Effect of vitamin K2 on the recurrence of hepatocellular carcinoma.

UNLABELLED: Hepatocellular carcinoma (HCC) is characterized by frequent recurrence, even after curative treatment. Vitamin K2, which has been reported to reduce HCC development, may be effective in preventing HCC recurrence. Patients who underwent curative ablation or resection of HCC were randomly assigned to receive placebo, 45 mg/day, or 90 mg/day vitamin K2 in double-blind fashion. HCC recurrence was surveyed every 12 weeks with dynamic computed tomography/magnetic resonance imaging, with HCC-specific tumor markers monitored every 4 weeks. The primary aim was to confirm the superiority of active drug to placebo concerning disease-free survival (DFS), and the secondary aim was to evaluate dose-response relationship. Disease occurrence and death from any cause were treated as events. Hazard ratios (HRs) for disease occurrence and death were calculated using a Cox proportional hazards model. Enrollment was commenced in March 2004. DFS was assessed in 548 patients, including 181 in the placebo group, 182 in the 45-mg/day group, and 185 in the 90-mg/day group. Disease occurrence or death was diagnosed in 58, 52, and 76 patients in the respective groups. The second interim analysis indicated that vitamin K2 did not prevent disease occurrence or death, with an HR of 1.150 (95% confidence interval: 0.843-1.570, one-sided; P=0.811) between the placebo and combined active-drug groups, and the study was discontinued in March 2007. CONCLUSION: Efficacy of vitamin K2 in suppressing HCC recurrence was not confirmed in this double-blind, randomized, placebo-controlled study.

Efficacy and cost-effectiveness of consensus interferon monotherapy with high-dose induction for hepatitis C patients with genotype 2.

OBJECTIVE: Several treatment strategies for patients with chronic hepatitis C have been compared mainly in terms of their efficacy, and it has been found that pegylated interferon (IFN) plus ribavirin has become the standard therapy, but aged patients may not tolerate ribavirin and the cost-effectiveness of treatment should also be further considered. We conducted a study to evaluate the efficacy, safety, and cost-effectiveness of consensus IFN monotherapy with high-dose induction for patients with chronic hepatitis C in clinical practice. MATERIAL AND METHODS: We consecutively enrolled 104 patients with chronic hepatitis C. Patients were scheduled to receive 12 or 18 µg of consensus IFN daily for 2 weeks, then three times a week for 22 weeks. Efficacy, safety, and cost-effectiveness were assessed. A Markov model was developed to investigate cost-effectiveness in patients with chronic hepatitis C treated by different IFN-based treatment strategies. RESULTS: Of the 104 study patients, a sustained virological response (SVR) was achieved in 66 (63%). Logistic regression analysis revealed that genotype 2, lower hepatitis C virus RNA levels, and patient age were independently associated with SVR. The response rate was significantly higher in patients with genotype 2 (51/66, 77%) versus genotype 1 (15/38, 40%). Cost-effectiveness analysis in patients with genotype 2 revealed that high-dose induction with consensus IFN monotherapy was as highly cost-effective as pegylated IFN plus ribavirin. CONCLUSION: Consensus IFN monotherapy with high-dose induction shows high efficacy and cost-effectiveness in chronic hepatitis C patients with genotype 2 infection. Thus, it may be a reliable alternative in aged patients and for those excluded from standard combination therapy.

Time-dependent analysis of predisposing factors for the recurrence of hepatocellular carcinoma.

