Review article: hepatitis B core-related antigen (HBcrAg): an emerging marker for chronic hepatitis B virus infection.

BACKGROUND: Chronic hepatitis B (CHB) cannot be completely eradicated due to the presence of covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes. While quantification of intrahepatic cccDNA requires liver biopsies, serological markers can be non-invasive alternatives to reflect intrahepatic viral replicative activity. Recently, hepatitis B core-related antigen (HBcrAg) has been advocated as a novel serum marker for disease monitoring and prognostication of CHB. AIM: To examine the virological aspect and clinical application of HBcrAg with respect to the natural history and treatment of CHB. METHODS: We reviewed all papers published in the PubMed journal list and abstracts from major international meetings that included the keyword "HBcrAg" or "hepatitis B core-related antigen" until March 2017. Selected studies were compared and summarised on the basis of existing theories, as well as the authors' experience. RESULTS: HBcrAg exhibited good correlation with intrahepatic (ih) cccDNA, ih total hepatitis B virus (HBV) DNA, serum HBV DNA and to a lesser extent HBV surface antigen (HBsAg). In situations where serum HBV DNA levels become undetectable or HBsAg loss is achieved, HBcrAg can still be detectable. This marker is helpful in differentiation of HBeAg-negative chronic hepatitis from HBeAg-negative chronic infection, predicting spontaneous or treatment-induced HBeAg seroconversion, sustained response to nucleos(t)ide analogue (NA), risk of HBV reactivation in occult HBV infection under immunosuppressive therapies, and risk of hepatocellular carcinoma (HCC) development as well as post-operative HCC recurrence. CONCLUSIONS: HBcrAg is a potential surrogate marker of cccDNA. It may soon become a useful marker for disease monitoring, predicting treatment response and disease outcome of chronic hepatitis B.

Relationship between HBsAg, HBcrAg and hepatocellular carcinoma in patients with undetectable HBV DNA under nucleos(t)ide therapy.

We examined the relationship between hepatitis B surface and core-related antigens (HBsAg, HBcrAg) and hepatocellular carcinoma (HCC) development in patients with undetectable serum HBV DNA receiving nucleos(t)ide analogue (NA). Seventy-six HBV carriers with undetectable HBV DNA (<20 IU/mL) who subsequently developed HCC were compared with 152 matched controls. Clinical and laboratory parameters (including novel assays to measure linearized HBsAg [HQ-HBsAg] and HBcrAg) were analysed. There were no significant differences in HBsAg/HQ-HBsAg levels between the two groups. There was a significant difference in the median values of both pre- and post-NA HBcrAg levels between the HCC and control groups (pre-treatment: 279.0 vs 35.4 kU/mL, P=.005; post-treatment: 10.2 vs 1.7 kU/mL, P=.005, respectively). For the whole HCC group, a cut-off value of post-treatment HBcrAg level ≥7.8 kU/mL yielded an area under receiver operating curve (AUROC) of 0.61 with a negative predictive value (NPV) of 77.0%. The OR of HCC development was 3.27. For noncirrhotic patients, the median values of post-treatment HBcrAg level of HCC group and controls were 10.2 and 1.0 kU/mL, respectively (P=.001). A cut-off value of HBcrAg level ≥7.9 kU/mL yielded an AUROC of 0.70 with a NPV of 80.6%. The OR of HCC development was 5.95. A higher pre- and post-NA treatment HBcrAg level (but not HBsAg) was associated with an increased risk of HCC development in patients achieving undetectable serum HBV DNA while on NA therapy. HBcrAg may serve as a novel risk marker for HCC in this group of patients.

Effects of nucleoside analogue prescription for hepatitis B on the incidence of liver cancer in Hong Kong: a territory-wide ecological study.

