Long-term entecavir therapy results in falls in serum hepatitis B surface antigen levels and seroclearance in nucleos(t)ide-naïve chronic hepatitis B patients.

Entecavir (ETV) is reported to result in suppression of hepatitis B virus DNA (HBV DNA) replication with minimal drug resistance. However, information on the long-term effect of such therapy on serum hepatitis B surface antigen (HBsAg) level and elimination of HBsAg is not available. ETV therapy was started in 553 nucleos(t)ide-naïve patients with chronic hepatitis B infection (HBeAg positive: 45%) in our hospital. Serum HBsAg levels were measured serially by the Architect assay. The median baseline HBsAg was 2180 IU/mL (0.12-243 000 IU/mL), and median follow-up period was 3.0 years, with 529, 475, 355, 247 and 163 patients followed-up for 1, 2, 3, 4 and 5 years, respectively. At year 5, the mean log HBsAg decline from baseline was -0.48 log IU/mL, and the cumulative HBsAg clearance rate was 3.5%. Multivariate analysis identified HBV DNA level at baseline (<3.0 log copies IU/mL, odd ratio = 10.2; 95% confidence interval = 1.87-55.5, P = 0.007) and HBsAg level (<500 IU/mL, odd ratio = 29.4; 95% confidence interval = 2.80-333, P = 0.005) as independent predictors of HBsAg seroclearance. These results indicate that although serum HBsAg level declines gradually during ETV therapy, HBsAg seroclearance remains a rare event.

Virological response and safety of 24-week telaprevir alone in Japanese patients infected with hepatitis C virus subtype 1b.

Hepatitis C virus (HCV) subtype 1b, which infects approximately 70% of Japanese carriers, is likely to be more eradicable by a telaprevir regimen than subtype 1a because of the higher genetic barrier of Val(36) and Arg(155) substitutions. The aims of this exploratory study were to evaluate the virological response and safety of 24-week oral administration of telaprevir alone in chronic HCV subtype 1b infection. Fifteen treatment-naïve patients were treated with telaprevir 750 mg every 8 h for 24 weeks. All patients were Japanese whose median age was 58.0 years (range: 45-68), and six patients (40%) were men. Median baseline HCV RNA level was 6.80 log(10) IU/mL (range: 3.55-7.10). The HCV RNA levels decreased to undetectable in five patients (33%) within 8 weeks. Three patients (20%) with negative HCV RNA by Week 4 achieved end of treatment response. One patient (7%) who achieved sustained virological response had a low baseline viraemia of 3.55 log(10) IU/mL. Most of the adverse events including anaemia and skin disorders were mild to moderate. Developed variants were T54A and A156V/T/F/Y with or without secondary substitutions rather than V36M ± R155K. Telaprevir alone for 24 weeks in Japanese patients with HCV subtype 1b resulted in an sustained viral response rate of 7% (1/15) and was well tolerated for 24 weeks. These results will support the implementation of further studies on oral combination of telaprevir with other direct-acting antiviral agents in patients infected with HCV subtype 1b.

Safety, pharmacokinetics and resistant variants of telaprevir alone for 12 weeks in hepatitis C virus genotype 1b infection.

BACKGROUND: Telaprevir in combination with peginterferon and ribavirin is a promising advancement in chronic hepatitis C treatment. However, the safety, tolerability, pharmacokinetics and antiviral profiles of telaprevir alone beyond 2 weeks have not been studied. METHODS: In a phase 1b study in Japan, 10 treatment-naïve patients infected with hepatitis C virus genotype 1b with high viral load (>5 log(10) IU/mL) received telaprevir 750 mg every 8 h (q8h) for 12 weeks. We examined the safety, tolerability, pharmacokinetics, hepatitis C virus (HCV) RNA levels and resistant variants of telaprevir. RESULTS: Neither serious adverse events nor discontinuations of study drug owing to an adverse event occurred. The most common adverse drug reactions were rash (80%) and anaemia (70%). Telaprevir concentration reached its steady state within 2 days after the first administration without abnormal accumulation. Telaprevir alone provided potent antiviral activity: a median log(10) decrease of 2.325 at 16 h and 5.175 on Day 14. During the treatment, HCV RNA levels at the nadir were below the limit of the quantification in seven patients and undetectable in three of 10 patients. Viral breakthrough associated with mainly Ala(156) -substituted variants occurred in eight patients, and only one patient showed end-of-treatment response. The selected variants reverted to the wild-type during the 24-week follow-up period. CONCLUSION: Telaprevir alone was well tolerated at 750 mg q8h for up to 12 weeks. The safety profile and emergence of resistant variants of genotype 1b under telaprevir monotherapy for 12 weeks will become increasingly important in evaluating an oral combination of telaprevir with other direct-acting antiviral agents.