BACKGROUND/AIM: There are many reports dealing with the risk factors for hepatocellular carcinoma (HCC) recurrence. However, in most of these reported studies, factors were analysed only at the initial treatment stage, and the predisposing factors for the recurrence during follow-up have not been well studied. The aim of this study is to evaluate the predisposing factors after treatments. METHODS: Two hundred and seventy-one consecutive HCC patients curatively treated between January 1994 and March 2004 were followed up and analysed. The recurrence rate was estimated by the Kaplan- Meier method and the predisposing factors were evaluated by time-fixed Cox regression analysis and by time-dependent covariate analysis using multiple parameters. RESULTS: The mean follow-up period was 4.86 years and recurrence was observed in 169 patients (62.4%). The recurrence rates were 27.9, 65.1 and 84.3% at 1, 3 and 5 years respectively. Among the variables determined before treatment, predisposing factors for recurrence were low serum albumin [< or =3.5 g/dl, hazard ratio (HR)=1.47, 95% confidence interval (CI)=1.07-2.01] and multiple tumour number (HR=2.04, 95% CI=1.46-2.84) by time-fixed multivariate analysis. In the time-dependent analysis, six variables with 12 013 plots were examined. The multivariate analysis revealed that high des- gamma-carboxy prothrombin (DCP > or =40 mAU/ml, HR=2.33, 95% CI=1.61-3.39), high alpha-fetoprotein (AFP > or =100 ng/ml, HR=2.01, 95% CI=1.3-3.35) and high alanine aminotransferase (ALT > or = 40 IU/L, HR= 1.52, 95% CI=1.1-2.1) were significant predisposing factors for recurrence. CONCLUSION: Predisposing factors for the recurrence of HCC after treatment are different from those before treatments and special cautions are required when AFP, DCP or ALT is high during follow-up.

Does pretreatment with lansoprazole influence Helicobacter pylori eradication rate and quality of life?

BACKGROUND/AIMS: It is controversial whether pretreatment with a proton pump inhibitor (PPI) before Helicobacter pylori eradication treatment decreases the eradication rate. To determine the effects of pretreatment with lansoprazole alone, followed by an H. pylori eradication regimen (lansoprazole 30 mg, amoxicillin 750 mg and clarithromycin 200 mg twice daily for 1 week), on the eradication rate and quality of life (QoL) of the patient. METHODS: Patients with H. pylori-positive peptic ulcer were randomly assigned to two groups. The patients received either lansoprazole (30 mg) once daily for 6-8 weeks before H. pylori eradication (group A), or eradication treatment and then lansoprazole (30 mg) for 6-8 weeks (group B). To assess the QoL of the patients, the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire was evaluated. RESULTS: A total of 116 patients were enrolled. The cure rates were 78.9% in group A and 78.0% in group B. In both groups, GSRS analysis showed a significant improvement of the overall GSRS score at the assessment of eradication efficacy, compared to baseline; there was no difference between the groups. CONCLUSION: With this H. pylori eradication regimen, there was no difference in the cure rates and QoL associated with PPI pretreatment.

Factors associated with adherence to combination therapy of interferon and ribavirin for patients with chronic hepatitis C: importance of patient's motivation and physician's treatment experience.

BACKGROUND/AIMS: Adherence to combination therapy with interferon (IFN) or pegylated IFN plus ribavirin for chronic hepatitis C patients is important for a better virological response. However, the impact of the patient's treatment experience and treatment centre on adherence to combination therapy has not been fully analysed. In this prospective study, we analysed the factors that might have an effect on adherence to therapy in patients who had initial or retreatment IFN therapy. PATIENTS AND METHODS: We consecutively enrolled 363 patients with chronic hepatitis C; 221 were IFN naïve and 142 were undergoing retreatment. The mean ages of the naïve and retreatment groups were 54.8 and 55.7 years respectively. IFN alpha-2b was administered daily for 2 weeks, followed by three times per week for 22 weeks, while ribavirin was administered daily. We evaluated the tolerability and response to combination therapy and analysed its relevant factors. RESULTS: Of the 363 patients, 189 (52%) achieved 80% adherence. The multivariate logistic regression analysis revealed that retreatment, centre with more patients treated, patient age (<55 years), male, genotype 2 and dosage of IFN per weight (<0.13 million units/kg) were associated with achievement of 80% adherence to combination therapy. Accordingly, the achievement of 80% adherence was more frequent in the retreatment (62%) than that in the naïve group (46%) (P<0.01) and in centres with more patients treated (57%) than in those with less patients treated (46%) (P=0.03). CONCLUSION: The present data suggest that the patient's motivation and the physician's treatment experience may be important for a better adherence to combination therapy for patients with chronic hepatitis C.