BACKGROUND: The temporal relationship between nucleoside analogue therapy for chronic hepatitis B (CHB) and liver cancer development has not been evaluated at a population level. AIM: To investigate the impact of nucleoside analogue prescription on liver cancer incidence in a CHB-prevalent region. METHODS: We obtained territory-wide nucleoside analogue prescription data from 1999, when nucleoside analogue was first available in Hong Kong, to 2012 and the population-based liver cancer incidence data from 1990 to 2012. We compared the liver cancer incidences from 1990 to 1998 and 1999 to 2012 with adjustment for local hepatitis B surface antigen seroprevalence. RESULTS: Nucleoside analogue prescription patient headcount increased from 2006 per year in 1999 to 26 411 in 2012. Prescription volume in 2012 was highest among 55-64 years (30.3%), higher than 65-74 years (13.0%) and ≥75 years (5.8%). Age-standardised liver cancer incidence 1999-2012 decreased by 1.88%/year (95% CI 3.34% to 0.42%/year). NA therapy was associated with decline in age-adjusted liver cancer incidence (2.7 per 100 000 persons, P < 0.001, 95% CI 1.4-4.0 per 100 000 persons). Fifty-five to sixty-four years age group had the most significant decline (men: 24.0 per 100 000 persons, P = 0.001, 95% CI 11.4-36.6 per 100 000 persons; women: 8.5 per 100 000 persons, P = 0.009, 95% CI 2.3-14.6 per 100 000 persons). No significant association was noted in age groups 65-74 years and ≥75 years (both P > 0.05). CONCLUSIONS: Nucleoside analogue prescription was associated with a reduction of overall liver cancer incidence in a CHB-prevalent region. The lack of association among individuals of ≥65 years was consistent with the low nucleoside analogue prescription volume in elderly patients, mitigating the impact of CHB treatment on liver cancer.

Body-mass index is associated with fibrosis regression during long-term nucleoside analogue therapy in chronic hepatitis B.

BACKGROUND: Factors influencing changes in liver stiffness measurements during long-term nucleoside analogue therapy for chronic hepatitis B (CHB) have not been thoroughly investigated. AIM: To identify determinants of on-treatment fibrosis regression in CHB. METHODS: We performed follow-up liver stiffness and controlled attenuation parameter measurements on nucleoside analogue-treated CHB patients with severe liver fibrosis, according to EASL-ALEH criteria, diagnosed by transient elastography in 2006-2008. Anthropometric measurements and different metabolic parameters were recorded. RESULTS: Among 257 patients with severe liver fibrosis by initial transient elastography, 123 (47.9%) were recruited for reassessment. Median treatment duration was 87.5 (interquartile range 75.3-102.2) months; 97.5% had undetectable HBV DNA. There was a significant reduction in median liver stiffness from 14.6 to 8.3 kPa (P < 0.001). A total of 29.3% had fibrosis regression, with lower rates of 17.9%, 14.9% and 11.5% noted in patients with body-mass index (BMI) ≥25 kg/m2 , metabolic syndrome and diabetes, respectively. Absence of BMI ≥25 kg/m2 , diabetes and metabolic syndrome, when compared with presence of any one of these three factors, was associated with increased fibrosis regression (43.1% vs. 16.9%, P = 0.001). Multivariate analysis found a lower BMI to be the only factor independently associated with fibrosis regression (P = 0.034, odds ratio 0.68, 95% CI 0.48-0.97). No association was noted between controlled attenuation parameter measurements and fibrosis regression (P > 0.05). CONCLUSION: An increased BMI hindered fibrosis regression in patients with chronic hepatitis B during nucleoside analogue treatment, suggesting that control of metabolic risk factors, in addition to virologic suppression via antiviral therapy, might be needed to halt the fibrogenic process in chronic hepatitis B.

NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia.