Efficacy and safety of telaprevir, a new protease inhibitor, for difficult-to-treat patients with genotype 1 chronic hepatitis C.

The aims of this phase III study were to assess the efficacy and safety of telaprevir in combination with peginterferon alfa-2b (PEG-IFN) and ribavirin (RBV) for difficult-to-treat patients who had not achieved sustained virological response (SVR) to prior regimens in Japan. The subjects were 109 relapsers (median age of 57.0 years) and 32 nonresponders (median age of 57.5 years) with hepatitis C virus genotype 1. Patients received telaprevir (750 mg every 8 h) for 12 weeks and PEG-IFN/RBV for 24 weeks. The SVR rates for relapsers and nonresponders were 88.1% (96/109) and 34.4% (11/32), respectively. Specified dose modifications of RBV that differed from that for the standard of care were introduced to alleviate anaemia. RBV dose reductions were used for 139 of the 141 patients. The SVR rates for relapsers did not depend on RBV dose reduction for 20-100% of the planned dose (SVR rates 87.5-100%, P < 0.05). Skin disorders were observed in 82.3% (116/141). Most of the skin disorders were controllable by anti-histamine and/or steroid ointments. The ratios of discontinuation of telaprevir only or of all the study drugs because of adverse events were 21.3% (30/141) and 16.3% (23/141), respectively. A frequent adverse event leading to discontinuation was anaemia. Telaprevir in combination with PEG-IFN/RBV led to a high SVR rate for relapsers and may offer a potential new therapy for nonresponders even with a shorter treatment period.

Study of charged particle activation analysis (II): Determination of boron concentration in human blood samples.

Boron Neutron Capture Therapy (BNCT) is a radiotherapy for the treatment of intractable cancer. In BNCT precise determination of 10B concentration in whole blood sample before neutron irradiation of the patient, as well as accurate neutron dosimetry, is crucial for control of the neutron irradiation time. For this purpose ICP-AES and neutron induced prompt γ-ray analysis are generally used. In Ibaraki Neutron Medical Research Center (iNMRC), an intense proton beam will be accelerated up to 8 MeV, which can also be used for Charged Particle Activation Analysis (CPAA). Thus, in this study, we apply the CPAA utilizing the proton beam to non-destructive and accurate determination of 10B concentration in whole blood sample. A CPAA experiment is performed by utilizing an 8 MeV proton beam from the tandem accelerator of Nuclear Science Research Institute in Japan Atomic Energy Agency. The 478 keV γ-ray of 7Be produced by the 10B(p, α)7Be reaction is used to quantify the 10B in human blood. The 478 keV γ-ray intensity is normalized by the intensities of the 847 keV and 1238 keV γ-rays of 56Co originating from Fe in blood. The normalization methods were found to be linear in the range of 3.27 µg 10B/g to 322 µg 10B/g with correlation coefficients of better than 0.9999.

Occult hepatitis B virus infection increases hepatocellular carcinogenesis by eight times in patients with non-B, non-C liver cirrhosis: a cohort study.

An impact of serum hepatitis B virus (HBV) DNA on hepatocarcinogenesis has not been investigated in a cohort of patients with non-B, non-C cirrhosis. Eighty-two consecutive Japanese patients with cirrhosis, who showed negative hepatitis B surface antigen and negative anti-hepatitis C virus, were observed for a median of 5.8 years. Hepatitis B virus core (HBc) region and HBx region were assayed with nested polymerase chain reaction. Both of HBc and HBx DNA were positive in 9 patients (11.0%) and both were negative in 73. Carcinogenesis rates in the whole patients were 13.5% at the end of the 5th year and 24.6% at the 10th year. The carcinogenesis rates in the patients with positive DNA group and negative DNA group were 27.0% and 11.8% at the end of the 5th year, and 100% and 17.6% at the 10th year, respectively (P = 0.0078). Multivariate analysis showed that men (P = 0.04), presence of HBc and HBx DNA (hazard ratio: 8.25, P = 0.003), less total alcohol intake (P = 0.010), older age (P = 0.010), and association of diabetes (P = 0.005) were independently associated with hepatocellular carcinogenesis. Existence of serum HBV DNA predicted a high hepatocellular carcinogenesis rate in a cohort of patients with non-B, non-C cirrhosis.

