Safety and efficacy of cell-free and concentrated ascites reinfusion therapy against cirrhotic ascites in comparison with malignancy-related ascites.

BACKGROUND AND AIM: Cell-free and concentrated ascites reinfusion therapy (CART) has been performed against cirrhotic ascites, one of the most common complications seen in patients with decompensated cirrhosis. The aim of this study is to investigate its safety and efficacy, and differences in clinical profiles from CART against malignancy-related ascites with different pathological background. METHODS: The present investigation involved a sub-analysis of data obtained from a prospective observational study of CART performed at 22 centers. The condition of each procedure, therapeutic options, laboratory data, performance status, dietary intake, and abdominal circumference of participants were analyzed. Clinical parameters were compared between before and after CART, with or without albumin infusion, and also primary diseases including cirrhosis and malignant disease. RESULTS: Between January 2014 and January 2015, a total of 48 and 275 CART procedures were performed in patients with cirrhosis and malignancies. In cirrhotic patients, serum albumin concentration increased significantly in groups both with and without concomitant albumin infusion (P = 0.002 and P = 0.023), and no significant difference in CART interval was seen between these groups (P = 0.393). CART interval was not significantly different between cirrhosis and malignancy groups (P = 0.334). Dietary intake significantly improved after CART in both groups (P = 0.043 and P < 0.001). Adverse events were with no clinical significance as observed in patients with malignancies. CONCLUSIONS: Cell-free and concentrated ascites reinfusion therapy was performed safely and effectively in patients with ascites related to decompensated cirrhosis and offers the potential efficacy to maintain plasma colloid osmotic pressure after paracentesis as well as in patients with malignancy.

Clinical usefulness of cell-free and concentrated ascites reinfusion therapy (CART) in combination with chemotherapy for malignant ascites: a post-marketing surveillance study.

BACKGROUND: Cell-free and concentrated ascites reinfusion therapy (CART) has been suggested to be able to treat malignant ascites more safely and effectively with chemotherapy because of its ability to retain serum protein and albumin. Although the characteristics of cancer types and CART and the clinical implications of combination therapy with antitumor agents are becoming widespread, there are limited reports on its efficacy and complications. METHODS: In this prospective observational national post-marketing study, 128 patients with malignancies received 300 CART sessions at 22 centers. After excluding other malignancies, the patients were divided into four groups: gynecological malignancies with chemotherapy (GYC+; 18 cases and 36 times) and without chemotherapy (GYC-; 35 cases and 52 times), and gastrointestinal malignancies with chemotherapy (GIC+; 8 cases and 16 times) and without chemotherapy (20 cases and 58 times). RESULTS: There were significant reductions in the body weight in all groups and significant reductions in abdominal circumference and significant improvements in the diet and Eastern Cooperative Oncology Group performance status only in the GYC+ group. The total serum protein and albumin increased significantly in all groups, except for the GIC+ group, before and after CART. There was no significant difference in the presence or absence of antitumor medication. CONCLUSION: With CART, there were differences in the improvement of the clinical symptoms between malignancy groups. The combination of CART and antineoplastic agents may be as safe as CART alone in cases of exudative malignant ascites.

Safety and efficacy of cell-free and concentrated ascites reinfusion therapy (CART) in refractory ascites: Post-marketing surveillance results.

We performed post-marketing surveillance to evaluate the safety and efficacy of cell-free and concentrated ascites reinfusion therapy (CART). In total, 356 CART sessions in 147 patients at 22 centers were performed. The most common primary disease was cancer (128 cases, 300 sessions). Mean amount of ascites collected was 3.7 L, and mean concentration ratio was 9.2. Mean amount of reinfused protein was 67.8 g (recovery rate, 72.0%). Performance status, dietary intake, urine volume, body weight and abdominal circumference were significantly improved after CART. Body temperature increased significantly, by 0.3°C on average. Concomitant steroids and/or NSAIDs use before reinfusion was significantly and negatively associated with increases in body temperature. Most adverse events were fever and chills. This study examined a large number of patients compared with previous studies, and showed that CART is an effective and relatively safe treatment for refractory ascites, such as malignant ascites.