A recent study identified a variant of the NUDT15 gene (rs116855232 C>T) associated with intolerance to thiopurine in Korean patients with Crohn's disease. This study prompted us to substantiate the finding in a Taiwanese population. Four hundred and four children with acute lymphoblastic leukemia (ALL), and 100 adults with chronic immune thrombocytopenic purpura or localized lymphoma having normal bone marrow were examined. Two candidate gene approaches, pyrosequencing for NUDT15 and TaqMan assay for thiopurine methyltransferase (TPMT) genotyping (rs1142345 A>G), were performed. We showed a risk allele frequency of NUDT15 of 11.6% in children with ALL and 15.5% in adults. By contrast, the risk allele frequency of TPMT was only 1.6% in children with ALL and 0.5% in adults. The high frequency of risk variant for NUDT15, but not the very low frequency of risk variant for TPMT, was closely associated with the intolerance to mercaptopurine in children with ALL in Taiwan, contrast to that of European descent. In regard to NUDT15 polymorphism, the maximal tolerable daily doses of mercaptopurine in homozygotes, heterozygotes and wild-type groups were 9.4 mg m-2, 30.7 mg m-2 and 44.1 mg m-2, respectively. The outcomes did not differ significantly among the different genotypes.

High prevalence of human herpesvirus type 8 infection in patients with pulmonary tuberculosis in Taiwan.

Blood samples were collected from 101 untreated pulmonary tuberculosis (TB) patients and 101 age- and sex-matched healthy control subjects. TB patients had lower lymphocyte and a higher monocyte counts than control subjects (p <0.0001 for both). The seropositive rate of human herpesvirus (HHV) type 8 antibody was higher in patients (30/101) than in control subjects (15/101) (p = 0.01). Antibody titres in patients also exceeded those in control subjects (p 0.006). Lymphocyte and monocyte counts between seronegative and seropositive subjects were not different. Four patients were positive for HHV-8 DNA. The study revealed a significantly higher HHV-8 seroprevalence in untreated pulmonary TB patients than in general population.

Significant changes in liver stiffness measurements in patients with chronic hepatitis B: 3-year follow-up study.

For patients with chronic hepatitis B (CHB) infection, changes in liver stiffness measurement (LSM) over time are not known. We examined changes longitudinally in a cohort of patients. Four hundred and twenty-six patients with CHB underwent transient elastography. Patients were followed regularly, and repeat elastography was performed at 3 years. Hepatitis serology, viral load and routine liver biochemistry were monitored. Of the 426 patients, 38 (9%) were hepatitis B e-antigen (HBeAg)-positive, 293 (69%) were HBeAg-negative and 95 (22%) were patients with prior hepatitis B surface antigen (HBsAg) seroclearance. A total of 110 patients received oral antiviral therapy. There was a significant decline of LSMs at the follow-up measurement compared to baseline (6.1 vs 7.8 kPa respectively, P = 0.002) in treated patients who had elevated alanine aminotransferase (ALT) at baseline and subsequent normalization after 3 years (normal ALT limit being 30 U/L for males and 19 U/L for females). In nontreated patients, only the patients with persistently normal ALT at both time points had significantly lower LSMs at the follow-up measurement compared to baseline: 4.9 vs 5.3 kPa, respectively, in patients who remained positive for HBsAg (P = 0.005) and 5.1 vs. 5.4 kPa, respectively, in patients who had HBsAg seroclearance (P = 0.026). In patients who remained positive for HBsAg, independent factors associated with a significant decline in LSM of ≥1 kPa included antiviral therapy (P = 0.011) and the ALT levels at the follow-up time point (P = 0.024). Thus, in patients with CHB, a significant decline in LSM after 3 years was observed in treated patients with ALT normalization and in untreated patients who had persistently normal ALT. Antiviral therapy and follow-up ALT levels were independent significant factors associated with a decline in LSM.

Prognostic significance of liver stiffness for hepatocellular carcinoma and mortality in HBeAg-negative chronic hepatitis B.