Investigation of the neutron spectrum measurement method for dose evaluation in boron neutron capture therapy.

In boron neutron capture therapy, it is important to evaluate the dose administered to a patient's body outside the tumour area. The exposure dose is evaluated by calculation; however, the calculated value must be validated using a measured value. The dose evaluations based on the measured neutron spectrum are investigated. Multi-foil activation, combined with a LiCaAlF6 scintillation detector and an imaging plate, is proposed as a measurement method. The proposed method can measure the neutron spectrum at various points quickly.

Demonstration of inter- and intracellular distribution of boron and gadolinium using micro-proton-induced X-ray emission (Micro-PIXE).

Micro-proton-induced X-ray emission (Micro-PIXE) was applied to determine inter- and intracellular distribution of boron (10B) and gadolinium (157Gd), the capture atoms used to kill tumor cells in neutron capture therapy (NCT). Cultured 9L gliosarcoma cells on Mylar film were exposed to sodium borocaptate (BSH) and gadobenate dimeglumine (Gd-BOPTA). To analyze the inter- and intracellular distribution of 10B and 157Gd in 9L gliosarcoma cells, the cells were irradiated using a proton beam of 1.7 or 3 MeV energy collimated to 1 microm diameter and emission X-ray was detected. The distribution of 10B and 157Gd in 9L gliosarcoma cells was then examined. In this study, we could directly analyze the inter- and intracellular distribution of 10B and 157Gd elements in 9L gliosarcoma cells directly using Micro-PIXE. This is the first report on the distribution of 10B employing a method to detect gamma-rays resulting from the nuclear reaction of 10B using particle-induced gamma-ray emission (PIGE). These results show that the distribution of 157Gd elements was correctly measured using micro-PIXE. 157Gd should have the same tendency as 10B in cultured 9L gliosarcoma cells and agree with the distribution in 9L gliosarcoma cells. Further investigation is necessary for a higher spatial resolution and optimization of the measurement time or improvement of the sampling method. In the future, it will be possible to employ this method to analyze the intracellular microdistribution of the capture element and in the development of new drugs for NCT.

Plasma Fas ligand, an inducer of apoptosis, and plasma soluble Fas, an inhibitor of apoptosis, in patients with chronic congestive heart failure.