Impact of alpha-fetoprotein on hepatocellular carcinoma development during entecavir treatment of chronic hepatitis B virus infection.

BACKGROUND: Entecavir (ETV) is one of the first-line nucleoside analogs for treating patients with chronic hepatitis B virus (HBV) infection. However, the hepatocellular carcinoma (HCC) risk for ETV-treated patients remains unclear. METHODS: A total of 496 Japanese patients with chronic HBV infection undergoing ETV treatment were enrolled in this study. The baseline characteristics were as follows: age 52.6 ± 12.0 years, males 58%, positive for hepatitis B e antigen 45 %, cirrhosis 19%, and median HBV DNA level 6.9 log copies (LC) per milliliter. The mean treatment duration was 49.9 ± 17.5 months. RESULTS: The proportions of HBV DNA negativity (below 2.6 LC/mL) were 68% at 24 weeks and 86% at 1 year, and the rates of alanine aminotransferase (ALT) level normalization were 62 and 72%, respectively. The mean serum alpha-fetoprotein (AFP) levels decreased significantly at 24 weeks after ETV treatment initiation (from 29.0 ± 137.1 to 5.7 ± 27.9 ng/mL, p < 0.001). The cumulative incidence of HCC at 3, 5, and 7 years was 6.0, 9.6, and 17.2%, respectively, among all enrolled patients. In a multivariate analysis, advanced age [55 years or older, hazard ratio (HR) 2.84; p = 0.018], cirrhosis (HR 5.59, p < 0.001), and a higher AFP level (10 ng/mL or greater) at 24 weeks (HR 2.38, p = 0.034) were independent risk factors for HCC incidence. HCC incidence was not affected by HBV DNA negativity or by ALT level normalization at 24 weeks. CONCLUSIONS: The AFP level at 24 weeks after ETV treatment initiation can be the on-treatment predictive factor for HCC incidence among patients with chronic HBV infection.

Serum fucosylated haptoglobin in chronic liver diseases as a potential biomarker of hepatocellular carcinoma development.

BACKGROUND: Fucosylation is one of the most important glycosylation events involved in cancer and inflammation. We previously developed a lectin antibody ELISA kit to measure fucosylated haptoglobin (Fuc-Hpt), which we identified as a novel cancer biomarker. In this study, we investigated Fuc-Hpt as a biomarker in chronic liver diseases, especially in hepatocellular carcinoma (HCC). METHODS: We measured serum Fuc-Hpt levels using our ELISA kit in 318 patients with chronic liver diseases, including 145 chronic hepatitis (CH) patients, 81 liver cirrhosis (LC) patients, and 92 HCC patients. During a long-term follow-up period of 7 years (1996-2003), Fuc-Hpt levels were measured at three different time points in 19 HCC patients. Serum Fuc-Hpt levels were also examined with a short-term follow-up period of 3 years (2009-2012) in 13 HCC patients. RESULTS: Fuc-Hpt levels increased with liver disease progression. Patients with LC and HCC showed significantly increased Fuc-Hpt levels in comparison to CH patients or healthy volunteers. Fuc-Hpt levels tended to be higher in HCC patients than in LC patients. Fuc-Hpt was better than α-fetoprotein (AFP) and AFP-L3 for predicting HCC [diagnosed by computed tomography (CT) or ultrasound] in LC patients with long-term follow-up. More than 80% of LC patients with long-term follow-up showed increased Fuc-Hpt during hepatocarcinogenesis, and 38% of early-stage HCC patients with short-term follow-up showed a gradual increase in Fuc-Hpt before imaging diagnosis. CONCLUSIONS: These results suggest that Fuc-Hpt is a novel and potentially useful biomarker for predicting liver disease progression and HCC development.