The prognostic value of liver stiffness measurements for chronic hepatitis B (CHB) is not known. The present study aimed to investigate the use of transient elastography in predicting hepatocellular carcinoma (HCC) development and mortality in patients with CHB. Five hundred and twenty-eight patients with HBeAg-negative CHB underwent liver stiffness measurements and were prospectively followed up every 3-6 months for a median length of 35 months. The patients were divided into those with liver stiffness < 10 kPa (group 1) and ≥ 10 kPa (group 2). Of the 528 patients, 324 (61%) were men. The median age was 42 years. Compared with group 1, group 2 had a higher percentage of men, with higher median levels of age, liver biochemistry, and viral load. At the third year of follow-up, the cumulative incidence of HCC was higher in group 2 compared with group 1 (9%vs 0%, respectively, P < 0.001). The cumulative liver-related mortality was also higher in group 2 compared to group 1 (4%vs 0%, respectively, P < 0.001). After multivariate analysis, only liver stiffness measurement (LSM) was significantly associated with HCC development and mortality. There was also a higher cumulative incidence of hepatitis flares in group 2 compared to group 1 (46%vs 14%, respectively, P = 0.001) in patients with normal ALT, with higher LSM and AST being significantly associated with subsequent flares. In HBeAg-negative CHB patients, a liver stiffness measurement of ≥ 10 kPa was associated with a significantly increased risk of subsequent HCC development and mortality.

Hepatitis B and C virus-related carcinogenesis.

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are the most important causes of hepatocellular carcinoma (HCC), accounting for the majority of the cases worldwide. The geographical distribution of HCC therefore coincides with the distribution of HBV and HCV infections in those areas. Similar to nonviral liver diseases, HBV and HCV infection can cause chronic injury to the liver, with subsequent progression to severe fibrosis and cirrhosis. The presence of cirrhosis is a major risk factor for the development of HCC. However, HCC can occur in the absence of cirrhosis, suggesting that both HBV and HCV may be directly involved in hepatocarcinogenesis. Several HBV factors have been implicated in hepatocarcinogenesis, including the HBx gene, the pre-S2/S gene and the HBV spliced protein. Furthermore, HBV can be integrated into the host genome, leading to changes in genomic function or chromosomal instability. By contrast to HBV, HCV cannot integrate into the host genome. Various HCV proteins, including the core, envelope and nonstructural proteins, have been shown to have oncogenic properties. For HBV infection, antiviral therapy and vaccination have been shown to decrease the risk of HCC. Antiviral therapy for HCV can also reduce the risk of HCC.

Health-related quality of life of Southern Chinese with chronic hepatitis B infection.

BACKGROUND: Few studies have evaluated the health-related quality of life (HRQOL) of Southern Chinese with chronic hepatitis B (CHB) infection. AIM: To evaluate the HRQOL of Chinese patients at different stages of CHB infection and to find out factors associated with HRQOL. METHODS: 520 Chinese adult CHB patients of whom 156 were uncomplicated, 102 had impaired liver function, 139 had cirrhosis and 123 had hepatocellular carcinoma (HCC) were interviewed with a structured questionnaire, the SF-36 Health Survey version 2 (SF-36v2), and the Chronic Liver Disease Questionnaire (CLDQ). The differences in SF-6D health preference values and SF-36v2 scores between each CHB group and Hong Kong population norms were assessed by t-test. ANOVA was used to compare the mean SF-6D health preference, SF-36v2 scores, and CLDQ scores among CHB groups. Multiple linear regressions were performed to identify determinants of HRQOL. RESULTS: CHB patients had significantly lower SF-36v2 scores than the population norm. The SF-6D values of CHB patients with uncomplicated disease, impaired liver function, HCC and cirrhosis were 0.755, 0.745, 0.720 and 0.701, respectively, all significantly lower than the population norm of 0.787. Advanced stage of CHB illness, anti-viral treatment, bilirubin level, psychological co-morbidity, younger age and female were associated with poorer HRQOL. CONCLUSION: CHB infection had a negative impact on HRQOL. There was a progressive decrease in health preference values with CHB disease progression. The results can be used for the estimation of quality adjusted life years (QALYs) for CHB patients in cost effectiveness or cost utility studies. TRIAL REGISTRATION: http://www.hkclinicaltrials.com; HKCTR-151.

