Hie-Won L. Hann

Prognostic Factors in Neuroblastoma

Known prognostic factors in neuroblastoma were analyzed in 124 children to determine which were independent and which were most useful in predicting outcome. The following factors were analyzed: age, sex, stage of disease, serum neuron‐specific enolase (NSE), serum ferritin, E‐rosette inhibition, urinary catecholamines, and histologic type according to the criteria of Shimada. Estimates of survival were calculated using the method of Kaplan and Meier. The overall survival for 124 patients was 60% at 2 years. There were significant differences in survival by pathology, age, NSE, ferritin, vanilmandelic acid (VMA): homovanillic acid (HVA) ratio, and stage. There was a strong association among NSE, age, stage, and ferritin. Using the recursive partitioning approach, it was possible to subdivide patients into three groups (based on diagnostic values of ferritin, age, and stage) with a good, intermediate, and poor prognosis and estimated 2‐year survival of 100%, 62%, and 19%, respectively. Further analysis could not be done because of small numbers in the subgroups, but the results suggest that combinations of age, stage, serum ferritin, and histologic type may be able to define two populations: favorable with 80% + 2‐year survival and unfavorable with less than 20%.

Early Hepatitis B Virus DNA Reduction in Hepatitis B e Antigen-Positive Patients with Chronic Hepatitis B : A Randomized International Study of Entecavir Versus Adefovir

This study was undertaken to compare the early antiviral activity and viral kinetic profiles of entecavir (ETV) versus adefovir (ADV) in hepatitis B e antigen positive nucleoside‐naïve adults with chronic hepatitis B (CHB). Sixty‐nine nucleoside‐naïve CHB patients with baseline HBV DNA of 108 copies/mL or more were randomized 1:1 to open‐label treatment with entecavir 0.5 mg/day or adefovir 10 mg/day for a minimum of 52 weeks. The primary efficacy analysis compared mean reduction in HBV DNA at week 12 adjusted for baseline levels using linear regression. Entecavir was superior to adefovir for mean change from baseline in HBV DNA at week 12 (−6.23 log10 copies/mL versus −4.42 log10 copies/mL, respectively; mean difference −1.58 log10 copies/mL; P < 0.0001). Both drugs demonstrated biphasic viral kinetics, with a first phase of rapid decline lasting 10 days. A significant difference favoring ETV was reached at day 10 (day 10 ETV−ADV difference estimate: −0.66 log10 copies/mL; 95% CI [−0.30, −0.01]). Early virological response was found to be predictive of subsequent virological response, with those having lower HBV DNA levels at day 10 being more likely to achieve HBV DNA of less than 300 copies/mL at week 48. In addition, there was considerably less variability in the extent of HBV DNA reductions in patients treated with entecavir versus adefovir. Both the mean decrease in serum HBV DNA and the proportion of patients achieving HBV DNA less than 300 copies/mL were greater in entecavir‐treated than adefovir‐treated patients at weeks 2, 4, 8, 12, 24, and 48. At week 48, one (3%) ETV‐treated versus 15 (47%) ADV‐treated patients had HBV DNA of 105 copies/mL or more. Both antivirals were well tolerated. Conclusion: Entecavir therapy resulted in earlier and superior reduction in HBV DNA compared with adefovir in nucleoside‐naïve HBeAg‐positive patients with CHB. (HEPATOLOGY 2009;49:72‐79.)

Antitumor Effect of Deferoxamine on Human Hepatocellular Carcinoma Growing in Athymic Nude Mice

Background. Iron is essential for the growth of all living cells. One of the important intracellular roles for iron is in the activation of ribonucleotide reductase, the enzyme that catalyzes the first step in DNA synthesis. Thus, the intracellular iron level may serve as a regulator of cell growth. The authors tested the hypothesis that lowering body iron concentration inhibits the growth of human‐derived hepatocellular carcinoma (HCC) cells by depleting these cells of iron. Deferoxamine (DFO), an iron‐chelating agent, was used to lower intracellular iron level.

Biologic differences between neuroblastoma stages IV-S and IV. Measurement of serum ferritin and E-rosette inhibition in 30 children.