Post-treatment levels of α-fetoprotein predict incidence of hepatocellular carcinoma after interferon therapy.

BACKGROUND & AIMS: In patients with chronic hepatitis C virus (HCV) infection, lack of sustained virologic response (SVR) 24 weeks after the end of interferon therapy is a significant risk factor for hepatocellular carcinoma (HCC). Although many pretreatment factors are known to affect HCC incidence, less is known about post-treatment factors-many change during the course of interferon therapy. METHODS: We performed a prospective study, collecting data from 2659 patients with chronic hepatitis C without a history of HCC who had been treated with pegylated interferon (Peg-IFN) plus ribavirin from 2002 through 2008 at hospitals in Japan. Biopsy specimens were collected before treatment; all patients received Peg-IFN plus ribavirin for 48 to 72 weeks (HCV genotype 1) or 24 weeks (HCV genotype 2). Hematologic, biochemical, and virologic data were collected every 4 weeks during treatment and every 6 months after treatment. HCC was diagnosed based on angiography, computed tomography, and/or magnetic resonance imaging findings. RESULTS: HCC developed in 104 patients during a mean observation period of 40 months. Older age, male sex, lower platelet counts and higher levels of α-fetoprotein at baseline, and lack of an SVR were significant risk factors for HCC. The cumulative incidence of HCC was significantly lower in patients without SVRs who relapsed than those with no response to treatment. Levels of α-fetoprotein 24 weeks after the end of treatment (AFP24) were significantly lower than levels of α-fetoprotein at baseline in patients with SVRs and those who relapsed, but not in nonresponders. Post-treatment risk factors for HCC among patients with SVRs included higher AFP24 level and older age; among those without SVRs, risk factors included higher AFP24 level, integrated level of alanine aminotransferase, older age, and male sex. AFP24 (≥10 ng/mL, 10-5 ng/mL, and then <5 ng/mL) was a better predictor of HCC incidence than pretreatment level of AFP among patients with and without SVRs. CONCLUSIONS: In patients with chronic HCV infection, levels of α-fetoprotein decrease during interferon therapy. High post-treatment levels of α-fetoprotein predict HCC, regardless of whether patients achieve an SVR. University Hospital Medical Information Network Clinical Trials Registry: C000000196, C000000197.

Novel image analysis method using ultrasound elastography for noninvasive evaluation of hepatic fibrosis in patients with chronic hepatitis C.

It has been established that the long-term infection of chronic hepatitis C leads to the increased risk of hepatic fibrosis and hepatocellular carcinoma. Currently, histological diagnosis by invasive and painful liver biopsy is the gold standard for evaluating the hepatic fibrosis stage. Because of a side effect or patient inability to cope with the pain, it is difficult to assess the fibrosis stage frequently using liver biopsy. Recently, instead of liver biopsy, many articles have been published showing the usefulness of ultrasound elastography to evaluate the stage of hepatic fibrosis. We also reported the usefulness of real-time tissue elastography (RTE) for liver fibrosis staging in 2007. However, in our previous report, fibrosis classification was performed manually and the number of patients involved was also small. In the current study, the fibrosis staging is performed automatically using software by characterizing the elastography images. We have also increased the number of patients from 64 to 310. Thus, the aim of this study is to increase objectivity by using a newly developed automatic analysis method. We obtain the Liver Fibrosis Index (LFI), which is calculated from image features of RTE images, using multiple regression analysis performed on clinical data of 310 cases as the training data set. The correlation coefficient obtained between the LFI and the stage of hepatic fibrosis was r = 0.68, and significant differences exist between all stages of fibrosis (p < 0.001). Our new method seems promising since it has the ability to diagnose fibrosis even in the presence of inflammation.

Assessment of liver fibrosis with real-time tissue elastography in chronic viral hepatitis.