Efficacy and safety of entecavir in nucleoside-naive, chronic hepatitis B patients: phase II clinical study in Japan.

BACKGROUND AND AIM: Entecavir has demonstrated clinical efficacy for chronic hepatitis B. This study evaluated the efficacy and safety of entecavir in nucleoside-naive Japanese chronic hepatitis B patients. METHODS: In this multicenter, double-blind study, 66 nucleoside-naive Japanese chronic hepatitis B patients were randomized to 0.1 mg entecavir (n = 32) or 0.5 mg entecavir (n = 34) daily for 52 weeks. The primary endpoint was the proportion of patients whose serum hepatitis B virus (HBV) DNA decreased from baseline by > or =2 log(10) copies/mL or became undetectable (<400 copies/mL by polymerase chain reaction assay) at week 48. RESULTS: One hundred percent of patients in both treatment groups achieved the primary efficacy endpoint, with 81% and 68% of patients achieving undetectable HBV DNA in the 0.1 mg and 0.5 mg treatment groups, respectively. Mean changes from baseline in HBV DNA were -4.49 log(10) and -4.84 log(10) copies/mL for the 0.1 mg and 0.5 mg groups, respectively. Significant improvements in necroinflammation were seen in both groups, as assessed by Knodell and New Inuyama classifications. Most adverse events were transient and classified as grade 1 or 2. There were no clinically significant differences in adverse events across the two treatment groups and no discontinuations due to adverse events in either group. CONCLUSIONS: In Japanese nucleoside-naive patients with chronic hepatitis B, 0.1 mg or 0.5 mg entecavir daily provided excellent efficacy and was well tolerated. The 0.5 mg dose was selected for the treatment of nucleoside-naive patients.

Enteral nutrition improves health-related quality of life in Crohn's disease patients with long disease duration.

BACKGROUND/AIMS: Although enteral nutrition therapy has been highlighted as maintenance therapy for Crohn's disease, few reports have investigated the impact of enteral nutrition on the health-related quality of life of Crohn's disease patients. METHODOLOGY: We cross-sectionally evaluated the effect of multiple clinical factors including enteral nutrition on the health-related quality of life of Crohn's disease patients focusing on patient disease duration using the Inflammatory Bowel Disease Questionnaire. RESULTS: Of all 126 patients examined, 95 patients were receiving enteral nutrition. Multiple linear regression analysis using 18 clinical parameters revealed that disease activity was a dominant factor that affected the health-related quality of life of Crohn's disease patients, and that enteral nutrition was also an independent factor that improved the Inflammatory Bowel Disease Questionnaire total score, bowel symptoms, and systemic symptoms for patients with a disease duration of 10 years or more (P = 0.0090, 0.0033, and 0.016, respectively). CONCLUSIONS: Enteral nutrition improved the health-related quality of life of Crohn's disease patients with long-term disease duration. Thus, enteral nutrition should be recommended as one of the options for maintenance therapy for Crohn's disease.

Fibrosis progression rates between chronic hepatitis B and C patients with elevated alanine aminotransferase levels.