OBJECTIVES: This study sought to examine plasma levels of soluble Fas/APO-1 receptor (sFas), an inhibitor of apoptosis, and soluble Fas ligand (sFas-L), an inducer of apoptosis, and their relation to each other and to other clinical variables, such as New York Heart Association functional class, tumor necrosis factor (TNF) and interleukin-6 (IL-6) in congestive heart failure (CHF). BACKGROUND: It has been recently reported that apoptotic cell death occurs in myocytes of dogs with CHF. Hypoxia is frequently seen in advanced CHF and can stimulate Fas/APO-1 receptors (Fas) to induce apoptosis in cultured myocytes. Fas and Fas ligand (Fas-L) are cell-surface proteins and representative apoptosis-signaling molecules. Fas on the cell membrane induces apoptosis when it binds Fas-L or sFas-L. However, plasma sFas, a molecule lacking the transmembrane domain of Fas, blocks apoptosis by inhibiting binding between Fas and Fas-L or sFas-L on the cell membrane. At present, it is unknown whether plasma sFas-L and plasma sFas increase in the presence of cardiac disease. METHODS: The study included 70 patients (mean [+/-SEM] age 65 +/- 2 years, range 21 to 93) with chronic CHF (coronary artery disease in 28, dilated cardiomyopathy in 27, valvular heart disease in 15) and 62 age- and gender-matched normal control subjects. Plasma levels of sFas, sFas-L, TNF-alpha and IL-6 were measured by enzyme-linked immunosorbent assays using monoclonal anti-human antibodies. RESULTS: There was no significant difference in sFas-L levels between normal subjects and patients in functional classes I to IV; however, sFas increased with severity of functional classification, independent of the underlying disease. sFas levels were significantly higher even in patients in functional class II than in normal subjects and those in functional class I, and were highest in patients in functional class IV (normal subjects; 2.2 +/- 0.1 ng/ml; functional class I: 2.2 +/- 0.2 ng/ml; functional class II: 3.1 +/- 0.2 ng/ml; functional class III: 3.9 +/- 0.3 ng/ml; functional class IV: 5.1 +/- 0.6 ng/ml). Plasma sFas levels were significantly higher in patients with elevated pulmonary artery wedge pressure and a decresed cardiac index than in those with values in the normal range. In patients in functional class IV, there was no significant difference in plasma sFas levels between the survivors and non-survivors during 6-month follow-up. However, plasma levels of sFas tended to decrease in nine patients with clinical improvement (baseline sFas: 5.2 +/- 0.8 ng/ml; 6-month sFas: 4.3 +/- 0.5 ng/ml, p = 0.07) but were similar in patients with no change in functional class. TNF-alpha and IL-6 were increased significantly only in patients in functional class IV, as previously reported, but were not related to sFas. CONCLUSIONS: We found elevated levels of plasma sFas and no increase in plasma sFas-L in human CHF. The increase in sFas may play an important role in the pathophysiologic mechanisms of CHF.

Combination of boron and gadolinium compounds for neutron capture therapy. An in vitro study.

In neutron capture therapy, the therapeutic effect of the boron compound is based on alpha particles produced by the B(n, alpha) reaction while with the gadolinium compound the main radiation effect is from gamma rays derived from the Gd(n, gamma) reaction. The uptake and distribution within the tumor may be different among these compounds. Thus, the combination of the boron and gadolinium compounds may be beneficial for enhancing the radiation dose to the tumor. Chinese hamster fibroblast V79 cells were used. For the neutron targeting compounds, 10B (BSH) at 0, 5, 10, and 15 ppm, and 157Gd (Gd-BOPTA) at 0, 800, 1600, 2400, 3200, and 4800 ppm, were combined. The neutron irradiation was performed with thermal neutrons for 30 min. (neutron flux: 0.84 x 10(8) n/cm2/s in free air). The combination of the boron and gadolinium compounds showed an additive effect when the gadolinium concentration was lower than 1600 ppm. This additive effect decreased as a function of gadolinium concentration at 2400 ppm and resulted in no additive effect at more than 3200 ppm of gadolinium. In conclusion, the combination of the boron and gadolinium compounds can enhance the therapeutic effect with an optimum concentration ratio. When the gadolinium concentration is too high, it may weaken the boron neutron capture reaction due to the high cross-section of gadolinium compound against neutrons.

Fatal carotid blowout syndrome after BNCT for head and neck cancers.

Boron neutron capture therapy (BNCT) is high linear energy transfer (LET) radiation and tumor-selective radiation that does not cause serious damage to the surrounding normal tissues. BNCT might be effective and safe in patients with inoperable, locally advanced head and neck cancers, even those that recur at previously irradiated sites. However, carotid blowout syndrome (CBS) is a lethal complication resulting from malignant invasion of the carotid artery (CA); thus, the risk of CBS should be carefully assessed in patients with risk factors for CBS after BNCT. Thirty-three patients in our institution who underwent BNCT were analyzed. Two patients developed CBS and experienced widespread skin invasion and recurrence close to the carotid artery after irradiation. Careful attention should be paid to the occurrence of CBS if the tumor is located adjacent to the carotid artery. The presence of skin invasion from recurrent lesions after irradiation is an ominous sign of CBS onset and lethal consequences.

Role of protein kinase C in the reduction of infarct size by N-methyl-1-deoxynojirimycin, an alpha-1,6-glucosidase inhibitor.