OBJECTIVE: The aim of this study was to assess prospectively the accuracy of measurement of liver fibrosis with real-time tissue elastography (RTE) in patients with chronic viral hepatitis. METHODS: Two hundred and forty-five patients were prospectively enrolled. Nine image features were measured from strain images, and Liver Fibrosis Index (LFI) was calculated from these features. Fibrosis stage was diagnosed from pathological specimens obtained by ultrasound-guided biopsy. LFI and serological markers were compared with pathological diagnosis, and the diagnostic performance of RTE was compared. RESULTS: LFI in stages F0-F1, F2, F3 and F4 was 1.58, 2.03, 2.40 and 2.86, respectively, demonstrating a stepwise increase with increasing severity of liver fibrosis (p < 0.001). LFI in F2 did not significantly differ from that in F3, whereas for all other combinations of stages, there were significant differences. The area under the receiver operating characteristic curve of the LFI, platelet count, aspartate/alanine aminotransferase ratio, aspartate aminotransferase-to-platelet ratio, and FibroIndex for predicting F3 stage or higher (F0-F2 vs. F3-F4) was 0.865, 0.824, 0.708, 0.789 and 0.828, respectively. CONCLUSIONS: RTE is useful for diagnosis of liver fibrosis, regardless of stage, in patients with chronic viral hepatitis.

Chronic hepatitis B in patients coinfected with human immunodeficiency virus in Japan: a retrospective multicenter analysis.

A nationwide survey in Japan revealed that about 6 % of human immunodeficiency virus (HIV)-positive patients are coinfected with hepatitis B virus (HBV). To further analyze the features of liver disease in HIV/HBV-coinfected patients, we analyzed 252 patients from six hospitals in the HIV/AIDS (acquired immunodeficiency syndrome) Network of Japan. The mean age was 39.5 years, and the proportion of male patients was very high (243 of 252; 96 %). The main transmission route was male homosexual contact (186 of 252; 74 %), followed by heterosexual contact. The HBV genotype was determined in 77 patients. Among them, genotype A HBV was the most frequent (58 of 77; 75 %) and was detected almost exclusively in homosexual patients. Acute hepatitis B was documented in 21 patients (8 %). Three of the 252 HIV/HBV-coinfected patients developed advanced liver disease with the complication of ascites, hepatic encephalopathy, or hepatocellular carcinoma. A comparison between patients not treated and those treated with antiretroviral drugs including anti-HBV drugs revealed that the baseline liver function was worse in treated patients. However, the serum albumin levels and platelet counts in both groups increased after treatment and were similar. Liver disease-associated death was not observed. Here, we characterize the clinical features of liver disease in HIV/HBV-coinfected patients in Japan for the first time. The findings suggest that antiretroviral therapy with anti-HBV drugs may retard the progression of a liver disease and prevent liver disease-associated death in such patients.

Non-invasive evaluation of hepatic fibrosis for type C chronic hepatitis.

OBJECTIVE: The aim of this study was to investigate liver fibrosis using non-invasive Real-time Tissue Elastography (RTE) and transient elastography (FibroScan) methods. METHODS: RTE, FibroScan and percutaneous liver biopsy were all performed on patients with chronic liver disease, particularly hepatitis C, to investigate liver fibrosis. RESULTS: FibroScan and RTE were compared for fibrous liver staging (F stage), which was pathologically classified using liver biopsy. In FibroScan, significant differences were observed between F1/F3 and F2/F4, but no such differences were observed between F1/F2, F2/F3 and F3/F4. In RTE, significant differences were observed between F1/F2, F2/F3 and F2/F4. But for F3/F4, no significant differences were observed. CONCLUSION: FibroScan and RTE correlated well with F staging of the liver. In particular RTE was more successful than FibroScan in diagnosing the degree of liver fibrosis.

Nucleotide sequence analysis of the enterotoxigenic Escherichia coli Ent plasmid.