BACKGROUND: We evaluated the annual rate of fibrosis progression in chronic hepatitis B and C patients with elevated alanine aminotransferase (ALT) levels. METHODS: Forty-nine chronic hepatitis B patients and 21 chronic hepatitis C patients, each of whom had undergone two or more liver biopsies at an interval of more than 1 year, were enrolled in this retrospective clinical research protocol. The annual rate of fibrosis progression was calculated by dividing the change in fibrosis stage between the first and second liver biopsies by the interval in years between them. RESULTS: The median interval in chronic hepatitis B and C was 3.4 (first and third quartiles, 1.8-4.7) and 3.2 (2.1-6.5) years, respectively. Overall, the mean fibrosis progression rate was 0.21 +/- 0.31 (mean +/- SD) fibrosis units (FU) per year in 49 patients with chronic hepatitis B, and 0.13 +/- 0.18 FU/year in 21 patients with chronic hepatitis C. The ALT level was an independent variable correlating with fibrosis progression. In patients whose median ALT level was 70 IU/l or more, the mean fibrosis progression rate was 0.28 +/- 0.32 FU/year in 36 patients with chronic hepatitis B, and 0.22 +/- 0.23 FU/year in eight patients with chronic hepatitis C. CONCLUSION: This paired-biopsy study of untreated chronic hepatitis B or C demonstrated that fibrosis progression occurred largely in patients with continuously elevated ALT levels even over a relatively short period, and that liver fibrosis might progress by one stage within an average of 4-5 years of follow-up in patients with elevated ALT of 70 IU/l or more.

Risk factors for high-grade dysplasia or carcinoma in colorectal adenoma cases treated with endoscopic polypectomy.

OBJECTIVE: Our aim is to establish the risk factors for carrying high-grade dysplasia or carcinoma by analyzing endoscopically treated adenoma cases. METHODS: Patients who underwent endoscopic polypectomy at our hospitals between January 2003 and August 2004 were analyzed. RESULTS: A total of 889 patients (mean age: 63+/-11 years), and 1486 adenomas resected from these patients, were included in the analysis. Seventy-five adenomas (5%) from 72 patients (8%) were found to have high-grade dysplasia or carcinoma. Among patient factors, female sex [odds ratio (OR) 2.25, 95% confidence intervals (CI)=1.34-3.76], presence of multiple adenomas (OR=2.15, 95% CI=1.15-4.00), older age (OR=1.02, 95% CI=1.00-1.04), and rectal bleeding as the indication for colonoscopy (OR=2.57, 95% CI=1.34-4.92) were identified as the significant risk factors for carrying high-grade dysplasia or carcinoma using the multivariate analysis. In addition, a size of > or = 10 mm (OR=10.83, 95% CI=5.86-20.0), flat appearance (OR=3.91, 95% CI=2.20-6.95), and location on the left side of the colon (OR=1.80, 95% CI=1.03-3.13) were identified as tumor risk factors. CONCLUSION: Distinct factors were proved to be associated with high-grade dysplasia or carcinoma. These results are useful to select lesions that require immediate treatment. Moreover, female sex as a risk factor raises an interesting problem regarding the progression from adenoma to carcinoma.

Clinical factors that impair health-related quality of life in ulcerative colitis patients vary with the disease duration.

BACKGROUND AND AIM: The health-related quality of life (HRQOL) of patients with ulcerative colitis (UC) can be impaired because of the chronic symptoms. Although UC patients suffer from such symptoms over the long term, there have been few reports on the changes of HRQOL with disease duration. The aim of this study was to clarify these changes. METHODS: The HRQOL of 331 Japanese UC patients was examined using the validated Japanese version of the Inflammatory Bowel Disease Questionnaire (J-IBDQ). HRQOL and factors affecting HRQOL identified using multiple linear regression analysis were stratified by disease duration. RESULTS: Of the 15 clinical factors examined, the clinical activity index score was the strongest determinant (P<0.0001) of all the scores of IBDQ regardless of disease duration. HRQOL did not differ significantly among patients with different disease durations. The factors, however, that affected HRQOL varied according to disease duration. In patients with disease duration of less than 5 years, the clinical activity index score was the predominant factor affecting HRQOL. Being 'on sick leave or hospitalized' was a significant factor impairing HRQOL in patients with disease duration of 5-9 years. Moreover, complications due to corticosteroids significantly impaired all of the IBDQ scores in patients with disease duration of 10 years or more. CONCLUSION: Factors that affected the HRQOL of UC patients varied according to the patients' disease duration. Our findings should assist in the development of a long-term strategy for the treatment of UC patients.