Preischaemic treatment with N-methyl-1-deoxynojirimycin (MOR-14), an alpha-1,6-glucosidase inhibitor, attenuates glycogenolysis and lactate accumulation during ischaemia and markedly reduces infarct size in rabbit hearts. In the present study, we have investigated whether protein kinase C (PKC), a principal mediator of ischaemic preconditioning, is also involved in the cardioprotective effect of MOR-14. To assess the effect of PKC inhibition on infarct size in MOR-14-treated hearts, 38 rabbits were subjected to 30 min of ischaemia followed by 48 h of reperfusion. Infarct size, as a per cent of area at risk, was significantly smaller in rabbits administered 100 mg kg(-1) of MOR-14 10 min before ischaemia (17+/-2%, n=10), than in a control group (46+/-5%, n=10). This beneficial effect of MOR-14 was abolished when 5 mg kg(-1) of chelerythrine, a PKC inhibitor, was given 10 min prior to MOR-14 injection (39+/-4%, n=10), although chelerythrine alone did not alter infarct size (43+/-4%, n=8). Further, chelerythrine had no effect on MOR-14-induced attenuation of glycogen breakdown and lactate accumulation in hearts excised at 30 min of ischaemia. Immunoblot analysis of PKC in homogenates of Langendorff-perfused rabbit hearts revealed that MOR-14 significantly increased levels of PKC-epsilon in the particulate fraction at 20 and 30 min of ischaemia and in the cytosolic fraction at 30 min of ischaemia. Taken as a whole, our data suggest that PKC acts downstream of the inhibition of glycogenolysis by MOR-14 to reduce infarct size. Thus, activation of PKC is a more direct mediator of the cardioprotection afforded by MOR-14 than is inhibition of glycogenolysis.

Chemical structure of the 2-keto-3-deoxyoctonate region of lipopolysaccharide isolated from Porphyromonas (Bacteroides) gingivalis.

Structural analysis of the 2-keto-3-deoxyoctonate region of lipopolysaccharide (LPS) isolated from Porphyromonas (Bacteroides) gingivalis was carried out. The substitution of the polysaccharide portion on the KDO was determined by gas chromatography/mass spectrometry of the product obtained by sequential derivatization of the LPS, including dephosphorylation, permethylation, carboxyl reduction, partial hydrolysis, carbonyl reduction, complete hydrolysis and O-acetylation. It was revealed that the KDO carries the polysaccharide on its position C5 and is phosphorylated on either position C7 or C8, although its exact position is not determined. The structure of the KDO region of P. gingivalis LPS in Gram-negative bacterial LPS had not hitherto been elucidated.

Evaluation of quantitative measurements of hepatitis C virus RNA to predict sustained response to interferon by genotype.

Hepatitis C virus (HCV) virus load is one of the most important predictive factors for the outcome of interferon (IFN) therapy. Recent technological advances have allowed a more precise measurement of HCV load. However, the exact cutoff values that could be used to predict the outcome of IFN have not been established for each assay. Five recent quantitative assays were evaluated for the measurement of HCV (Amplicor monitor ver 1.0, Amplicor monitor ver 2.0 (GT), Amplicor monitor ver 2.0 (Cobas), Quantiplex branched DNA amplification (bDNA) ver 2.0 and HCV core protein level by enzyme immunosorbent assay) in 209 consecutive patients with chronic hepatitis C, who received IFN therapy. The results of the two second generation Amplicor monitor tests (GT and Cobas) showed the best correlation (r = 0.930), but the other tests also showed relatively good correlations (r = 0.646-0.925). Each method predicted the effect of IFN with comparable predictive efficacy, ranging from 77.0 to 80.8%. Receiver operating characteristic (ROC) curve analysis showed that Amplicor monitor ver 2.0 and bDNA ver 2.0 are superior in predicting the response in genotype 2a. The best cutoff value for predicting the response to IFN was different by genotype, which should be considered in selecting candidates for IFN treatment.

Increased response rate to interferon therapy after a second course in hepatitis C patients who show relapse after the initial course.

