastric or duodenal ulcers and massive bleeding that was uncontrollable by endoscopic procedures were included in this study. All patients were subjected to TAE (without NBCA in 23 and with NBCA in seven patients). Coils and/or gelfoam were also used. The achievement of haemostasis, occurrence of rebleeding and the time taken for TAE were compared between patients who received TAE without and with NBCA. Eighteen of 23 patients (78.3%) who received TAE without NBCA and six of seven patients (85.7%) who underwent TAE with NBCA achieved complete haemostasis without rebleeding. The time for TAE was significantly shorter in patients who received NBCA compared with those who did not (P= 0.0095). TAE using NBCA or a combination of NBCA and coils achieved a rapid, complete embolization regardless of vascular distribution or arterial diameter. Thus NBCA is considered to be useful as a secondary embolization material in TAE that is urgently conducted to control massive bleeding from gastric or duodenal ulcers.

Comparison of serum hepatitis C virus RNA concentration by branched DNA probe assay with competitive reverse transcription polymerase chain reaction as a predictor of response to interferon-α therapy in chronic hepatitis C patients

A study was carried out to assess the correlation between the serum concentration of hepatitis C virus RNA (HCV‐RNA) in patients with chronic hepatitis, as measured by competitive reverse transcription polymerase chain reaction (cRT‐PCR) and branched DNA probe assay (bDNA), and response to interferon‐α (IFNα) therapy. The serum HCV‐RNA concentration was evaluated by both cRT‐PCR and bDNA in 54 patients who had received a total dose of 480 MU of IFNα. HCV subtypes were also identified in all patients. The measurement of serum HCV‐RNA concentration by bDNA correlated significantly with that of cRT‐PCR. The concentration of HCV‐RNA in subtype 1 patients was significantly higher than that in subtype 2 patients when measured by bDNA, but not when measured by cRT‐PCR. The correlation of HCV‐RNA concentration between bDNA and cRT‐PCR was associated with both subtypes 1 and 2. The difference in serum HCV‐RNA concentration between complete and incomplete responders was more significant when measured by bDNA probe assay than by cRT‐PCR. Moreover, only 1 of 26 patients with a HCV‐RNA concentration of more than 1 × 106 eq/ml as measured by bDNA probe assay attained a complete response, while 19 of 28 patients with that of less than 1 × 106 eq/ml achieved it. Measurement of serum HCV‐RNA concentration by bDNA probe assay was a better predictor of clinical response to IFNα therapy than measurement by cRT‐PCR.

Treatment of small hepatocellular carcinoma

SummaryOf the 692 patients with hepatocellular carcinoma (HCC) who were admitted to our hospital between 1976 and 1990, 60 (8.8%) had small HCC with a maximal diameter of below 2 cm. The outcome of these 60 cases was analyzed after they had been divided into 4 groups based on the therapeutic method used: operation group (17 cases), percutaneous ethanol injection therapy (PEIT) group (20 cases), transcatheter arterial embolization (TAE) group (13 cases), and oral anticancer drug therapy (per os) group (10 cases). The 1-, 2-, 3-, 4-, and 5-year survival values obtained for the operation group (100%, 87.5%, 87.5%, 87.5%, and 87.5%, respectively) were significantly higher than those found for the per os group (P<0.01). The best therapeutic results were achieved in the operation group. Although the follow-up period for the PEIT group was short, the 2-year survival of this group was nearly equal to that of the operation group. Whereas the duration of survival tended to increase in inverse proportion to the severity of the underlying liver cirrhosis, the survival values did not differ between solitary and multiple tumors or among the different histological grades of HCC. In this series, 20 patients died; 9 deaths (45.0%) were due to progressive disease and 3 deaths (15.0%) were attributed to hepatic failure. Because the operation group included many patients who displayed relatively good liver function, we cannot rule out the possibility that their excellent outcome may have been associated with this background factor. Therefore, further prospective investigation is necessary to compare the efficacy of various therapies in patient groups with a homogeneous background.

Role of leukotrienes in hydrochloric acid-induced gastric lesions in rats

This study was designed to clarify the role of leukotrienes (LTs) in 0.6 N hydrochloric acid (HCl) — induced gastric lesions. In rats given 1 ml of 0.6 N HCl intragastrically, severe hemorrhagic lesions were observed in the gastric corpus mucosa 15 min, and 1, 3, and 5 hr after HCl administration. In the control rats treated with physiological saline, LTs in gastric mucosa were not observed throughout the experiments. Peptide LT contents (sum of LTC4 and LTD4) after 1 or 3 hr were increased to 13.2±2.9 ng/g tissue and 6.3±1.9, respectively, although peptide-LTs were not observed 15 min and 5 hr after HCl administration. Premedication with AA-861, a lipoxygenase inhibitor, decreased dose-dependently peptide LT contents 1 hr after HCl administration. Furthermore, gastric lesions caused by 0.6 N HCl were significantly prevented by 300 mg/kg of AA-861 3 hr after HCl administration, although the dose of AA-861 did not significantly prevent gastric lesions 1 hr after HCl administration. Administration of YM-638, a peptide LT antagonist, showed similar protective effects to AA-861 except inhibition of increase in LT levels after HCl administration. These results suggest that peptide LTs contribute to persistence of gastric lesions, although they might not participate in the onset of 0.6 N HCl-induced gastric lesions.