A model for estimating cirrhosis in patients with type 1 autoimmune hepatitis.

UNLABELLED: Longstanding cirrhosis has been recognized as a risk factor for the development of hepatocellular carcinoma in patients with autoimmune hepatitis (AIH). Thus, the accurate determination of cirrhosis is important for prognostication, decisions regarding treatment and monitoring of disease progression. The aim of this study was to identify independent predictors of cirrhosis and to develop a model for estimating cirrhosis in patients with type 1 AIH. METHODS: Using the training sample, consisting of 121 patients with type 1 AIH, we retrospectively examined independent predictors of cirrhosis and constructed a model for estimating cirrhosis. Validation was prospectively performed in the validation sample, consisting of 35 patients. RESULTS: Using a stepwise multiple linear regression analysis, three predictors of serum immunoglobulin A level, ratio of aspartate aminotransferase to alanine aminotransferase, and platelet count were elicited, and a model for estimating cirrhosis was determined as follows: risk score = -0.113 + 0.0006056 x immunoglobulin A (mg/dL) + 0.155 x ratio of aspartate aminotransferase to alanine aminotransferase - 0.007079 x platelet (x10(4)/mm(3)). In the training sample, the sensitivity and specificity were 90% and 83%, respectively, when patients presenting a risk score >/=0.20 were estimated to be cirrhotic. When this model was applied to the validation sample, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 83%, 97%, 83%, 97% and 94%, respectively. CONCLUSION: It is suggested that this model could be useful for the estimation of cirrhosis in patients with type 1 autoimmune hepatitis.

Human leukocyte antigen DR status and clinical features in Japanese patients with type 1 autoimmune hepatitis.

AIM: Human leukocyte antigen (HLA) DR status affects the clinical features of autoimmune hepatitis. In Caucasians, patients with DR3 have poorer outcomes. In Japan, the relationship between HLA DR status and clinical features has yet to be fully examined. METHODS: We investigated 79 patients with type 1 autoimmune hepatitis who underwent liver biopsy and were screened for HLA DR status by the polymerase chain reaction sequence specific oligonucleotide hybridization method. RESULTS: Fifty-five patients had DR4 and 23 had DR2. Thirteen patients had both DR2 and DR4. None had DR3. Of patients aged <30 years, 70% did not have DR4. A tendency toward higher serum levels of immunoglobulin G was seen in patients with DR4 compared to those without, while patients with neither DR2 nor DR4 had lower serum levels of immunoglobulin G than those with only DR2 and those with only DR4. Patients with DR2 had a lower frequency of concurrentautoimmune disease. Concurrence of thyroid disease was seen only in patients with DR4. The cumulative incidental rate of the normalization of serum alanine aminotransferase levels within six months after the introduction of corticosteroid treatment was not associated with HLA DR status. CONCLUSION: HLA DR status is considered to affect the clinical features of Japanese patients with type 1 autoimmune hepatitis. Japanese patients with DR2 may have different clinical features from others. In addition, diagnoses of type 1 autoimmune hepatitis should be made carefully in Japanese patients with neither DR2 nor DR4 and in those aged <30 years.

Differences between right- and left-sided colon cancer in patient characteristics, cancer morphology and histology.