Some patients with chronic hepatitis C become HCV-RNA seronegative during interferon (IFN) therapy. However, about one-half of these patients show a relapse, evident by high serum alanine aminotransferase (ALT) level. In some patients with biochemical relapse, the serum HCV-RNA level becomes low immediately after the ALT relapse. Here, we assessed the changes in serum HCV-RNA level in patients with ALT relapse after IFN therapy, and evaluated the efficacy of a second course of IFN, started at the recovery stage after ALT relapse. Two hundred and seventy-seven patients who showed HCV-RNA seronegativity by reverse transcription nested-polymerase chain reaction (RT nested-PCR) and normalization of ALT during the initial IFN therapy, and had positive HCV-RNA with ALT relapse (> 100 IU/l) within 3 months after completion of the initial IFN course were enrolled in this retrospective study. Two hundred and sixty patients were followed-up without further IFN retreatment after the ALT relapse (group 1), and 17 patients received another 6-month course of IFN after the ALT relapse (group 2). The median level of serum HCV-RNA, determined with a branched DNA probe assay (version 1; Chiron-Dai-ichi Kagaku Tokyo, Japan), in group 1 was 3.1 Meq/ml before IFN therapy, 1.3 Meq/ml at the time point of the ALT peak after the completion of IFN therapy, and 0.7 and 2.6 Meq/ml at 2-4 and 6-8 weeks after the ALT peak, respectively. The serum HCV-RNA level at 2-4 weeks after the ALT peak was lower than that before IFN therapy. The eradication rate of HCV-RNA (complete response; CR) in group 2 (47.1%; 8/17) was significantly higher than that in group 1 (1.5%; 4/260; P < 0.001). In conclusion, our data suggested that: (1) patients who showed biochemical relapse after initial IFN therapy had a significantly lower serum HCV-RNA level at recovery after ALT relapse compared with that before initial IFN therapy. (2) A high response rate was noted after a second course of IFN administered at the recovery stage of the ALT relapse, compared with patients without IFN retreatment.

Hepatitis C virus subtype 3b infection in a hospital in Japan: epidemiological study.

To elucidate the epidemiology of infection with hepatitis C virus (HCV) subtype 3b (a rare subtype thought to have originated in Southeast Asia) in Japan, we examined the genotypic subtype in 1397 patients with HCV-related chronic liver diseases. Of 1330 patients with identified HCV RNA genotypes. 960 had subtype 1b, 243 had subtype 2a, 97 had subtype 2b, 14 (1.1%) had subtype 3b, and 16 had other types of HCV or mixed subtypes. The age, gender, and severity of liver disease in patients with HCV subtype 3b did not differ from these features in patients with other subtypes. Eleven of the 14 patients with the 3b subtype had once worked at Company A in Tokyo, Japan. Multivariate logistic analysis showed that working history at that company was independently associated with the incidence of the subtype; the risk ratio was 207.2 (P < 0.0001). All 11 patients from Company A had received medical services, between 1953 and 1981, at Clinic C, which undertook medical care of the company staff. All 11 patients had received repeated intramuscular or intravenous injections for treatment of various diseases or for preventive vaccination for contagious diseases. The rare HCV subtype 3b, appeared to have been transmitted among the employees of a company through the performance of certain medical practices.

Effect of arterial administration of a high molecular weight anti-tumor agent, styrene maleic acid neocarzinostatin, for multiple small liver cancer--a pilot study.

To assess the efficacy of the zinostatin derivative, the anti-tumor agent, styrene-maleic acid neocarzinostatin, in treating multiple small liver cancers, 29 patients with multiple hepatocellular carcinoma of 3 cm or less in diameter were treated with intraarterial injections of this high molecular weight agent, mixed with Lipiodol. Computed tomography 3 months after the first therapy showed complete deposition of Lipiodol in the entire area of the original tumor in 8 patients (27.6%), 50%-99% deposition in 4 (13.8%), 10%-49% in 10 (34.5%), and less than 10% in 7 (24.1%). After repeated injections, Lipiodol deposition in the entire area of the original tumor was found in 11 patients (37.9%). The degree of Lipiodol deposition depended on the angiographic vascularity of the tumor and on the images of the computed tomogram during arterial portography. Although complete deposition of Lipiodol was found in all tumors in 10 (58.8%) of the 17 patients with well demarcated round hypervascularity, only 1 (8.3%) of 12 patients with ill demarcated tumors showed complete deposition of Lipiodol in the tumors. Taking into account that hypervascularity on angiograms was closely correlated with the degree of Lipiodol accumulation on computed tomograms taken later, it appears that well demarcated round-shaped liver cancer is the best candidate for styrene-maleic acid neocarzinostatin therapy.