In an examination of the biologic differences between neuroblastoma Stage IV-S (metastases to liver, skin, or bone marrow but not to bone), which has a high likelihood of spontaneous regression, and Stage IV (metastases to bone), which is usually fatal, 13 children with Stage IV-S disease and 17 with Stage IV were studied at diagnosis or shortly thereafter. Serum ferritin levels were elevated in 15 of the 17 children with Stage IV diseases, but not in the 13 with Stage IV-S. E-rosette inhibitory factor was not present in the serum of 12 of 13 Stage IV-S patients, but was detected in 12 of 17 Stage IV patients. All 12 Stage IV patients with inhibitory factor was not present in the serum of 12 of 13 Stage IV-S patients, but was detected in 12 of 17 Stage IV patients. All 12 Stage IV patients with inhibitory factor had elevated serum ferritin levels. Elevated ferritin levels and E-rosette inhibitory factor appear to distinguish Stage IV neuroblastoma from Stage IV-S.

Relative telomere length: a novel non-invasive biomarker for the risk of non-cirrhotic hepatocellular carcinoma in patients with chronic hepatitis B infection

BACKGROUND AND AIMS Telomere length has emerged as a promising risk predictor of various cancers including hepatocellular carcinoma (HCC). However, the majority of studies in this area measured telomere length in hepatocytes and one in lymphocytes with conflicting results. Moreover, no studies have been reported on using circulating DNA telomere length as a non-invasive HCC biomarker. METHODS We conducted a nested case-control study to determine the relative telomere length (RTL) in serum DNA from 140 hepatitis B virus (HBV)-related HCC cases and 280 frequency-matched cancer-free HBV controls. RESULTS Cases had a significantly longer RTL (median, 0.31; range, 0.02-2.31) than controls (median, 0.20; range, 0.01-1.60) (P = 0.003). Consistently, longer RTLs conferred a significantly increased HCC risk compared to short RTLs in a univariate logistic regression analysis (odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.02-2.33, P = 0.038). This association attenuated after multivariate adjustment (OR = 1.40, 95% CI = 0.90-2.19, P = 0.132). In a quartile analysis, a significant dose-response relationship was noted in univariate analysis (P(trend) = 0.017) which was again attenuated in multivariate analysis (P(trend) = 0.079). Further analyses revealed that the significant association between serum RTL and HCC risk was evident in non-cirrhotic (OR = 3.54, 95% CI 1.58-7.93 P = 0.002), but not cirrhotic (OR = 0.95, 95% CI 0.55-1.64, P = 0.860) HBV patients. Moreover, the significantly increased HCC risk conferred by cirrhosis was modulated by RTL with a significant interaction effect (P(interaction) = 0.013). CONCLUSIONS RTL in circulating cell-free serum DNA could potentially be used as a novel non-invasive biomarker for non-cirrhotic HCC. Prospective cohort studies are warranted to validate this finding and assess its clinical significance in HCC prevention.

Prognostic importance of serum transferrin and ferritin in childhood Hodgkin's disease

The relationship of iron‐binding proteins to prognosis was studied in 50 children at the Childrens Hospital of Philadelphia, newly diagnosed with Hodgkins disease (HD). There were five patients with Stage I, 18 with Stage II, 14 with Stage III, and 13 with Stage IV. Initial serum ferritin, transferrin, iron, hemoglobin (Hb), erythrocyte sedimentation rate (ESR), and A or B symptoms were analyzed for their association with progression‐free survival (PFS). There was a linear increase of mean and median ferritin levels and a decrease of mean and median transferrin levels with advancing stages. Also, there was a significant inverse correlation between ferritin and transferrin (P < 0.001). in univariate analyses, high ferritin (> 142 ng/ml) (P = 0.02) and low transferrin (± 250 mg/dl) (P = 0.008) were significantly associated with poor PFS. Serum iron, Hb, ESR, and A or B symptoms were not associated with PFS. Stepwise proportional hazards regression analysis of all factors showed that transferrin was the only factor significantly associated with PFS. These preliminary results suggest that serum transferrin can also be used as a prognostic factor in addition to serum ferritin and that it may be helpful to assay both serum ferritin and transferrin as prognostic factors in childhood HD. Further testing of large groups of patients is needed to determine whether they are independent of tumor bulk and other established prognostic factors.