BACKGROUND AND AIM: Recently, the clinical and biological differences between right- and left-sided colon cancers have been widely debated. However, close analyses of these clinical differences, based on large-scale studies, have been scarcely reported. METHODS: A total of 3552 consecutive Japanese colorectal cancer cases were examined and the clinical differences between right- and left-sided colon cancer cases were investigated. RESULTS: The proportion of right-sided colon cancer was relatively high in patients aged less than 40 years (33%) and more than 80 years (43%). The proportion of right-sided colon cancer in patients aged 40-59 years was relatively low (male 22% and female 29%). In male patients the proportion increased in the 70-79 years age group (30%), while in female patients the proportion increased in the 60-69 years age group (39%). Right-sided colon cancer was more likely to be detected at an advanced stage (T1 stage; left 22%, right 15%) (P < 0.01) with severe symptoms. Polypoid-type early cancer was dominant in the left colon (left 59%; right 40%) (P < 0.01), while the proportion of flat-type early cancer in the right colon was significantly higher than that in the left colon (left 25%; right 44%) (P < 0.01). CONCLUSIONS: Specific age distribution of right-sided colon cancer was observed and the difference between male and female patients was highlighted. Other clinical features also differed between right- and left-sided colon cancer, suggesting that different mechanisms may be at work during right and left colon carcinogenesis.

Cost-effectiveness of the surveillance program of hepatocellular carcinoma depends on the medical circumstances.

BACKGROUND AND AIM: The clinical features of hepatocellular carcinoma (HCC) and the medical environment are diverse in different geographic areas. The aim of this study is to evaluate the cost-effectiveness of the surveillance of HCC in different medical circumstances. METHODS: The Markov model focused on variables that differ from country to country and may change in the future, especially in regards to the proportion of small HCC detected incidentally. The target population was 45-year-old patients with Child-Pugh class A cirrhosis, and the intervention was surveillance with ultrasonography every 6 months. RESULTS: The additional cost of the surveillance was $US15 100, the gain in quality-adjusted life years (QALYs) was 0.50 years, and the incremental cost-effectiveness ratio (ICER) was $US29 900/QALY in a base-case analysis (annual incidence of HCC = 4%). If 40% of small HCC were detected incidentally without surveillance, the gain in QALY decreased to 0.15 and the ICER increased to $US47 900/QALY. The increase in the annual incidence of HCC to 8% resulted in the increase of QALYs to 0.81, and the decrease of the ICER to $US25 400/QALY. The adoption of liver transplantation increased the gain in QALYs and the ICER to 0.84 and $US59 900/QALY, respectively. CONCLUSIONS: The gain in QALYs and the ICER due to the surveillance of HCC varies between different patient subgroups and it critically depends on the rate of small HCC detected incidentally without surveillance, as well as the annual incidence of HCC and the adoption of liver transplantation.

Risk factors for local and distant recurrence of hepatocellular carcinomas after local ablation therapies.

BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) recurs frequently after local ablation therapies. Recurrence following the therapies may be of two types: local recurrence and distant recurrence. The aim of the current study is to separately elucidate the predisposing factors for each recurrence. METHODS: Among the 2141 consecutive patients with HCC who were admitted to our institute and affiliated hospital between May 1997 and April 2004, 621 patients who had undergone local ablation therapies as the initial treatment were enrolled. Correlations between the clinical backgrounds of the patients and the type of recurrence were analyzed by the Cox proportional hazard model. RESULTS: A multivariate analysis revealed that tumor size (>30 mm; risk ratio 2.80; 95% confidence interval, 1.77-4.45; P < 0.0001), tumor number (> or =2; 1.74, 1.23-2.47, P = 0.002), and the serum alpha-fetoprotein level (>100 ng/mL; (1.62, 1.09-2.41, P = 0.014), which were classified as "tumor factors", were significant predisposing factors for the local recurrence of HCC. In contrast, a low platelet count (<100,000/microL; 1.34, 1.04-1.74, P = 0.03) and the presence of ascites (1.73, 1.16-2.57, P = 0.008), which were classified as "background factors", as well as tumor size (1.83, 1.11-3.01, P = 0.02) and tumor number (2.23, 1.72-3.00, P < 0.0001) were predisposing factors for distant recurrence. CONCLUSION: The predisposing factors for local and distant recurrence of HCC differ and different precautions must be observed to prevent recurrence, depending on the HCC status and background liver functions.

A prospective and comparative cohort study on efficacy and drug resistance during long-term lamivudine treatment for various stages of chronic hepatitis B and cirrhosis.