Fluctuation patterns of HCV-RNA serum level in patients with chronic hepatitis C.

The serum level of hepatitis C virus (HCV)-RNA is clinically important as a predictor of the response to interferon (IFN) therapy in patients with chronic hepatitis C. If serum HCV-RNA levels fluctuate during follow-up, and IFN therapy is begun at the time of a low HCV-RNA level, the IFN therapy may be more effective. We evaluated the fluctuation of HCV-RNA serum levels for 2 years in 212 patients with chronic hepatitis C, untreated with IFN who had HCV genotype 1b and an HCV-RNA level of 10 Meq/ml or more at first consultation. The HCV-RNA level was measured monthly for 2 years with an HCV branched DNA probe assay (b DNA probe assay). We classified HCV-RNA patterns into three types by the ratio of maximum HCV-RNA level (a) to minimum HCV-RNA level (b). In pattern 1 (constant type, 151 patients; 71.2%) the a/ b ratio was 1-5. In pattern 2 (slight fluctuation type, 46 patients; 21.7%) the a/b ratio was 5-10. In pattern 3 (severe fluctuation type, 15 patients; 7.1%), the a/b ratio was 10 or more. Next, we evaluated the factors associated with the three patterns. Acute exacerbation of chronic hepatitis was regarded as an increase in serum alanine aminotransferase (ALT) level to more than 250 IU/l. The incidence of acute exacerbation for a 2-year follow-up was 13.9% (21/151) in pattern 1, 19.6% (9/46) in pattern 2, and 53.3% (8/15) in pattern 3. Multivariate analysis showed that acute exacerbation was the most important factor in the manifestation pattern 3. In conclusion, we found that: (1) about 70% of patients had a constant HCV-RNA levels for 2 years. (2) A few patients had severe fluctuation of serum HCV-RNA level after acute exacerbation of chronic hepatitis.

Hepatic vascular side effects of styrene maleic acid neocarzinostatin in the treatment of hepatocellular carcinoma.

Styrene-maleic acid neocarzinostatin (SMANCS) sometimes causes hepatic vascular side effects, including arterial stricture, obstruction, and arterio-portal shunt. A total of 128 intra-arterial SMANCS injection treatments, performed for 89 patients with hepatocellular carcinoma, were analyzed to determine the relationship between angiographic findings and subsequent hepatic vascular injuries. After SMANCS therapy, hepatic arterial stricture or obstruction occurred in 5 patients (5/128; 3.9%), arterio-portal shunting in 12 (12/128; 9.4%), liver shrinkage in 4 (4/128; 3.1%), and cholangitis or biloma in 2 (2/128; 1.6%). Among 23 patients whose plain abdominal X-ray films just after SMANCS injection showed Lipiodol retention in the hepatic artery, 5 patients developed arterial obstruction, 10 developed arterio-portal shunt, and 2, cholangitis or biloma. Among 26 patients with Lipiodol retention in the portal vein, 4 developed hepatic lobe atrophy with aggravation of liver function. Among 3 patients with Lipiodol retention in both the hepatic artery and the portal vein, 1 developed arterio-portal shunt. In 76 treatments without excessive Lipiodol retention, only 1 of the patients developed arterio-portal shunt. Excessive retention of Lipiodol in hepatic vascular beds just after SMANCS therapy was significantly associated with future vascular side effects (22/52 vs 1/76; P < 0.0001). Lipiodol retention in arteries just after SMANCS injection was closely associated with subsequent arterial obstruction or arterio-portal shunt, and Lipiodol retention in the portal vein was related to subsequent hepatic lobe atrophy.

Interferon therapy for flare-up of hepatitis B virus infection after emergence of lamivudine-induced YMDD motif mutant.

A 61-year-old man with chronic hepatitis B was treated with interferon (IFN)-alpha for flare-up after the emergence of a lamivudine-induced YMDD motif mutant. The YMDD mutant emerged 13 months after the initiation of lamivudine therapy. Despite this, lamivudine therapy was continued. Acute exacerbation occurred 25 months after the emergence of the YMDD mutant. Treatment with IFN-alpha resulted in rapid loss of hepatitis, B virus DNA, resolution of hepatitis, and clinical recovery.