Preneoplastic Markers of Hepatitis B Virus-Associated Hepatocellular Carcinoma

Hepatitis B virus (HBV) carriers are at high risk for the development of hepatocellular carcinoma (HCC), but there are no reliable markers that will identify such high-risk carriers. The objective of this work is to identify serologic markers that may indicate the early presence of HCC. Since HBV-encoded X antigen (HBxAg) likely contributes to HCC by up- or down-regulation of host gene expression, X positive and negative HepG2 cells were made and subjected to cDNA subtraction. When specific ELISAs were constructed measuring differentially expressed antigens and corresponding antibodies, antibodies to several differentially expressed genes were detected. In cross-sectional and longitudinal studies, antibodies were predominantly present in patients with HBV-associated cirrhosis and HCC, but not in most carriers with hepatic inflammation alone or without active liver disease. Antibodies were also present in patients with hepatitis C virus (HCV)-related HCC, but rarely detected in sera from uninfected individuals, those with tumors other than HCC, or those with drug-induced hepatitis. Statistical analysis showed that HCC patients with four or more antibodies detectable before the appearance of HCC had decreased survival, suggesting that these markers may reflect stepwise hepatocarcinogenesis. Hence, these antibodies may serve as preneoplastic markers for HCC in HBV carriers with chronic liver disease, and may be identified by a simple blood test.

Symptomatology and health attitudes of chronic hepatitis B patients in the USA.

Summary.  This study was conducted to understand the symptomatology, attitudes, and behaviours of chronic hepatitis B (CHB) patients in the USA. CHB patients enrolled in this study were recruited through multiple methods, including newspaper advertisements. Interviews were conducted in multiple languages, and all participants had a history of CHB infection for at least 6 months. Patients with documented human immunodeficiency virus or hepatitis C virus coinfection were excluded from data analyses, resulting in a total study population of 258 respondents who completed interviews between April and June 2004. The majority of monoinfected patients were male (57%) and non‐Asian (92%, including 52% Caucasian, 32% African American and others). Length of diagnosis was 5.8 years for all participants (9.1‐year Asian and 5.1‐year non‐Asian). Ninety‐five per cent of CHB patients reported symptoms of differing severity in the 12 months prior to the survey. The most common symptoms included fatigue/loss of energy (90%) and loss of appetite (79%). Non‐Asian patients described greater symptomatology, and were more likely than Asians to consider CHB an overriding concern in their daily activities. Patients were treated either currently or previously with interferon (IFN) described greater symptomatology than those treated without IFN. Survey results indicate that CHB patients may have greater symptomatology than recognized. Disease perceptions and treatment attitudes differ between Asian and non‐Asian ethnic groups, with the former appearing to be more accepting and less concerned about the disease. Additional research about CHB symptomatology and health attitudes by ethnicity is needed to ensure that individuals with CHB are educated on the potential health risks and the availability of current treatment options.

Hepatocellular Carcinoma Associated with Hepatitis B Virus

Hepatocellular carcinoma (HCC) is one of the most common malignant neoplasms in the world. Current data indicate that hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most significant hepatocarcinogens for the majority of HCCs in the world. Globally about 80% of HCC is considered to be causally associated with chronic infection with HBV. Although HCC is rare in the United States, it is perhaps the most prevalent cancer in Asia and West Africa where the prevalence of HBV infection is high. Without proper intervention for HBV infection, the HBV carriers are at risk for developing HCC. In a large prospective study of 3,653 HBV carriers in Taiwan, 164 persons developed HCC in a 12-year follow-up period; the most important risk factors for HCC were increased baseline and persistently elevated HBV DNA levels. During the last decade, great strides have been made in the treatment of HBV infection. Prospective and retrospective studies of large numbers of chronic hepatitis B patients with advanced liver disease have demonstrated that the treatment with anti-HBV agent not only delayed the disease progression but also reduced the incidence of HCC.

IRON AND IRON BINDING PROTEINS IN PERSISTENT GENERALISED LYMPHADENOPATHY AND AIDS

Hoofnagle et al suggested that this antibody may represent spontaneous maturation of antibody-producing clones of lymphocytes or exposure to unrelated environmental antigens with shared epitopes. Although subdeterminant specificity was not determined in the present case, the fact that it appeared to be IgM antibody and decreased with the appearance of HBsAg, suggests that it may be similar to the antibody described by Hoofnagle et al. The implication of this case report is that anti-HBc, not anti-HBs, should be used to determine the susceptibility or immunity of an individual to HBV and to decide whether HBV vaccine should be used. In our own medical centre, we screen high risk employees for anti-HBc. Those who are positive are tested for anti-HBs, and if the anti-HBs is negative, their sera are tested for HBsAg. This identifies those who are immune or susceptible, and those who are chronic carriers.