Androgen receptor CAG repeat polymorphisms in canine prostate cancer.

BACKGROUND: Relatively shorter lengths of the polymorphic polyglutamine repeat-1 of the androgen receptor (AR) have been associated with an increased risk of prostate cancer (PC) in humans. In the dog, there are 2 polymorphic CAG repeat (CAGr) regions. OBJECTIVE: To investigate the relationship of CAGr length of the canine AR-gene and the development of PC. ANIMALS: Thirty-two dogs with PC and 172 control dogs were used. METHODS: DNA was extracted from blood. Both CAG repeats were amplified by polymerase chain reaction (PCR) and PCR products were sequenced. RESULTS: In dogs with PC, CAG-1 repeat length was shorter (P = .001) by an increased proportion of 10 repeats (P = .011) and no 12 repeats (P = .0017) than in the control dogs. No significant changes were found in CAG-3 length distribution. CAG-1 and CAG-3 polymorphisms proved not to be in linkage disequilibrium. Breed difference in allelic distribution was found in the control group. Of the prostate-disease sensitive breeds, a high percentage (64.5%) of the shortest haplotype 10/11 was found in the Doberman, whereas Beagles and German Pointers had higher haplotype 12/11 (47.1 and 50%). Bernese Mountain dogs and Bouvier dogs both shared a high percentage of 11 CAG-1 repeats and 13 CAG-3 repeats. Differences in (combined) allelic distributions among breeds were not significant. CONCLUSIONS AND CLINICAL IMPORTANCE: In this preliminary study, short CAG-1 repeats in the AR-gene were associated with an increased risk of developing canine PC. Although breed-specific differences in allelic distribution of CAG-1 and CAG-3 repeats were found, these could not be related to PC risk.

Cooperating mutations of receptor tyrosine kinases and Ras genes in childhood core-binding factor acute myeloid leukemia and a comparative analysis on paired diagnosis and relapse samples.

c-KIT mutations have been described in core-binding factor (CBF) acute myeloid leukemia (AML) at diagnosis. The role of c-KIT mutations in the relapse of CBF-AML is not clear. The role of CSF1R mutation in the pathogenesis of AML remains to be determined. We analyzed receptor tyrosine kinases (RTKs) and Ras mutations on 154 children with AML. Also, we examined the paired diagnosis and relapse samples in CBF-AML. CBF-AML accounted for 27% (41/154). c-KIT mutations were detected in 41.5% of CBF-AML at diagnosis (6 in exon 8, 10 in exon 17 and 1 in both exons 8 and 17) , FLT3-TKD 2.7%, N-Ras mutations 7.3% and K-Ras mutations 4.9%. FLT3-LM and CSF1R mutations were not found in CBF-AML. The mutations of RTKs and Ras were mutually exclusive except for one patient who had both c-KIT and N-Ras mutations. Eight of the 41 CBF-AML patients relapsed; four patients retained the identical c-KIT mutation patterns as those at diagnosis, the remaining four without c-KIT mutations at diagnosis did not acquire c-KIT mutations at relapse. Our study showed that 54% of childhood CBF-AML had RTKs and/or Ras mutations; c-KIT but not CSF1R mutations play a role in the leukemogenesis of childhood CBF-AML.

Risk for hepatocellular carcinoma with respect to hepatitis B virus genotypes B/C, specific mutations of enhancer II/core promoter/precore regions and HBV DNA levels.