We report here the complete nucleotide sequence of pEntH10407 (65 147 bp), an enterotoxigenic Escherichia coli enterotoxin plasmid (Ent plasmid), which is self-transmissible at low frequency. Within the plasmid, we identified 100 open reading frames (ORFs) which could encode polypeptides. These ORFs included regions encoding heat-labile (LT) and heat-stable (STIa) enterotoxins, regions encoding tools for plasmid replication and an incomplete tra (conjugation) region. The LT and STIa region was located 13.5 kb apart and was surrounded by three IS1s and an IS600 in opposite reading orientations, indicating that the enterotoxin genes may have been horizontally transferred into the plasmid. We identified a single RepFIIA replication region (2.0 kb) including RepA proteins similar to RepA1, RepA2, RepA3 and RepA4. The incomplete tra region was made up of 17 tra genes, which were nearly identical to the corresponding genes of R100, and showed evidence of multiple insertions of ISEc8 and ISEc8-like elements. These data suggest that pEntH10407 has the mosaic nature characteristic of bacterial virulence plasmids, which contains information about its evolution. Although the tra genes might originally have rendered pEntH10407 self-transferable to the same degree as R100, multiple insertion events have occurred in the tra region of pEntH10407 to make it less mobile. Another self-transmissible plasmid might help pEntH10407 to transfer efficiently into H10407 strain. In this paper, we suggest another possibility: that the enterotoxigenic H10407 strain might be formed by auto-transfer of pEntH10407 at a low rate using the incomplete tra region.

Chronic hepatitis C in patients co-infected with human immunodeficiency virus in Japan: a retrospective multicenter analysis.

AIM: A nationwide survey in Japan revealed that nearly one-fifth of human immunodeficiency virus (HIV)-positive patients are co-infected with hepatitis C virus (HCV). We conducted a study to further analyze the features of liver disease in HIV-HCV co-infected patients. METHODS: We analyzed 297 patients from eight hospitals belonging to the HIV/AIDS Network of Japan. RESULTS: HCV genotypes 1, 2, 3, 4 and mixed genotypes were detected in 55.2, 13.7, 18.9, 0.9 and 11.3% of patients, respectively, in contrast to the fact that only genotypes 1 and 2 are detected in HCV mono-infected patients in Japan. This is compatible with the transmission of HCV through imported blood products contaminated by HCV. Sixteen of 297 HIV-HCV co-infected patients had advanced liver disease accompanied by ascites, hepatic encephalopathy or hepatocellular carcinoma. The average age of such patients was 41.1 +/- 14.0 years, which was much younger than that of HCV mono-infected patients with the same complications. The progression speed of liver disease estimated from the changes in the levels of serum albumin, bilirubin, or platelet was slower in patients who achieved sustained virological response with interferon treatment than in those who did not receive it. The overall sustained virological response rate to interferon treatment was 43.3%. CONCLUSIONS: Our findings suggest that liver disease is more advanced in HIV-HCV co-infected patients than in HCV mono-infected patients, and interferon treatment may retard the progression of liver disease in such patients.

Effect of interferon alpha-2b plus ribavirin therapy on incidence of hepatocellular carcinoma in patients with chronic hepatitis.

AIM: The objective of this study was to elucidate the long-term effects of interferon (IFN)alpha-2b plus ribavirin combination therapy and to clarify whether this therapy can reduce the incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. METHODS: A total of 403 patients infected with hepatitis C virus (HCV) were enrolled in a multicenter trial. All patients were treated with a combination of IFN-alpha-2b plus ribavirin therapy. We examined the incidence of HCC after combination therapy and analyzed the risk factors for liver carcinogenesis. RESULTS: A sustained virological response (SVR) was achieved by 139 (34%) of the patients. The cumulative rate of incidence of HCC was significantly lower in SVR patients than in non-SVR patients (P = 0.03), while there was no difference in the cumulative incidence of HCC between the transient response (TR) group and the no response (NR) group. Cox's regression analysis indicated the following risk factors as independently significant in relation to the development of HCC: age being > 60 years (P = 0.006), advanced histological staging (P = 0.033), non-SVR to IFN therapy (P = 0.044). The cumulative incidence rate of HCC was significantly lower in patients who had average serum alanine aminotransferase (ALT) levels of < 40 IU/L than in those who showed average serum ALT levels of >== 40 IU/L after the combination therapy (P = 0.021). CONCLUSIONS: These results suggest that the attainment of SVR or continuous normalization of ALT levels after IFN therapy can affect patients apart from HCC development.