BACKGROUND AND AIMS: A prospective, non-randomized cohort study on long-term lamivudine treatment, comparing efficacy, drug resistance, and prognosis for various stages of chronic hepatitis B virus (HBV)-related liver disease was performed to elucidate the significance and indication of lamivudine for individual patients at each stage of disease. METHODS: A total of 158 cases consisting of 87 chronic hepatitis, 28 compensated cirrhosis, and 43 decompensated cirrhosis, with serum HBV-DNA > 5 log(10) copies/mL and with elevated alanine aminotransferase (ALT) over twice the upper normal limit or complications of hepatic insufficiency, were administered 100 mg of lamivudine daily and monitored for HBV markers, biochemistry, and prognosis. RESULTS: Lamivudine reduced HBV-DNA and ALT equally in all groups. Serum albumin, prothrombin time (%), and platelet count increased in all groups. The increased margin of albumin was the highest in the decompensated cirrhosis and higher in the compensated cirrhosis than the chronic hepatitis groups. Cumulative incidence of virologic breakthrough was 16%, 42%, 49%, and 53% at 12, 24, 36, and 48 months, respectively, and the strongest predictive factor for lamivudine resistance was persistent HBV-DNA at 3 months. Ascites, encephalopathy, and jaundice improved in the majority of patients with decompensated cirrhosis. On the other hand, hepatic failure developed or deteriorated in 10 patients after virologic breakthrough, and nine of them had decompensated cirrhosis. CONCLUSIONS: Lamivudine was effective in reducing HBV-DNA and improving hepatic reserve at all stages and was most beneficial and significant for decompensated cirrhosis. Meanwhile, close monitoring of viral load and immediate rescue treatment for lamivudine resistance is necessary to prevent hepatic failure in decompensated cirrhosis.

Identification of XAGE-1 isoforms: predominant expression of XAGE-1b in testis and tumors.

XAGE-1 is a cancer/testis (CT) antigen and has been shown to be immunogenic in lung cancer patients. Among 4 alternative splicing variants, XAGE-1a, b, c and d, XAGE-1b mRNA was dominantly expressed in cancer. In this study, we generated a XAGE-1b mAb, USO9-13. The B cell epitope recognized by the USO9-13 mAb was in the C-terminal region of the XAGE-1b protein and is also recognized by sera from patients with lung adenocarcinoma. Using USO9-13 and an anti-Flag mAb, we examined the translation products of the 4 transcripts. The XAGE-1a and b transcripts translated to the XAGE-1b protein. The XAGE-1c transcript possibly translated to 9- and 17-aa polypeptides. The XAGE-1d transcript translated to a protein consisting of 69 amino acids. Immunofluorescence analysis using USO9-13 mAb showed that the XAGE-1b protein is located in the nuclei of cells. Immunohistochemically, nuclear staining was heterogeneously observed in 25/47 lung adenocarcinomas, 1/12 hepatocellular carcinomas and 1/11 gastric cancers, but not in adjacent normal tissues. These findings suggested that XAGE-1b is a promising target molecule for a cancer vaccine against lung cancer.

Short-term high-dose followed by long-term low-dose hepatitis B immunoglobulin and lamivudine therapy prevented recurrent hepatitis B after liver transplantation.

Hepatitis B immunoglobulin (HBIg) and lamivudine combination has been accepted as the best way to control hepatitis B recurrence after liver transplantation. However, the optimal dose of HBIg and the target titer of hepatitis B surface antibody (HBsAb) remain unclear. We report our satisfactory experience with high-dose HBIg in the early period followed by low-dose HBIg with lamivudine. Subjects comprised five patients with fulminant hepatitis (FH) and 18 patients with liver cirrhosis (LC) who underwent liver transplantation. HBIg at a dosage of 200 IU/kg per day was administered for one week postoperatively. Thereafter, HBIg was administered only for HBsAb titer <100 IU/L. After six months, HBIg was withdrawn in FH and administered in LC only for HBsAb titer <10 IU/L. Lamivudine was administered to two FH and all LC cases. Although two patients with LC showed transient hepatitis B surface antigen (HBsAg) recurrence, all patients remained HBsAg-negative at the final follow-up date. This method allows reliable and cost-effective control of hepatitis B recurrence.