BACKGROUND/AIM: To examine the risks for hepatocellular carcinoma (HCC) with respect to hepatitis B virus (HBV) genotypes, specific viral mutations (MT), serum HBV DNA levels, and cirrhosis. METHODS: HBV genotypes, 1653/1753/core promoter (CP)/precore MT and HBV DNA levels were determined in 248 HBV patients with HCC and 248 HBV controls. RESULTS: Genotype C, CP-MT, T1653, HBV DNA levels >or=4 log(10) copies/ml and cirrhosis had a higher risk for HCC compared to patients with genotype B (p = 0.001, OR 1.9), CP wild-type (WT) (p<0.001, OR 4.1), C1653 (p = 0.028, OR 2.4), HBV DNA <4 log(10) copies/ml (p = 0.003, OR 2.1) and without cirrhosis (p<0.001, OR 4.0) respectively. Multivariate analysis showed that CP-MT, T1653, HBV DNA >or=4 log(10) copies/ml and cirrhosis were independent factors for HCC (all p<0.05). A receiver operating characteristics curve showed no cut-off HBV DNA level associated with minimal chance of HCC. Patients with CP-MT and cirrhosis had a 22.2-fold increased risk of HCC compared to patients with CP-WT and without cirrhosis. Patients with CP-MT and HBV DNA levels >or=4 log(10) copies/ml had a 7.2-fold increased risk of HCC compared to patients with CP-WT and HBV DNA levels <4 log(10) copies/ml. Patients with CP-MT and T1653 had a 9.9-fold increased risk of HCC compared to patients with wild-type for both regions. CONCLUSIONS: CP-MT, T1653, HBV DNA levels >or=4 log(10) copies/ml and cirrhosis are independent factors for development of HCC. The risks increased substantially in patients having these factors in combination.

Low serum HBV DNA levels and development of hepatocellular carcinoma in patients with chronic hepatitis B: a case-control study.

AIM: To investigate the level of hepatitis B virus (HBV) DNA in Chinese chronic hepatitis B (CHB) patients below which hepatocellular carcinoma (HCC) is unlikely to occur. METHODS: A total of 92 CHB patients diagnosed with HCC were recruited; 184 CHB patients without HCC, matched for age, sex and HBeAg status were included as controls. HBV DNA levels were performed at the time of HCC development and at the same age time points for control group. RESULTS: The median HBV DNA level in HCC patients was 1.7 x 10(6) copies/mL compared with 2.2 x 10(5) copies/mL in controls (P = 0.006). In HCC patients, 21 (22.8%) were HBeAg(+), with no significant difference in HBV DNA levels compared with controls. Seventy-one (77%) HCC patients were HBeAg(-) with median HBV DNA level of 3.2 x 10(5) copies/mL, compared with 6.0 x 10(4) copies/mL in controls (P = 0.006). In HBeAg(-) patients, the control group had significantly greater proportion of patients having HBV DNA levels <10(5) and <10(4) copies/mL compared with HCC patients. Fifteen per cent of all HCC patients had HBV DNA levels <10(3) copies/mL. CONCLUSIONS: In HBeAg(+) patients, HBV DNA levels were high in both HCC and control patients. In HBeAg(-) patients, HCC was more likely to develop in patients with HBV DNA level >10(4) copies/mL. However, 15% of the patients with HCC had HBV DNA levels <10(3) copies/mL.

Quantitative analysis of HBV cccDNA from clinical specimens: correlation with clinical and virological response during antiviral therapy.

Attempts to investigate changes in various forms of intrahepatic hepatitis B virus (HBV) DNA during antiviral therapy have been hampered by limitations in technologies and scarcity of adequate tissue for analysis. We used a sensitive, specific assay to detect and quantitate covalently closed circular DNA (cccDNA) from total intrahepatic HBV DNA in clinical liver specimens. Total HBV DNA and cccDNA from 21 needle-biopsy specimens were quantified, with levels ranging from 0.1 to 9.8 copies/cell and 0.3 to 491.0 copies/cell, respectively. Then, we performed the same determinations on baseline and week-52 liver needle-biopsy specimens from eight patients enrolled in a clinical trial and evaluated the association between intrahepatic HBV DNA levels and serological and virological endpoints. In most patients, levels of intrahepatic HBV DNA, including cccDNA, decreased over the 52-week study, regardless of therapy or serological outcome. Higher ratios of cccDNA to total HBV DNA were detected at week 52 than at baseline indicating a shift in predominance of nonreplicating virus in posttreatment specimens. In patients who achieved treatment-related or spontaneous hepatitis B e antigen (HBeAg) responses, including those harbouring tyrosine-methionine-aspartate-aspartate-mutant HBV, levels of intrahepatic and serum HBV DNA suppression were greater than those in patients without HBeAg responses. In conclusion, this pilot study of intrahepatic HBV replicative forms in patients with chronic hepatitis B indicated that total intrahepatic and, specifically, cccDNA levels are not static but change as a reflection of serological and virological events.