Serum levels of soluble major histocompatibility complex (MHC) class I-related chain A in patients with chronic liver diseases and changes during transcatheter arterial embolization for hepatocellular carcinoma.

Soluble forms of major histocompatibility complex (MHC) class I-related chain A and B (MICA/B) are increased in the sera of patients with malignancy and impair the antitumor immune response by downregulating expression of their cognate immunoreceptor natural killer group 2, member D (NKG2D). Recently, soluble MICA/B were reported to appear even in some premalignant diseases, raising questions about the impact of soluble MICA/B produced from tumors on the expression of NKG2D. The present study examined soluble MICA/B in chronic liver disease and hepatocellular carcinoma (HCC) and their involvement in the immune-cell expression of NKG2D during transcatheter arterial embolization for HCC. The levels of soluble MICA/B were significantly higher in chronic liver disease and HCC patients than in healthy volunteers. The progression of liver disease and that of the tumor were independent determinants for soluble MICA/B levels. Immunohistochemistry revealed that MICA/B were expressed not only in HCC tissue but also on hepatocytes in cirrhotic livers. The transcatheter arterial embolization therapy significantly decreased serum levels of soluble MICA, but not soluble MICB, and increased the NKG2D expression on natural killer cells and CD8-positive T cells; there was an inverse correlation between changes in soluble MICA levels and in NKG2D expression. In conclusion, although soluble MICA/B are produced from both HCC and premalignant cirrhotic livers, therapeutic intervention for HCC can reduce the levels of soluble MICA and thereby upregulate the expression of NKG2D. Cancer therapy may have a beneficial effect on NKG2D-mediated antitumor immunity.

Adding interferon to lamivudine enhances the early virologic response and reversion of the precore mutation in difficult-to-treat HBV infection.

BACKGROUND: The virologic impact of adding interferon to antiviral nucleoside therapy was studied in Japanese patients having perinatally transmitted hepatitis B virus (HBV) genotype C. METHODS: Sixty-four patients including 41 positive for hepatitis B e antigen (HBeAg) were assigned to receive either (1) a combination of interferon-alpha (6 million units daily for 2 weeks, then three times weekly) plus lamivudine (100 mg daily) for 24 weeks followed by lamivudine alone for 28 weeks (n = 30) or (2) 52-week lamivudine monotherapy (n = 34). RESULTS: The combination treatment enhanced the early virologic response, and HBV clearance was more frequent at week 8 for patients with baseline HBV DNA < or = 7 log copies/ml (90% vs. 33%, P = 0.013) and at week 24 for patients with baseline HBV DNA > 7 log copies/ml (75% vs. 40%, P = 0.080). In the combination arm, YMDD mutants emerged less often at week 52 (8% vs. 30%, P = 0.047). However, reversion of the precore mutation was more prominent with combination treatment than with monotherapy (McNemar test, P = 0.014 and P = 0.103, respectively). HBeAg seroconversion (P = 0.429) and sustained off-treatment HBV suppression to < or =5 log copies/ml (log-rank test, P = 0.195) were not improved. CONCLUSIONS: Simultaneous commencement of treatment with interferon and a nucleoside analog may be worthy as a treatment option to augment the early virologic response and prevent drug resistance in difficult-to-treat patients. Combination treatment was also shown to enhance reversion of the precore mutation. Further studies are warranted to clarify the therapeutic implications of this phenomenon.

Declining incidence of hepatocellular carcinoma in Osaka, Japan, from 1990 to 2003.