Tumor-specific expression of the RGD-alpha3(IV)NC1 domain suppresses endothelial tube formation and tumor growth in mice.

Angiogenesis plays an essential role in tumor growth. This study investigated expression of the noncollagenous domain of alpha3(IV) collagen (alpha3(IV)NC1) transduced into tumors and its inhibition of tumor growth. We hypothesized that if a human telomerase reverse transcriptase (hTERT) promoter-driven RGD motif containing alpha3(IV)NC1 (hTERT/RGD-alpha3(IV)NC1) were expressed in telomerase-expressing tumor cells, it would inhibit tumor growth by its anti-angiogenic property. Adenoviral transduction of hTERT/RGD-alpha3(IV)NC1 expressed RGD-alpha3(IV)NC1 in hTERT-positive tumor cell lines. However, hTERT/RGD-alpha3(IV)NC1 did not express RGD-alpha3(IV)NC1 in hTERT-negative cells such as keratinocytes and fibroblasts. The secreted RGD-alpha3(IV)NC1 in the conditioned medium from tumor cells inhibited cell proliferation as well as tube formation in cultured endothelial cells, but had no effect on other types of cells. In an in vivo model, adenoviral hTERT/RGD-alpha3(IV)NC1 gene therapy showed limited expression of RGD-alpha3(IV)NC1 in tumors and resulted in a significant decrease of vessel density in tumors. The growth of subcutaneous (s.c.) tumors in nude mice was significantly suppressed by treatment with hTERT/RGD-alpha3(IV)NC1. In addition, long-term inhibition of tumor growth was achieved by intermittent administration of hTERT/RGD-alpha3(IV)NC1. In conclusion, our findings demonstrate that tumor-specific anti-angiogenic gene therapy utilizing RGD-alpha3(IV)NC1 under the hTERT promoter inhibited angiogenesis in tumors, resulting in an antitumor effect.

Systemic inflammatory response syndrome strongly affects the prognosis of patients with fulminant hepatitis B.

BACKGROUND: Hepatitis B virus infection is the most frequent cause of fulminant hepatic failure. Recently, systemic inflammatory response syndrome has been reported to be important in patients with fulminant hepatic failure. However, prognostic factors for fulminant hepatitis B have not been fully examined. In this study, we analyzed prognostic factors for fulminant hepatitis B in order to accurately identify patients with fatal outcomes. METHODS: Of 110 consecutive patients with fulminant hepatic failure, 36 (33%) were diagnosed with fulminant hepatitis B. Five of the 36 patients received liver transplants, and we analyzed prognostic factors associated with fatal outcomes in the other 31 patients, who consisted of 15 men and 16 women with a median age of 45 (range, 20-74) years. RESULTS: Eleven patients (35%) survived without liver transplantation, and the remaining 20 (65%) died. Nonsurvivors were older and had a higher prevalence ratio of systemic inflammatory response syndrome than survivors. Treatments were similar between survivors and nonsurvivors. Using a multivariate Cox proportional hazard model, age (>45 years), systemic inflammatory response syndrome, and ratio of total to direct bilirubin (>2.0) were associated with fatal outcomes. In particular, 1-week and overall survival rates of patients with systemic inflammatory response syndrome at the time of diagnosis were 39% and 8%, respectively, while those of patients without systemic inflammatory response syndrome were 94% and 56%, respectively. CONCLUSIONS: Systemic inflammatory response syndrome strongly affects the short-term prognosis of patients with fulminant hepatitis B, and patients with systemic inflammatory response syndrome might need urgent liver transplantation.