Long-term administration of natural interferon-α in patients with chronic hepatitis C: Relationship to serum RNA concentration, HCV-RNA genotypes, histological changes and hepatitis C virus

To virologically assess the efficacy of interferon therapy in chronic hepatitis C, either 5 or 10 MU/day natural interferon‐α (IFNα) was administered to 57 patients with chronic hepatitis C for 38 weeks. A complete and sustained response (CR‐SR), as evidenced by the absence of serum hepatitis C virus (HCV)‐RNA during the administration period and at 6 months after the final administration of IFNα and a normal GPT level at 6 months after final administration, occurred in 42.6% (23/54) of subjects. Liver tissue was histologically evaluated using the histological activity index (HAI) score before and after the administration period. In CR‐SR cases, significant improvements (P <0.01) occurred in periportal necrosis, intralobular necrosis, portal inflammation and total score. A comparison, by HCV genotypes, revealed that CR‐SR occurred in 60% (9/15) of subjects with type 2a and 30.3% (10/33) of subjects with type Ib. A comparison by virus concentration revealed that CR‐SR occurred in 71.4% (15/21) of those subjects having a virus concentration of < 105 copies/mL, but in only 24.2% (8/33) of those having a virus concentration of > 105 copies/mL. Analysis by a multiple logistic model revealed a strong correlation between the therapeutic effect of interferon therapy and the pre‐administration virus concentration (P=0.0061) and genotype (P=0.0015). These results suggest that the preadministration virus concentration and genotype are both key factors affecting the therapeutic effect of interferon therapy in chronic hepatitis C and that the therapeutic effect of interferon is satisfactorily high, irrespective of virus concentration, in subjects with type 2a HCV, but varies depending on virus concentration in subjects with type 1b.

Serum Levels of Soluble Interleukin-2 Receptor in Chronic Hepatitis C Treated with Interferon-Alpha

BACKGROUND Serum levels of soluble interleukin-2 receptor (sIL-2R) seem to serve as a marker for the activation of T lymphocytes. The aim of this study was to evaluate the clinical significance of such levels in patients with chronic hepatitis C (CHC) treated with interferon. METHODS We measured serum levels of sIL-2R in 37 patients with CHC before and after treatment with recombinant interferon-alpha. Serum receptor levels were then compared with the response of the hepatitis C virus (HCV)-RNA level in serum after interferon. RESULTS Receptor levels were significantly higher in the patients with chronic persistent hepatitis and chronic active hepatitis than in normal controls (p < 0.01). There was a weak correlation between serum sIL-2R and alanine aminotransferase (ALAT) levels (r = 0.14, p = 0.010). Patients were then classified into three groups on the basis of the effect of interferon treatment on HCV-RNA levels in serum: sustained response (SR; n = 21), non-sustained response (NSR; n = 14), and nonresponse (NR; n = 2). Before and during interferon treatment the serum sIL-2R level remained increased in the SR group and in the combined groups with NSR or NR. However, after interferon was withdrawn, the serum sIL-2R decreased in the SR group but remained significantly increased in the combined response group (p < 0.01-0.05). CONCLUSION This finding seems to reflect the disappearance of HCV-RNA from the serum of the patients with an SR, and monitoring of sIL-2R levels may therefore be of value as an adjunct to the measurement of serum ALAT and HCV-RNA in evaluating the response to the interferon therapy for CHC.

The role of prostaglandin D2 in the genesis of indomethacin-induced gastric lesions in rats.

Four kinds of prostaglandins (PGs), 6-keto-PGF1 alpha, PGF2 alpha, PGE2 and PGD2, in rat gastric mucosa were decreased at 1 or 6 h after oral administration of indomethacin (2 or 12 mg/kg). With 2 mg/kg of indomethacin, the PG levels had slightly recovered 6 h later. Gastric lesions were observed 6 h after administration of indomethacin (12 mg/kg), but not with 2 mg/kg. Omeprazole (20 mg/kg, i.p.) prevented ulcer formation caused by indomethacin, without improvement of the reduced gastric mucosal PG levels. PGD2 (0.5 mg/kg, p.o.) reduced indomethacin-induced gastric lesions and considerable amounts of PGD2 existed in the gastric mucosa. We conclude that H+ is a determining factor in the genesis of indomethacin-induced gastric lesions and persistent decreases in tissue PG levels also participate in ulcer formation.

The effect of a new gastric proton pump inhibitor on serotonin-induced gastric mucosal lesions in rats

SummaryThe anti-ulcer effect of NC-1300, a new proton pump inhibitor, and its effect on gastric mucosal blood flow were studied in rats. Acute gastric mucosal lesions were induced by the subcutaneous administration of serotonin, 20 mg/kg. Using the electrolytically generated hydrogen gas clearance technique, it was determined that such gastric ulceration resulted mainly from a decrease in gastric mucosal blood flow. These lesions could be inhibited to a statistically significant extent by the intravenous administration of NC-1300, 20 mg/kg, which markedly inhibited gastric acid secretion. However, the serotonin-induced decrease in gastric mucosal blood flow could not be prevented by pretreatment with 20 mg/kg of NC-1300. It was concluded that protection against serotonin-induced gastric ulceration can be achieved by markedly inhibiting gastric acid secretion.