BACKGROUND: Japan has the highest incidence rate of primary liver cancer attributed to chronic hepatitis C virus (HCV) infection among developed countries. Molecular clock analysis of HCV sequences revealed that the spread of HCV took place earlier in Japan than in other countries. This might influence recent temporal trends in hepatocellular carcinoma (HCC) incidence. OBJECTIVE: To characterize the contribution of HCV-related hepatocellular carcinoma (HCC) to recent changes in HCC incidence in Osaka, Japan. DESIGN: Population-based survey. SETTING: Osaka Cancer Registry and 10 hospitals in Osaka. PARTICIPANTS: 63,862 patients with HCC that was diagnosed between 1981 and 2003 in Osaka Prefecture, including 5253 HCV-seropositive patients with HCC that was diagnosed between 1990 and 2003 at 10 hospitals. MEASUREMENTS: Incidence of HCC and estimated incidence rate of HCV-related HCC, measured by multiplying the prevalence of anti-HCV by the corresponding HCC incidence rate. RESULTS: Between 1981 and 2003, peak incidence of HCC among men age 50 to 59 years, 60 to 69 years, and 70 to 79 years occurred in 1986, 1995, and 2000, respectively, with marked downward trends thereafter (average annual change, -7.9, -22.3, and -12.4 per 100,000 persons, respectively). Similar trends were observed in women. Estimated sex- and age-specific incidence of HCV-related HCC (per 100,000 persons) decreased from 255 to 92 cases at the maximum in men age 60 to 69 years and from 61 to 34 cases in women age 60 to 69 years, whereas estimated incidence of non-HCV-related HCC did not change between 1990 and 2003. LIMITATION: Infection was determined only by HCV seropositivity. CONCLUSION: The incidence of HCC in Osaka started to decrease by 2000, mainly because of decreased HCV-related HCC.

Comparison of complete sequences of hepatitis B virus genotype C between inactive carriers and hepatocellular carcinoma patients before and after seroconversion.

BACKGROUND: Most patients who acquire chronic hepatitis B virus (HBV) infection by perinatal transmission become inactive carriers (IC) after hepatitis B e (HBe) antigen seroconversion, whereas some patients have persistent abnormal serum transaminase levels and develop hepatocellular carcinoma (HCC) in the anti-HBe-positive phase. The aim of this study was to investigate the HCC-related mutations of HBV. METHODS: Complete sequences of HBV were examined among eight IC and eight HCC patients infected with HBV genotype C before and after seroconversion. RESULTS: The frequency of the T1653 mutation tended to be higher among HCC patients after seroconversion (16.7% vs. 62.5%; P = 0.086). The prevalence of a basal core promoter double mutation (T1762/A1764) was high among both IC and HCC patients after seroconversion (83.3% vs. 87.5%; P = 0.825). Among the HCC patients, a pre-S deletion mutant was detected in 62.5% patients before seroconversion, and in 37.5% patients after seroconversion. The core deletion mutant was also detected in 50% of HCC patients only before seroconversion. Deletion mutants of the pre-S or core region before seroconversion were significantly associated with HCC patients (0% vs. 62.5%; P = 0.007, 0% vs. 50%; P = 0.021, respectively). CONCLUSIONS: Our data showed a significant association of pre-S and core deletion mutants before seroconversion with HCC development. The T1653 mutation after seroconversion was frequently found in HCC patients infected with HBV genotype C. These results suggest that mutations may be predictive factor for development of HCC.

Phase II study of protracted irinotecan infusion and a low-dose cisplatin for metastatic gastric cancer.