Clinical features, biochemical parameters, and virological profiles of patients with hepatocellular carcinoma in Hong Kong.

BACKGROUND: Clinical features of hepatocellular carcinoma patients are changing because of screening. AIM: To examine the clinical features of hepatocellular carcinoma patients in Hong Kong and validity of different staging systems. METHODS: A total of 223 Chinese patients with hepatocellular carcinoma were studied. RESULTS: Seventy-eight percent of hepatocellular carcinoma patients had chronic hepatitis B (43% diagnosed by screening). Hepatitis B positivity, weight loss, jaundice, encephalopathy, alpha-fetoprotein level, portal vein thrombosis, extrahepatic metastasis, and treatment were shown to be independent factors affecting survival. Of chronic hepatitis B patients, hepatitis B virus DNA levels (P = 0.001) and portal vein thrombosis (P = 0.008) were independent factors affecting survival. Seventy-six percent of chronic hepatitis B patients with hepatocellular carcinoma were hepatitis B e antigen negative. Screening patients had hepatocellular carcinoma detected at an earlier stage and better survival (median survival: 21 vs. 4 months, P < 0.0001). All staging systems had good stratification of survival. Prognosis and median survival generated were different when compared with the US data. CONCLUSIONS: Chronic hepatitis B was the most common cause of hepatocellular carcinoma in Hong Kong. High-risk chronic hepatitis B patients should be followed irrespective of the hepatitis B e antigen status. Hepatitis B virus DNA levels at the time of diagnosis are an important survival predictor. Screening detected hepatocellular carcinoma at an earlier stage and prolonged survival. Staging systems should be validated in different populations.

Characterization of fusion partner genes in 114 patients with de novo acute myeloid leukemia and MLL rearrangement.

The fusion transcripts of MLL rearrangement [MLL(+)] in acute myeloid leukemia (AML) and their clinicohematologic correlation have not be well characterized in the previous studies. We used Southern blot analysis to screen MLL(+) in de novo AML. Reverse transcriptase-polymerase chain reaction was used to detect the common MLL fusion transcripts. cDNA panhandle PCR was used to identify infrequent or unknown MLL partner genes. MLL(+) was identified in 114 (98 adults) of 988 AML patients. MLL fusion transcripts comprised of 63 partial tandem duplication of MLL (MLL-PTD), 14 MLL-AF9, 9 MLL-AF10, 9 MLL-ELL, 8 MLL-AF6, 4 MLL-ENL and one each of MLL-AF1, MLL-AF4, MLL-MSF, MLL-LCX, MLL-LARG, MLL-SEPT6 and MLL-CBL. The frequency of MLL-PTD was 7.1% in adults and 0.9% in children (P<0.001). 11q23 abnormalities were detected in 64% of MLL/t11q23 and in none of MLL-PTD by conventional cytogenetics. There were no differences in remission rate, event-free survival and overall survival between adult MLL-PTD and MLL/t11q23 groups. Adult patients had a significantly poorer outcome than children. The present study showed that cDNA panhandle PCR can identify all rare or novel MLL partner genes. MLL-PTD was rare in childhood AML. MLL(+) adults had a poor outcome with no difference in survival between MLL-PTD and MLL/t11q23 groups.