AIM: To test protracted irinotecan infusion plus a low-dose cisplatin in this Phase II trial to decrease its toxicity. METHODS: The eligibility criteria were: (1) histologically proven measurable gastric cancer; (2) performance status of 0 or 1; (3) no prior chemotherapy or completion of prior therapy at least 4 wk before enrollment; (4) adequate function of major organs; (5) no other active malignancy; and (6) written informed consent. The regimen consisted of irinotecan (60 mg/m(2)) on d 1 and 15 by 24-h infusion and cisplatin (10 mg/m(2)) on d 1, 2, 3, 15, 16, and 17. Treatment was repeated every 4 wk. RESULTS: Thirty-one patients were registered between April 2000 and January 2001. The response rate for all 31 patients, 20 patients without prior chemotherapy, and 11 patients with prior chemotherapy was 52% (16/31), 60% (12/20), and 36% (4/11), respectively. The median survival time was 378 d. The median number of courses given to all patients was 2. Grade 4 neutropenia occurred in 11 (35%) patients, while grade 3 to 4 diarrhea or nausea occurred in 1 (3%) and 3 (10%) patients, respectively. Fatigue was minimal as grade 1 fatigue was found only in 3 (10%) patients. Other adverse events were mild and no treatment-related deaths occurred. CONCLUSION: This regimen showed a high level of activity and acceptable toxicity in patients with metastatic gastric cancer.

Squamous cell carcinoma as a rare entity of primary liver tumor with grave prognosis.

The development of primary squamous cell carcinoma (SCC) of the liver has only rarely been reported in association with pre-existing hepatic cysts and biliary tract diseases. This report describes an unusual case of SCC originating in a cirrhotic liver. A 63-year-old male alcoholic was incidentally found to have a 6-cm liver tumor which showed mixed echogenic by sonography and a low-density area with rim enhancement by computed tomography. Tumor biopsy led to a diagnosis of SCC with a sarcomatoid change. The tumor showed fatal rapid growth accompanied by abdominal pain. Transcatheter arterial embolization and chemotherapy were not effective, and the tumor increased to 13cm in diameter over an 8-month period. A post-mortem search revealed no alternative primary tumor site other than liver. Review of the literature shows that abdominal pain is a chief symptom of primary liver SCC. Only three of the nine patients treated with hepatic resection survived without recurrence during 8 months to 4 years of follow-up. We propose that SCC with a grave prognosis should be considered as a rare entity of primary liver tumor even in cirrhotic patients.

Specific mutations in enhancer II/core promoter of hepatitis B virus subgenotypes C1/C2 increase the risk of hepatocellular carcinoma.

BACKGROUND/AIMS: Hepatitis B virus genotype C (HBV/C) has been classified into two geographically distinct subgenotypes; HBV/C1/Cs (Southeast Asia) and HBV/C2/Ce (East Asia). METHODS: Viral differences in enhancer II/core promoter and precore regions between the subgenotypes and their association with hepatocellular carcinoma (HCC) were assessed in a matched cross-sectional control study of 118 carriers (from Hong Kong) with HBV/C1/Cs (48.0 years, 81% male, 40% HBeAg+, 44% HCC) and 210 HBV/C2/Ce (172 from Japan, 38 from Hong Kong) (50.2 years, 78% male, 30% HBeAg+, 46% HCC). RESULTS: Univariate analyses showed that mutation V1753 was predictive for HCC among HBeAg-positive-C1/Cs-carriers (P=0.0055), and T1653 among HBeAg-positive-C2/Ce-carriers (P=0.018), and T1653 or V1753 or T1762/A1764 among HBeAg-negative-C2/Ce-carriers (P<0.05). In the multivariate analysis on all HBV/C subjects, independent predictive factors for HCC were subgenotype C2/Ce (odds ratio, 4.21; 95% confidence interval, 1.07-16.23), T1653 (3.64; 1.93-6.86), V1753 (3.07; 1.66-5.65) and T1762/A1764 (2.58; 1.21-5.49) mutations, age (50 years), gender (male) and HBeAg (positive). CONCLUSIONS: Our data indicate that T1653 and/or V1753 mutations in addition to T1762/A1764 are differently associated with HCC in context of HBeAg status among HBV/C1/Cs and C2/Ce-carriers. HBV/C subgenotypes have specific mutation patterns, which is probably responsible for increased carcinogenesis of HBV/C2/Ce.